The Fabric Of Mind

RichardBergland

TheFabricof lillind

VIKI/VG

VIKING Penguin Books Ltd, Harmondsworth, Middlesex, England Viking Penguin Inc., 40 West 23rd Street, New York, New York 10010, U.S.A. Penguin Books Australia Ltd, Ringunod, Victoria, Australia Penguin Books Canada Limited, 2801 John Street, Markham, Ontario, Canada L3R 184 Penguin Books (N.2.) Ltd, 182-190 Wairau Road, Auckland 10, New T,ealand First published in Australia by Penguin Books Australia 1985 First published in Great Britain by Viking 1986 Copyright @ Richand Bergland, 1985 Illustrations copyright O Kati Bnomley, 1986 AU rights reserved. Without limiting the rights under copyright resenrcd above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photoopying, rcconding or otheryise), without the prior written permission of both the copyright ovmer and the aborrcpublisher of this book Tlpeset in Century Old Style Reproduoed, printed and bound in Great Britain by Hazell Watson & Viney Limited, Member of the BPCC Group, Aylesbury, Bucks British Librwy Cata.lnguing in Publicotion Dota auailable

To the genesthat were passedinto me by Viking explorersandthe memesthat were passedinto me by surgicalexplorers

Confenfs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Preface ix Paradigms;Pifonsof Progress 1 ThePowerof the Paradigm 9 Questions,not Answers 17 Academies:Placeswifh Answers 25 The FirstOld Boys'Network 29 Paganin Saint'sClothing 37 OnePictureis Wortha ThousandYears 47 TheUnderstanding of BrainElectricity 59 Confiteor:NeurosurgicalMalfeasances 75 TheGianfsof the BrainGland 83 TheYearthe Brain becomesa Gland 95 Paracrinology 111 Whyis fhe BrainHollow? 123 /ssuesFor ThoseWhoAre Well 139 /ssuesFor Ihose WhoArelll 161 Bibliography 179 lndex 195

Preface

There is now little doubt that the brain is a gland;it produces hormones,it has hormonereceptors,it is bathedin hormones, hormonesrun up and down the fibres of individualnerves,and everyactivity that the brainis engagedin involveshormones. The implicationsof this are immense,not only for those who think about thinking- philosophers and scientists- but for virtually every intellectualwho reveresthe mysteriousworkings of the mind.Most unsettlingto established dogmais the realization that regulatoryhormones- the new stuff of thought- are foundall over the body. Canthinking go on outsidethe brain?Much scientificevidence pointsto that disturbing,previouslyunthinkable,possibility. In this newestintellectualrevolution,the disciplinesof philosophy,medicine,andsciencehavemovedbackto a positiontaken 2,000 yearsagoby the great Greeks:Plato,Aristotle and Galen. All of them acceptedthe fact that the brainwasa secretorygland. The notionthat electricityis the stuff of thoughtis a very recent idea- lessthan 2A0yearsold. My professionallife as a neurosurgeonbeganin this electrical era,a periodwhenscientistsanddoctorswereconvincedthat electricity was the driving force in the brain. Much that I did in my earlier yearswasrootedin that premise:electricalcircuitsin the brain were to be brokenor electricitywas to be pumpedinto the brain- all in the nameof therapy. The new view that brain hormonesfuel the fires of the mind makesthe notionthat somegoodwouldcomeout of manipulating the brain's electricity seem as irrational as the blood-lettingof Galen(begunin ao 160) or the frontal lobotomiesof EgasMoniz

(first performedin 1936). Neither Galennor Moniz lived to see a day of regret for the simple-mindedsurgicalproceduresthat they performedon their fellow men;I have. My book is a saluteto scientists,a public call to action, and a compendiumof new knowledgeaboutthe treasuryof hormonesin the brain. RichardBergland Melbourne,1985

Pitonsof Progress Paradigms:

\ fou havetwo brains:a left andright. Modern brain scientistsnow know that your left brain is Y I your verbal and rationalbrain; it thinks seriallyand reduces its thoughts to numbers,letters and words. You might refer to your well-taught,well-read,well-spokenleft brainasyour sauant, sincewhateverwisdomyou receivefrom, or communicateto, the world surroundingyou, coursesthroughyour left brain. Your right brain is your non-verbalandintuitive brain;it thinks in patterns,or pictures,composedof 'wholethings',anddoesnot comprehendreductions,either numbers,letters or words. You might call your right brain your mystic,since its wisdomcomes from somehiddensource,perhapsa cosmicsource.Sinceyour mysticdoesn'tread,doesn'twrite, andcan't do arithmetic,it can't learnmuchat school(seeFig. 1.1). I, too, havea savant-likecharacterliving in my left brain and a mystic-like character lurking in the shadowsof my right brain. Sincemy mystic can't write and your mystic can't read, you are hoping that my savant writes well, and I am hoping that your savantreadswell; both of us are dependingon our left brains. For my part, my savanthas a new-foundrespectfor my rightsidedmystic. My left brain- andprobablyyours- was not taught much respectfor the right brain. My teachersheraldedrational thought and left-brain reductions.The intuitive thoughtscoming from the right braincouldnot be 'true', they said;real 'truth' could expressedandstoredin a computer.That viewbe mathematically point is the predictableendpointof left-brain logic and underlies the scientificreductionismthat has permeatedWesternthought for many centuries.But in the past decade,as scientistshave changedtheir thinkingaboutthe primarymechanisms of the mind, the right brain,which housesthe cosmicwisdomof your mystic, has gainedimmenseintellectualrespect: many brain scientists believethat new ideastake root there.

THEFABRICOF MIND

My brains- my savantand mystic- are convincedthat the left brainandthe right brainare glandsandthat 'hormones',whichare specialkindsof wet molecules,modulateevery aspectof thinking. The word 'hormone'was first usedin 1905 and stemsfrom the Greekword meaning'to arouse'.The term may be foreignto you; if it hasbeenfiled in the word-storagebanksin your left brainat all, it is mostlikely listedunder'sex', 'puberty',or 'the pill', certainly not under'brain'. Your two brains may not wish to listen to my brains' new notions. Predictably, they think of themselvesas electrically driven computers,'dry' rather than 'wet'. The notion that the brainis drivenby electricity,that electricityis the stuff of thought, is acceptedby most of the left brainsof the world. It is taught in school,written in booksandunderliesmost thoughtsaboutthinking. Somy left brainhasa toughjob if it is goingto get the view that 'the brain is a gland' into your head;it must confrontthe old view that 'the brainis a computer'andall of the other teachers,writers, andthinkerswho gaveyou that view in the first place. What doesthis different point of view meanto you?If you are well, knowing about hormones in the brain could make you smarter; you could use your mind more efficiently.If you are ill, knowingaboutthesehormonescouldmakeyou feel better; powerful healingforces can flow from your brain to your body, or vice versa. Knowingthat the stuff of thought is not an etherealspirit or a transientsparkcan give you more control over your brain; it can help you use it better. Molecules,which you eat or drink and are releasedwhenyou laughor cry or exercise,spill into your brainall the time. Thesedeterminemost of the eventsin your day:pleasure, love, appetite,satisfaction,joy, sleep,pain, memory, sex, digestion,sadnessandanxiety. The reahzationthat the brain is a gland, controlled by the hormoneswithin it, is lessthan ten yearsold. In the pastdecade, scientistsof all kindshaveacknowledged that the brain is 'wet'. It is suddenlyclearthat the unravellingof the mysteriesof behaviour can comethrough a better understandingof brain hormones.But morethanthat: manykindsof illnesses,especiallythoserelatedto stress,will be more easilytreatedby understandingthe hormonal signalsthat movebackandforth betweenthe bodyandthe brain. Lessthana decadeafter scientistsbeganto lookat the brainasa gland,psychiatristsare concernednot only with warpedrelationshipsbut alsowith crookedmolecules.Neurologistsare searching for 'missing'hormones,believingthat certainbraindiseases canbe

PARADTGMS: P/IONSOF PROGRESS

treatedby hormonereplacementas simplyas diabetesis treated havebegunto measure with the hormotr€,insulin.Neurosurgeons the peptides,the tiniest hormones,in the ventriclesof the brain; notingthat glandtissuetransplantedinto the brainsof animalscan cureanexperimentalParkinson-like disease,surgeonsstandready to do the samethingfor patientswith Parkinson'sdisease.Psychologistsare looking f or memorypeptides,not memorycircuits. Not everyscientistanddoctorwill agreewith my notionthat the brainis a gland,that 'wet' molecules, endocrinehormones,are the stuff of thought.Many still think of the brain as a 'dry' computer, whichis drivenby brain electricity.Thesepeoplewill be upsetby my belief that the commitmentthat sciencemadeto the understandingof brain electricity did not help patient care. Knowing aboutbrainelectricityhasgivenscientistsknowledgeof the shape of the brain,of its innercircuits,but it hasprovidedphysicians who carefor patientswith brainillnessesvery few toolsfor therapy. From the traditionallyquiet laboratoriesof the scientistswho study brain hormoneshas erupteda volcanoof new ideasabout brain illnesses.The sameanatomists,physiologists, chemistsand cell biologistswhowere pulledor pushedfrom eachother by brain electricityare nowseenhuddledtogetherin commonlaboratories,

Keplels model of the universe I

Fig. 1.1 The splitbrain:the leftbrainthinksverbally;the rightbrainusespatternsand pictures

THE FABRICOF MIND

projectsand multi-disciplinarymeetings.Thesepeoplesubscribe to the notionthat hormonesregulatewhatthe braineats,whenthe brainsleepsandhowthe brainfeels.A lackof thesehormonesmay explainbrain 'failure', suchas the memorylossof senilityor the spirituallossof depression. Feedingthe braintoo manysuchhormonesmayunderliebehavioural addictions,such as those to alcohol,nicotine,coffeeand narcotics.These scientistsacceptthe possibilitythat the brain mayproducecrookedhormonesthat cancausecrookedbehaviour, suchas schizophrenia. By nature,brain scientistsand physiciansare sceptics.Therefore it is astonishingto note that they herald a new champion: NormanCousins,a writer who preachesthat 'hormonesof happiness'may be releasedby pleasure,joy, humour,andsatisfaction. The rejuvenatingpowerof bellylaughter,whichCousinsfound,he first describedin America'stop medicaljournal, TheNewEngland Iournal of Medicine and later in a book, The Anatorny of an Illness.His journalarticlereceivedmore positiveletters thanany other article in the journal'shistory, y€t a decadeago his story would havebeenregardedas that of a mindlessquack.Now it is lookeduponas the recordof a carefulobserver. Manyof the brainhormonesthat are importantto diseases have long Latin names,forcingdoctorsto useshorterabbreviations. In yearsto come,theseabbreviations may becomepart of everyday speechas you hearyour friendssay: 'I think Phyllisis too fat for diet therapyalone;sheneedssome CCK.' This abbreviationCCK is shorthandfor cholecystokinen, a hormonethat limits appetite.Your friends,like the scientists,will avoidthe tongue-twister. Or: John is not simply sad,he has a depressionthat could be easily fixed by CRF.' This abbreviationCRF is used by brain scientistsin placeof corticotropinreleasingfactor. In laboratory animals,syntheticCRFcanbe employedto releasethe 'hormones of happiness' whichmayhavehealedNormanCousinsandcouldbe employedto treat depression. Or this: 'My Aunt Nellie can't remembera thing; I bet shehas exhaustedher brain'ssupplyof AVP.' Argininevasopressin, called AVP, is a brain hormonethat improvesmemory and sharpens learningin manylaboratorysituations.Manypredictthat AVP will be employedin future yearsto treat patientswith seniledementia. Beforethesehope-filledconversations becomeeverydayrealities, manyrevolutionarychangesmust occur in the way patients

P/IONSOF PROGBESS PARADTGMS;

and doctors view the stuff of thought. Yet without much doubt, thosechangeshavebegun. Few non-scientistscomprehendthe significanceof the simple statement'the brainis a gland',but time may bearout my prediction that this phrasewill be of more benefit to mankindthan the more succinctstatementE-MC2. That coldcalculationseparated personfrom personand unchainedas much violencein people's heartsasit did in the heart of the atom.In the centuriesthat follow, peoplewill be involvedin establishinglinks betweenthe hormones of the brainandhumanbehaviour.The scopeof this undertakingis immense,andentirely positive. Both thosestill committedto the scientificreductionismof the Westandthosedevotedto the holisticview more acceptableto the East will gain by understandingthat hormones,not electrical sparks,are the prime moving forces of the brain. Those in the West directedtowardsmore precisecorrelationsbetweennewly discoveredbrain hormonesand old, poorly understooddiseases can be more sharplyfocused;they can quickly apply on-the-sheH techniquesof endocrinologyto their reductionism.Those in the Eastcango forwardknowingthat the new knowledgeconcerning the ebb and flow of hormonesbetweenthe brain and the body supportsmuchof what they havetaughtfor centuries.Religionmeditationandprayer- is suddenlyin the mainstreamof scientific concern. Learningaboutthe historyof brainscienceandaboutsomeof its current problemsmay changethe way you think not only about your brain, but alsoaboutthe institutionsin our societythat are dedicatedto the careandfeedingof our brains. Hospitals,the placesthat carefor the brainsof thosewho are ill, must surely changeas a result of the new knowledgeabout the brain. Both those who are ill and the doctorswho care for them have been disservicedby the scientists who for more than a centuryhavebeenpreachingthe importanceof the paradigmthat the brain is an electricallydriven computer.The new information aboutbrainhormonesshouldbring helpandhopeto thoseshackled by brain illnesses,thosewho havetaken their brainsor thoseof their lovedonesto hospitalsto find neithercure nor explanation. Perhapswhat is moreimportant,universities,the placeswhich feedthe brainsof thosewho are well, will alsoaddressthe issues that springfrom the new knowledgeaboutthe mechanisms of the mind. I hope my commentswill lend supportto the millions of studentswho take their query-filledbrains to academicinstitutions,oftento be turnedoff or drivenaway.

THEFABRICOF MIND

In the effort to understandthe human mind there has been continuoustensionbetweenthe institutionsthat gaincomfortfrom the securityof the centre andthe individualswho seekthe uncertain, productiveexcitementof the edge.To look in at one'sown brain in a new way while lookingout at the academicinstitutions that at oncefeed and suck from the humanbrain shouldbenefit scholarsof all kinds. 'The known is finite, the unknowninfinite; intellectuallywe stand on an islandin the midst of an illimitable oceanof inexplicability.Our businessin every generationis to reclaima little more land,'wrote T. H. Huxleyin 1887. No matter what you do in your life, you standwith me on suchan island.We bothrecognizethe treasuryof the interrelatedanswers at the centreandthe magnetismof the unansweredquestionsvisible from the shoreline.As our island of knowledgegrows, our shorelineof wondershouldexpand.But the treasuryof information at the centre must be defendedby our mates- our institutions. And the shorelinesof wondermust be exploredby individuals- by you andme. A specialkind of tensionat oncelinksusto andseparatesusfrom our intellectualinstitutions.It may grow from this: you and I are meant to find new 'truths' at the shoreline;the institutions ate supposed to keep'truths' at the centre. Even greater tensionwill developbetweenthosewho standat the centre defendingthe old paradigmthat the brain is an electrically driven computer and those who find themselveson a new shorelineadvocatingthe new view that the brain is a hormonally modulatedgland,It is this competitionthat instigatesthe 'Shoreline of Wonder'sectionswhichendeachchapter;I hopethesewritten parentheseswill encouragethosereaderswho reachthe new shorelineto look at social,philosophicalandreligioushorizonsin a new way.

Shorelineof Wonder

As we think, somethingmustfloat like a shuttlecockfrom the right sideof the brain to the left, andvice versa.We couldcall this stuff electricityor informationor ideasor modelsfor thought.In Indiait might be called'citta'. But noneof theseterms is perfectlysuited for the complexinterrelatedthoughtsaboutthe brainthat we will

PARADTGMS; P/IONSOF PROGRESS

be considering.'Idea-chord'might be a goodchoice;it comesfrom DouglasHofstadter'sstatementin Godel,Escherand Bach: Perhaps whatdifferentiates highlycreativethoughtsfromordinaryones is somecombinedsenseof beauty,simplicity,and harmony - deeply relatedideasareoftensuperficially disparate. The analogyto chordsis natural:physically closenotesareharmonically distantandharmonically closenotesarephysically distant. . . harmoniou s idea-chords[my italicsJ are oftenwidelyseparated as measured on an imagin ary keyboardof concepts. 'Mem€s', a neologisminventedby Richard Dawkinsin his book The Selfi'shGene,would be a trendy descriptiveterm for these shuttlingthoughts.Dawkinsemphasizedthe importanceof genes to cells,but arguedthat memesexercisethe samekind of control in the mind. Even thoughthey are powerful,geneshavenot been the shaping force of our culture. The genetic distinction of Beethovenor Einstein is lost in three or four generations;their splendidgenes,oncepouredinto the extraordinarilylarge vat of the human genetic pool, are lost forever. But the tt e*es of Beethovenand Einstein, their good ideas,are passedfrom one generationto anotherandhavean eternalsignificance. All animals are genedependent.But the evolutionof our culture, of our civilization,is memedependent. Genesare bodyshapers,actuallycell shapers,whichmay infect the cell; onceinside,they causeit to 'selfishly'replicatemore and more identicalgenes.Memes,Dawkinscontends,are mind shapers' whichpassfrom brain to brain like an infectiousvirus. Not all of the ideasthat passfrom onebrainto anotherbrain,however,are goodideas;someare mistakes.TheseI call 'mismemes'. 'Paradigm' is anotherpossibilityandcertainlythe best term for the modelsfor thought about the brain. ThomasKuhn describes the term in his book TheStructure of ScientificReaolutiorn: Withoutcommitment to a paradigm therecanbenoscienc€ . . . thestudy of paradigms prepares is what a studentfor membership in a particular

scientificcommunity.Men whoseresearchis basedon sharedparadigms are committedto the samerules andstandardsfor scientificpractic" . . . scientificrevolutionsare inauguratedby a growing sensethat an existing paradigmhas ceasedto function adequatelyin the exploration of an aspectof nature. I believe the existin g parudigm about the brain has ceasedto function adequately.

2 ThePowerof theParadigm

I t is easy to trace the path that Sir EdmundHillary took up I Mount Everest; the basecampsthat he set up have become I shrinesto thosewhofollowedhim. Manyof the pitons,the small metalspikesdriveninto the mountainwallsby climbers,canstill be found, defining the path along which his rope-linked climbers ascended. It is alsoeasyto trace the path that scholarshavetakenin their effort to understandthe brain. The paradigmsthat scientistshave put forward on the mechanicsof the mind standas pitonsof intellectualprogress;eachnew paradigmhaslifted our understanding of the mindto a higherplateau,andthesemodelsfor thoughtchart a courseof mankind'smost challengingintellectualascent. My bookwill leadyou alongthe ascendingpathsthat the studyof the mind hastaken.Along eachpath intellectualbasecampshave been constructedby teams of climbers who decidedit was a propitioustime to break campandmoveto a higher place.Few if any of thesenew basecampswere foundby teamsof scouts;most of the upwardstepswere takenfirst by peopleactingalone. Kuhn describessuch steps well in his book about scientific revolutions,pointingout againand againthat the plansof future scientific developmentdeterminedby the group seldomlead to paradigmshifts. The dents in the frontiers of science,the new paradigms,havealmostalwaysbeenmadeby lonescouts. A paradigmshift, a movementto a higher intellectualplateau, occurswhen a lone scout returns with informationabout a new path. The scout must convincethosein the basecampthat it is time to moveup. The debatewill be carriedon by the group,alwayslinkedby a commonconcernfor receivinginformation,connectingit, deciding if it is 'true', and then answeringall possiblecriticisms.These intellectualfunctionsdependupon verbal communications, and modernbrain scientistsaffirmthat suchwork is performedby the

10

THE FABRICOF MIND

left brain. Letters, words and numbersare stored there and, 'groupmentality'couldbe regardedas a linkageof left indeed,all brains. By contrast,the lonelyViking-likerisk-takerswho discovered the better pathsfor intellectualascentwere generallydrivenby the pattern-dependentmental qualities of searching,probing, It wasRogerSperrywho first affirmed balancingandquestioning. thinkingtakesplacein the right brain,and that pattern-dependent for this discoveryhe wasgiventhe NobelPrizein 1981. If mind mechanismsin the right brain guide the scoutswho implantthe pitonsof progressduringintellectualascents,it would be expectedthat they wouldact alone,sinceright brains,unableto with oneanother,cannotlink themselvestogether. communicate first byPythagoras. wasdiscovered Theimportanceof paradigms generatedin his were second, paradigffi, andthe The first scientific mind. Pythagoraswasborn 582yearsbeforeChrist on the tiny Greek at Islandof Samos.He receivedscanteducation,but nonetheless the laid had he the time of his death,at the age of eighty-two, cornerstonesfor both art andscience. Pythagoraswas the first to understandthe scientificprinciples of harmoniousmusic. His tools of inquiry were simple: the stretchedstrings of the lute, the favourite musicalinstrumentof the day.He establishedthat a string vibrating alongits full length producesa constantnote. Another vibrating string, stretchedto the sametension,whichis one-halfaslong,or one-thirdaslong,or one-fourthaslong,producesa harmonioussound.Any other length of vibrating string producesdiscordantsound. Thesesimpleexperimentswrestledfrom naturea simplesecret that had eludedmusiciansfor centuries.It was the first scientific paradigm.Music, until Pythagoras,had comefrom pluckedsingle Ittingr. His discoveryof these mathematicalprinciplesallowed two musicalnotes, or a thousandmusicalnotes, to be played togetherin harmony. From that time forward, musichada language.It couldbe read copied, by the €y€,not onlyheardby the ear.It couldbe composed, scientific generation. His learnedand passedfrom generationto discoveryestablishedthe only truly universallanguage,a breathtakingachievement, Y€tso simple. pyttragorasconstructedanother paradigmthat altered mathematics forever after. Again he brought order to disorder by observations. simple,pattern-dependent right-angledset squarethat hadbeen the of utility Slnsing the

THEPOWEROF THEPARADIGM

11

usedby buildersin constructionprojectsfor many centuries,he discoveredconstant numerical relationshipsbetween its three sides.No matter what shapeor size,if the lengthof the longestarm of the triangle,the hypotenuse,wassquared(lengthtim.r l.ngth), it wouldequalthe sumof the squaredlengthsof the other two riaet of the triangle. This helpedbuildersimmensely;they would waste less wood. Knowing that the length of a vertical beamwas 6 feet and the lengthof its right-angledhorizontaljoiningmemberwas8 feet, for example,the buildercouldsawa joining timber that wasprecisely 10 feet long. The calculationwas simple: 6 x 6 = 36. Then 8 x $ = 64. Adding36 to 64 gave100. The squareroot of 100 is 10. Why was this simpleobservationso important?Not becauseit allowedbigger, taller buildingsandmore efficientcarpentry.The Pythagoreantheoremprovedthat there is an internalconsistency betweennumbers.It gavethe numbersof equations,for example, 6 x $ = 36, a reality of their own.In a stroke,theoreticalrelationshipswere givena substanceas solidas bricks or wood. After Pythagoras,theoreticalthoughtwaspossiblefor the first time. The mind could now fly into the world of the intangible;it couldconceptualwefor the first time, invent paradigms,knowing that such modelspossesseda substanceof their ow1. Again, a breathtakingachievement. A discipleof Pythagoras's namedEmpedocles (b00-430Bc)and his studentssaw that everythingPythagorashad accomplished involvednumbers.They constructeda religionbasedon the premise that numberswere the buildingblocksof the universe:by their mystical, eternal relationshipsnumbers controlled all humans, godsanddemons.Avid geometrists,they concludedthat the circle was the perfect two-dimensional form and the spherethe perfect three-dimensional form. The circle andthe spherewere symmetrical in every way: eachhalf wasthe sameno matter how they were sliced,and every point on a circle or a spherewas the sameas every other point. To them this wasperfection. They sawthat right-angledtrianglescouldbe broughttogether to form an equilateraltriangle that would fit exactly both *ittrin andarounda circle.The simplejuxtapositionillustratedin Fig. Z.L linkedthe eternaltruth of the Pythagoreantheoremto the perfect circle, enhancingthe importanceof both. Thesescholarsconcludedthat right-angledtriangleswere the basicbuildingblocksof nature;they couldbe broug[t togetherto form different two-dimensionalshapes,which in turn could be

12

THE FABRICOF MIND

brought together to form three-dimensionalatoms. Four such atomssharedin the perfectionof the sphere- they wouldfit both within andaroundit - leadingthem to concludethat theseperfect atomscomprisedall thingson earth. Watchinga log burn, Empedoclesand his followerscould see that it was a combinationof four different substances.First, fire cameout of it. Second,smoke,a kind of air, camefrom it. Third, in wet logswater camefrom the endof the log as it burned.Fourth, whenall of thesethingshadgoneaway,earth,the ashes,remained. Sincethey hadascertainedthat the tiny atomswith the triangular shapescouldonly form four objects,they jumpedto the conclusion that the four elementsso obviouslyjoined together in the log by naturewere the four naturalelements. of the pyramid-likeatom, wascomposed Fire, saidEmpedocles, the four-sidedtetrahedron. Earth was composedof six-sided cubes.Air was composedof eight-sidedoctahedrons.Water was composedof twenty-sidedicosohedrons. The groupnot only linked one of their triangular-skinnedatoms to eachof earth's four elements,but alsoassignedforces of love and strife to them. The good forces of love could bring fire and

8$O@0 of Fig. 2.1 The circle,the sphereand four of the Platonicbodiessharedthe eternalrelationships not did dodecahedron the triangle; the right-angled

THEPOWER OFTHEPARADIGM

r3

water together to form steam;the badforcesof strife wouldmake it impossiblefor fire and water to co-exist;fires could be snuffed out by dashingthem with water. The goodforceswouldbring earth and water together to form clay, then pots. The opposini force would separateearth andwater into dry land and the ocean.The seasonsof the macrocosmandthe humoursof the microcosmwere both determinedby the comingtogether of these atomic forces. The four-squarerelationshipbetweenthe four elementsdescribed in Fig.2.2 hasbeenhungon classroomwallsfor manymorecenturies than the periodic tables of the atomic elements that you memorwedinschool. lt wasa rationalassessment of how thingsmight be, the kind of paradigmthat couldeasilybe passedfrom left brain to left brain, especiallyif eachpersonin the group was dedicatedto the notion that numbersruled the world. This madethe leapinto the world of self-deceptionmucheasier.Oncethis mismemewas implantedin mathematicallyfertilizedleft brains,it wouldflourish,as indeedit did. It survivedin the left brainsof thosewhofollowedEmpedocles for nearly2,000years.

F ig' 2 ' 2 T h e a n ci e n t Gre e ks th o u g h t the for ces of ' love' br ought Platonic bodies together to for m t h e fo u r h u m o u rs a n d th e fo u r se a sons

14

THE FABRICOF MIND

was not One 'truth' that was discoveredby the Pythagoreans taught to those outsidetheir school.It was hiddenas a secret becauseit did not fit their triangle-basedparadigm.The mathewhich was maticiansthere found an atom, the dodecahedrotr, formed not by triangularplanes,but by twelve pentagons.It was more like a spherethan any of their other atoms.It couldalsofit perfectlyinto andarounda sphere. did not containanyright-angledtriangles But the dodecahedron andcouldnot sharein the rnysticalqualitiesof that form. Oneof the instructors,Hippasus,revealedthis secret to outsidersbut later died in a shipwreck.Justice,said Empedocles,more concerned aboutthe securityof the secretthanthe securityof the fellow. whom Empedoclesled conjuredup another The Pythagoreans falsenotionthat there were four humoursin manthat were linked Thesewere blackbile,yellowbile, to the four naturalsubstances. phlegmand sanguine.Eachof thesewas formedby the forcesof love or strife interactingwith fire, ait, earth or water. four humourspassedinto the minds The beliefin Empedocles's suchasHippocratesandGalenandled them off of great physicians men cameto espousethe four humours of these Both track. the and this mistaken belief, an outgrowth of the Pythagorean mismerl€,permeatedmedicinein the dark ages. But medicinewas not the only intellectualdisciplinethat was misdirectedby a beliefthat Platonicbodieswere nature'sbuilding blocks.Philosophy,religion,indeed,astronomywerb heldin chains by this mismeme.It was taught in all the schoolsin the Western a longworld from the time of Empedoclesuntil the Renaissance, paradigm. power the of lastingdemonstrationof the

of Wonder Shoreline

AdarnandEve,placedin the centreof man'sfirst physicalgard€o, 'sin'. failedto honourtheir Creator;theirs was the first religious placedin the centreof man'sfirst intellectualgarden, Empedocles, 'sin'. failedto honourcreativethought;his wasthe first scientific Modern brain scientistsacknowledgethat the functionsof the 'split': some tasks are performedin the right humanbrain are hemisphere and others in the left. Pattern recognition is performedby the right brain and verbal tasks,such as reading,

THEPOWEROF THE PARADIGM

15

writing, speakingand hearing, by the left brain. Modern-day dynamicbrain scansare able to confirm Sperry's 'split-brain' observationswith remarkable precision; during reading, for example,only a smallpart of the left brainis at work. Sincethe two paradigmsof Pythagoraswere so clearly dependent uponpatterns- the pattern of movementof musicalstrings andthe patternof linesandanglesin triangles- it canbe assumed with confidencethat his right brainwasat work duringthe invention of his paradigms.But his right brain,like all right brains,could not communicate. It couldneitherhear,speak,readnor write. It is no accident that mankind's first paradigmsinvolved patterns;it is difficultto conceiveof modelsfor thoughtthat do not involvepatternsin oneway or another. Two modernparadigmsemphasize the importanceof patterns. AugustKekule(1829-96),after dreamingof a snakethat hadswallowed its tail, conceivedof a circle of carbon atoms coming together in the form of a benzenering. This simplepattern is the basisfor all organicchemistry,indeed,the basisfor all organiclife in plantsandanimals.JamesWatsonandFrancisCrick actuallycut out patternedpiecesof cardboardto discoverthat the geneticcode of all living cellswasformedby a twisted doublehelix of DNA. The right brain,the body'sonlypatternmaker,musthavebeen involvedin all of this. If youlookbacktwo millenniato Pythagoras, onecenturyto Kekule,or three decadesto WatsonandCrick,you see the same thing: patterns influencingthe direction of new thoughts.In every age and for every new paradigffi,the right brain's contributionis crucial.Oncenew modelsfor thought ire constructedby the brain,they are heldup againstthe reality of the outsideworld andthe questionasked,'Doesthe modelfit?'In this model-verification process,again the right brain must be most responsible, especiallyif a patternof somekind is involved. Thus the non-communicating right brain seryes dually as the creator of pattern-dependentparadigms and the verifier of paradigmreliability. ln groupmentalitysomeexclusionof the right brainmust occur; this sideof the braindoesnot involveitself in verbaldiscussions. A newparadigmarisingin the right brainof a personis regardedasa 'dream'by the group;only a modelthat canbe describedin words andnumberscanpassas a memebetweenthe interconnectedleft brainsof the group. This phenomenon, andits disastrousconsequences, is especially obviousamongthose who followedPythagoras:they formed the first committeeandwere boundtogetherby their left brainsasany

16

THEFABRIC OF MIND

committee must be. Guided by left-brain thinking, they were concernedmore with well-spokenanswers and well-calculated numbers. New unexpressableand uncalculableparadigmswere regardedas untrue dreams,the model-verificationprocessof the right brain was excludedffom the group mentality and with that exclusion, honest questions about group-honoured answers became impossible.Soon the group gave answers from their group-connected left brains before there were questionsor new modelsfrom any individualright brains. They piled one unquestionedansweron top of another.With no right brainsto construct newmodelson thoseof Pythagorasandno right brainsencouraged to ask,'Doesthe modelfit?' the committeecouldneitherbuildnew paradigmsnor verify old ones. After Empedocles,manycenturiespassedbeforethe questioning spirit of the right mind was again allowedto participate in geared scientificinquiry.Sciencebecamea cataloguingendeavour, Aristotle and Plato Both neatly to the abilities of the left brain. 'burninglog' breakdownof the naturalelements,and acceptedthe a Aristotle gavethe atomwith pentagonalskin,the dodecahedron, God-likesignificance. Plato and Aristotle were bright men, by the measureof most teameverto walkon scholars,the mostintelligentteacher/student the humbugof the by up caught were them of earth. Yet both Pythagoreanatomists. In the history of brain science,the institutionsthat have been 'truth' haveset in placebureaucracies responsiblefor keepingthe But the by Empedocles. that havebeensimilarto that established 'truth' the from havedifferent attributes individualswho find the institutionsthat keepit. The finderscan trace their intellectualheritageto Pythagoras who was concernedwith questions,the unknowr, the future and the next paradigm. The keeperscantracetheir lineageto the schoolof Empedocles andthe security-mindedbureaucratsconcernedwith answers,the known,the past,the last paradigm. Findersare leaders;it is the right brainthat leadsleadersto the edge.It is the left brainthat keepskeepersat the centre.

notAnswers Quesfions,

I i lh^tSocrates(470-399nc) thoughtaboutthe brainwe will V ll never know. He was not a writer. Most of what we know J J about his thoughts comesto us through the writing of Plato, his student.But in discussingparadigms,and the development of newparadigms,we mustacknowledge that it wasSocrates who first said that questionsare more important than answers. Only questions,he said,couldkeeppeopleintellectuallyhonest. It washis ability to frame questionsthat kindledthe intellectual revolutionthat beganin Athens 2,400 years ago. His questions were concernedentirely with social,ethicalandpoliticalrelationships betweenpeople.He thought that the study of nature was belowthe dignity of a philosopher.Oneof his studentswrote that Socratesconsideredthe astronomythat captivatedthe minds of other Greeksof that eraa wasteof time. What was the fate of Socrates,the first great question-asker? His wife regardedhim asa lary, unemployed,andunreliablene'erdo-well.He publishednothingdespitehis prodigiousmentalactivities. His concernsfor a better societywent unheededas his own city crumbledinto chaos.This man,acknowledged as our intellectual father,wasjudgedby his peersto be a menaceto the youthof Athensandaskedto go a\rrayandkill himseH. What went wrong between Socrates and his institutional colleagues we canneverknowfor certain,but from Plato'sdescription in the Apology,the Atheniancity fatherswantedanswers,not questions.Transferring answersfrom one brain to another has fairly predictableconsequences: answersare safe.Infectingyoung mindswith questionsis hazardous;it is impossibleto predict the outcome,andsomeof thoseinfectedmay decidethat they prefer the questionsto the answers.Society,in Athensor an)ryyhere, is most predictableand hence most controllableif it is strung togetherby answers.

THE FABRICOF MIND

Why didn't Socrateswrite?The world did not receiveone word fromhispen.It is certainlyobviousthatquestionsreignedin hismind. 'I If you recallhis statement, know nothing'andhis repeatedques'Whatdo you mean?',you must wonderwith me if he wasn't tion, Thewritten inforleft cerebralhemisphere. blessedwith a weakened They are people received. well be cannot to such mationthat comes 'dyslexics'. as regardedby modernschoolteachers Socratesmay havebeenthe first of manygreat question-askers who were right-braindominant.The mostwell knownis Leonardo da Vinci (ao 1452-1519) whose mirror-writing is proof of dyslexia. Leonardo'sproblem becamehis creative advantage.His private diariesrecord clearly that questionsdominatedhis brain, but they were not seenuntil a century after his death.His diaries containedpicturesthat were often drawnone on top of the other, eacha clear descriptionof an importantquestionaboutthe world, but few linkedin orderlyfashion.The wordsthat were appendedto his pictureswere all written backwards. Leonardo'smirror-writing is shownin Fig. 3.1 in his drawingof the ventricles,the hollow,fluid-filledspacethat is in the centre of the brain. Leonardodiscernedthis pattern by filling the ventricles with meltedwax;oncehe hadremovedthe braintissue,the form of the ventricleswas maintained.The processthat he employedis very similar to the casting techniquesculptorsemploy to form bronzestatues. A secondgiant of biologywhosemind's eye was doomedto residein the right brainwasJohnHunter (AD1728-93),my greatest hero and modern medicine'smost prolific original thinker. Hunter never entered the portals of a schoolas a child, even

spacesin the centreof the brain.To Fig. 3.1 The firstdrawingof the ventricles,the fluid-filled showtheirshape,Leonardoput a needlein the ventricles,filledthemwith wax and removedthe brain

QUESI/ONS,NOTANSWERS

19

Fig. 3.2 Castsof the humanventricles

thoughschoolingwasa strongtraditionin his well-educated upperclassScottishfamily.Sent by his family to work as the scut boy in his elder brother's Londonlaboratory,Hunter did what any dyslexicmustdo:observefor himself.Single-handedly, he beganthe revolutionin biologicalthought that is still going on. He is now regardedasthefatherof surgery,infectiousdiseases, endocrinology andexperimental biology.Yet, like Socrates,Hunterdid not leavea written intellectuallegacy,andit is believedthat someof the things that were 'written' by him were actuallyghost-writtenby his close associates in an effort to polishhis academic reputation. JohnHunter securedmost of his new thoughtsin thousands of glassbottles that he filled with his delicatedissectionsof the patternsnatureusedto form the body.Thiscollectionwaspartially destroyedin the bombingof London,but muchof it remainsasthe centralportionof the HunterianMuseumin London.The museum containsmanycastsof humanventricles,whichwere producedby usingthe samecastingtechniquesthat Leonardohadusedin the brainto discernthe patternof the ventricles.Theseeye-catching statuesare shownin Fig. 3.2.

THE FABRICOF MIND

The best universities in the world still employ the Socratic methodof teaching,still insist, as Socratesdid, that real learning will only occur if questionsprecedeanswers.The best teachers still recognrzethat it is the probing,Qu€stioningmind that allows oneto surviveindependentlyin the world. The bestresearchersin the world recognizetheweaknessof the left hemisphere;they still worry aboutgetting the right answerto the wrong question. 'in 'patterns' Are the smartestamongus those with the best their right brains?Can they hold up better patternsagainstthe sameouter world that you andI seeto generatebetter questions, decisionsand new thoughts?Was the ability to form better patterns the secret to the intellectual successof Socrates, LeonardoandHunter? Anotherof my heroes,CharlesSherrington(an 1857-1952),is regarded as the father of experimentalneurology. He once 'Research remarkedto HowardFlorey,who discoveredpenicillin, with natureandlike anygoodconveris essentiallya conversation good on goodquestions.' hinges research sation, SocratestaughtSherringtonthat; Socratestaughtus all that the answercanbe goodonly if the questionis good.

of Wonder Shoreline

'truth', rnostoften A few times in this bookI haveusedthe word taking care to put it in quotationmarks.As ThomasKuhn points 'truth' is funny stuff. Not out in his bookon scientificrevolutions, 'true' one,but manyof the paradigmsthat havebeenjudgedto be 'false' that It is nowestablished observations. in the pastcontained tables Mendel,the father of genetics,calculatedon mathematical the changesthat wouldoccurin fruit fliesbeforehe did the experiments.Thougha religiouspriest, he fudgedhis data to fit more 'true'. Someof the neatlywith the paradigmthat he knew to be 'found' anddescribedasevolutionhave skullsthat anthropologists ary links are outright frauds,and againthesewere presentedto 'true'. Kuhnand buttressa paradigmthat wasfor the greatestpart other historiansare remarkablycharitableaboutsuchdeceptions, that the fervourof Westernscientiststo establisha acknowledging 'truth' They commonlyleadsthemto theseembarrassments. new take a kind philosophicalview that the human mind can never

QUESnONS,NOTANSTVERS

actually'containthe truth'; it canonly describea paradigffi,a best estimate.The best estimatesmust be incompleteand, in that sense'are not wholly true. But just as frequentare omissionsof troublesome'truths', which if acceptedwould makebelief in the greater paradigmimpossible. Lamentably,I havelived in academicinstitutionsnow notedfor scientificfraud, andin recent yearshavewrestledpersonallywith the issuesof 'truth' in my own science.Sincemy conclusionsabout the matter entaila respectfor questions,rather thananswers,it is appropriateto includetheseobservationshere. I have been interested in the pituitary gland, the tiny beanshapedorgan that hangsfrom the brain into a specialcup in the baseof the skull,for the pasttwenty years(seeFig. 3.3). I amnot certainwhatforce,or meme,cameinto my life that ledme to go deeperinto the relationshipsbetweenthe brain andthe pituitary, but eventuallyI cameto the pointwhereI knewasmuchabout thisminusculepart of thebodyasanybodyonearth.I saythat without conceit,andwouldtell anyyoungpersonthatwith enoughdedication, focus,gumptionandtime anybodycanreachandshapea frontier.

Fig. 3.3 The pituitaryglandresidesin a bonycup, yet hangsfromthe baseof the brainby a stalk, muchlikean applefromits stem

THE FABRICOF MIND

In writing down my observationsfor the journal, Science,it 'truth' concerningbrain-pituitaryrelationdawnedon me that the shipscould not be movedeasilyfrom my left brain, where I had stored my observations,to the pagesthat I was writing. If the 'truth' aboutthis topic existedanywhere,it was in my brain.But then I realizedthat the organrzedthoughts,the paradigffis,that were in my brainwere sometimesall answersandat other timesall questions.The paradigms seemed to bounce back and forth AlthoughI andtheir answer-phase. betweentheir question-phase felt compelledto pushthe paradigmsout of my left brain through my right hand,I knewthat only the paradigmsthat were formedof answerswouldmakesenseto the editors,reviewersandreaders.I experiencedan epistemologicalcrisis, knowing that my written 'true', eventhoughthey embodiedmy words were not constantly 'truth' out. bestattemptto pushthe Most unsettlingwas the personalrealiratronthat there was no 'truth'. Every answerwouldproducemore questionswhich steady conceptscould wouldproducemore answers.In the answer-phase, that seemed answer an then even be more easilydescribed,but correct in the morningcouldseemincorrect in the eveningin the light of somefact I hadforgotten to includein the morningthink'truth' was more in the question-phase, there was ing. Whenthe links, onewith progress. Answersneeded muchmore intellectual another. That required almost a mathematicallyprecise understandingof both the anatomyand the chemistry of the issue in focus.Any answerthat didn't fit wasquicklydismissed.Questions, by contrast,did not haveto interlock.They couldbejuxtaposedin oddways.By positionalonethey couldinducethe accidentalcrosslinkages that make intellectual evolution- creative thoughtpossible.Questionswere not quickly dismissed;they couldhang aroundfor days on end, totally unrelatedto other thoughts,but influencingthem nonetheless. It wasaboutthen that I realizedthecreativeadvantageof Leonardo: if progresswas my goal, I must keep the questionsin my brainasmuchaspossible.That methodof thinkingwouldaffordme a muchbetter chanceof untanglingthe puzzlethat wasbeforeme. 'thought' in pictures,and And at that time I realizedwhyLeonardo why John Hunter collectedhis thoughts in bottles; both were convenientwaysto store questions. Most of my questionsaboutthe pituitary havebeenstored in a singlephotograph(Fig. 3.4). This is a modernscanningelectrorlmicrographof the pituitary of a rhesus monkey.All the blood vesselsare filled with plastic, but the pituitary tissue and the

QUFSI/ONS,NOTANSWERS

23

Fig. 3.4 A cast of the bloodvesselsof a monkey'spituitary,showingthat thereare many pathwaysfor bloodinto but not out of the pituitary

surroundingbonehavebeendigestedwith a iye-likesolution.It is a cast,a modern-day versionof the techniqueemployedby Leonardo andHunter. This picture has been reproducedin many textbooks,yet it confoundsme; indeed,it confoundsmost of the scientistswho know most about the pituitary. It shows that the pituitary is extremelyvascular;there are manypathwaysby whichbloodcan get into the pituitary, but very few pathwaysthat can caffy blood to the surroundingveins. It suggeststhat the pituitary should explode;bloodcanget in but not out. Not monthsbut yearsof my life havebeenspentponderingthe pituitary bloodvesselswhichform this elegantcast.I canseethe anatomicalpattern,but I can't discernthe physiological pattern. Out of respectfor the pattern-dependent questionsof Socrates, LeonardoandHunterandfor my ownunanswered questionsabout the pituitary hascomethe convictionthat if the brain is to look at itself andknowitself, the questioningmirror shouldbe heldby the left handof the pattern-formingright brain.

4 Academies;Placeswith Answers

o contrast in academichistory is as vivid as the fates of Socratesand his student Plato (427-34T Bc). Socrates's awfuldeathcamein largemeasurefrom his incessantquestions.Plato'sglorioussuccesscamefrom his skilledanswers.The samecity fatherswho reviled Socratescameto revere Plato. After Socratesdrankthe hemlock,Platoleft Athens(in 399 Bc) and travelled to many places in the Mediterranean,probably Egypt,but morecertainlyItaly andSicily.In Sicilyhe studiedin the schoolof the Pythagoreans, andwhenhe returnedto Athensin 387 sc he set up his ownschoolin a gardencalledthe Academy.He was so taken by the Pythagoreanconceptthat atomswith triangular skinswere the buildingblocksof naturethat thesemythicalmoleculesbecamecentral to muchof his teaching.For manycenturies after, they were known as 'Platonic bodies' even though the conceptdid not originatewith Plato. The gardenschoolthat Platoestablishedin Athensbeganin 380 sc andcontinuedto teachstudentswithout a breakuntil np 529,a spanof 909 years.It wasin this gardenthat Aristotle spenttwenty yearsat the feet of Plato. Plato had all the skills that one would expectto comefrom the left brain; he was an orderly thinker, a gifted writer, a splendid organrzeranda masterfulpolitician.He wasnot a scientist,yet he wasthe first to pronounceto the world that he knewwhat the brain did. His conclusionwasstrange,almostludicrous,but like manyof the mismemesthat camefrom the Pythagoreans, it persistedfor nearly2,000yearsandhadimmensesocialconsequences. Platowas an avid astronomer,very differentfrom Socrates,his teacher.He becamefamiliarwith the movementof the heavenly bodiesand pronouncedthat the heavenswere clearlyalive: they moved.Moreover,they movedperfectly,in circles.As he believed that the universeitselfwasperfect,it mustbe of perfectshape;the

THE FABRICOF MIND

only perfect shapehe hadlearnedfrom his Pythagoreaneducation was the sphere.He leapt to the conclusionthat stars movedin perfect circlesin a perfectlysphericaluniverse. The circular movementthat Plato gave to the stars took on a scientific, philosophical and religious significance that held thoughtfulpeoplein intellectualchainsfor 1,900years. The churchacceptedPlato'sview that only the heavenlybodies couldmovein never-endingcircles.WhenMichaelServetuspro'circulation',he nouncedin ao 1553that bloodcouldalsomoveby wasburnedat the stake. Copernicus,born in ao 1470, knew for certain in his fortieth year that the sun,not the earth, was the centre of our universe. Knowingthat the churchadamantlyheld to Plato'sview, Copernicuswas slow to publiclydescribehis discovery.His book was publishedthirty yearslater, in the yearof his death:AD1543. Galileo,nearly a century later, supportedCopernicusbut was forcedin ap 1633to write: thefalseopinionthat the sunis the centreof I mustaltogetherabandon the world andimmovable, andthat the earthis not the centreof the world,andmoves,andI mustnothold,defend,or teachin anywaywhatsoever,verballyor in writing,thesaiddoctrine,afterit hadbeennotified to methatthesaiddoctrinewascontraryto HolyScripture. No other mismemehashadthe impactof Plato'sfalsenotionthat the universewas a perfect sphereandthat stars movedin perfect circles. It was Plato's belief in the perfect sphere that led him to concludethat the rationalsoul of man, 'the divinestpart of us', must be in the brain. Why?Quite simply, becausethe headwas sphericalin shape.Havingplaced'the divinestpart' of manin the sphereof the head,Plato assumedthat geneticmaterialmust be formedin that place,andhe postulatedthat the brainwasthe organ that producedsemen. The view that the malebrain producedsemenwas a mismeme that passedfrom brain to brain for centuries.The proof of this paradigm'slongevityis givenin the Leonardocartoondrawn1,900 years later (see Fig. 4.1). That anatomicaldrawing definesan open,continuouspathwaythat couldcarry spermfrom the brain, through the spinal cord and a fictitious tube into the penis of a copulatingmaleandinto the femalevagina. This paradigmgavethe femalebrain no role at all andregarded womenonly as flower pots for maleseeds.The acceptanceof this paradigmled to the exclusionof womenfrom the governanceof

ACADEMIES, PLACES WITHANSWERS

27

academic,religiousandgovernmentalinstitutionsfor 2,000years or longer.This is perhapsthe best evidencethat the form of our culture and our civilizationcan be shaped- or misshaped- by the scientificviews concerningthe brain. Plato was the first to assigna functionto the humanbrain and suggestedthat it was a secretoryorgan,indeed,? gland.He was correct,but for the wrong reasons.

6rtl \

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'.. F i g . 4 . 1 L e o n a rd o 's a n a to mi ca l dr awings show an open continuous pathway fr om the s pi nal c or d t o t h e p e n i s, re fl e cti n g th e vi e w that sem en was for m ed in the br ain and ca r r i ed dow n the s pi nal cord

of Wonder Shoreline

On a tiny islandcalledCos,500 miles to the East of Athens,lived another Greek who would profoundlyinfluencemedicalthought. This man, Hippocrates(460-370 Bc), was not given to writing, muchlike Socrates.Most of his thoughtswere passedalongby the studentswho gatheredat his side.From thosestudentscomesthe followingstatementaboutthe brain: Menoughtto knowthatfromthebrain,andfromthebrainonly,ariseour joys,laughterandjests,aswell asour sorrows,pains,griefs, pleasures, andtears.Throughit . . .'we. . . think,see,hear,anddistinguish theugly fromthebeautiful, thebadfromthegood,thepleasant fromtheunpleasant. Inexplicably,the very correctview of the brainheldby thosein Cos never madeit to the schoolthat Plato establishedin Athens. Plato'sview was that of 'hard' science;it gavethe brain something physicalto do: producesemen.Hippocrates'sparadigmwas that of a 'soft' scientist;he involvedit with joy andsorrow,ugliness andbeauty,goodnessandbadness,andpleasantness andunpleasantness.Sincethen, a'hard'/'soft', scientific/spiritual dichotomy haspersistedbetweenWesternandEasternbrainscientists.Only now, in the past decade,has a scientific reconciliationbegun betweenthesepolarizedviewpoints. How couldPlato,who was correct aboutso manythings, be so wrongaboutthe brain?Like the committeesof Empedocles, those who surroundedPlato madeno experimentaleffort to verify his well-describedparadigms.The right brain was excluded;the left brain'swell-worded,well-calculated descriptionswere 'true', and the greatest writers were enthronedas the greatest thinkers. Plato's writing skills guaranteedthat his unquestionedanswer aboutthe brainwouldpersistas a mismeme. But criticismsof Plato'sviews aboutthe brain shouldbe generouslycouched.The modernview that the brain's raison d'\tre is to produceelectricity now seemsto be as erroneousas Plato's view that the brainwascreatedto producesem€n.Both are exarnples of scientificobservationsdescribedso well in written words and numbers- in redrctions- that question-askingright brains concernedwith holisticpatternshaveno say.

5 TheFirstOldBoys'Nefwork

ristotle (384-322 sc) was born into a wealthy family in Macedonia,an area in northern Greece.His father, the king's physician,sent Aristotle to the Academyin Athens, andhe studiedthere,with Plato,for the next twenty years. WhenPlatodiedin 348 BC,Aristotle left Athens,movedto the coast of what is now Turkey, and lived on a tiny island,Lesbos. Four yearslater he wasaskedby his father's employer,King Phillip, to return to Macedoniato teachthe king'sson,Alexander,later knownas Alexanderthe Great. After his pupil set off on his conquests,Aristotle returned to Athens and establisheda school,the Lyceum,severalmiles from Plato'sAcademy.He becamethe father of biologyandeventoday his scientific accomplishmentsare herald€d, yet he gave his students, both in scienceand philosophy,an erroneousnotion aboutthe stuff of thought that createdimmenseand long-lasting confusion.One of the graduatesof the Lyceum was selectedto headthe libraries in Alexandriaand carried Aristotle's mismeme there. These wrong ideaswere defendedas the 'truth' by the librariansthere for nearly 600 yearsandbecamethe cornerstone for both scienceand religion. In recountingthe developmentand the preservationof Aristotle'smistakethere are manylessonsfor modernbrainbiologists. Aristotle was a keen and carefulobserverwho insistedthat he join in the grisly taskof animaldissection.His independent searching in all fieldsof nature,especiallybiology,hasnot beenmatched. Alexanderthe Great gave him 1,000 servantsfor his biological laboratory,andwith this helphe dissectedmorethan540 different species.From thesestudieshe producedtextbooksof embryology, anatomyandreproductionthat remainedwithout equalfor 1,900 years.In them, he describeda 'hierarchyof creatures'that was very close to the principlesof evolutionenunciatedby Charles Darwinin 1856.

THE FABRICOF MIND

Aristotle differsfrom his predecessors immensely:noneof them valued the orderly accumulationof anatomical observations. Indeed,Plato had taught his studentsthat the sensescouldonly deceive;to him, pure contemplation,unencumbered by observation of anykind,wasthe onlymethodby whichmancouldknowthe 'truth'. By emphasizing the value of biological observation, Aristotle laid the cornerstoneof biologicalscience,muchasPythagorashaddonefor mathematicsnearlytwo centuriesbefore. Despite his penchantfor observation,however, Aristotle acceptedwithoutanyevidencemanytheoriesonthe make-upof the and to Empedocles universethat hadbeenpassedfrom Pythagoras to his teacher,Plato. Like his ancestors,Aristotle was convincedthat the heavens were sphericaland'alive'. The life he believedto be in the heavens wasthe prime movingforce for the universe,his famousprimutn mobile. As Plato had done,he acceptedthe notion that the earth was composedof four kinds of atoms\trith triangular skins.Although the atoms of the heavenlybodiesremainedin perfect order, the earthly elementswere generallydisordered.Yet earthly bodies had a natural tendencyto assumeorderly positionsbasedupon their divinity, or nobility. To him, the heavenswere more noble thanfire, fire more noblethan ait, air more noblethanwater, and water more noble than earth. The 'holiness'of heavenbeganin Plato'smind,but it wasa key portionof Aristotle'sphilosophy.His supportof this conceptguaranteedthat it wouldbe acceptedlater by the librariansof Alexandriaandthereafterby religionsof many kinds,for both librariansand priests held Aristotle in the highest esteem.His conceptof the primum mobilein the heavensclosely resemblesthe Judaeo-Christian conceptof a 'God in heaven'; ThomasAquinas(eo L225-74) madethe fact that therewasa prime movingforceat the edgeof the universehis first prooffor the existenceof God. Aristotle'smyth-filledviewof earthandheavensetthe stagefor an incrediblemistakethat determinedmuchof the courseof scienceand religion. He believedin the 'burning log' assessmentof the four naturalelements.It wassomethingthat he couldsee.The log really did containfire, air, water andearth.After the log wasburned,the fire, air and water were gone- ascendedinto the heavens.The ashes,the earth,remained. But animalswerevery differentfromlogs,saidAristotle.Theyhad to haVea 'fifth essence'in their make-up.He called the stuff

THEF/RSIOLDEOYS'NETWORK

31

'quintessence', a term that survivesto this that gavelife to animals day. 'quintessence'? Therewasonly Whatkindof atomcouldmakeup one choice,the one formed by pentagons,not triangles,the dodecahedron.Aristotle assignedthis fifth atom the greatest nobilityof anyof theearthlyatoms,? positionthatplacedit aboveall the other atomson earthandjust belowthoseof heaven.It linked manto the primuln mobilethathe believedto be at the edgeof the sphericaluniverse. Aristotle was no armchair naturalist; he was an anatomist activelyinvolvedin animaldissectionsandwas particularlyinterestedin arteries and veins. He discoveredthat bloodvesselsin decapitatedanimalswere especiallyhard to find and trace and electedto kill the animalshe studiedby the gruesometechniqueof strangulation.This madehis dissectionseasier,but set the stage for his scientificerror. Aristotle's dissectionshad verified that there was a large rigid air tube that connectedthe mouth and noseto the lungs;this he namedthe'tracheaarteria',or the roughair tube.It is now called simplythe tracheaandis rough,or furrow€d,sinceit is composed of many separateround rings of cartilage. Strangulation,he realized,blockedthe trachea.The deaththat followedwasproofthat quintessence, called'pneuma',wasimportantto whichhesometimes life. It wasevidence,moreover,whichsupportedhisnotionthat man was linkedby somekind of ether to the prime movingforce in the heavens. But Aristotle's insistenceon killing animalsby strangulationled him off the track.If animalsarestrangled,the pressurein the lungs eventuallyexceedsthe pressureof the pumpingright heart. Less bloodcanthen flow throughthe lungs,andthe left heart, in turn, receives less blood to push into arteries. Although the veins containmuch more blood than is normal after strangulation,the arteriescontainmuchless. ThusAristotle'scarefuldissections weredoneonanimalsthat had overflowingveinsandrelativelyemptyarteries.Whenthe arteries, which havea rigidity of their own, were openedby his scalpel,he foundair andnot muchblood. Many scientific historians have suggestedthat Aristotle's discoveryof air in the arteriesof deadanimalswasa colossalerror in observatioll.This is not true. He observedsomethingthat most modern anatomistshave missed. Although scientists cannot explainwhy, air doesaccumulate in arteriesafter animalsdie.This

32

THE FABRICOF MIND

air accumulatesin days, not hours, and does not develop in carcasseswhich are refrigeratedor dissectedsoonafter death. The best scientificevidencefor this phenomenon is in deadhuman foetuses:the accumulationof air in the heart and arteriesof the deceasedfoetusis so commonplace that it is usedby doctorsto confirmintrauterinedeath. Aristotle began his experiments believing in four Platonic bodies,a sphericaluniverse,a prime movingforce,anda life-giving frfth essence.From his studiesof strangulation,he concludedlogically that quintessence,or pneuma,was carried from heaven through the tracheainto the lungs and then into the heart. His subsequentdiscoveryof hollow,air-filledtubesradiatingfrom the heart led logicallyto the conclusionthat pneumaflowed through thesetubesto all organsof the body(seeFig. 5.1). Theseconclusions led Aristotle to makean evenlarger mistake: he assignedthe functionof intelligentthoughtto the heart,not the brain. How couldthat happen?Aristotle was a studentof plants, fish and animals and deeply interested in the hierarchy of creatures.He recognizedthat all thesethingswere alive;they had a 'soul'that couldpassout of them andleadto death.He concluded that a soul was a necessityfor any living thing, then postulateda hierarchyof soulswhich matchedhis hierarchyof creatures. Plants,the lowestform of life, hada vegetativesoulthat allowed them to grow andto reproduce.Animals,a higherform of life, had a vegetativesoul for growth and reproduction,but they had an additionalsensitivesoul that allowedthem to feel and to move. Man,the highestform of life, wascapableof growth andreproduction, like a plant, and sensationand movement,like an animal.A vegetativeand a sensitivesoul allowedthese activities.But man had a ftfth ability: intelligent thought, which Aristotle believed camefrom the highestkind of soul,the rationalsoul. This separationof souls,like manyof Aristotle's other observations, wouldpersistfor centuriesandwould becomeincorporated in manyWesternreligions. If pneumaor quintessencewas the fuel for rational thought, wherewasthe organof rationalthought?There wasonly onelogical place:in the heart. It not only receivedpneumafrom the lungs, but alsodeliveredit to the bodythroughthe air tubes. Eventhoughother peoplebeforeand after Aristotle recognized that the brain was the seatof intelligence,his designationof the heart as the home of the highestsoul and the organ of rational thoughtpersistedfor centuries.Many biblicalscripturesspeakof

THEF/RSIOLDEOYS'NEMORK

33

the heart asthe organof thought.'Believe,'the Bible admonishes, 'with all thine heart.' What did Aristotle think the brain did?Like Plato,he concluded that the brain wasa gland.He believedit wasa coolingglandthat was placedin the headandnear the nosefor the purposeof regulating the temperatureof the pneumathat wasbroughtto it by the arteries. Thuswe seethat bothPlatoandAristotleconceivedof the brainas a gland;bothwere correct,but for differentandwrongreasons.

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F i g . 5 . 1 Ho l l o w a rte ri e s w e re centr al to Ar istotle' s belief that the hear t was the or gan of i ntel l i gent thought. He gave the dodecahedron a higher position than the otfrer Pfatonic bodres and betieved t h a t i t w a s p u sh e d b y a p ri me moving for ce in heaven into the body

34

THE FABRICOF MIND

(300-2608c) described thenervous A centurylater,Erasistratus system in detail. Yet he held to Aristotle's notion that the rationalsoulresidedin the heart.Findingthree tubularstructures goingto every organin the body- an artery, a vein anda nerveErasistratuspostulatedthat pneumawas carried by the carotid arteriesfrom the heart to the brain andflowedthroughnervesto all organs. It wasnearly2,000yearsbeforeAristotle'sbeliefin the imporAlthoughGalenfoundblood tanceof quintessence waschallenged. years in arteries550 later, he still maintainedthat pneumamoved to and fro in arteries and supportedAristotle's notion that an from heaveninto the arteries of ether-likesubstancedescended man. It was the intellectualchicaneryof Galenthat ensuredthe longevityof this mismeme:he continuedto supportit evenwhen he hadmadeexperimentalobservations that madeit untenable.It wasnot until AD1628,the yearin whichWilliamHarveypublished his classic book on the circulation of blood, that the belief in quintessence cameinto question.

Shorelineof Wonder

To understandthe longevity of Aristotle's mismeffi€,we must recallthe dayswhenAristotle servedasthe tutor to the teenager, Alexander.Aristotle'sinfluenceon Alexanderwasimmense;years later Alexanderwouldwrite: 'To my father I owe my life; to Aristotle the knowledgehow to live it worthily.' During all his military campaignsAlexander slept with two things under his pillow: a daggerand a copy of Homer. Perhapsno other leaderhas held intellectualmatters in suchhigh regard. As Alexanderthe Great rnovedalonghis route of conquest,he hadtakenwith him the bestengineers,surveyors,draftsmenand scribesfrom Greece.His reverencefor rationalthoughtandscholarship led him to insist that his conqueringarmy preserveany materialof academicinterest.Thus,when they arrivedin Egypt, not only the ideasof their conquered they hadin their possession landsbut alsothe scrollsandtabletsthat containedtheseideas.In his well-plannedfortified city a library was built that becamethe repositoryfor this material. Now you canseehow the mismemeof Aristotle couldso easily

THEF/RSIOLDEOYS'NETWORK

passfrom the left brain of onescholarto the left brain of the next, andon for centuries.His greatsuccesswith his studentAlexander, his founding-fatherrelationshipwith the Lyceum,his Macedonian birthplace,andhis reverencefor scholarshipplacedhim at the hub 'old boys' of what might have been the first of the world's of privileged,educated,wellnetwork', a complexamalgamation politically adroit men. connected,financiallysecureand Inherentin any old boys'network ib a beliefthat the members privileges.Whether in ancient have specialinformation-handling institutional bureaucracies,an unnatural, modern .Alexandriaor divisiveandinhumanconspiracyof silencecomesto thesekindsof organizations. Cantherebeanydoubtthat the oldGreeks'networkin Alexandria or the oldboys'networksin the schools,churches,andgovernments that followedare heldtogetherby the informationin the left brain? of fromtheright braincanonlydisruptthesmooth-running Questions places. must networks, in command boys' those In old academic such useanswersmuchasMafialeadersusebullets. Aristotle's error survivedin large part becauseit assuredthe safe,central positionof those in power in Alexandria.They had beenselectedfor their ability to employinformationin the defence of the besiegedgroupandknewthat Aristotle'sparadigmwasthe strongestammunitionthat existed.In that ancientacademicplace, asin mostschoolssince,studentsgainedadmissionby their ability to answer, not question.Socrateswould not have passedthe admissiontest for Alexandria;his incessantquestionswould have incensedthe teachersthere as much as they did his judges in Athens.Hunterwouldhavebeenexcludedfrom Alexandriabecause he hadneverbeento primaryschoolandcouldn'treador write. And Leonardo? He wouldnothavebeenalloweda secondsheetof papyrus after his teachershadseenhis mirror-writing. In looking at Aristotle and the thinkers who precededhim, a patternemerges:'truths' arefoundby individuals,not institutions. They may be kept anywhere- in a cave,ESthose of Pythagoras were;or in a gard€D,asthoseof Platowere;or in a library,ESthose of Aristotlewere.But always,whenthe truth-keepersacceptparadigms that close out questions,or selfishlyuse answersas the bulletsfor their own defence,intellectualgrowth ceases.

6 Paganin Sainf'sClothing

ount Everestwasclimbed,GeorgeMallory said,because it wasthere. For centuriesthe mountainchallengedmen to make it to its pe&k,but during those attempts many unlucky climbers, including George Mallory, tumbled from its uncertainedgesto their deaths.It is that wayat the edge;somefall off. On the next intellectual plateau, thinking people plunged, chainedto eachother, into the darkestintellectualabyssmankind hasknown.Their leaderwasClaudiusGalen(eo 129-99). In ancientGreecethere were three kinds of medicine:that of Pythagoras, that of the Aesculapians, andthat of Hippocrates.The hthagorean medicinewas basedon mysticism;the Aesculapians believedin the healingpower of snakes;and Hippocratesadvocateda commonsense, nature-knows-best approachto medicine. By far the best organizedsystem of medicinewas that of the Aesculapians; they hadmorethan 300 templesscatteredthroughout the world. Their largest centre was in Pergamon,the birthplace of Galen,who could not have escapedtheir influence;he remainedan Aesculapianthroughouthis life. At the ageof fourteenGalen'smedicalstudiesbeganandby the ageof twenty-onehe felt he hadoutgrownhis hometownteachers. He left for Corinth only to discoverthat his teacher had moved acrossthe Mediterraneanto the library at Alexandria.Galen followedhim and remaineda student in Alexandriauntil he was twenty-seven.In Alexandriahe learnedthe medicallore, including the mismemes,of his honoured,ancientGreekforebears,HippocratesandAristotle. After his medicaleducationin Alexandria,Galenreturnedhome andworkedas the surgeonin the amphitheatre,aidinggladiators woundedby eachotheror by maulinglions.He, like nuny surgeons since, initially found his employmentin treating victims of violence.

3B

THE FABRICOF MIND

It is almostimpossibleto be longin an emergencymedicalsituation andavoidthe terror of anopenedcarotidartery. This is a most frighteningsight. A patient'slife bloodmay drain out beforeyour Galencouldnot have eyes.Not oozeout,but spurtout - in seconds. been many days in the amphitheatrewithout witnessinga slit throat.It needonlybe seenonceto realizethat the carotidartery containsblood,not air. Galenhadlearnedhis anatomyin Alexandria,wheredissections were performedby slaves,but he constructeddifferent laboratories,first in Pergamonandlater in Rome,in whichhe did all his own dissections.Remarkably,these were performed in alive, awakeanimals.In his dissectionroom in Pergamonhe performed the experimentswhich proved that his revered teachers,especiallyAristotle,were wrong. Galenmay havebeenthe first physicianto take a patient-based observation to an animal laboratory. His experiment is well describedin oneof his manybooks.In a living animalhe exposedan artery in the groin andtied a ligaturearoundit. Beyondthe point of ligation,the artery stoppedpulsating.There he openedthe artery and placeda hollow quill into it. He securedthe quill within the lumenof the artery with a secondligature,then releasedthe first. No air cameout of the now-pulsatileartery, ooly blood. By this first surgicalexperimentGalenprovedthat Aristotle was wrong; blood, not air, was flowing through arteries. With this single observation Galen could have challenged Aristotle's paradigmthat thoughtsare pneumaticand donewhat noneof his Alexandrianteachershadbeenableto do: bring sciencebackto a commitmentto questionsrather thananswers. Galen connectedhis new-found information about blood in arteries to the paradigmchainthat linked Pythagoras,Empedocles,Plato,Aristotle,Hippocrates,Erasistratusandall of thoseat Alexandria.To makeit fit, the other paradigmsthat Galenrevered neededvery little modification.But Galenmust haveknown that without pneumain arteries, nearly everythingthat Aristotle had taught aboutthe nature of man, indeedthe nature of the world, wouldcomeinto question. Galen at this pivotal moment elected to construct his own paradigm and used each paradigm of the ancient Greeks to buttresshisnotions.With little modificationhe acceptedthe atoms with triangutrarskin of the Pythagoreans,the fire/earthlwaterlan elementsof Empedocles, the perfectlysphericaldivineuniverseof Plato, the prime moving force of the universeof Aristotle, the vegetable,animalandrationalsoulsof Aristotle,the quintessence

PAGAN /N SA/NT'S CLOTHING

39

of Aristotle,the four humoursof Empedocles andHippocratesand the notionof Erasistratusthat nervesare hollowtubeswirichcarry quintessence from the brain. Aristotle had employedthe notion of 'hollow arteries' as a centralconceptuponwhich he skeweredseveralunrelatedparadigms.Galen'sdiscoveryof bloodin the carotidscouldhavebeen the antidoteto that perniciousmismeme. Galen,however,performeda feat of intellectuallegerdemainin forming a compromisebetweennew facts and old myths. He contendedthat arterial blood was intermixedwith the quintessenceof Aristotle- that bothwerecarriedin arteries- andby that maintainedthe viabilityof Aristotle'smismeme. Galenwas quick to recognizethat the bloodthat he found in arterieswas very differentfrom that in veins;it was bright red, rather thandark red, anddidn't drainout, but wasforciblypushed from an openvessel. Arterial bloodis not easilyobtain€d,eventoday.The arteriesof the bodyare generallyhiddendeepin the centreof the abdom€o, arm, or leg, but the veinsare quite superficial. Needlesandsyringeswere not inventeduntil the Americancivil war in 1865 andbeforethat time thosewho wishedto drain blood from a humanor an animalresortedto 'cupping'.In this procedure a cupwasheldunderanopenvessel,typicallyopenedwith a scalpel or lance,andbloodwasallowedto flow into the cup.Since.upping was a superficialprocedure, it drained blood from veins, not arteries.Oncein a cupbloodcoagulates, then separatesinto a dark purpleclot at the bottom and an overlyingpool of yellow serum. Most often, the clot is visibly coveredwith a thin layer of white material.No doubt this had been observedfor centuriesbefore in barnyards and slaughterhouses; common -together. people know that blood contained three substances mixed In the amphitheatre or in the animal laboratoW, Galen must have witnessed this separation of blood. Until the experimentsof Galenprovedthere was bloodin the carotid arteries, there was no need to considerthe make-upof arterial blood.But lackingsyringes,eventhoughGalenknew that arteriescontainedblood,it wastechnicallydifficultto collectsuch bloodandcompareit to venousblood. Galen'sstudyof bloodgainedhim everlastingfame:he saidthat bloodcontainedfour differentkindsof humours- just as the burning log was composedof four different Platonic bodies. He concluded that venousbloodwasa mixtureof threehumours:black bile, yellow bile and phlegm.The clot that he saw was the black

THE FABRICOF MIND

bile, the serum was the yellow bile, and the white material that separatedclot from serum was the phlegm.Arterial blood was madeof different stuff. It wasbright red anddrivenwith suchforce from the artery that it wasnot easilycollectedinto a cupfor analysis.This waspure blood- sanguine. AlthoughGalencouldseeonly four humoursin blood,he heldto Aristotle's concept that quintessencewas carried from the heavensinto the lungs, through the heart and into the arteries. Moreover, he went further. He postulatedthat pneumaentered the bodyin two places:throughthe lungsandthe poresof the skin. The pulsationof sanguinewithin arteries, he contended,came from the rhythmicalentranceof pneumainto arteries,first into the lungsandthen into the pores.It was pneumathat gavelife to the arteries, not the pulsatingheart. It was pneumathat enteredthe lung andpushedarterial bloodout of the chest;it waspneumathat 'mouths' of the arteries to enteredthe pores of the skin and the pusharterial bloodbackinto the chest.This to-and-fromovement of bloodcameentirely from pneuma;the heart was not involved (seeFig. 6.1). Sanguinewas Galen'sdiscovery.He could put it wherever he wantedto put it (in arteri€s),assignwhateverbehaviouralqualities to it he wished (goodness),and allow it to co-mingle with Aristotle'sarterial quintessence. Galencouldrewrite history accordingto his own views,andhe rewrote it very clearly: - fire,air,water,andearth;andin therearefourelements In theuniverse blackbile,yellowbile,sanguine, thelivingbodytherearefourhumours, of these or misproportion andphlegm.Out of the excessor deficiency by restoringthe correctproportion four humourstherearisedisease; arecured. diseases For the next fifteen centuriesbarbersurgeonswouldemployscalpels, cups or leechesto drain patients of their bad humours. duringthis period to modernphysicians, Alchemists,predecessors magicaltreatand herbal paradigm their to design usedthe same ments. Medicine,philosophyand religion becameimbuedwith Galen's view that humourslinkedpeopleto their worlds,indeed,controlled their mindsand'souls'.To Galen,andto the priestsandphilosophers who heededhim, the mysterioussoulwasof far greaterimportance than ttre mind. Galenhad acceptedAristoth's view of a vegetative,an animal and a rational soul. But he was more specific;lre took the three

PAGAN/N SA/ruT'SCLOTHING

41

largestsolidorgansin the body- the liver, the heart,andthe brain - to be the anatomicalhomesfor thesethree souls. Venous blood, Galen thought, was formed in the liver and propelledby the force of the vegetativesoul through the body's veins. This view of the liver was acceptedfor centuries. It is

ffi *

..| .:

r0ond fro mo

F ig' 6 ' 1 G a l e n d i sco ve re d th a t a rte ries wer e filled with blood, not air , but m aintai ned hi s bel i ef i n Aris t o t l e ' s q u i n te sse n ce . H e a ssu med quintessence enter ed ar ter ialpor es and c aus ed the to- andf ro m o v e m e n t o f b l o o d

42

THE FABRICOF MIND

reflected in the anatomicaldrawings of the sixteenth-century anatomistAndreaVesalius(no 1514-64). Galenviewedthe heart as a mixing place,where somevenous 'pores'into the arterialblood,wherethe bloodcouldpassthrough 'sooty stuff' couldpassout of veinsthrough the heart and out the lungs,whereheatcouldbe addedto the venousandarterialblood that moved in and out, and where pneumacould be added to arterial blood.But what wasmost important,the heart housedan animalsoulthat generatedheat andmovement. Galenbelievedthat the bestsoul,the rationalsoul,residedin the brainandin that beliefwasthe first of all the ancientGreeksto link the brain to intelligent thought. To each soul Galen assigneda 'vital' spirit. 'Natural' spirit cameto the body through the liver, 'animal'spirit was addedby spirit camein through the heart, and the brain.His viewsof animalspirit are especiallyimportantto the history of brain science,for what he preachedremaineda central dogma until the Renaissance.Animal spirit was the stuff of thought. Erasistratus,five centuries before Galen,had discoveredthe neryous system that Aristotle had overlooked. Erasistratus claimedthat Aristotle'spneumawascarriedby hollownervesfrom the brainto all other organs.Galenacceptedthis and,as surelyas he maintaineda placefor pneumain hollowarteries,he maintained a placefor pneumain the hollow brain; he believedthat pneuma wastransformedby the brain into animalspirit, whichin turn was carriedthroughthe tubular nervesto the body. Galen extendedthe importanceof animal spirit to muscles. Noting that musclesbulgedwhen they contracted,he postulated that animalspirit, releasedfrom nerve endsinto muscles,caused the muscleto puff up andcontract.This mechanisticview of brain and nerve activity was maintaineduntil the eighteenthcentury; Fig. 6.2, a drawingfrom Ro L739, showssuchmysteriousstuff beingpushedout of the spinalcord of a frog to makethe muscles contract. Galendid with the four humoursof the bloodwhat Empedocles, PlatoandAristotle didwith the four elementsof the burninglog:he assignedgoodnessor badnessto eachof them. Galenwasvery positiveaboutsanguine,the humourthat flowed in arteries, andreasonedthat thosewho were blessedwith a rich supplywere direct€d,robustandstrong,muchlike arterial blood itself. 'melancholy',he assignedthe To black bile, which he called negativequalityof sadness.It wasthis stuff he believedthat led to

PAGAN /N SA/NT'S CLOTHING

43

Fig. 6.2 'Animalspirit'is pushedout of the spinalcord of a frog to makethe frog,s muscles contract,accordingto Galen

melancholicdepression.This term hasbeenlinked to that kind of behaviourever since. To yellowbile, 'choler',Galenassignedthe negativequalitiesof bitternessand anger. Ever since,hot-temperedirasciblepeople havebeendescribedas choleric. To 'phlegm'he assignedthe negativequalitiesof dull, sluggish inactivity and ever sincepeoplewith that kind of behaviourhru" beencalledphlegmatic. All three of the old humoursare bad humours;only one good humourexisted- the stuff that Galenhaddiscoveredin arteri.r. The third venoushumour, 'phlegm',was of most concernto Galen, a practisingphysician.Sadness andanger,the result of the first two humours,were both tolerableandnot causesof disease, he reasoned.But an accumulationof phl€gffi,he believ€d,could disrupt the body'sfunctions.Galen,u goodobserver,might have notedan excessof phlegmin his patientswho were ilt andmight havereasonedthat it wasthe causeof the disease,not the result. To this day,the quantitativemeasurement of the white layerfound betweenthe red cellsandthe serumof clottedbloodis employedto

44

THE FABRICOF MIND

diagnoseinfectionsof manytypes,for this layer is noneother than white cells, the scavengercells that accumulatewithin the blood during infection. The presenceof excessivephlegmin the blood,coupledto the notion that this was the causeof phlegmaticbehaviour,led Galen 'cupping' in patients who were sick to the point of to push for sluggishness.In moderntimes someof the best of men, George Washington,andthe worst men,AdolphHitler, havebeencupped; Washingtonwith lancesandHitler with leeches. Galensawa uniquesafetyvalveattachedto the brain that could remove its excessivephlegmand thus cleansethe rational soul. 'Pituita' is an ancientcolloquialword This wasthe pituitary gland. 'snot'.Galen in or runsfromthenose: for themucusthataccumulates believed that pituita came from the pituitary gland, not the nose,andreasonedthat duringillnessit wasdrainedfrom the brain throughthe pituitary into the nose.In that day,asin this, excessive secretionsfrom the noseand throat are commonlyseenin infectious diseases.Thus Galenmay haveobservedvery sick, phleg'pituita' from the airway and, given his matic patients draining starting point, this wouldhavebeena logicaldeduction. Galen'sview of the pituitary emphasizesthe lengths that he 'humoural'. would go to support his paradigmthat thoughtsare Althoughhe was a careful anatomistand skilled at dissection,he postulatedmany unseen anatomicalstructures whenever his 'mouths'in arteries fictionneededphysicalsupport.He described 'pores' in the near the skin throughwhich pneumacouldflow and 'sootystuff' of venousblood septumof the heart throughwhichthe couldpass;andhe wrote aboutboneperforationsbeneaththe pitui'phlegm'to reachthe nose.Arteries do not have tary that allowed 'mouths',the septumof the heart doesnot have 'pores',and the skull beneath the pituitary has no perforations. Galen wrote 22,000pagesof descriptiveanatomyihe wasno amateuranatomist. Yet to serve his paradigmhe literally pokedthe body full of holesthat didn't exist. 'truth' only slightly,Galenwasableto keepthe By bendingthe ancientGreek paradigmssecure,and his own paradigmbecame centralto all the others. Chemistswere pleased.By his four humours,the four elements - fire, utr, earth, and water - were validated and with them teacherscouldcontinueto teachaboutthe four Platonicbodiesin the burninglog. were pleased.Includingpneumain arteriesandin Philosophers allowedteachersto espouseAristotle'sbetief nerves and brain the

PAGAN/N SA/NT'SCLOTHING

45

that quintessence linkedmanto his maker. Theologians werepleased.Stressingthe importanceof 'souls'as propellingforcesfor bloodpreservedthe priest's high regard for an etherealsoul. Astrologerswere pleased.The perfectlysphericaluniversewith perfect circular movementof the heavenlybodieswas left undisturbed by his to-and-fro movement of blood in arteries and veins. Physicians were pleased.The medicalbeliefof Hippocratesthat humourswere importantcausativeagentsof dise6l wasnot only supportedbut alsoextended. By keepingAristotle'spneumain arteries,sanguinewasallowed to mix with the most nobleof all elements:quintessence. By his paradigm that thoughts are 'humoural' he had explained the earthlyelements,the body,the soulandthe mind. Galen'smismemekept the old Greeks' network together. It survivedas the'truth'from AD 160 until ep L628,the year that WilliamHarvey convincedthe world that bloodwas not driven to andfro by 'souls',asGalenhadpreached.

Shoreline of Wonder

Galen'sparadigmfor brainfunctioo,like all ancientandall modern paradigms,involved'scientificreductionisrn'.The complexitiesof the mind were reducedto elementsthat could be describedin wordsandnumbersandthen passedfrom teacherto student. All the reductionsprecedingGalenhadmaintainedthe view that the brainwasa gland.Platothoughtthat it secretedsemen.Aristotle concludedit wasa coolinggland.Erasistratusthoughtit pushed fluid downhollownerves. Galen'sconceptof the brain was the bestformed,for his paradigm allowedsomesecretionsto come to the brain and allowed other secretionsto drain from the brain. Centralto his paradigm was the reductionof both physicaland mentaldiseasesto simpt. causes,humours,whichcouldbe dealtwith by simpletechniques. The therapythat he popularized,cupping,wasso simplethat the untutoredcoulddo it. "u"n Boththe Christianandthe Islamicreligionshelpedto ensurethe passageof Galen'smismemefor seventygenerations.Both reli-

THE FABRICOF MIND

'truth' about gionsmaintainedthat Galenhad giventhe world the ift. body; it was written in his words, and pictures were not needed.In their rejectionof pictures,the priestsandscribes,the ,keepersof the truth', did what Empedocleshad done with the they excludedthe right brain,whichserves wisdomof Pythagoras: dually as the crLator of pattern-dependentparadigmsand the verider of paradigmreliability. It was this exclusionthat allowed Galen'smismemeto pass,without challengeor change,for sucha longperiod. gy hir anatomicalstudiesandhis knowledgeof blood-filledarteries, Galenwas within an ace of discoveringthe circulationof the blood.But imbuedby the ancientGreeknotionthat only the stars couldmovein circles,he assignedblooda to-and-fromovement. of this intellectualcompromisewasimmense: The consequence 'nobility of it left Aristotle unscathedand allowedthe belief in the the elements'to remainin Place. If RichardDawkinsis correct in sayingthat genesare only body shapers,that memesshape civilization,then certainly we must look aboutfor somemismemethat enteredthe mindsof peopleand mis-shapedcivilizationduring the dark ages.No wrong paradigm of that era comparesto that of Galen;it was of the appropriate elements,in the right place,at the right time andsupportedby the right institutions.Galen,by my measure,cannot escapeblame. Galenwasa paganand,certainly,he did not supportthe Roman church.That a pagan'swritten wordsbecamereligiousfoundation stonesis oneof history'sgreatestironies.

7 OnePictureisWortha Thousand Years

ndreaVesalius(eo 1514-04)may havebeenmute because he usedfew wordsto leadmankindout of the quagmireof Galenichumours.His pictures,publishedin no 1543,in his book, TheFabric of Man, speakfor themselves. Few publisheddocumentshavechallenged asmanymajorissues at onceas TheFabric of Man.Itwas obviousfrom the frontispiece (Fig. 7.L) that Vesaliuswas 'desecrating'the humanbody. He presentednot only the bare skin of man but also bare muscles, nerves,bloodvesselsandbones.

8

A

S I

L

E AE.

F ig. 7 . 1 T h e f r o n ti sp i e ce o f V e sa l i u s' s lhe Fabr icof M an

48

nudefemale Fig.7.2 Vesalius's

THE FABRICOF MIND

/S WORTHATHOUSAND YEARS ONEPICTURE

Fig.7.3 Vesalius's nudemafe

49

50

F i g . 7 . 4 V e s a l i u s ' ss k i n l e s sm a l e

THE FABRICOF MIND

ATHOUSANDyEARS ONEPICTUBElS L/VORTH

7.5 Vesaliuson nervesof the body

52

F i g . 7 .5 V e sa l i u s o n ar ter ies

THE FABRICOF MIND

/S WORTH A THOUSAND YEARS ONEPICTURE

Fig.7 .7 Vesaliuson vens

THEFABRICOF MIND

The seriesof pictures(Figs7.2-7.7) freedpeople'smindsfrom the chainsof Galen'sparadigm.Thesepictureswere publishedten yearsbeforeMichaelServetuswasburnedat the stakefor claiming that blood'circulates'from the heart to the lungsandbackto the heart.The churchwasstill very muchin power,controllingnot only the writers' pensbut alsothe painters'brushes,still contending that bodiesshouldnot be dissected,and still preachingthe infallibility of Galen. Until the publicationof The Fabric of Man, the reverencethat was given to the skin and flesh of the humanbodyforeclosedany questionsaboutit; without suchquestionsthere could be no bio'form' presaged logicalprogress.Everydrawingthat Vesaliusdid of a questionconcerning'function';hisanatomybookbecamethe guidbooksthat wouldfollovg.As Vesalius ing chart for the physiological strippedthe skin and the flesh from the body,he broke apart the chainof answersthat Galenhad lvrappedaroundpeople'sminds. Questionsaboutthe validity of Galen'swritten words,the Platonic the sphericaluniverseof PlatoandAristotle's bodiesof Empedocles, prime rnovingforce were now mandatory. Seventy-threeyearsafter the publicationof TheFabric of Man, Galen was dethroned: on LT April 1616, William Harvey in Londonthat blooddid not moveto andfro in arteries announced andveinsasGalentaught.It circulated. Harvey'sdiscoverycanbe tracedbackto Vesalius,whowrotein AD1555: Not longagoI wouldnot havedaredto divergea hair'sbreadthfrom Galen'sopinion.But the septumof the heart is as thick, denseand asthe rest of the heart.I donot see,therefore,howeventhe compact smallestparticlecanbe transferredfromthe right to the left ventricle throughit. Harveystudiedin Paduain AD1603with the academicsuccessors of Vesaliusandlearnedthen that Galen'sparadigmwasno longer accepted.He returned to London and performed experiments initiallyin sheepbut later in forty otheranimalspeciesto provethe observationof Vesalius.He cut awaya portionof the beatingheart and showedthat no blood came through the septum.By mathhe verifiedthat the volumeof bloodpassing ematicalcalculations, hourwasfar greaterthanthe weightof the in an heart throughthe proof that bloodwascirculating. entire animal; Harveydid not publishhis immortalbook, On theMotion of the Heart and Blood,until no 1628,twelveyearsafter his discovery. There,Harveywrote:

ONEPICTURE/S WORTHA THOUSANDYEARS

Sincecalculations andvisualdemonstrations haveconfirmedall my suppositions, to wit, that the blood is passedthrough the lungs and the heart by the pulsationof the ventricles,is forciblyejectedto all parts of the body,therein stealsinto the veinsand porositiesof the flesh,flows backeverywherethroughthosevery veinsfrom the circumferenceto the centre,from smallveinsinto larger ones,andthencecomesat last into the venacavaandto the auricleof the heart;I amobligedto concludethat in animalsthe bloodis driven round a circuit with an unceasing,circular sort of movement,that this is an activity or functionof the heart whichit carriesout by virtue of its pulsation,andthat in sumit constitutesthe sole reasonfor the heart'spulsatilemovement. To buttress his arguments about circulation Harvey included the drawing shown in Fig. 7.8. One of Vesalius's pictures, shown in Fig . 7 .9, stands apart. It subtly describesthe predicament of thinking people,then and now. Vesalius has positioned the bones between a precipice and a judge's table - between the uncertain edge and the certain solid centre - and then thrown a skull on the judge's table. He has drawn the lonely bones, stripped of everything, between the centre and the edge, not only pondering the skull but fondling it, right under the nose of the authorities who had said to him that neither questions, nor drawings, nor dissections were permitted. It is a selfportrait. In this drawing, Vesalius has challenged those at the centre to either accept his questions, dissections, drawings - his desecrations- or push him off the edge.

Shorelineof Wonder

The term 'lateralthinking'comesfrom a bookby that namewritten someyearsagoby EdwardDe Bono.In it he describesthe kind of intellectualend-runsthat the humanmindcanmakearoundthe problems and puzzlesit faces. It is the quality that cannot be taught;somepeopleare better at it than others. I haveseena specialkind of 'lateral thinking' in the ascending brainsof studentsandin the descending brainsof thosewho are ill. Being with those who are very sick has allowedme to watch hundredsof face-to-face encountersbetweenthe humanmind and its problems.Countlesstimes I have watchedmy patientstwist

56

THE FABRICAF MIND

Fi g . 7 .8 H a rve y's d ra wing to show one- way venous valves. This s i m pl e obs er v ati on pr ov ed that ve n o u s b l o o d mo ve d towar ds the hear t

their problemsinto opportunities:I have seenaveragestudents becomesuperior studentswhen they becameparaplegic,those drive with night-timepainrise to write, andthe threat of headache manyto near-perfectperformances. As a bystanderit appearsto me that the humanmind,in its darkesthours,seeksthe brightest guidingstar. It seemsto thrive on the conversionof problemsto opportunities. If you think aboutthe mirror-writing of Leonardo,the dyslexia of JohnHunter, or, in more moderntimes,the blindnessof Helen Keller, the paraplegiaof FranklinRoosevelt,or the discrimination againstGandhiand Martin Luther King, you haveto ask, 'What drivesthe mindsthat converttheir problemsto opportunities?' The magnificentaccomplishments of eachsuggeststhere is a mentalforce that wells up from their most tragic flaw. Somehow thesepeopleare ableto drawon a forcethat providesinnerhealing andoverflowsin a creativeforcethat healsthe world aroundthem. use Doesthe magicof their livesspringfrom the moreharmonious of the right andleft brain?I doubtit. Whatis it andwheredoesit comefrom?I havecometo believe that from somedeeprecessin the right brain springsa 'senseof beauty',perhapsthe humanmind'shighestintellectualability.The

ONE PICTURE/S YVORTHATHOUSANDYEABS

57

great individualsof the past- Leonardo,Vesalius,Hunter- and Keller,Roosevelt,Gandhi,King- my modernrole models,the best studentsI havetaught,andthosewhohavecopedmostsuccessfully with their illnesseshaveall beenimbuedwith a senseof beauty.This 'blackhole':a hiddenstarthat is onlyseenwhenall maybethemind's aroundis totallywithoutlight. senseof beautyin the right brainof It wasthe pattern-dependent of the darkages. out led humankind Vesaliusthat

Fig. 7.9 A self-portrait of Vesalius?Thelonelyfigurestandsat the edge of a cliff, figuratively askingthosein authorityto accept his dissectionsor push himoff the edge

8 TheUnderstanding of Brain Electricity

Tnte burninglog was important to the thoughtsof all ancient philosophersand scientists.The four Platonicbodieswere I I basicto their understandingof the heavens,the earth, the sea,animalandplantlife, andthe body,soulandmind of man. Modern physicistsbelievethat the burning log is composedof four separateforces:a strongnuclearforce,whichholdstogether the big piecesof the atomicnucleus,a weaknuclearforce,which influencesthe little piecesof atoffis, gravity, which pulls things towards the central masspoint of the earth, and an electromagnetic force,whichpermeatesall matter. Althoughno onehasseenanyof thesefour forces,the brightest amongus - the modernday Platos- insist that they exist. Moreover, scientistsare convincedthat there is a fifth force that unites anddrivesthe otherfour. Einstein,like mostgreatphysicists,went to his gravetrying to provea 'unifiedfield theory' that wouldbring the other four forcestogether. The beliefthat electricity,the fourth of the modernforces,is the stuff of thoughthaspermeatedbrainsciencesincethe late 1700s. Yet this hasledto a deepschismbetweenbrainscientistsandother biologists;while the brain was regardedas 'dry', all other organs were conceivedof as 'wet'. Doubtlessthe studyof brainelectricity helpedin the understanding of the internalcircuitsof the brain,but it solvedfew problemsof braindisease. Our next intellectualascentwill trace the step-by-step developmentsthat led to the beliefthat the brainwasdrivenby electricity. Eachof the guidesfor this ascentintroduceda new paradigm,and in eachcasethe new discoverywas an outgrowth of a previous paradigm.At the bottomis BenjaminFranklin;at the top is Egas Moniz:

THE FABRICOF MIND

lobotomy) 1940 EgasMoniz(pre-frontal (electrical nerveimpulse) 1936 HerbGasser neurotransmission) 1934 HenryDale(chemical (synaptic function) 1906 CharlesSherrington (nerve y synapses) 1900 Ramon Cajal psychiatry) Freud(fundamental 1890 Sigmund (fundamental neurology) 1890 HughlingsJackson neurosurgery) 1890 VictorHorsley(fundamental 1885 CamilloGolgi(nervehistology) 1856 ClaudeBernard(neuralnetworks) (animalcells) Schwann 1839 Theodore (animal L792 LuigiGalvani electricity) L753 Benjamin Franklin(electricity) Ben Franklin's creative geniusextendedto publishing,politics, finance, insurance, statesmanship,machitr€ry,writing, optics, heatingandscience.Ben Franklin,the electrician,hadoften participatedin 'parlor trick' experimentsthat usedthe Leiden jar, a Dutchinvention.By rapidlyrotatinga suHurballinsideaninsulated glasscontainer,a current of electricitywasgeneratedwhichcould reversemagnets,melt metal,createanaudibleexplosionandeven kill someanimals. On a rainy dayin Philadelphia in 1752,Ben Franklinperformed some momentousoutdoor experiments.Certainly aware of the risk, Franklinflew a kite into a thundercloud.By attachingone of the kite strings to a Leidenjar, he was ableto 'trap' the electrical forces of the heavensin the earth-boundvessel.In doing this he verified that the swirling raindropsin the thundercloudand the rotating sulfur ball in the Leidenjar were producingthe samekind of electricity. He knew instantly that all matter and all animals were linkedto the heavensby this mysteriousstuff. The parallelbetweenAristotle's pneumaand Franklin'selectricity is glaring. Aristotle postulateda paradigmthat carried unseenstuff- pneuma- into the soulof man.Franklinpostulated anotherkind of unseenstuffthat wascarriedinto the bodyof man. yet it carriedmankind Pneumawasassigneda life-givinggoodness, down a wrong-way non-productiveintellectual path for 2,000 years.Electricityhada life-threateningbadnessaboutit, yet it has steeredscientistsalongtheir mostfertile intellectualpath. The followingdiscoveriesall sprangfrom Ben Franklin'srainyday experiment:Galvani'sunderstandingof animal electricity, Volta's developmentof the voltaic cell - the battery, Oerstad's developmentof the electromagneticmotor, Faraday'sdevelop-

OF BRAINELECTRICIW THEUNDERSIAND/NG

61

dynamo,Faraday'smarriageof ment of the electricity-producing light wavesand electromagneticwaves,Maxwell's electromagnetic wave-formequations,Hertz's productionof electromagnetic waves,Morse'sdevelopmentof the telegraph,Bell's development of the telephone,Marconi'sdevelopmentof radio, Edison'sdevelopment of the incandescentlight, Edison'sdevelopmentof the phonograph,Zworkin's developmentof television, Neumann's developrnentof the computer and Shockley'sdevelopmentof the transistor. Geniusessuchas Franklin havethe ability to askquestionsthat havea transparentquality;they canlook out of themselvesandsee substancein a thing that everyoneelselooksthroughas if it were not there. All of the greatestintelhctual advancesof sciencegrow from suchtransparentquestions.Franklinwas not the first to see the Leidenjar, a lightningbolt or a kite, but he sawthe connecting issue.He gavesubstanceto the issueby asking,'Couldan unseen electricalforce extendthroughour universe?'The sparkof genius wasnot in the experimentor evenin the toolsof the experiment;it wasin the transparentquestionthat startedit all. Luigi Galvani (L737-98), an Italian anatomist, discovered animalelectricity.He was educatedto believethat animalspirit flowedthrough nerves.An anatomist,doubtlesshe had seenthe drawingof the beheadedfrog on page43 andhadreadthis statementby ReneDescartes(1596-1660): The cavitiesof the brainare centralreservoirs. . . animalspiritsenter thesecavities.Theypassinto the poresof its substance andfromthese poresinto the nerves.The nervesmaybe compared to the tubesof a waterworks;breathingor otheractionsdependuponthe flow of anirnal spiritsintothenerves.Therationalsoul(thepineal)takestheplaceof the engineer,liuing in that part of the reservoirthat connectsall of the varioustubes.Thesespirits arelike the wind.\{hen they flow into a muscletheycauseit to becomestiff andharden,just asair in a balloon makes it hard.

Most probably,Galvanihad also comparedthe drawingsof the ventricle of his countrymso,Vesalius,to those of Descartes(see Fig.8.1). In the centuriesbetweenGalenandDescartes,the bestthinkers believedthat musclescontractedbecausethey were puffedup by brain fluid, or animalspirit, which was transportedto them by hollownerves.Thus the view that thoughtsare driven by water was a scientificfact in no L791,the year that Galvanidiscovered animalelectricity.

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THE FABRICOF MIND

Fig.8.1 Vesalius(left)and Descartes(right)believed,as Galendid, thatfluidwas storedin the ventriclesof the brainbeforeit was pusheddown hollownervesinto muscles

F i g . 8 .2 Ga l va n i u se d many differ ent kinds of electr ical stim uli to sh ow that el ec tr i c i ty c aus ed muscles to contract

THEUNDFRSTANDING OF BRAINELECTRICIW

Galvanidescribedthe discoverylike this: Prepared frogs,whichwerefastened bybrasshooksin theirspinalcordto aniron railingwhichsurrounded a certainhanginggardenof my home, fell intocontractions not onlywhenlightningflashed, butevenwhenthe skywasquiet. . . I beganto pressthebrasshooksupontheironrailing. . . and. . . I observedfrequentcontractions whichhadno relationto the changes in theelectrical stateof theatmosphere. Oncehe had madetheseinitial observations,Galvaniwas ableto take electricityfrom a variety of sourcesandproducetwitchingin frog legs (see Fig. 8.2). In makingthese observationsGalvani destroyedapandigm that hadsurvivedfor 2,200years. Initially Galvani'sobservationwas greetedwith enthusiasmby hiscolleagues. Theysharedhisbeliefthat the frog, like the torpedo fish,containedelectricity,andthey acceptedhis view that this, not animalspirit, controlledmuscularactivity. Perhapsthe mostvisibleof his earlysupporterswasAllessandro Volta (I7 45-L827),afellowltalian.But Volta'ssupportwasshortlived;he repeatedthe experimentsandverifiedthat the twitching only happenedif the metals employedwere dissimilar.In doing that he challengedGalvani'snotion that the frog itself produced electricity; to Volta the frog musclewas only storing electricity. This controversyled Volta to invent the voltaic cell that produces electricityby the interactionsof certainmetalsandotheracids;the batteriesthat are importantto your dailylife sprangfrom the argument that went on betweenGalvaniandVolta. Despitehis critics, Galvanistuckto his beliefthat the response to an external electrical stimuluscould only meanthat a similar stimuluswithin the animalitself forced musclesto contract.This has been confirmedmillionsof times since L792, in all kinds of animalsincludingpeople. Againwe seethe powerof the paradigm:onemanlookedat one string - this time threaded through frog legs. What he saw changedthe world. TheodoreSchwann(1810-82) was a brilliant anatomistwho first describedanimalcells. Convincedby thosearoundhim that the brainwasdrivenby animalelectricity,hemadea mistakeat the very beginningof brain studiesthat matchesthe 'hollowarteries' of Aristotle andthe 'four humours'of Galen. AlthoughSchwannacknowledged that all other cellsin the body wereseparatedby a cellmembrane,he proposedthat all braincells were unitedin a giant network that carriedGalvani'sbrain electricity. He stronglydeniedthe bridgingpointsbetweennervesthat

THE FABRICOF MIND

we now call 'synapses',andhis statureas the world'sseniorbrain anatomist cemented that erroneous view in place for seven decades. Schwann'sdiscoveriesdependedupon improvedmicroscopes and the developmentof microtornes- the laboratorydevicesthat cut tissueinto ultra-thin slices.ThomasKuhn,in TheStructure of ScientificReuolutions,observedthat most new paradigmsspring from technologicaladvances,andthe discoveryof animalcellsis a classicexarnpleof creativethought'stechnological dependency. A Londonphysician,Robert Brown, first employedthe microscopein 1831to observethe nucleusof the plantcell.Usingbetter equipment,MathiusSchleiden(1804-81) in 1838founda clearly definedcell membranearoundeachplant cell nucleus.Schleiden saidthat eachcell was like an egg; it containeda central nucleus similar to the yolk, a surroundingcytoplasmsimilar to egg-white andan outer membranelike the eggshell.All plants,he said,were bundlesof separatecells,andeachcell hada 'life' of its own;the life of the plant camefrom the symbioticworking-togetherof many differentkindsof cells. TheodoreSchwatrtr,working in Louvain,was quick to employ the microtomeand better microscopesto see the samething in animals.In 1839Schwannproposedthat animals,like plants,were aggregates of individual membrane-boundcells. His friend, RudolphVirchow (1821-1902) in Berlin, taught a generationof pathologistsandother physiciansaboutthe importanceof cells to diseaseand,in 1858,wrote: Everyanimalis a sumof vital units,eachof whichpossesses the full characteristics of life. Thecharacterandunityof life cannotbefoundin onedefinitepointof higherorganvation, for example, in thebrainof man, but only in the definite,constantlyrecurringdispositionshownindivjduallyby eachsingleelement.It followsthat the composition of the majororganisffi,the so-calledindividual,must be likenedto a kind of socialarrangement or soci€ty,in whicha numberof separate existencies are dependent uponone another,in sucha way, however,that each elementpossesses its ownpeculiaractivityandcarriesoutits owntaskby its ownpowers. Schwannacceptedthis descriptionof animalcellsandtaughtthat organswere composedof individualcellsliving in symbiosis.Each cellwastotallyenvelopedby its cellmembrane.But he arguedthat braincellsneededto knowwhat their neighbourswere doing;they couldnot haveprivate envelopesthat fencedthem off from other cells.He proposedthat the brainwascomposedof a giantnetwork

THEUNDEfrSTANDINGOF BRAINELECTRICITY

65

spiderweb composedof millionsof of cells,a three-dimensional threads,butthatin thiswebeverynervecellwasdirectlyconnected to everyothernervecell(seeFig. 8.3).

Fig.8.3 Schwann'sviewof nerveconnections

He was led to this erroneouspositionby the limitation of his microscopefor he couldnot, with his techniques,seethe synapses that we now know connectonenerveto another.But as certainly asAristotle'sbeliefin 'quintessence' led to his readyacceptance of hollowarteries,a beliefin Galvani'sbrain electricityled Schwann to acceptthe notion that a giant circuit of cell wires united the brain; without a'circuit', electricity could not flow through the brain. It wasRamony Cajalwho discoveredsynapses in 1900,but the father of cellularanatomy,TheodoreSchwarr, and the father of cellularpathology,RudolphVirchow,bothadheredto the network theoryof braincells.More important,perhaps,wasthe acceptance of this theoryby ClaudeBernard(1813-78),the Parisianfatherof physiology.Bernardkept a little red notebookby his bedsideand would write in it randomnight-timethoughts.In 1856 we find thesewordswritten in Bernard'snotebook:'Considerthe brainto be a gland;put cathetersin the veinsof the brainandstimulatethe

THE FABRICOF MIND

sympatheticnerves.'His daytimeteachingswere very different. Although he urged scientistsof all kinds to study the 'internal milieu' of the body,he acceptedSchwann'sdictumthat the cellsof the brain were wired together in a way that madethe internal milieusuperfluousto neuronalactivity. During this period, patient care strategies and educational programmesin psychiatry, neurology and neurosurgery were beingdeveloped. The foundingfatherof eachof thesedisciplinesSigmundFreud (1856-1939) in psychiatry,HughlingsJackson (1835-1911)in neurologyand Victor Horsley(1857-1916)in neurosurgery- were all infectedwith Schwann'smismeme.The early respectthat psychiatry,neurologyandneurosurgerygaveto Schwann'swrongview of the brain haswarpedthe developmentof eachof thesebranchesof medicine. Very few physiciansnow caringfor patientswith brain illnesses are awarethat their specialtywasrooted in suchshakysand:only now.a centuryafter this lamentablemistake,are brainphysicians aware that brain cells are in every way like all other cells in the body. Perhapsno other namehasbeenso inextricablywoveninto the languageof the brain as Schwann's.Schwanncells are often the first cells that are describedto youngmedicalstudentsand,for whateverreason,long after all other neuroanatomical facts are forgotten,physiciansof all kindsstill rememberthesenerye cells andcandescribethem in detail.Schwannwas correct aboutmost cellularmattersbut wrong aboutbrain cells;this hasa specialkind of historicalirony.A Schwanncell is illustratedin Fig. 8.4. In the pastdecadeit hasbecomeobviousthat the secretsof the brain will only be understoodby lookinginsidethe cell, not at the electricity that flowsalongthe surfaceof the cell. Thus,not for his network theory andnot for the cellsthat bearhis naffi€,but for his fundamentalcontributionsto biology,all brain scientistsare in debt to Schwann. In their natural state, cells have a very transparentqualitythey resemblejellyfish- andonly by stainingthem with a dye can their detailsbe seen.The dyesthat areusedby anatomiststo paint or stain the cell are numerousandeachcell, indeed,eachpart of every cell, canbe stainedwith a differentdye. In L871the network theory of nerveswas givena tremendous boostby the developmentof a new methodof stainingbraincells. Camillo Golgi (1843-L926) discoveredthat silver salts, which wouldbindto the surfaceof the nervesandnowhereelse,couldbe addedto brain tissue.Why this shouldbe remainsa biochemical

OF BRAINELECTRICITY THEUNDERSTANDING

Fig . 8 . 4 A s c hw a n n ce l l wi th i ts j e lly- likemyelin wr apper ( left) and a ner ve without m y el i n ( r i ght)

mystery,but the picturesthat Golgipresentedto the world were thingsof beauty. Golgi'sphotographsseemedto confirm that a giant spiderweb united the neryes,of the nervoussystem.But at the end of that century a quiet Spaniard,SantiagoRamony Cajal,employedthe samestainsthat Golgihadusedto demonstrate somethingstartlingly different. Cajal noted that every nerye was separateand drew picturesof tiny bulbsat the endof individualnervefibresthat looked like little handsextendingfrom onenervecellto caressits neighbour (seeFig. 8.5). Thosewho a few yearsearlierhadusedGolgi'snew methodto support their network theory of brain function were eventually forcedto concedethat Cajalwascorrect:eachnervecellin the brain was separatefrom every other nerve cell. In 1906 GolgiandCajal sharedthe NobelPrrzefor their discoveries. With the recognitionof the validity of 'the neuronaltheory', some rapprochementbetweenchemistswho knew about molecules and physicistswho knew about electricity might have occurredin brainscience.This wasnot the case.The century-old commitmentto brain electricity would not die easily;electricity remainedthe stuff of thoughtfor manymore decades. One of the bright Cambridgegraduateswho visited Berlin in 1885 to learn aboutthe cell from RudolphVirchow was Charles

THE FABRICOF MIND

Sherrington(1857-19b2).Sherringtonreturned to Englandand establishedfirst in Liverpoolandlater in Oford a laboratorythat was the centre of experimentalneurology.He was the first to graspthe significanceof the caressingpawsthat Cajalhadfoundon nerve endingsandgavethem the name'synapse',borrowingfrom the Greek word for 'clasp'. Starting with a convictionthat all nervousinformationmust be transferredacrossthe,synapse, but not ableto measurethat transfer, Sherrington performed surgical experiments that demonstrated the'importanceof the synapseto brain function and was able to discern relationships between groups of neurons that dependeduPon synapses.Sherrington deducedthat controlling inforrnation frorn thousandsof individual nerve cells must be firnnelledinto a 'finalcommonpathway'.He alsodescribeda 'reflex arc', which brought information into the nervous system and dumpedit into the final commonpathway,which in turn carriedit out of the nervoussystem. To those brain scientists who held to the network theory, synapseswere disastrous'circuit breakers';it was difficult to see how electrical currents could scoot around inside the brain if circuits were not continuous.But more than that, the presenceof synapsessuggestedthat'bodyjuicescouldleak into thesespaces. The uncertaintythat synapsesbrought to the conceptof a 'hard-

'claspingpaws'that Fig.8.5 Synapses: connectnerves

OF BRAINELECTRICIW THEUNDEFSTANDING

wired' brainthreatenedthe supremacynot only of Galvani'selectricity, but alsoof the brainoverthe body. Sherrington'slaboratorybecameMecca for brain scientists from all over the world, especiallyAmericans.Thosewho visited sawexperimentsthat were almostentirelygearedto the eventual of the circuitryof the brain.To Sherrington'sLiverunderstanding poollaboratorycameHarveyCushing,the fatherof modernneurosurgery, to join in experimentaloperationson apes.When he returnedto Baltimoreandbeganto performneurosurgery,Cushing wasquickto stimulatethe cortexof a humanwith an electrical current muchashe haddonein Liverpoolon apes. The report of that operation(on6 July 1908)seemedto confirm dramaticallythat the humanbrain was driven by the samestuff that madeGalvani'sfrog legstwitch:electricity.Cushingdidnot do morewith brainelectricity;in that sameyearhe switchedhisenerof the of the endocrinology giesdramaticallyto the understanding brain, especiallythe pituitary. But in the decadesthat follow€d, performedmanydifferentkindsof operations otherneurosurgeons basedon the premisethat electricitywasthe stuffof thought,most of whichwere onlycopiesof Sherrington'sanimaloperations.The gaveto Sherrington'snotionsthat the blessingthat neurosurgeons 'integration'of the nervoussystemdependeduponits hard wires did muchto ensurethat other clinicaldisciplines,especiallyneurology andpsychiatry,wouldfollowalong. Although many of Sherrington'sprecepts were helpful to bedsidediagnosis,they left physicianstrying to helppatientswith braindiseasewithoutammunition.In somecasesit wasworse.The Sherrington-likesurgicalmodificationsof the nervoussystemdid more harm than good.For these reasonsa still-existingschism developedbetweenbrainscientistsandbrainphysicians. Sherringtonemployedthe techniquesof reductionisticscience to take the brain apart into smallerand smallerpieces;but once apart,like Humpty-Dumpty,it couldnot be put togetheragain. cell Manyaspectsof Dalton'satomictheory(1809),Schwann's theory(1839),Bernard'sinternalmilieu(1856),Cajal'ssynapses (1895), and Sherrington'sstudiesof neural integration(1906) suggestedthat moleculesmightbe importantto brainfunction,but the beliefin brainelectricityforeclosedseriousstudyof that possibility for more than a century.The brain was an electricalorgan, andthat wasthat. In 1924 in Germany,Otto Loewifounda chemicalthat modified the rhythmicbeatingof the heart;he calledit 'vagusstuff' sinceit clearlycamefrom the vagusnerve.Whenanalysedby chemists,it

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wasfoundto be acetylcholine. Oneof the youngJewishscientists working there, WilhelmFeldberg,was forced to flee to England wherehe cameto work for Sir Henry Dale.In his headhe carried the specificinformationaboutacetylcholine measurements, andin 1934 he beganto look for acetylcholinein the nerveendingsthat are attachedto muscles.In twenty-sixscientificpapersDale and Feldbergdescribedthe presenceof acetylcholinein thesenervemusclesynapses, but in 1936 Feldbergwas forcedto leavethe laboratorybecauseof 'lackof support'.He went to Australiawhere almostimmediatelyhe receiveda letter sayingthat Daleplanned to publishthe chemicalneurotransmission story withouthis name. publisheda paper Quickly and quietly Feldbergsinglehandedly describing'chemical neurotransmission'. paper Dale'ssubsequent omitted Feldberg'snamebut for more than one year Feldberg's obscurepublication wasthebestsourcefor the 'truth' aboutchemical neurotransmission. Dale and Loewi sharedthe Nobel Pnze for chemical neurotransmissionand shortly afterwards Feldberg returnedto England. Acetylcholinewas the first chemicallinked to the electrical signalthat is measuredon the surfaceof nerves,but in shortorder there were several others includingnoradrenalitr€,adrenaline, dopamineand serotonin.It appearedto Dale and his colleagues that these 'neurotransmitters'were producedby the nerve and carried to the synapse;on their releasein the synapticcleft, an electricsignalpassedfrom onenerveto another. In this conceptof synaptictransmission,heldfor forty years,it was assumedthat one nerve containedone kind of neurotransmitter. Nerveswere designatedby the chemicalsignalthat each contained:somenerveswere adrenergic,someserotonergicand some dopaminergic,and so on (ergic = 'driven'). This concept becameknownas Dale'slaw, but we seein it a grudgingkind of willingnesson the part of brain electriciansto let moleculesinto the brain. If they were presentat all, it was only in the synaptic cleft, and then one nerve couldonly haveone molecule.Now we know that Dale'slaw is in error. Many nervescontainmanydif(seeFig 8.5). ferentkindsof neurotransmitters The discoveryof chemicalneurotransmission did not dissuade brainscientistsfrom their commitmentto brainelectricity.Dale's discoveryonly enhancedthe scientificnobility of Galvani'sbrain electricity. madeit easyto peekin at The adventof the electronmicroscope 'balls'of neurotransmitters that the nervefibresandseethe little (see pictures, in first available Fig. 8.6). Such are stored there

THEUNDERSTANDING OF BRAINELECTRICITY

71

1958,seemedto put the mindsof the brainelectricians at ease: neurotransmitters were positionedat a placewhere they could push'sparks'from onenerveto the next. As the creativegeniusof America'smany clever electricians becamemoreobvious,the centreof electricallybasedbrainstudies movedto this country.The forerunnerof the televisionset, the cathoderay oscilloscope, was the inventionthat cappedthe brain electricians'efforts. Before the oscilloscope, scientistshad been forced to employ the 'smokeddrum', a mechanicaldevice that recordedmusclemovementas a scratchon a movingroll of sootblackpaper.The oscilloscope providedelectronicamplificationof very weaksignalsandit, more than anyother scientifictool, glued the brain to the benchof brain electricians.They couldmeasure the tiniest sparks,eventhosein the synapse.As the cathoderay tube becamecentral to both televisionand the computer,the notionthat electricitywascentralto the brain'sinternalcommunicationswas buttressed.Most brain scientistsbelievedthat this providedconvincing,irrefutable evidencethat the brain was a biologicalcomputer. By stimulatingin onepart of the nerveandrecordingin another, Herbert Gasserand JosephErlanger were able to confirm that electricalsignalswere carriedalongthe nerveat differentratesof speed.Usingthis technieu€,theyfoundthat the velocityof conduction of nervefibreswasdependentuponthe diameterof the nerve; largenervefibrescarriedimpulsesvery rapidlyandsmallernerves moreslowly.For theserecordings,GasserandErlangersharedthe NobelPrize. Oneof the first tissuesto be examinedwith the electronmicroscopewas nerve, and to everyone'ssurprise the material that wrappedGasser'snerve fibres was little more than a jelly-roll wrappingcomposedof Schwanncells. As oscilloscopeswere linked to computers,the similarities betweenthe brain and the computerbecameclearer.The reverberatingcircuits of the computerwere describedas 'cybernetic currents' by Norbert Weiner in L948, and many scientists proposedeleganttheoriesdesignedto provethat brainelectricity, flowingin never-endingcircuits,was the stuff of thought.Today, manypeoplestill believethat cyberneticcurrentsreverberatein the brain. Someof the observationsthat havecomefrom neurosurgical operating theatres have done much to support this concept,but perhapsthe greatestboostfor the cybernetictheory of brainfunctionwasthe electroencephalograph. Inventedby Hans Berger in Germanyin L924, it is now commonlylinked to the

THE FABRICOF MIND

computer.To manywho seethem, the sparksemanatingfrom this mechanicalmarriage of the computer to the brain validate the paradigmthat the brain is an electricallydriven computer. Perhaps the best known brain operation that came to the bedsidefrom the laboratoriesof the brain electriciansis 'frontal lobotomy'. This operationis the natural outgrowth of a scientific belief in an electrically driven brain. The inventor of frontal lobotoffiy,EgasMoniz of Portugal,was given a NobelPr:?Efor it, yet it sprang from the behaviouralchangesin an experimental monkeycalled'Becky'. The socialandmedicaldisasterof lobotomy canbe traceddirectly to this onehastilydone,wrongly interpreted neurosurgcalexperiment. This operationhasbeendiscreditedenoughalready;but if scientists saythat the brain is composedof hard-wired,dry circuits like a wire-filled computer, then those doctors who care for patients with brain illnessesmight be excusedfor cutting the circuits of the brain or for overstimulatingthe circuits - giving electroconrnrlsive therapy- for both are logicalendpointsof that paradigm. A far greater neurosurgicalmismemewascreatedin this era. In 1911, Walter Dandy, a neurosurgeonin Baltimore, performed experimentsthat were just as bad as those on 'Becky'. Dandy

Fig. 8.6 An electronmicrograph of cut-acrossnervefibres

THEUNDERSTANDING OF BRAINELECTRICIW

postulatedthat brain water was formed solely as a 'hydraulic cushion'for the electricallydrivenbrain.In doingthis he gavethe world a false raison d'\tre for the hollownessof the brain and allowedthe bestphysiologists of the dayto focusexclusivelyon the electricalcircuitsof the brain.It was Dandy'sparadigmfor brain water more than any other factor that allowedbrain scientiststo focuson the sparksrather than the juices of the brain. He also basedmuchof his paradigmon an observationin a singleexperimentalanimal.Dandy'smistakewasfar moreimportantthanthat of EgasMoniz. Dandy'sparadigmfor brain water has proVideda paradigm whichat oncekeepsthe brain'dry' andgivesbrainscientistsa false answerto the mostimportantquestionin biology:'Whyis the brain hollow?'

Shoreline of Wonder

The brain becamean electricalorgan before any of the details were known aboutelectricity itself, beforethe battery, dynamo and motor, and long before the electrically based devices of communications. After Galvanithe brainbecamea testingground for the best gadgetsof electricians,who were not so muchinterestedin the brainasin the demonstration of their newestandfinest equipment.Their devices did demonstrateelectrical currents emanatingfrom the brainandfrom individualnerves.And asthese - telegraphs, same devices were employedin communications telephones, radios,andmuchlater television both physicistsand biologistsjointly concludedthat electrical signals were also responsible for communications in the brain. Linkingelectricityto the braingaveelectricitynobility.But the reversealsohappened: brainbiologists,ableto link their subjectof inquiry to the most exciting branch of science,slipped their research activities into the exciting mainstreamof scientific inquiry.For mostof this century,the studyof brainelectricityhas been the darling endeavourof the researchcommunity.Whole buildingsand entire divisionsof academicinstitutionshave been focusedon the mysteriousstuff that makesfrog legstwitch; only a casualglanceat Nobelawards,RoyalSocietyrosters,or National Institute of Healthgrantscandemonstratehow muchour society

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hasbelievedthat somegoodwouldcomefrom the effort to know moreaboutthe electricalcurrentsin the brain. These researchefforts, however, have done very little for who havebeenleft at the bedsidewithout patientcare.Physicians scientificpartners,wonderingwhy somuchis knownaboutthe rat brain and so little aboutthe humanbrain,will now havean alterlaboratoriesin the native: they can look to endocrine-based knowledgethat hormonesdrive the mind. knowsmostaboutsynapJuliusAxelrod,the Nobellaureatewho'Ten yearsagoonlythree 1984: tic chemistry,wrote in September nowaboutfifty . . . hadbeenrecognized; or four neurotransmitters havebeenidentified.It now appearsthat the brain is a complex peptides.' endocrineorganthat releasesa varietyof hormone-like in rel'olution dramatic the That statementsuccinctlysummarizes e; a two-century brainbiologythat hasoccurredin the pastdecad long scientificcommitmentto brainelectricityhasbeenreplaced by an interestin brainhormones.

I Confiteor:Neu rosurgical M alfeasances

et me tell you aboutmy involvementin a tragedy.Elisehad been the leadingdancerin one of the world's best ballet companies. Shehadgiventhe besthoursof every day since childhoodto the danceandhadcometo loveher lithe,stronglegs. Born slightly bow-legged,she had recognizedearly on in her careerthat this gaveher tremendousleapingability. At the age of thirty, at the pinnacleof her success,disaster struck.Overa two-dayperiodshedevelopedtotal paralysisof both legs.Her doctors,the bestin the world,diagnosed her conditionas 'transversemyelitis' andlistedthe possiblecauses.Somehadbeen optimisticat the beginning,but as the weekswore on and there wasno signof recoverythe truth wasclear:shewouldnevermove her legsagain. In the yearsthat followed,the numbsensationin her paralysed legswasreplacedby a sensationof pain.Woefully,anystimulation of her legs, the lightest touch, the weight of the bedclothes,a breeze,wouldcausea crescendoof pain so severethat she cried out in anguish. The doctors,againthe bestin the world,calledthis 'anesthesia doloross',a conditionin which the anestheticparts of her body were painful. Her pain separatedher from her supportivefriendsand bound her more andmore to her doctors.Soonan appetitefor foodwas replacedby an appetitefor narcotics.Then a love of narcotics becamethe driving force in her life but, even in dosesstrong enoughto causesleep,her painneverrelented. Fifteenyearsafter the illnessbeganI wasaskedto seeher by a physicianwho was more conservativethan most. He suggesied that I surgicallyremoveher spinalcord.He arguedthat it wasno good to her, and that some kind of crookedregenerationhad occurredwithin it that allowedtouchsensation, or any sensation,

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to beinterpretedby her brainas'pain'.As I haddonemorethanmy share of spinalsurgery, he selectedme to perform this heroic, desperateprocedure.The operationwas intendedto nid Eliseof the unbearable,untreatablepainin her legs.Shewouldtrade her persistentpainfor persistentnumbness. At operation,I madea lengthymidlineincisionin the upperback, removedthe bonesthat formed the roof of the spinalcanaland removedall the spinalcordbelowthe levelof the myelitis.The cord was abnormallysmalland abnormallycoloured- certainlydeadandasI closedthe woundI wasconfidentthat cordremovalwasthe correctchoice. WhenEliseawokefrom the operationher hopes,her husband's hopes,her personalphysician'shopes,her nurse'shopesand my hopeswerecrushed.Her paincontinuedasbefore,not changedone bit by my heroicremovalof her spinalcord. The operationon Elisestemmedfrom the studiesof anatomists whohadlocatedthe'painpathway'.Knowingthat manymillionsof nervesconnectedthe body to the brain, they separatedout the They hadreducedthe problem bundlesthat carriedpainmessages. failedoperationwas basedon my and pain signal, to a one-way of that simplisticreductionof a very complexproblem.It wasmy faith in that paradigmthat led me to perform every kind of nervecutting operationfor painthat hasbeendevised. Most of my operationsfor pain have failed in one way or another, and I have lost confidencein my ability to i'elieve pain by surgical 'trigeminal neuralprocedures. Only in patients with facial pain gia'- can I confidently predict a successfuloutcome of a destructive operation. Now, fifteen years after my operation on Elise, it is obvious to me and to most brain scientists that the brain is a gland. Pain is not something that can be effectively treated by dividing electrical circuits in the brain. Now we know that brain hormones modulate virtually every aspect of pain; the brain makes its own opiate-like hormones,enkephalinand endorphin,and has its own opiate receptors. It is the interaction of these hormones and receptors that underlie pain tolerance, pain intolerance and addiction to painrelieving drugs. But many other brain hormones besides enkephalin and endorphin are involved in pain modulation; somatostavasopressin,substanceP, vasoactiveintestinal tin, cholecystokinen, peptide and neurotensinall may be involved.Eachhormone appears to be effective by virtue of hormone and hormone receptor interaction in much the sameway as the opiate and opiate receptor relationship. Each of the new brain peptides that are involved in

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77

painmodulationseemsto interactwith the othersin patternsthat are compl€x,but increasinglyit is apparentthat the electrical signalsthat are involvedin pain are akin to the sparksthat are producedby a fire. Hormonesin the brain govern the fires that producethesesparks. The reductionismof the paradigmthat the brain is an electricallydrivencomputergavea narrowlyfocused,at best,half-tru€, startingpremiseto all brain doctors.Knowingnow of the holistic relationshipsthat are involvedbetweenbrain andbodyhormones makesour electricallybasedreductionistictherapiesappearnot only wrong but alsodumb. My disastrousexperiencewith Elise came shortly after the 'gate-control' theory of pain had been describedin lg6b. This revolutionaryconceptwas advancedin that year by Patrick Wall andRonaldMelzack,andit provideda rationalexplanationfor the failureof nerve-cuttingoperationsto relievepain. The gate-controltheory proposedthat nature has set in place two very differentsystemsthat carry painmessages to the brain. Althoughthey work together,naturehasgivenus onesystemthat protects us from outer injury during attack, and another that protectsus from inner injury,from hurting ourselves. This paradigmfor pain modulationis named 'gate control' becauseone of thesesystemsclosesgatesafter the first newsof painreachesthe brain.The other opensgatesafter the first pain message is sentto the brain. Naturehasgivenhumansa wonderfulmechanism that closesthe gatesthroughwhichpainsignalsmustpassontheir wayto the brain. This mechanismis ordainedto protect us from outsideinjury. If someone is attackedandphysicallywounded,for example,thl initial painservesas an alertingmechanism. But quicklythe gatesclose, andtheindividualis ableto carryonin defencewithoutthinkingof the painfulwound.This mechanismis set in placefor one purpose: to protectthebodyfromexternalattack.Themechanism must6equick andis carriedto the brainalongthe largestnerves,whichcarry the fastestsignals(seeFig.8.3).Themechanism mustbesensitive andis carriedbyneryesthathavethemostsensitivehairtriggers.But once the quick, sensitivemechanismis activated,it closesthe gates throughwhichit passed. This gate-closing mechanismis seencommonlyby thoseof us whomanemergencyroomsfor accidentvictimsor battalionhospitals for soldiers.There it is often observedthat very ,.u.r.ly injuredpeopledo not complainof pain.Youhaveprobatly experiencedthe protectionof the gate-closingmechanism:when the

7B

THE FABRICOF MIND

humanthumbtouchesa hot stoveor is slammedby a misdirected hammer,the initialpainpullsthe handbackby reflexaction.Then for a few minutesthe gatesare closedandthe intensityof the pain It is laterin the day,or in the night,whenthe is greatlydiminished. gatesare openagainthat the full intensityof the pain is appreciatedby the brain. This is a commonexperiencewhich did not rousemuchscientificcuriosityuntil 1965. Nature carriespain originatinginsidethe body by a different mechanism.This one is slow; there is no needfor quick reflex movement,andit canbe carriedalongthin, delicatenervefibresat a slowrate. It is not very sensitive,andthe stimulithat activateit mustpushagainstfirm triggers,not hair triggers.But oncethese to the brain,they openthe signalsare carriedby this mechanism Onceopen,thesegateswill allow gatesthroughwhichtheypassed. evenmild stimuli,thosethat ordinarilywouldnot be at all bothersome,to reachthe brainandto be interpretedaspain. Together these two systemsprovide a beautifullybalanced defence:the gate-closingmechanismprotects againstexternal protectsagainstinternal mechanism injury,andthe gate-opening injury againstdisease. Mostof the chronicpainsthat cometo humansarecarriedby the slow-conductingmechanismsthat open gates. Arthritis, disc stomachcrampsandanginaare typicalexamplesof interdisease, nal causesof pain.Naturewantssuchpatientsto rest, not necessarilyto take to their bed,but at least,to take'it easy,confident problems.As patientswith such that rest will curethe pain-causing mechanismis activated,all painknowwell, oncethe gate-opening kinds of ordinary and non-noxiousstimuli are perceivedby the brainas painful. The hingesof thesegatescanbe controlledby the brain.Some signalsflow out from the brainto set the tensionof the gates.The gatescan be adjustedby the brain to stay in the closedposition. The Indianfakir lying on a bedof nailshasdevelopedsuchcontrol gatesthat he can closethem at will and over his pain-modulating limit the numberof painsignalsthat reachhis brain.The harried housewifewho is insecure,lonely and depressed,on the other hand,cannotmusterthe brainenergyto put any pressureon the brainsideof the gatesthat controlpain.Withoutthat forcecoming from the brain, her gates stay open. Any sensationcan pass throughthe gatesand on to the brain. Backache,neckacheand of this situation.The pains arethe naturalconsequences headache are not imagin€d,they are real, but they result from a changein the thresholdof gateopeningandclosing,not from anyreal disease

CONFITEOR: NEUROSURG/C AL M ALFEASANCES

in the back, the neck or the head. The gate-controltheory makesgood sense,and for lessthan five years gate control appeared to be the best paradigm for understanding and treating pain. Like many others in my profession,I welcomedit, for it gave me a reasonto slow down on nerve-cutting operationsand a rational explanationfor my failures. During the time that the details of the gate-control paradigm were being worked out, America was racing to the moon. A crucial aspectof the moonshotprogramme was the ability of our scientists to broadcastradio signalsto distant satellites. The gate-controlparadigm dependedupon two kinds of nerves: one had a firm trigger and the other a hair trigger. The nerves that closedgates required only a one millivolt stimulus; the nerves that opened gates required a stimulus ten times as strong: ten millivolts. This differencein threshold made electrical counterstimulation possible;brain scientistsknew that a low-poweredstimulus would closegates and not be interpreted as pain. To moonshotscientists, broadcastingradio signalsinto the brain or spinalcord was far less difficult than broadcastingto and from distant satellites. Knowing that there was a ten-fold difference between the gate-closing stimulus and the gate-openingstimulus made their task easier. Two devicescame off the NASA shelvesand on to the shelvesof neurosurgeonswhich allowed electrical counterstimulationto be usedin patient care. Both dependedupon the very sensitivenerves that closedgates;both were designedwith the hope that a scarcely detectable'buzz' could replace high-intensity pain. The simplest of these is the 'transcutaneouselectrical nerve stimulator', or TENS, a battery-operateddevice that delivers an electrical signal to a nerve locatedjust below the skin. The TENS has the sophisticated space-ageminiaturization that allows the patient to twist the dials of the device to a frequency and strength that closesgates and reducesthe brain's perception of pain. A more complicateddevice is the 'dorsal column stimulator', ?r ingeniousradio receiver ltransmitter that can be implantedpermanently beneath the skin. The signal of this internal broadcasting station is carried along wires beneath the skin to platinum electrodes that are placedon the surface of the spinal cord. The radio does not have its own power supply; it is turned on by a batteryoperated 'wand' or external coil that is held over the skin just above the receiver ltransmitter. Activating the battery pack turns on the radio station,which sendsits signalsto the dorsalcolumnsof the spinal cord.

THE FABRICOF MIND

It seemedthen, in I97 0, that the gate-controltheory was a happymarriageof mankind'stwo greatestintellectualfrontiers, the mindandspace. For the next few years,thousandsof dorsalcolumnstimulators were implantedwith resultsthat werefar lessimpressivethanthe gate-controlparadigmwould have predicted. This electrically basedparadigmfor brainfunctionlookedwonderfulin the laboratory but, at the bedside,didn't work well at all. The operationis seldomdonetoday. The TENS device,becauseit is innocuous, is still usedwidely, andmanyclaimthat it is the Westernequivalentof acupuncture. In my experienceit is helpful in about one third of patients,but placebomedicationsmaymatchthat level of effectiveness. Dorsal columnstimulationand percutaneousstimulationhave been therapeuticfailures, certainly not the panaceafor pain. Despitethosefailures,the gate-controltheory of painmodulation is valid. It is certainlythe most usefulparadigmthat a patientin paincanknow,for it encourages the useof the gate-closing ability that lies dormantin the brain. My surgicalfailures- first in attemptsto break the circuits of the brain and secondin attemptsto stimulatethe circuits of the brain- are recountedto underscorethe failure of the paradigm that the brain is an electricallydriven computer.Howevereasily electricalpotentialscan be measuredon the surfaceof individual nervesor on the surfaceof the brain,whenthis paradigmis taken to the bedsideit is not very helpful.Yet from the story of gatecontrolcomesoneof the bestsurprisesin the historyof the mind: - for the as scientistssoughtan explanationfor this phenomenon pain toleranceof the Indianfakir and the pain-intolerance of the harriedhousewife- they cameto realizethat the brainis a gland. Hormones, not electricity, determine all brain/body and brain/behavioural relationships.

Shoreline of Wonder

If you have accepted the double-think of modern medicine and 'Molecules shape the body, but electricity shapes the scienceyou have unwittingly limited what your brain can do. mind'

whv?

CONFITEOR: N EUFOSURG ICAL M ALFEASANCFS

B1

Electricity,of any kind, is somethingthat you fear; you cannot control it. The terror of its shock,the sight of its spark,and the lightningbolt are long-lastinglessonsthat this stuff is not easily managed.Its control can only come by reduction:transformers reduceits power,insulatorsreduceits threat, switchesreduceits pathways.You give away that controllingreductionto someone else- to the powercompanies that reducecurrent,to the manufacturers who insulatewirqs and to the electricianswho direct the currentsthroughyour home. If you believethat electricity is the stuff of thought,you will treat your brainlike anythingelseelectrical;whenthingsgo wrong insideit, you will seekan outsideexpert- a doctor- muchas you seek an outsideexpert for your radio, telephone,or television set. Your doctor,motivatedin part by the honestbeliefthat you are unableto cope,too often will assumeit is a therapeuticduty to reducebrainpowerwith sleepingpills,insulatebrainactivity with tranquillizers,or direct the brain's patternsof thoughtby analysis. But more important,acceptingthe notion that the brain is an electrically driven computer makes it impossiblefor you to considerthe therapeuticoptionof addingsomethingto the brain that couldmakeit work more efficientlyandeffectively;reduction is your only option.You are then trappedby the silent snaresof Westernscience:breakingthingsinto smallerand smallerbits reductionism- is espoused,for smaller things are more easily controlled;joiningthingstogetherinto a largerwhole- holism- is eschewed,for controlbecomesmore difficult. The double-thinkthat grows from scientificreductionismis as perilousto our societyas a wholeas it is to you as an individual.I can write about the pros and cons of Westernreductionismas Conradwrote aboutwhaling:from personalexperience.For much of my life I have been both a bedsidedoctor and a laboratory researcher.In both of these activities,reductionism- specialization - hasbeenmy drivingmindmechanism. Yet in the pastdecadelaboratorystudiesof the brainhavebeen given a new preamble:hormonesmovingfrom the brain to the body and from the body to the brain modulateevery aspectof brain/behaviourrelationshipsand brainlbody relationships.In acceptingthis preamble,brain scientistshavesuddenlycometo espouseholismandare trying to put togetherthe bits andpiecesof the brainthat havebeenbrokenapartby their reductionisticforefathers.

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The newparadigmviewsthe brainasa complexwhole,anorgan that doesnot standapartfrom the rest of the body,run by different stuff,but sharesthe sameinternalmilieuas other organs.At first glancethe new holistic understandingof brain hormonesseems too complexto either understandor to be usefulin mind-boggling, designingbetter forms of therapy.But we now haveno choice:we the unity of the brain andthe body,admitthat must acknowledge brain hormonesare really body hormonesand recognizethat hormonaltherapiesaimedat makingthe brain wholeagainmust replace reductionistictherapiesaimed at bridling its electrical currents.

10 TheGiantsof the Brain Gland

academicsurgeons,the names John Hunter, William To Halsted, andHarveyCushinghavea ring that matchesthose I I of Socrates,PlatoandAristotle.As the threeancientGreeks set in placeguidelinesfor Westernthought,the three surgeons establishedthe principlesthat have guided Western surgery. Remarkably,eachof these surgeonscontributedsignificantlyto the understanding of endocrinology, andtheir individualparadigms came together as the foundationstones for a new science, neuroendocrinology. Medicalhistoriansrank JohnHunter (L728-93)as medicine's greatestcreativegenius;he is mostremarkablebecause he never received any formal education.The principles of infectious disease,immunization,bonegrowth, inflammationand lymphatic flow are a few of his discoveries.Many counthim as the father of endocrinology,becausehe understoodso clearly that endocrine organsinfluencebehaviourandbodyfunction.He was the first to transplantglands,andthoseexperimentsare still on displayin his museumin London. Noting the changedbehaviourin a hen that had receivedthe transplanted testiclesof a cock,Huntersaid:'The testiclesare the causeof changedinclinations,yet they do not direct theseinclinations. The inclinationsbecomean operationof the mind after the mindis oncestimulatedby the testicle.' Hunter did manyremarkablethings.Most notable,somemight s?y,washis self-inoculation with the germsof syphillisto ascertain that it was an infectiousdisease.But in the yearsthat follow historiansmayrecognrzethat his discoveryof the hormonalcontrolof the mindwashis greatestcontribution. Fred Mettler, an eminentmedicalhistorian,has accumulated evidenceto demonstratethat Hunter's lack of educationstems from severe dyslexia.It was this handicapthat forced him to observethingsfor himselfandto storehis observations in bottles,

B4

THE FABRICOF MIND

rather than in words.Two decadesafter Hunter died,his papers This earnedHunter'sfriendthe were burnedby a closeassociate. Britain,butMettler believesit wasanoblegesture wrathof academic performedto protectHunter'sacademicreputation:it appearsthe else'shand.Huntermayhavebeen paperswere written in soxneone nearlyilliterate. William Halsted (1856-L922) is regarded as the father of Americansurgery,He wasoneof the four peoplewho established America'spremier academicmedicalschool,JohnsHopkins,and the inventor of many operations,a new operative techniQU€, rubber gloves,endocrinesurgery and the strategy of residency educationfor youngsurgeons.Beforethe scienceof endocrinology was invented,Halstedhad worked out the basicprinciplesof the surgicaltransplantationof glands;in doingthat he was retracing stepstakenby JohnHunter a centurybefore. Halstedbecameaddictedto opiateswhile at BellevueHospital where,soonafter the inventionof hollowneedlesandsvringes,he usedhimselfas a guineapig to work out the detailsof localanaesthesia.Althoughhe spenttime in treatment,he neverescapedhis habit. He was recruited to Baltimorewhere he remainedproductive both in the laboratoryandin the operatingroom. HarveyCushing(1869-1939)is regardedasthe fatherof neurosurgery. He had attendedYale College and Harvard Medical Schoolbut soughtout Halstedfor his surgicaltraining. Cushing developedthe surgicalspecialtyof neurosurgetY, singlehandedly while maintainingan activerole in the laboratory.His legendary experimentsin the first decadeof this centuryestablishedthat the pituitary glandcontrolledthe functionof other endocrineglands. Cushingwas in manyways very much like Hunter; both were interested in dwarfs and giants, both devisednew methodsof controllingbleeding,both were interestedin new andbetter ways of treating infected wounds,both were military surgeons,both were collectors- Hunter of biologicalspecimensand Cushingof books- and both affixed their names to medical diseases:the 'Hunterian chancre'and penile ulcer of syphilliswas calledthe 'Cushing'sdisease'. excessiveadrenalglandactivity wascalled In anotherway Hunter and Cushingwere very different:while Hunter did not leavea written legacy,Cushingwasa prolific,gifted writer: his two-volumework on the life of WilliamOslerwon him the PuhtzerPrize: Most remarkably, Hunter and Cushing collaboratedin the evaluationof a patient,CharlesO'Brien,althoughthey were separated by more than a century.

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B5

Hunter's energiesled him to collect 10,000biologicalspecimens,andto that collectioncamethe wired-togetherskeletonof Charles O'Brien, a carnival giant more than eight feet tall. Referredto asthe 'Irish Giant',O'Briendiedwhenhe wastwentytwo, andnewspapers reportedthat he wasburiedat sea,but two yearslater a humanskeletonthat was eight feet tall appearedin Hunter'scollection. It is still in Londonin the HunterianMuseum. In 1910,shortlyafter Cushinghaddemonstrated that the pituitary was responsiblefor growth, he visited the John Hunter Museumandaskedthe curator,Sir Arthur Keith (whodiscovered the nervesof the heart), to saw openthe giant's skull to seeif a pituitary tumour had been the causeof his great growth. Keith obliged,andthey foundthe boneerosionthat is typicalof a pituitary tumour. This was very important to Cushing'sresearch, becauseit confirmedthat the pituitary secreteda substance, now called growth hormotr€,which causedthe body to grow. In O'Brien'scase,the pituitarytumourthat hadcausedthe erosionof the baseof his skull had secretedexcessiveamountsof growth hormone. These three surgeons- John Hunter, William Halsted, and HarveyCushing- all fit Koestler'sdescriptionof genius: Most geniuses responsible for the majormutationsin the historyof thoughtseemto havecertainfeaturesin common;on the onehandscepticism, often carriedto the point of iconoclasm,in their attitude towards traditionalideas,axioms,anddogmas,towardseverythingthat is taken for granted;on the other hand,an open-mindedness that vergeson naive credulitytowardsnew conceptswhichseemto holdout somepromiseto their instinctivegropings.Out of this combinationresults that crucial capacityof perceivinga familiarobject,situation,problem,or collectionof data,in a suddennewlight or new context;of seeinga branchnot aspart of a tree, but as a potentialweaponor tool; of associatingthe fall of an apple not with its ripeness,but with the motion of the moon. The discovererperceivesrelationalpatternsof functionalanalogieswhere nobodysawthem before. 'relational patterns' The new that Hunter saw in physiology, Halsted saw in wound healing, and Cushing saw in the pituitary were formed in the pattern-reco gnrzingright brain of each. In the last few decadesthere have been few, if any, surgeons who have contributed to the fundamental understanding of the endocrine system. Surgeons must be holists, and as scientific endeavours have become increasingly reductionistic, they have become less involved in laboratory studies. Yet the scientists who

THE FABRICOF MIND

pickedup the torch passedfrom Hunterto Halstedto Cushinghave the scientificreducbeena breedapart;they,too, haveeschewed tionismof their colleaguesin favour of holisticattemptsto bring the endocrinesystemand the nervoussystemtogether. These men were also remarkablefor their ability to put together new 'relationalpatterns'from the bits andpiecesother biologistshad takenapart. Their holistic endeavourshave been of two kinds. The first focusedon the controlthat the brainexertsover the glandsof the 'neurobody;theseresultedin a branchof sciencethat is called endocrinology'and beganin 1932.The secondis concernedwith the effectsthat the glandshave upon the brain; this scienceis called'endocrineneurology'andbeganlessthana decadeago. The manwhoconceivedof the notionthat the braincouldconvey its commandsby hormoneswas Joe Hinsey, and the man who verifiedthat this happenedwasGeoffreyHarris. 'architect' of the first bridge Hinseymight be regardedas the from the brainto the endocrinesystem.A superbphysiologistand anatomist,he madethe observationin L932,againstestablished no nerves.As an dogma,that the anteriorpituitaryglandcontained Iowa-bornfarmboy,Hinseywaswell awarethat after sexualcoitus many female animalsreleaseeggs from their ovaries.In the experimentallaboratoryhe wasableto verify that the insertionof a glassrod into the vaginaof femalesof thesespecieswoulddo the samething. To prove that the pituitary was important to reflex ovulation,he removedthe pituitaryin someanimalsandfoundthat post-coitalovulationdid not occur;the pituitary wasthe essential link. But howcouldthe informationget from the stimulatedvagina to the pituitary if there were no nervesin the pituitary? 'juices' In other unrelatedstudiesHinsey had observedthat were releasedfrom nerveendingsinto the surroundingtissue.He postulatedthat somethingsimilarmust be happeningin the pituitary. Sometissuejuice, a molecularmessenger,must carry the brain'sinformationto the pituitary. Hinsey'svery simpleexperimentswith reflex ovulationwere the first stepsin the realization that the brainis a gland. One mind that Hinsey'smeme infiltrated was that of George Wislocki,the anatomistat Harvardwho demonstratedthe route that Hinsey'stissuejuices could take to the nervelesspituitary. Wislocki brought together Hinsey's observationsand those of GregoryPopa,an anatomistfrom Bucharest.In 1930 Popawas briefly in Englandandcalledattentionto the similaritiesbetween

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87

the blood vesselsat the base of the brain and those in the abdomen. For centuriesit hadbeenknownthat a specialcirculationin the abdomencarriedbloodfrom 'portalto portal'.At oneport, the gut, foodwasaddedto the bloodandat the nextport, the liver, this food wasunloaded.Thesevesselsbecameknownasthe 'portalsystem' but are merelyveinsthat carry bloodfrom one capillarybed to a secondcapillarybedwithout helpfrom the arterial circulation. Poparecognizedthat the bloodvesselshe haddiscoveredat the baseof the brainwere 'portalvessels';onecapillarybedwasin the brainandthe othercapillarybedwasin the pituitary.He postulated that they carried bloodfrom the pituitary to the brain. Had he known of Hinsey's deductionthat molecular information was carried from the brain to the pituitary, doubtlesshe would have postulatedthat thesebloodvesselscarried bloodin the opposite direction:from the brainto the pituitary. In 1935 Wislockiconfirmedthat Popa'sportal vesselsexisted, but he claimedthat they carried bloodin the oppositedirection, from the brain to the pituitary.With that suggestionWislockilaid the anatomicalcornerstonefor neuroendocrinology. Wislockiregardedthe capillariesat the baseof the brain as a 'vascularswitchyard',muchlike the train tracksin a railroadyard, whichcoulddirect somebrainmoleculesto the bodyandothersto the anterior pituitary. Brain scientists, knowing about this, designedconceptsthat split the hormonalfunctionsof the brainin two: onepart, they contended,wouldmakemoleculesdestinedfor the bodyandthe otherpart wouldmakemoleculesdestinedfor the pituitary(seeFig. 10.1). Wislocki'svascularswitchyardbecamethe conceptualequivalent of a signalconverter,a transducer,whichconvertedelectrical signalsinto molecularsignals.That view is taught in most basic booksof sciencetodayeventhoughit is not whollycorrect. Inherentin Wislocki'sparadigmfor brain-pituitaryrelationships was an insistencethat all the bloodin the switchyardwasflowing 'south' towardsthe pituitary. That view separated 'electrical' an brainfrom a 'hormonal'endocrinesystemandset peoplethinking that electricity was flowing 'south' to the pituitary and that hormones,in turn, were flowing'south'to the body. After my neurosurgicaltraining, I spent sclveralyears in anatomicallaboratorieslookingcloselyat the pituitary. Many of my studieswere focusedon the blood vesselsthat connectthe brainto the pituitary.As certainlyasWislocki'sstudiessuggested

THE FABRICOF MIND

88

BodY

Wislocki's Y Y tJt\)v^' r porodigm Yv' vv'vt "

'vascularswitchyard'in the pituitarystalk Fig. 10.1Forfortyyearsscientiststhoughtthat a deliveredsomebrainhormonesto the anteriorpituitaryand otherbrainhormonesto the body as shown

'south',my studies to him that the brain's secretionswere carried suggestedthat somehormonesmight be carriedfrom the vascular switchyard'north' to the brain. My studies demonstrated five different routes by which hormonescouldbe carriedfrom the pituitary directly to the brain. I cannotacceptWislocki'snotionthat a vascularswitchyardseparates an electricallydriven brain from a hormonallydriven endocrine system.The switchyardthat Wislockidescribedunites two glands:the brain andthe pituitary. There is evidencethat brain hormonesdo passalongthe pathway that Hinsey and Wislockifound;it was the biochemistswho followedtheseanatomistsdownthe pathwaythat led to the major advancesin neuroendocrinology. One of these biochemistswas Vincent du Vigneaud(190180), tread of biochemistryat Cornell Medical School,who was awardedthe Nobel Prwe for the synthesisof the first peptide hormotr€,'vasopressin'.This hormoneis madein the brain and is

THEG/ANTSOF THE BRAINGLAND

carriedby nervesinto the switchyardthat Wislockidescribed.It is storedin nerveendingsthere until the commandcomesfrom the brainfor its release. 'protein', andas such,one of the basicbuilding Vasopressinis a blocksof the body. The term 'protein' is derived from the word 'protus', meaning'first stuff'. The tiny granulesthat form these blocks,the molecules,are called'amino-acids'and theseare often joined together like beadsof a necklace.There are only twenty 'essential'amino-acids, andthey seryein the formationof proteins much like letters of an alphabetare employedto form words. Du Vigneaudwas the first to untanglea protein necklaceand put it andits sistermolebacktogetheragain.He did this for vasopressin cule oxytocinin 1954, and sincethen hundredsof other proteins havebeenuntangledby scientistsandproducedsynthetically. 'balls' of vasoIn L967 I was able to visualizein humanslittle pressinmovingdownthe nervesprojectinginto Wislocki'sswitchyard (seeFig. L0.2).Thesegranulesare formed by the brain and conveyedin the nerve fibre, the axon, for nearly an inch. Sometimes these granulesbunchup in a nerve fibre that looks like it is constipated;that is, materialthat onewouldassumeto be moving 'down' towardsthe pituitary is held up for someunknownreason. Theseconstipatednervefibres were seenby Cushing,usingan He calledthem'Herringbodies'andthoughtthat opticalmicroscope. 'down'tolvardsthe pituitary. they moved'up' towardsthe brainnot Cushingfirst saidthat in 1909andmaintainedthat viewuntil he died in 1939;he believedthis soferventlythat in 1930he groundup the pituitary glandandplacedit in the ventriclesof humansto seewhat would happen.Long before I suggestedthat pituitary secretions

An electronnicrogroph

Fig. 10.2 Nerve cell secretionsgather as little balls within a Herring body

THE FABRICOF MIND

might be carriedtowardsthe brain,Cushingwasdoingexperiments to test that possibility. I believethat suchinjectionsoffer greathopeto thosewith many kinds of brain illness.But for many reasons,many of thern legal, Cushing'sexperimentshaveneverbeenrepeated. Two superblycreativeanatomists,Ernst and Berta Scharrer, lookedvery carefullyat the granulesthat were beingtransported downnerves.They concludedthat this wasa commonoccurrence not only in the pituitary but in virtually every nerve.They demonstrated,in insects,similargranulestravellingfrom the brainto the heart to control the way the heart beats.They describedthree kinds of neuroendocrine relationships,eachdependenton axonal transport of brain hormones.The Scharrerspointed ali their arrows from the brain to the body but, as we will see later, hormonesmove both into the brain and out of it by nerve transport. Without doubt the greatest contributor to the science of neuroendocrinology was GeoffreyHarris (1906-7I) who, in his lastyears,wasthe headof anatomyat Oxford.Harrisgot his start in scienceby looking at the blood vesselsthat unite the brain and the pituitary;by chancehe wasat CambridgewhenPopawasthere writing about the pituitary portal vessels. Although much of Harris's life was spent on the trail outlinedby Hinsey that led 'south' from the brain, he never lost his respectfor Popa who proposedthe opposite. Harris was the first to prove that electrical signals were convertedinto molecularmessagesas Hinsey had suggested. Decadesbeforeminiaturwedelectronicgadgets,Harris implanted wires into the brains of rabbits,maintaininga'coil' of the wire attachedto the scalp.He then placedthis strangelywired rabbit into the centre of a giant electricalinductioncoil. By passinga currentthroughthe outer coil,he generatedan electriccurrentm the wired rabbit.That currentpassedthroughthe brainand,asyou might predict,out poppedan eggfrom the ovary. Harris chasedafter the brain moleculesthat were releasedby electricalstimulation,knowingthat this codewould uncoverthe mannerin which the brain controlledthe pituitary. One of his students,however,RogerGuillemin,discoveredthat codefirst. To do that Guilleminhad to harvest5,000,000tiny brain fragments fragments from slaughterhouse sheepandreducethe accumulated to a singlemilligram of material.By his reckoningthe material that he recoveredwasmore expensive,ouncefor ounce,than the rocksthat were returnedfrom the moon.

91

THEG/ANIS OF THE BRAINGLAND

that brainsignalsare convertedinto Harris'swork established that are carriedby bloodvesselsto the pituimolecularmessages probablythe mostpowerful tary. Tiny amountsof thesemolecules, people of amplifhavefound,causea 'cascade biologicalsubstances ication'that racesfrom the brainto the pituitaryandthen to the wholebody.At eachstep of this amplificationprocessthe signals are louder,last longerandinfluencemore organs.His untangling processresultedin a book,TheNeural Control of this complicated paradigmof neuroendocrinoof thePituitary andthe fundamental in Fig. 10.3. logydescribed Bro,n

Adrenol Ktdney

F i g . 1 0 . 3 N e u ro e n d o cri n o l o g y :br ain hor m ones ar e r eleased by ner ves into the i n t o t h e a n te ri o r p i tu i ta ry,wh i c h in tur n r eleases hor m ones to m or e glands

'funnel '

that dr ai ns

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THEFABRICOF MIND

Duringmy yearsof neurosurgicaleducationwith BronsonRayin New York, manyhourswere spentin the operatingroom focused on the humanpituitary gland.It becameobviousto us that many descriptionsof the anatomyin this regionwere either incomplete or wrong. Encouragedby Bronson,I spentmany years studying the pituitary. These studies confirmedwhat I had seen in the operatingroom:there were very few veinsthat drainedthe pituitary. It lookedlike the pituitaryshouldexplode.It wasvery easyto trace the pathwaythat bloodtook into it but very difficult to find veinsthat could caffy bloodout of it. Lookingbackat the drawings of Wislockiconvincedme that he had not seenanterior pituitary veinseither. My anatomicalobservationshave been deliberately interspersedbetweenthe discoveriesof the giants of neuroendocrinology- Hunter, Halsted,Cushing,Hinsey,Wislocki,du Vigneaud, Scharrer,andHarris. My anatomicalstudiesshowedclear afiows pointingfrom the pituitafy 'north' to the brainandset the stagefor of later scientists,who in the past decade the accomplishments that the samehormonalcodesthat flow from the brain established to the glandsof the bodyalsoflow in the reversedirection:from the glandsto the brain.That informationconvincedscientiststhat hormones,not electricity, are the stuff of thought.

of Wonder Shoreline

It is the humanmind, not the humanbody,which hasshapedour civilization.The double-thinkof modern science,the view that 'moleculesshapethe body, but electricity shapesthe mind', is lamentable.Is it possiblethat Westernsocietyhasbeenbuilt on a foundationof double-think?Has scientific reductionismsprung 'reason' from the belief that humanthoughtsare electrical?Was giventhe brittle qualitiesof a robot, andthen pusheddowna path which becameincreasinglymechanical,disjointedand competitive?Is the nuclearwinter manyanticipatethe predictableconsequenceof the spiritualice agethat camefrom the notionthat the brain is drivenby fragmented,isolatedelectronslike a computer? Will the new view of the stuff of thought,which recognizesthe importanceof hormones,pushthe minddowna differentpath? were Notingthat manyof the giantswhohaveshapedphilosophy

THEG/ANIS OF THE BRAINGLAND

it maybe that the principlesof neuroendocrinology alsophysicians, will have a greaterimpact on the shapeof civilizationthan upon scienceitself. ThomasKuhn notes that scientistsoften become concernedwith philosophicalmatters during a scientificrevolution,writing: During a scientificrevolution. . . scientiststake a differentattitude andthe natureof their researchchanges towardexistingparadigffis, thewillingness articulations, of competing Theproliferation accordingly. the recourseto of explicitdiscontent, to try anything,the expression - allthesearethesymptoms philosophy andto debateoverfundamentals research. of a transitionfromnormalto extraordinary At present the world of brain scienceis in the middle of such a revolution.Scientistsnow regardthe brainasa hormonallydriven gland,not an electricallydrivencomputer.Holismreplacesreductionismin a newparadigmthat giveshumanthoughtsqualitiesthat arewarm,soft,wet, colourful,qualitative,timeless,communaland united. In espousingthe holismthat is essentialto neuroendocrinology, the pathfinders- JohnHunter, WilliamHalstedandHarveyCushing - mayhaveshownus not only a better way to think aboutthinking but alsoa better way to live.

11

a Gland theBrain becomes TheYear

-7Fhe discoveriesof Hinsey and Harris beganthe scienceof and gavethe first clue that the stuff of I neuroendocrinology other than Galvani'sbrainelecsomething be I thoughtmight tricity. This was the first suggestionthat there might be another different,but equallydefensible,view of the brain. The searchto understandthe importanceof brainhormoneshas produceda new branch of science,endocrineneurology,which that hormonesmadein the body may influencethe acknowledges brain.The new paradigmsthat led to this changedway of thinking aboutthe mechanicsof the mindare shownin Fig. 11.1. THEBRAIN THE SAMEHORMONES CONTA|NS BODY; THATARE \OUNDIN THE ISA GLAND THEBRAIN

Noloxoneblocks'Gotecontrol'

3l -Kfoundinpituitory foundinpituitorylipotropin Enkepholin foundin broin Enkepholin Opiotesfoundin broin Opiotereceptors'found in broin Fig. 11.1 The majorstepstakenby scientistsas they cameto knowthat the brainhas all the qualitiesof a gland

THEFABRICOF MIND

Opium,the drug that separatesthe mindfrom the body,brought aboutthis revolutionaryholisticview of the brainandthe body. An accidentof natureplacedopiumboth in the brain andin the sapthat flowsfrom the seedpod of the poppyflower. Thosewho havetastedopiumsay that the pleasureit bringsexceedsthat of love,wine,foodor any other drug. A very similarkind of bonding developedbetweenopiumandbrain scientists.They foundopium in the brainin 1975 and,like junkies,becamehooked;brainopium becamecentralto their dreams,andthe searchfor it wasfilledwith the frenry of an addictin needof a fix. The scientificdalliancewith this drug gavea new visionof the brainthat reshapedall previous thoughtsaboutthinking. Becauseof its strongaddictivepowers,opiumwasbannedin the United States despite pharmaceuticalcompanies,doctors and patientsrecognizingthat opiumwas the drug of choicefor pain. Knowingthis,pharmacologists beganto makenewsyntheticdrugs that wouldmimic the effectof opiumbut havelessof its addictive qualities,andmanyof the tricks that weredevelopedin the process becamethe wedgesthat split openthe brainto reveala cornucopia of brainhormones. Thirty years?go,cleverchemistsconstructeda syntheticmolecule,naloxoil€,that hada structuresimilarto opium.But naloxone had no pain relieving ability; indeed,if an animalwere given a naloxoneinjection,a later injectionof opiumhadno effect.Quickly it was realizedthat'naloxonewas working like a dummykey; it wouldfit into a lock that wasdesignedfor opiumbut not openit. If it were stuck in the lock, the opium moleculecould not work. These 'locks' are called 'receptors' by biologistsand in this instance'opiatereceptors'.Naloxonewasoneof the first synthetic drugsthat functionedasa 'receptorblocker'(seeFig. Ll.z).

Fig. 11.2 The structureof the opiatedrug morphinecomparedto the structureof naloxone, the opiateblocker

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97

Avram Goldstein, In Palo Alto in 1973, a pharmacologist, the presenceof the opiatereceptorsin the brainsof demonstrated in a machinevery similarto a animals.Brainswere homogenized was placedin a funnelmush This blender. kitchen vegetable poured through it. Generally,all shapedfilter and different drugs the drugscamethroughthe mush,but if there were receptorsin the brain that wouldbind the drug, the drug wouldremainin the tissuein the funnel.By attachinga radioactiveisotopeto the drug and then measuringthe radioactivity in the fluid that had been pouredthrough the tissue, the presenceor absenceof specific receptorscouldbedetermined.Goldsteinfoundopiumreceptorsin the brain by this method. If opiate-like drugs such as heroin were pouredthroughthe brain,they were bound.To confirmthis, 'dummykey', it naloxonewaspouredthroughthe brainfirst; like a 'lock' of the opium receptor. Then drugs such as stuck into the poured throughthe brainwithout binding.This was heroincouldbe evidencethat the braincontainedopiatereceptors. Goldsteinemployedthis techniqueto find that most opiate-like drugswere boundby brain tissue.In the next few months,opiate receptorswere localizedin very specificpartsof the brainby scientists working in Baltimore,New York andSweden. 'Is Almostin unisonscientistsasked, the braina gland?Doesit haveits own set of opiumreceptorsandits ownopium?Is it ::Canizedin sucha way that it cantreat itself?Canit give itself its own 'high' by the releaseof its internalopium?'By L975it wasverified that the brainproducedits own opiate-likehormones. The vas deferensis the tiny tube that carries spermfrom the testesto the urethrain males.For reasonsthat are clearto no one, the vasdeferenshasopiatereceptors;whentheseare boundto an opiate,the vasdeferenswill contractvigorously. To seert a new drug behaveslike an opiate,a smallstrip of vas deferensfrom a mouseor a guineapig is placedin a bath of fluid with oneend attachedto the bottom of the bath andthe other end to a gaugeat the top of the bath.The gaugerecordsthe muscle's movement.If an opiateis placedin the surroundingfluid, the vas deferenswill contractrhythmically. If a new drug causesthe vasdeferensto contract,it is probably an opiate.To make this relationshipmore substantial,naloxone canbe addedto the fluid;if naloxonepreventsthe contractions,the new drug is boundby opiatereceptorsin the vasdeferens.To the drug companyperformingthese experiments,this suggeststhat the new drug wouldalsobindto the brain'sopiatereceptorsand,if so,couldbe usefulin the treatmentof pain.

9B

THE FABRICOF MIND

The vasdeferenstest for opiate-likeactionhasbeenpart of the processfor nearlyall the drugindustry'snew 'paindevelopmental killers'.Coupledto today'smodernautomatedmachines,this test canscreenmanythousands of drugsin a shorttime. Armed with the informationthat opiatereceptorswere in the brain and stimulatedby the hunchthat an opiate-likesubstance might alsobe presentin the brain,biochemistsbeganto searchfor 'brain opiates'.The searchbeganin much the sameway as the searchfor opiatereceptors.The brain was placedin a kitchen blenderandreducedto a liquidslurry. To search for brain opiates,the many different molecules presentin the slurry can be placedin a specialkind of track- a 'column'- and forced 'race' to through it. If the column,is long enough,'purepopulations' of moleculeswill passout of the endof the column,separatedonefrom the other by their 'racingspeed'. It was this techniquethat was employedby John Hughesand Hans Kosterlitz in Aberdeen,Scotland,to conductthe winning searchfor brain opiates.As the moleculescameracingout of the endof the column,eachwasplacedin a bathcontainingthe device that measuredcontractionsof the vas deferens.Pig brainswere usedand,in a most importantscientificreport, in L975,Hughes and Kosterlitzdescribedopiate-likeactivity in one of the populationsof brainmolecules. Oncethis moleculewas found and isolatedin the brain, there wasa race to understandthe chemicalstructureof this molecule; scientistswere keenlyawarethat knowingthis structurewouldbe the biologicalequivalentto decipheringthe Rosetta stone: the codewouldtell how the brainworked. Many hormonesof the bodyare 'peptid€s',designated as such becausethey are formedby ribbonsof amino-acidpeptides.The in our bodiescometogetherlike the twenty'essential'amino-acids letters of an alphabetto form different peptide 'words'. Some peptidesare short, formed by only three amino-acids, and fairly easyto untangleandreform. The team in Aberdeenwasquick to give its new brain opiatea name,'enkephalin',andto recognizethat it was a short peptide. But it was surprisinglydifficultto untanglethe individualaminoacidsfrom oneanother.They enlisted,thehelpof HowardMorris at ImperialCollegein Londonwho,in a shorttime,wasableto tell them that 'enkephalin'was really a mixture of two peptideseach and the One was called'met-enkephalin' with five amino-acids. becauseof the methioninein one and the other 'leu-enkephalin' leucinein the other.

THE YEARTHE BRAINBECOMESA GLAND

F i g . 1 1 . 3 Me t-e n ke p h a l i na n d l eu- enkephalineach contain five am ino- acids

Other brain peptideshad beendiscoveredbefore.Inde€d,two NobelPrizeshavebeenawardedfor suchdiscoveries,but in the earlierinstancesthe brainpeptideswere directedfrom the brainto of the discoveryof the distanttargetsin the body.The significance enkephalinsrests in the realizationthat these brain hormones were destinedfor the brain;the presenceof the opiatereceptors within the brainmadethat a certainty. Breakingthis codeestablished with certaintythat the brain is a gland;the peptidesequence of enkephalin(seeFig. 11.3)verified that it was a 'peptidehormone'similarin every way to hormones that areformedby manyglandsin the body. One of the best biochemiststo study pituitary hormoneswas C. H. Li in San Francisco.From the pituitary he recovered 'prolactin'a hormonecontaining199 amino-acids, and growth He found another hormoo€,which contains191 amino-acids. peptidein the pituitaryandcalledit 'lipotropin'.By 1965the entire (seeFig. 11.4). structureof lipotropinwasdiscovered Lipotropin'sstructurewasdiscovereda longtime beforeanyone knewwhatit did,andthe earlynotionthat it regulatedfat metabolism wasquicklyput away.By 1975 the sequenceof lipotropinhad beenestablishedin five differentspecies.Always,its ninety-two peptideswere arrangedin muchthe sameorder. Noneof thosewho hadworkedon the structureof lipotropin,a pituitaryhormone,hadconnectedit to enkephalin, the new brain hormone.But in L975,at a conferencein London,Derek Smythe

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THE FABRICOF MIND

o flr

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ii li

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o o o l \ J l -

Fig. 11.4 Unravelling the structureof lipotropin madeit clearthat the brainand the pituitarywere producingthe samehormone

gavea seminaraboutlipotropinandshowedslidesof its amino-acid sequence. Embeddedin the lipotropinsequencewasthe sequence of met-enkephalin. This was evidencethat the brain was makingnot only its own peptidehormones,but alsohormonesidenticalto thosemadeby other glands.The questionsthat flowedafter met-enkephalin, a brain hormoo€,wasfoundin the pituitary glandare too numerous to recount.But most scientistscorrectly sensedthat if the brain containedone pituitary hormotr€,it probablycontainedothers. The brainwasa gland,andthe understanding of it wouldcomeby studyinghormones,not electricity. One of the first things scientistsdid was take a closerlook at lipotropin.They discoveredthat a portion of this molecule,betaendorphin,'endorphin'for short, was an opiate quite similar to enkephalin.Even though it was bigger and found in different regionsof the brain, endorphinwas clearly a pituitary hormone with opiate-likequalities;it, too, would make the vas deferens contract. In 1978 it was ascertainedthat lipotropin,a very big hormor€, was only a fragmentof an even larger molecule.In most laboratories,this giantis referredto by its weight alone;sinceit weighs 31,000Daltons,it is calledsimply'31-K'. This hormotre,31-K, is referredto as a'pro-hormone', a large hormonethat is madeby the bodyandthencut into smallerparts.

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101

No one understandswhy the body producesbig moleculesthat must be brokendown into smallerfragmentsbeforethey can be arethe rule, ratherthanthe exception,in useful,but pro-hormones endocrinology.On the long ribbon of 31-K are several other hormones,eachwith a very distinctanddifferentfunction(seeFig. 11.5). functionmuchlike the largeSundayeditionof the Pro-hormones New York Times,the printer finds it easiestto ship out all the sectionstogetherknowingthat the readerswill decidewhat they want.The fanswill devourthe sportspages,the bankerswill read aboutfinances,andthe flat-hunterswill pourthroughthe tiny-print of the real estateads.The body,in sendingits endocrinesignals from point to point, has employedthis same communications strategy. Soonafter the discoveryof 31-K, biochemistsfound another monstrouslylarge peptidepro-hormoil€,this time in the adrenal glandin the abdom€tr, andcalledit '50-K'. Within its necklace-like arcangementof amino-acidswas an even greater surprise- the 'brain' hormonethat had repeatingsequenceof enkephalin,the begunthe endocrinestudiesof the brain(seeFig. 11.6). Knowing that both enkephalinand endorphinwere opiate-like hormones,scientistslookedmore closelyat the opiatereceptor that hadstartedthe activity. They foundseveraldifferentkindsof opiatereceptorsbut each,in a generalway, was like a door with two key-holes,onearrangedto be unlockedby endorphinandthe The knowledgethat oneof the unlockingkeys otherby enkephalin. was storedin greatestquantityas 31-K in the pituitary glandand the other was storedin greatestquantityas 50-K in the adrenal glandwasbaffling:althoughthe brain controlsthe releaseof both hormones,the tight capillariesin the brain limit the passageof thesehormonesinto the brain. between opiate-smartendocrinIn the cross-communication ologistsandthe electricallysmart brain scientists,the mysteries of the gate-control theory of pain were discussed.As that phenomenon was taken into the endocrinelaboratories,the fact that the brain was a gland,andthat behaviourwas modulatedby hormones,becameindisputable. The endocrineexplanationfor the gate-controltheory came from the employmentof a procedurethat is usedvirtually every painday by drug companiessearchingfor new andless-addicting killers.It is calledthe 'tail-flicktest'. For this test, rats are housedin specialcagesthat are not long enoughfor their tails,whichprotrudefrom the rear of the cage.A

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THEFABRICOF MIND

heatinglamp is appliedover the tail, which beginsto 'flick' if the heat is uncomfortable.The temperature can be regulated precisely,and the tails are not burnedin any way. Oncein this device, rats are given drugs of different kinds to see if pain is perceiveddifferently.Opium,for instance,wouldallow the rat to tolerate higher temperaturesbefore the tail twitched.Any new syntheticdrug canbe testedin this way without risks to humans. In 1969 the tail-flicktest was employedto searchfor the location of the 'gates' within the brain. Stimulatingelectrodeswere placedin variousspots in the brains of rats housedin tail-flick cages.A spot was discoveredin the middle of the brain that slammedgatesclosed.Whenthis spotwas stimulated,rats could feel no painat all. In L976 HudaAkil, then in California,electedto repeat these remarkableexperimentsin animalsthat hadbeengivennaloxooe, the opiate-receptorblocker. With naloxoneon board, mid-brain stimulationhadno effect;the rats felt every bit of pain.The pain relief that camefrom mid-brainstimulationdid not come from electricallyclosed'dry'gatesalone.Sincethe benefitof the electric current had been blocked by naloxotr€, some opiate-like

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THEYEARTHE BRAINBECOMESA GLAND

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hormonemust havebeenreleasedby the electricalstimulation.It was the hormotr€,not the electriccurrent, that stoppedthe pain. Most likely, the opium releasedby mid-brain stimulation was comingfrom the brain itseH. This wasa crucialbridgingexperimentthat broughtbrainscientists awayfrom the 'dry'electricalpathof Galvanibackto the 'wet' molecularpathof ClaudeBernard. Only monthslater, this was verified in humanswho were being treatedwith mid-brainstimulationfor their pain:whenstimulated, endorphincould be found in their spinalfluid, and the analgesic effects of their stimulation could be blockedby naloxonegiven beforethe stimulation.

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THE FABRICOF MIND

opiumis Out of theseserialexperimentscametwo conclusions: a hormone,and the brain is a glandthat can makethis hormolle. The bodyalsoprovidesthe brainwith pain-killingdrugswhenthe needarises;opiate-likehormoneshavebeenfoundin the gut, the pancreas,the gonadsandwhite cells. Enkephalinwas the first brain hormonethat was discoveredin the brain'sown pharmacy:endorphinwas the second.Now, ten yearslater, scientistshavefoundat leastforty-fivedifferentbrain Theremaybemanymore,but the principlesseenin the hormones. opiate-likehormonesare the samefor every other hormone:they arereleasedfrom one cell and trigger a responseby interacting with a specificreceptoron anothercell. Knowingthat the opiatehormones,indeedall hormones,are scatteredthroughoutthe brain and body gives scientiststhe 'intercept' the codedmessagesthat are flowing opportunityto betweenthe two. Usuallythey lookin the blood,knowingthat the brain and the body speaklo one anotherthrough that pipeline. 'release' will beginwith the Scientistsknowthat the conversation of a hormonefrom onecellandwill be completedwhenanothercell 'hears'the codedhormonalmessage.Like containinga receptor it is easierto knowthe cellsthat are'speaking', anyconversation, 'listening'The cellsthat are for theywill releasetheir messages. receivingthe codes- are more difficultto study. that involve31-K asthe coded conversations The brain-to-body these interceptionsit has From messageare best understood. that the braintriggersthe releaseof 31-K from beenestablished the pituitary by first releasingtwo other hormones,vasopressin and 'corticotropinreleasingfactor'- for obviousreasonscalled 'CRF'. (Theseare the Juices'that Hinseypostulatedmust flow from the brain to the pituitary.)Whenpituitary cellsthat produce from the brain,theyin turn release 3l-K 'hear'the codedmessage 31-Kinto the bloodstream. 'solo' by the Scientistsknow that pituitary cellswill listen to a or CRF- will release31-K), brain(eitherjuicealone- vasopressin (bothjuices: but the cells respondmuchbetter if two substances vasopressinand CRF) are sent to the pituitary at once. This 'solos'to the phenomenon suggeststhat the brain doesnot sing 'harmonies'. Brain/bodyrelationshipsmight depend body, but upona chorusof individualhormones- perhapsfifty, perhapsfive hundred- which are releasedtogether to sing hormonal harmoniesto the body. with the bodyin this manner,the If the brain is communicating 'solo' not be very helpful.Thus while will note decodingof a single

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more and more evidencesupportsthe notion that hormonesare the stuff of thought,it seemslesslikely that individualhormones control individual aspects of brain function. Combinationsof hormonescometogetherto do the brain'sbidding. It was assumedby Hinsey,Wislocki,du Vigneaud,and Harris, indeed by all neuroendocrinologists, that the hypothalamus convertsthe electricalsignalsof the braininto endocrinemessages that canbe carriedto the body.The 31-K systemshowsthis well: the greatest storehouseof it is in the pituitary; the greatest concentration of 31-Kregulatinghormones, vasopressin andCRF, is in the adjacentbrain. As anatomistshavebegunto look for the sitesof productionof 31-K, they have also looked for the presenceof other brain hormones.To their surprise,they found vasopressinand CRF, whichthey hadconsideredto be brainhormones,in manydifferent glandsof the body.This is perhapsbestillustratedin the ovaryand the gut: both vasopressin andCRF are foundthere. Whatis more surprising,cellsthat produce31-K are alsofoundin the ovaryand the gut. Thus the entire combinationof hormonesof the 31-K systemdiscoveredin the brain is found in the abdomen- in the ovary and the gut. Theseorgansmanufacturenot only their own 31-K but also the brain hormonesthat are responsiblefor its release(seeFig. LI.7). Both vasopressin and 31-K fragments-'ACTH' and 'MSH'havebeenlinkedto memory.Researchers in Hollandhaveshown this with suchcertaintyin animalsthat syntheticpreparationsof thesemoleculesare now beingusedto treat patientswith lossof memory. If memoryspringsfrom thesehormones,doesthe ovary have memory?Canthinkinggo on outsidethe brain? Before you dismissthis as madness,rememberthe disturbing conclusionthat Karl Lashley(1890-1958)reachedafter looking for the 'site of memory' in the brain. For twenty years he had searchedfor the placein the brain where learningis stored by training rats to perform in a mazeand then removingselective parts of the brain.Even thoughthe brain operationsproducedall kindsof deficitsof movement,the animalsdid not forget whatthey had learned;they couldstill find their way throughthe maze.He concluded:'I sometimesfeel in reviewingthe evidenceon localization of the memorytrace that the necessary conclusionis that learningis not possible.' Manypsychologists sincehavespeculated that memorymust be storedin the bodyas photographicinformationis storedin a holo-

THE FABRICOF MIND

Pituitory

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3t-K A

Ovory Fig. 11.7 31-K is producedby the brain,the pituitary,the ovariesand the gut. The brain hormonesthat release31-K,ADH and CRF,are alsofound in the ovariesand the gut. Can these glandscontributeto thinking?

gram.They contendthat there is no singlesite in the brainfor the 'pianolessons'andanothersite for the 'Frenchlessons'.They say that memoryis diffusedeveryrhere andfocusednowhere. If memoryis dependentuponhormonesandif memoryis holographic,findingthe hormonesof memoryin manysitesoutsidethe 'engramfor memory'that Lashleywassearching brainmovesthe for outsidethe brain. Many glandularorgans,however, can produce an electrical signalthat is carriedfrom onecellto the next.Findingelectricityin the endocrinesystemunitesthe brainandthe endocrinesystemin the reversedirection.As certainlyas hormoneshavefoundtheir way into the brain,electricityhasfoundits way into the endocrine

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system.If electricity,producedby combinationsof hormonesin the brain,can carrymessagesfrom the brain to the body,cannot electricity,producedby hormonesin the body,carry messages to the brain? The ovary and the gut haveall the machineryfor a'private' endocrineconversation; they producethe samejuices- vasopressin and CRF- that the brain produces,and they make31-K just like the pituitary.Althoughscientistsmight not easilyintercept the codedmessagesthat flow betweenindividualovarianor gut cells,they know that the machinesof the mind,indeedthe same brainhormones,are presentin the ovary,the gut andpredictably manymoreorgans. The giantmolecule31-K is specificallylinkedto specifickindsof 'thoughts',more so thananyother moleculeandmore so thanany electricalcurrent.Pleasure,pain,memory,appetiteandstressare eachmodifiedin specificwaysby tiny 31-K fragments.Eachfragment of the moleculebecomesone 'solo' note in the hormonal harmonyof thought,but if thesesolonotescomefrom the ovary, doesnot the ovarycontributeto thought?

Shoreline of Wonder

The philosophicalconsequences of the new notionthat the mind is modulatedby hormonesmaybe asgreat asthe medicalandscientific consequences. The double-thinkof modernscience-'Molecules shape the body, but electricity shapesthe mind' - ends abruptly with the realtzationthat regulatory hormonescontrol both brainandbodyfunctions. SincePlato'sdescriptionof the shadowson a cave,philosophers have held that somethingoutside the body shapesthoughts. Descartes'sdualismis the bestexampleof this; his world wascut horizontallyin half.Abovehis dividingplane,eventswere ruled by spirituallaws.Belowthat plane,eventswere governedby physical laws.In Descartes's scheme, thepinealglandprotrudedupintothe spiritualworld like a lightningrod that carriedthe soul into the body.Althoughmodernintellectualsdo not sharehis view of the pineal,his dualismlingersin the cornersof manyminds. The beliefthat the brain was driven by electricityhasbeenan importantfactor in the longevityof Descartes'sdualism.Elec-

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tricity obviouslycamefrom above- Franklin'skite experiments provedthat. Moreover,it hadthe invisible,mysticalqualitiesof a spirit. But to understandthe importanceof brain electricity to modern Western thought, consideragain the right/left split of humanbrainfunctions. The left brainthinksserially;it considersonething at a time - a letter, word or number. Ideas must be reducedto letters and words,and quantitiesmust be reducedto numbers.Reductionis the very essenceof left-brainthoughtprocessinglto enter the left brain'sthinkingmachinery,a thing must be reducedto something smallerthan itseH.Thesereductionsmust be kept separateandat a giveninstant,in reading,writing, listenitrg,or speaking,the left brain must focuson onereduction. By contrast,the right brainis committedto patterns.All that it does involveswholeness.The right brain alwaysconsidersthe wholeof somethingand,at anygivenmoment,the right brainmust focuson manyinterrelatedthings. The very natureof electricitydovetailswith left-brainfunction: electricalcurrents do flow serially.Electricalsparks,or smaller electrons,must remainisolatedonefrom anotheras thoughtsare isolatedin the left brain;the electricalsignalsthat areemployedin devicessuch as radios,telephones,televisions, communications andcomputersmustbe dealtwith oneat atime very muchlike the left brainfocuseson onereductionat a time. notionthat the pinealwasthe seat At the time that Descartes's of the soulwasheldto be absurd,anotherkindof spirit,oneformed on the surfaqeof the brain and from electricityand measurable individualnerves,was enthronedin the brain. The essenceof 'me', was assignedan electricalquality humanlife, the conscious serially:the andplacedin the part of the brainthat communicates which allowed, left brain.An Aristotleanhierarchyof organswas assignedthe left brain the highest place, gave electricity the highest function and gave reductionisticthoughts the highest priority. With all of this, the right brain was thought of as sub-human; those mystics, often from the East, who espousednon-verbal, holistic,mysticalthoughtswere regardedaslesserintellectuals. paradigmfor the mind acknowledges The new hormone-based that electricitydoesflowfrom nerveto nerveandcanbe measured on the surfaceof the brain or on the membranesof individual nerves. But these superficialsignalsare little more than dry echoesof deepermoleculareventsgoingon within the cell. Scientistsnow believethat the mindwill be best cornprehended

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by focusingon intracellularmolecularevents, rather than on superficialelectricalsignals.Although this is a new paradigffi, nearly all of the early experimentsdemonstratethat regulatory hormonesjoin in holistic patterns that may be understoodby organsother thanthe brain.The mechanisms of the mindare thus releasedfrom the conceptualconfinesof the reductionisticleft brain. The mechanisms that drive thoughtare foundall over the bodyand,whereverthey live, they functionat their highestlevel by recognizingthe molecular patterns of the combinationof hormonesthat modulatethought. As scientistsacceptthis new paradigffi,the primary mechanismsof intelligentthoughtmustbe vieweddifferently.The mindis madepattern dependentand comesto sharein the ubiquitous secretof evolutionarysurvival:patternrecognition. Patternrecognitionis the sine qua non of the geneticcode,of the DNA/RNAinteractions,whichprovidethe blueprintsfor life; pattern recognition underlies all immunology - the antigenantibodyreactionsthat recognizeanddefend'self';patternrecognitionis basicto all the hormone/hormone receptorinteractionsof cell regulation;and pattern recognitionis the highestform of thought.It is the synchrony, the synergism andthe spatialjuxtaposition of whirling hormonalforces that give life to the human soul. Is this molecularmaelstromdivine?I think so:it createslife, it is ubiquitous,it cannotbe broken apart,it cannotbe contained,it cannotbe copied,it is eternal. Arthur Koestlerobservedthat scientificreductionshaveled to a divorceof reasonandfaith. The ultimatereductionis a bleakand faithlessformula,p=MCz; it has placedmankindon the brink of globalself-destructionand createda spiritual ice age. The new view of the mindmayleadto the rapprochement betweenfaith and reason,for it seemscertainthat anunknowable'force' giveslife to the moleculesof the mind. Other formulae,espousingharmonious,symmetrical,beautiful, creative and joyful patterns, may lead mankindaway from the threat of nuclearwar, but it seemscertainthat thesepatternswill only be comprehended by minds which understandthat holistic thoughtis the humanbrain'shighestevolutionaryaccomplishment and,without doubt,the bestguideto evolutionarysurvival.

12 Paracrinology

I n L797, forty years before the cell theory, Xavier Bichat I $771-1802) proposedthat the work of the bodywassystema, tically divided:the bonescametogether to form the skeletal system,the esophagus, stomachandbowelscametogetherto form the digestivesystem,the tracheaandlungsformedthe respiratory system,and so on. Bichatdividedthe body into twenty-onesuch systems,but modern biologistsacknowledgeonly the nervous, skeletal, cardio-vascular, digestive, respiratory, muscular, immutre, lymphatic,reproductive,genito-urindty, blood,skin and endocrinesystems.In this decadea new system,the paracrine system,wasdiscovered. The nervoussystemwasrecognizedlong 2go,but the endocrine systemis very recent.Both the nervoussystemandthe endocrine systemareregulatorysystems,andthe work that they domightbe equatedto officework. Theseare the white-collarsystemsof the body. Historians describing the discovery of the paracrine systemmight equateit to an industry-like'takeover'.The parucrine system centralizesthe two managementteams, the old nervoussystemandthe new endocrinesystem.In this mergerwe seea new anddifferentkind of management style that directsthe management teamsout of their officesinto the factory-sitesof the body. The paracrinemanagementphilosophyassignsregulatory hormonesto the site of work: gut managersreside in the gut, kidneymanagerslive in the kidney,andbloodvesselmanagersare stationedin bloodvessels,andso on. It was the recent developmentof hormone-specific stainsthat allowedscientiststo seethe hormone-laden regulatorycellsthat are scatteredaboutthe body.Many scientistsfeel that the paracrine system,or its equivalent,is the oldestin biology,pointingto the presenceof regulatinghormonesevenin the earliestof singlecell evolutionaryanimalsto provetheir point.

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Most peoplearenot awareof the paracrinesystem,yet the term is aboutforty-fiveyearsold.It wasintroducedin 1938by Friedrich Feytrer (1895-L973), a pathologistin Danzig,to describehis observationthat somehormonesare carriedfrom onecell directly to a neighbouring cell,the 'parallelce11', hencethe name'paracrine system'.In 1966,a British biologist,A.G.E.Pearse,calledattention againto endocrinecellsthat were scatteredaboutin surprising places.But not until hormoneswere foundin the brainwasthe significanceof paracrinemanagementunderstood.With Roger Guillemin's Nobel acceptancespeech in I97 8, paracrinology entered the everydayvocabularyof scientists.The term is a biologicalportmanteauthat describesa host of biologicalevents involvingboth the nervoussystemand the endocrinesystem.In one surprisinglink, the brain to the testicles,many of the principlesof paracrinologybecomeevident. Many centuries before people were performing surgery on humans,they were operatingon animals.Crudeoperationswere performedwith the intent of modifyingbehaviour.Testicles,for example,havebeenremovedfrom horny,rapaciousmalesto tame themfor at least5,000years. In 177LHunterelectedto dothe reverseandaddthe maletesticle to a femaleanimal.In this simpleexperimentHunterconfirmed that the brain behavedlike a gland.Hunter's observationis what paracrinologyis 4ll about: regulating hormones modulate or controlthe functionof anorgan.AlthoughHunterfirst sawit in the brain,it is the rule for everyorgan. In the early part of the last century, d curiouslink betweenthe brain and the testicleswas againdescribed.Two French phrenologistsdescribedshrinkageof the left cerebellumif the right testicle was remov€d,or vice versa- right cerebellumand left testicle.What wasjust as remarkable,if the left cerebellumwas damag€d,the right testiclebecamesmaller. In 1959 a Hungariananatomist,JanosSzentagothai, described similarstructuralchangesin brain cellsafter removingendocrine glands- the ovary,testicle,or adrenal- andpresentedconvincing evidencethat therewasa two-waystreetbetweenonesideof the brainandglandson the other sideof the body.Szentagothai's laboratoryhasbeenworkingon theserelationships steadilysincethat time, andhis teamhasconfirmedthat lesionsin tiny areasof the left brainwill limit growth of glandson the right, andvice versa. Scientistsworking with Szentagothaihave also found shrunken braincellsin the sameareaof the left brain if the right glandsare removed(seeFig. t2.1). Thesechangesare not the resultof the

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Fig. 12.1 Directconnectionsexistbetweenthe glandsof the body and the brain

hormonalmessagesthat are carriedby the bloodstreambecause they havebeennotedin animalsthat do not havea pituitary. Few brain scientists paid much attention to these brain-totesticle links; they did not fit with the paradigmthat the brain is electricallydriven. Nor did they dovetailwith Wislocki'sview of the neuroendocrinesystem, which regarded the pituitary as a necessarylink betweenthe brainandthe endocrinesystem. The team in Hungarystuck to its belief and now scientistsare forcedto concedethat the observationsare fundamentallycorrect. Sophisticatedendocrinetests of the brain demonstratethat the brain is chang€d, it 'thinks' differently, if the gonads are removed. The significanceof this link is immense;it demonstratesthat messagesare carriedfrom the brain to the endocrinesystemand from the endocrinesystem to the brain within neryes. These messagesarenot electricalbut molecular.The codedsignalsmove down nerves from the brain to the glandsto nourish hormoneproducingcells,andmoleculesmoveup nervesfrom the glandsto the brainto nourishthought-producing cells. Regulatorymessagesor hormonesflow from specificregionsof the brain to specificglandswithin 'hollow' nerve fibres exactlyas Erasistratus,GalenandDescarteshadtaught.

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- the brain-to-pituitarylink The scienceof neuroendocrinology that wasdiscernedby Hinsey,Wislocki,du Vigneaud,andHarrisis dependentupon hormonesflowing within nerve axons.This phenomenon,axonalflow, was first noted by Ernst and Barta 'managers'were being Scharrer,who suggestedthat hormone sent by the brain to peripheralorgansthrough nerve fibres.For 'down', that axonalflow wasalways it wasassumed manydecades that is, it movedawayfrom the brain. In the pastdecadeit hasbecomeclearthat hormonesalsomove 'up' nervefibresfrom the bodyto the brain.This wasnotedusing many different experimentaltechniques:hormonesinjectedinto the eye are carried back to the brain, tracers injectedinto the tongueare carriedbackto the brainstemand,most remarkably, injectedinto the thigh musclemay be carriedinto the substances 'nerve growth spinal cord. The best-studiedsuch moleculeis factor'j Nerve growth factor wasdiscoveredabouttwenty yearsago:it is made in many placesbut chiefly in the salivaryglands.It is carriedas a hormonein the bloodstreamto the endingsof nerves and suckedup into the nerve in the way that an elephanttrunk sucksup water. Oncein the nerve,it is carriedon specialintracellular bargesseveralfeet backtowardsthe nervoussystem,where it nourishesspecialkinds of neryes. If the trunk-like nerve is pinchedin any way, the central nerve cell will die. Moreover,if antibodiesare injectedinto the bloodstream,the circulatingnerve growth factor is destroyedand,as a result, the central cellsthat dependuponnerve growth factor will die of starvation(seeFig. 12.2). Moleculesthat have no biologicalfunction but can be traced 'tracers'.Oneof the besttracersis wherevertheytravelarecalled an extractof horseradishthat canbe injectedinto living cellswithout ill effects.Injectionof this material,horseradishperoxidase, 'retrogradetransportpathinto differentglandshasdemonstrated experiways' very similar to those suggestedby Szentagothai's are that organs from pathways found have also been ments.Similar not thoughtof asglands.If this tracer is injectedinto the stomach, for example,it can be recoveredin very specificregionsof the brain.If it is injectedinto a leg muscle,it appearsin the spinalcord. If it is sprayedinto the nose,it appearsin the brain'solfactorytract (seeFig. t2.3). Moleculesmovenot onlyfrom the brainto the endocrinesystem but alsofrom the endocrinesystem,indeed,from all parts of the bodyto the brain.

PARACRINOLOGY

Fig. 12.2 Nervegrowthfactor is made in the salivaryglandsand makesits way into the bloodstream,where it is carriedbackwardsup the nerveas food for nervesnear the spinalcord

Fig. 12.3 Horseradish peroxidaseis a powerful'tracer':injectedinto a leg muscle,it is carried backwardsinto the spinalcord;injectedinto the stomach,it is carriedintothe brain

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Scientistscantakethe nucleusout of a singlecell from the inner cheekof a greenfrog andtransplantit into the eggof a brownfrog. In a few daysthe identicaltwin of the greenfrog popsout of the brownfrog'segg.If scientiststookout a thousandcellnucleiifrom themin thisw?y,theycouldproduce onegreenfrogandtransplanted 'cloning'.In every a thousandidenticalgreentwins.This is called cell in your bodyis the geneticcodefor your entire body.By transplantingthe cell nucleusinto an egg,you couldreplicateyourself, billionsof times,if you wished,andevery oneof your clonedchildren wouldbe your identicaltwin. that eachcell in the bodycontainsenough Cloningemphasizes produce an entire brain and endocrinesystem. informationto Knowingthis, the productionof regulatinghormonesby paracrine cellsbecomesmore credible. gland. JesseRoth, an Every organ is a hormone-producing believesthat every regulatorypeptide Americanendocrinologist, 'glands'producethe greatest canbe madeeveryvhere.Although quantitiesof regulatory hormonesand store them for sudden release,paracrinehormonesare foundvirtually everywherein the body. by the largersocietyof cells A singlecell maybe commissioned - to producea single by Virchow first described the society molecule.Sucha cell will first switchon the genesin its nucleus that carrythe instructionsfor suchproduction. If a genein the cell nucleusis switchedon, its DNA ribbonswill split apartandallowa xerox-likecopyof its codeto be made.The copyis formedfrom RNA. Like a preciousmanuscriptthat is not allowedto leavea library, DNA moleculesare not allowedto leave - the xerox the confinesof the cell'snucleus;only RNA molecules copies cando that. Duringmostof the pastthirty years,the periodof the revolution in molecularbiology,it was assumedthat the brain couldcontrol from the surfaceof the cell. But in the the releaseof substances pastfew yearsscientistshavecometo believethat the switchingon of genesmay alsobe controlledby the brain. by lookingcloselyatmuscleor, more Thismaybebestexplained 'dark' and 'white' meat of a turkey. White specifically,at the muscleis involvedin quickactivitiessuchaswingmovement.Dark muscleis involvedin slowmovementsuchaswalkingandstanding. If the nervesthat go to fast and slow musclesare switched- the nervesdestinedto controlthe wingsswitchedwith thosedestined to controlthe legs- the musclesthat movethe wingsbecomeslow andthosethat movethe legsbecomefast.Althoughscientistshave

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not yet determinedwhat it is that switcheson the genesthat produceslowmuscleinsteadof fast muscle,most of the evidence suggeststhat this messag€,which comes from the brain, is hormonalnot electrical.Thesebrainhormonesmaymoveinto the very centre of the cell, the nucleus,and modify the genesthat controlit. Onlyin the pastyearhavescientistsbeenableto seea switchedon gene;the method,devisedby JohnCoghlanin Melbourne,is called'hybridrzation histochemistry'.This techniqueallowsyou to look at the codedRNA that the cell hassent into the cytoplasm, that is, at the xeroxcopiesof the genes.SuchRNA will only be in the cytoplasmif the gene has been switchedon. Hybridization histochemistrywill allow scientiststo untanglethe puzzleof the 'dark' and 'white' meat, and many similar puzzLes, and thereby understandthe role that the brainplaysin geneticregulation. Centralto the paradigmthat the mindis modulatedby hormones is the recognitionthat the stuff of thoughtis not cagedin the brain but is scatteredall overthe body;regulatoryhormonesare ubiquitous.Goneare the dayswhenscientistsbelievedonehormonewas madeby onegland.Insulin,for example,may be madein greatest quantityin the pancreas,but it is madein other surprisingplaces, like the brain, and even by tiny one-cellorganismswithout a pancreas.The parameceum,for example,makesinsulin as do manyother smallanimalsthat do not havea pancreas. Roth has proposedthat every regulating hormone can be producedeverywherein the body,andthe cloningexperimentsof genetic engineersunderscorethe feasibility of this. The new scienceof paracrinology extendsRoth'sobservation by notingthat theseregulatinghormonesare not static;they movefrom cell to cell,indeed,from organto organ.Moreover,their movementlacks a predetermineddirection;to-and-fromovementis the rule not the exception. Untanglingtheserelationshipswill be muchmore difficultthan untanglingthe electricalcircuits of the brain. There are more placesto look, more things to look for and more directionsthat signalsmight take.Lookingfor a tiny circuit in the brainor looking for a singleopiate-likehormonein the brainboth involvedneedlein-the-haystack kindsof searches, but nearlyeveryparacrinerelationshipthat warrantsuntanglinginvolvescurrents of hormones that flow betweencells,in the bloodstream and nervefibres.At everylevelthe movementof the regulatinghormonesis bidirectional,compounding the difficultyof the untanglingeffort. The magnitudeof the puzzleis increasedfurther by the realiza-

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tion that regulatorypeptidesmay do differentthingsfor different organs, even in the same species.The hormoneinsulin, for for the bodybut doesquite example,performssugarmanagement anotherthing in the brain: injectedinto the brain of baboonsit modifiestheir behaviour.At the momentit appearsto be the best 'slimming'hormonethat exists,but for that functionto be reahzed it mustbe fed to the brain,not the body. To compoundthings, many hormone-controlledactivities dependuponpulsatilesecretion.The best exampleof this is the controlof eggreleasefrom the ovary:neithera singleinjectionnor a continuousinfusionof the responsiblebrain hormonesworks well. Six or eightinjections,interspersed at regularinte:rvals over severalhours,are necessaryfor 'controlled'ovulation.Scientists predict that many brain-controlledbody functionsdependupon similar well-timed,pulsatilebursts of hormonalharmoniesfrom the brain. Now paracrinology'sbiggest surprise: glandularcells 'turn over', that is, whena hormone-producing cell dies,a new cell will place. appearin its But for more than a century it has been assumedthat brain cells- neurones- do not turn over. Scientists claimedthat nature plantedbillions of neuronesin the brain at birth, but asthe yearspassedthe numberof thesecellsdiminished. Someexpertssaidthat manymillionneuronesdiedeachday,never to be replaced.But in 1984camethe solidexperimentalevidence that braincells,like glandcells,turn over;newneuronesarebeing producedin the brainall the time. Learningaboutneuronalturnoveris a scientificactivitythat has just begun,but evenat the beginningoneseesthat the fabricof the mindhasbeengivennewmystery.How doesa dyingneuronepass its informationto its replacement? Is there someten commandment-liketablet, chiselledinto the geneticcode,which is swallowedby the new cell andthen replicatedlike a gene?Doesthat cell,on its death,passthe sameinformationin the sameway?If a newbraincell canswallowsucha tabletproducedby a dyingbrain cell,canit swallowother tabletsproducedby other cells?Canthe brain,like a musclethat is exercised,grownewcellsthat will make it stronger;or conversely,doesthe unexcercised brain atrophy muchasa musclewithersawayif it is unused? It is unlikely that scientistswill untangle paracrinology's Gordianknot tomorrow or even in this century.Few biological yet no other processes are as complexas thosein paracrinology, aspectof biologycouldbring an equivalentgoodto humankind.

of Wonder Shoreline

Sincethe time of Aristotlebrainscientistshavebeentrying to label then a humour,then the stuff of thought;first it wasquintessence, animalspirit, then electricityand,mostrecently,hormones. As brain hormonesare placedat the top of the hierarchyof mind-stuff,what will be the new driving force? It is too early to tell. Both laboratoryworkers and clinicians, are silent on the issue. especiallypsychiatristsandpsychologists, Both groupsare sophisticatedhistorianswho note that the religious,philosophical of the driving force and socialconsequences may be of greaterimportancethan the stuff of thought.They are cautious. appropriately The wisestbrain scientistsseemto be watchingthe physicists who know most aboutthe elementaryparticlesin atoms.As they listen to physicistsdescribeelectrons,neutronsand protons as 'forces',not 'matter',theywonderif brainhormonesmayalsobe a force rather thana substance. Brain scientistshear physicistssaythat a singleelectron,spinning about a central atomic nucleus,may changeorbits by a mechanismthat knowsno time and space.Theseeventscompel physiciststo believethat 'forces',not matter,are the fundamental buildingblocksof nature.They claim that the parts of the atom that artists draw as concreteorbiting balls are not substantial of thingsat all, but forces;physicistssayyou are totally composed theseatomicforcesandhaveno real substance. What do physicistsbelieveis the stuff of matter?In two words: forces.Onephysicist,Ervin Schrodinger,wrote a interdependent now-famousessayto demonstrateto brain scientiststhat these importanceto brainfunctionandprovide forcesare of fundamental the stuff of thought a mysteriouslink to the stuff of matter. To provehis point, he describeda theoreticalexperimentin which a cat wasplacedin a box with a force detectorthat wouldtrigger a deviceto kill the cat.If the cat were left aloneit wouldlive, but Schrodingerdemonstratedthat the mere contemplationof the experimentby anoutsideviewerwoulddrainsome'force'from the box. If the force detector were fine-tunedto measurethis loss, then trigger the deathdevice,the cat woulddie. This now legendary experimentdemonstratesthat the stuff of matter and the stuff of thoughtare both interdependent forces.

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Although Schrodinger'sexperimentsuggeststhat physicists understandhow all of the physicalforcesof the world are intertwined,nothingcouldbe further from the truth. Three of the four primary forces- stronginteractions,weak interactions,andelec- have well-documentedinterrelationships;the tromagnetism fourth force,gravity,is not at all understoodandcannotbe related to the other forces.Scientistsbelievethat the discoveryof a fifth force, the unifyingforce, will explaingravity andshowthat all the physicalforcesare relatedby ubiquitous,fundamentalprinciples. As gravityis the greatunknownof physics,memoryis the great enigmaof brainscience. To thosebrain scientistscommittedto the paradigrnof an electrically driven brain, memory is often described by using computer-liketerms such as 'reverberatingcircuits' or 'cybernetics'.To the newbreedof scientistcommittedto the paradigmof a hormonallydriven brain,memoryhasa pattern-dependent molecularstructure.The first paradigmis basedon the physicalprinciplesof the electromagnetic force.The secondparadigm,depending upon molecularinteractions,invokesthat force but also the forces of strong interactionsand weak interactions,which hold molecules together. Neither of these competing paradigms invokesthe fourth force,gravity.Memorymaybe like gravity.And its understandingmay not comeuntil the fifth, unifyingforce, is comprehended. Consideran experimentperformedby Hunter more than 200 yearsago.Stagantlers,Hunter knew,grow morerapidlythanany other biologicaltissueandalwaysat the sametime of the year.It is the rapid elongationof the antlerswhile in 'velvet' that hasled to the centuries-oldview that wafer-thinslicesof velvet serveas an effectivemaleaphrodiasiac; to this daythe saleof thesewafersis a multi-milliondollarbusinessin the Orient. Hunterelectedto dividethe bloodsupplyto onehalfof the stag's skulljust at the time that the antlerswere scheduled to begintheir growth. rapid Only the antler with its bloodsupplyintact grew, provingthat bloodsupplywas importantto growth. But within a fortnight, after a new bloodsupplyhad grown into the skull, the stuntedantler beganto grow. Hunter was then ableto watch a minor miracle:the growth patternof the new antlerwasthe absolute mirror-imageof the previouslyformedantler- it hadthe same lengthandthe samenumberof tines,but wasa perfectreversal. Hunter was clever enough to ask, 'What force guides this growth?'In all other body systems'tropisms'are expected.A developingnerve, for example,is drawn towards an already-

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developedmuscle.But in the caseof the antler,the perfectlysymmetrical growth is without any 'tropic' influence.The molecules forming the bonehavea life of their own and somehow,as they reach towards the sky, carry within them a pattern for antler formation,not an identicalpatternbut a mirror-image.How could the moleculespossiblyknowtheywereon the right sideof the head andnot the left?Hunter only posedthe question.It is a question that cannotbe answeredby anyof today'sbiologistsor physicists, the ignoranceof us all. andit neatlyunderscores The miracle of the antler, like the miracle of gravity and 'force' of somekind - a unifyingforce.It memory,demandsa new is not explainedby any of the four forces that the physiciststalk about; neither brain hormonesnor brain electricity can move cleverlyinto'nothingness'. Wise men from India predictedthat mysticalforcesregulated the activitiesof the brain andthe body.Inherentin muchof what 'think'. they taughtwas the notionthat the bodycanbe taughtto Paracrinologyverifies their view: the chemicalmachinerythat producesrationalthought rests within the body and outsidethe brain.It is this view of the stuff of thoughtthat providesthosein the Easta respectfor karma- the mysteriouslife-givingforcethat flowsfrom life to life. Their view of karmais in every way like the 'matter' but modernphysicistsview of electrons.They sayit is not a 'force'. The Hinducommitmentto reincarnationis a wagerthat karma movesfrom one movinglife to anothermovinglife by the same'magic'that movesatomicelectronsbetweenorbits. natureof atomicparWith the discoveryof the non-substantial ticles andthe predictionof a unifyingforce, Westernsciencehas validatedmuchof the ancient,holisticwisdomwrittetr5,000years agoin vedicscriptures.The karmaof the Easternmindis sosimilar to the interdependentforces that scientistssuchas Schrodinger claimareboththe stuffof matterandthe stuffof thoughtthat yogis mightrightly claimthat karmadoesexistbecauseWesternscience hasprovedit. The reductionistsin the West,however,cannotacceptthe holistic wisdomof Easternmysticismeventhough,at the mostfundamentallevel,their own toolshaveverifiedit, andtheir bestphysicistsare committedto the conceptualneedfor a unifyingforcethat defiesreduction.

WhyistheBrain Hollow?

'ventricles',formedby injectig. 13.1showsan X-rayof the ing a dye into the hollow,fluid-filledcentre of a brain. All animalshavean inner fluid-filledspace.But why? Most teacherswouldsaysomethinglike this.The brainis sosoft that it mustfloat.If it were not floatingin water,you couldn'tturn footballwithout damaging somersaultsor play rough-and-tumble your jelly-like brain. The brain keepsa cushionof water inside itselfandanothercushionof water outsideitself sothat it is doubly protectedfrom forcefulinjuries. Most scientistsbelievethat water enters the ventricles- the 'choroidplexus',a structure that fluid-filledcentre- throughthe resemblesa bunchof grapesandwavesin the watersof the ventricle. They alsobelievethis water flowsout of the ventriclesinto space'.They would tell you that water then the 'sub-arachnoid flows aroundthe brain and returns into the venouscirculation granulations', throughothergrape-likestructures,the'Paccionian whichhanginto largeveinsat the top of the head. The neatly integrated paradigm for brain water shown in Fig. 13.2wasderivedfrom experimentsdoneby WalterDandyin Baltimorein 1911. It is one of the most frequentlyproduced diagramsin scienceandmedicineandhasbeenreproducedin the best textbooks of neuroanatomy,neurophysiology,psychiatry, neurologyand neurosurgery.As thesecomplexwater-flowpath'Dandy waysare not easilydescribed,I will refer to them as the paradigm'. Most brain scientistsand brain physicianshonourthe Dandy paradigmas a navigatorhonoursthe North Star. The arrows he drew for water-flowhaveguidedmanydifferentkindsof thoughts about the brain sincethe day he drew them, yet new scientific to accepttheseguidevidencemakesit difficult,if not impossible,

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Fig. 13.1 A needle has been placed in the ventriclesto fill them with dye

Fig. 13.2 Left:Once water escapesfrom the ventricles,it flowsover the surfaceof the brain. Right:The scan showsthe fluid-filledspace aroundthe brain

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ing arrowsanylonger.It is a mismeme;the experimentalfactsno longerallowit to be 'true', andwe needa paradigmswitch. Dandy'smismemeandits passage into the heads To understand of scientificteachers,let us go backto Galen. brain In the secondcenturyGalenperformedrathercomplicated animalsthat were strappedto surgeryon living unanaesthetized boards.He describesthe removalof differentportionsof the brain that convincesme that in animalswith vivid detailandan accuracy. he did what he sayshe did. He notesthe changesin brain volume causedby respirationexactlyas I haveseenthem countlesstimes in humansduringbrainsurgery.In his dissectionsGalendescribes the right and left cerebralventricles,the midlinethird ventricle and the aqueductthat connectsthe third to the fourth ventricle beneaththe cerebellum. Galengavethe differentventricleswell-definedfunctionseven thoughtherewasno reasonat all to link themto function.He said that new ideaswere generatedin the right and left lateral ventriclesandthat they were storedasmemoriesin the midlinechamber of the third ventricle.Whatdid the fourth ventricledo?It was the chamberof wisdomand judgement.This view was unquestionedfor at least1,500years. In AD 1500 Leonardofilled the ventriclesof the brain with moltenwax to form the first castof the ventricle.From thesehe producedthe first accuratedrawingsof it, but he did not question the universal belief that highest intellectual thoughts resided mysteriouslyin thesespaces. that the human The elegant art work of Vesaliusemphasized brainwashollow.But this hollownessdid not excitemuchinterest becauseit wasassumedthat animalspirit in the brainwasa liquid that neededstoragesomewherebeforeit waspushedout into the nerves.Descartes'sdrawingsof the ventricleswere crude and wrong,but he madethe waterworksin thesespacesdovetailwith his anatomicallylinked philosophy.His clever placementof the seatof the soulin the pineal,just aboveandbetweenthe chamber of memoryand the chamberof wisdomand judgement,attests againto the chicaneryof his blendof mechanicsandphilosophy. To Galen,Leonardo,Vesaliusand Descartes,the ventricles were cavitiesthat storedthe animalspirit that movedmuscles. Dissectionsperformedin 1768 in Hunter's laboratoryfound tubulesthat carrylymphback lymphatics,the tiny, gossamer-thin to the heart from most regionsof the body.He and his brother WilliamHunter calledthe networkthe 'secondcirculation'.Before their dissections,it was believedthat every organ in the body

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receivedan artery, a vein and a nerve. The discoveryof the lymphaticsby the Hunter brothersgaveeveryorgana fourth kind of tubularlinkage. But Hunter was carefulenoughto note that the brain did not haveits ownlymphatics.Instead,it wasfilledwith ventricularfluid. He postulatedthat the lymphof the brainwascarriedfrom it by the interconnectedinner ventricles.Noting that the third ventricle was connectedto the pituitary glandby a funnel,the 'infundibulum', he postulatedthat brainlymphwascarriedinto the pituitary, whichhe assumedto be a lymphgland.Hunter madethesedeductions beforemicroscopicstudiesof cells were possibleand there wasno reasonto believefrom observationthat the pituitary gland wasany differentfrom lymphglandselsewhere. For the entirenineteenthcenturythe brainwasconsidered to be a giantelectricalnetwork.The brainbiologistsof that periodwere contentto acceptHunter'snotionthat brainwater movedinto the ventriclesand then out of the brain by way of the pituitary. The paradigmkept the brainrelatively'dry', all the better for the electrical circuitsof the brain. Hunter'sparadigmequatingbrainventricularfluidto lymphwas accepteduntil 1871. In that year, pituitary tumourswere first found in humangiants by Pierre Marie. He assumedthat such tumoursallowedan accumulationof lymph in the brain, and that brainlymph,in turn, causedgiganticgrowth.Not until the birth of endocrinology in L902did scientistsquestionHunter'snotionthat the ventriclesand the pituitary together drainedthe brain of its lymph.By 1908 it becameclearthat the pituitary glandwas the master gland of the body and secreted a substance,growth hormooe, whichcausedanimalsto grow.Cushingsuggested in that year that excessivesecretionof growth hormonefrom the pituitary, not the accumulation of brain lymph within the ventricle, causedgigantism. SinceCushinghad given the pituitary anotherfunctiontotally unrelatedto the lymphaticfunctionassignedto it by Hunter, the ventricleswere quite suddenlyleft with no knownfunction.The question,'Why is the brain hollow?',then was unquestionably not transparent;it hada significance equalto the questiotr,'Whyis the heart hollow?',whichhadstimulatedHarvey.Dandy,oneyear out of medicalschool,soughtan answer. that he wanted Dandyhad decidedas a medicalundergraduate to be a brain surgeon.In those days,this meant that he would spendseveralyearsasa generalsurgeonwith Dr Halstedandthen training.Whenhe did his experiments extra time in neurosurgical

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on the hollowbrain,he had had no surgicaltraining.He had not evenbegunhis generalsurgicaltraining,but he performedneurosurgicalprocedureson animalsthat evenby today'sstandardsare very difficulttechnically. Dandy's experimentswere performed in dogs and were 'hydrocephalus'; in designedto learn more aboutthe diseaseof and thosedays,beforeantibiotics,meningitiswas commonplace 'water on the brain' or thosewho survivedwere often left with he reasoned, of hydrocephalus, The understanding hydrocephalus. 'Why is the brain would lead to an answer to the questioo, hollow?' In Dr Halsted's general surgical practice, operationsfor obstructedstomachsandobstructedbladderswere commonplace the lesson and,asa medicalstudent,Dandycouldnot haveescaped that 'outletobstruction'causedballooningof holloworgans. 'Couldoutlet obstructioncausethe Dandyquitenaturallyask€d, and designedexperiventriclesof hydrocephalus?' ballooned-up mentsto test that possibility.In dogs,he placeda'cork' in the aqueductthat linked the third and fourth ventricles (see Fig. 13.3). After this operationthe ventricleswere muchlarger,very simiTo Dandy,this development lar to thoseseenin hydrocephalus. meant that the ventricleshad beenblown up like a balloonas a of outlet obstruction. consequence

Normaldog

Experrmentcldog

F i g . 1 3 . 3 Da n d y p u t a co rk i n the aqueduct behind the thir d ventr icle in a dog's br ai n, noti c ed that 'outl et obs tr uc ti on' t h e v e n t r icl e s g re w l a rg e r a n d c oncluded that hydr ocephalus was a diseas e of

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Dandy'snext question,'Where couldthe water comefrom?', alsoprompteda directexperimental approach. He openedonehalf of the brain,the left cerebruffi,like a clamin order to removethe choroid plexus that lay in the floor of the ventricle. Then he insertedhis 'cork' in the aqueductashe haddonebefore.Now he foundthat only the right ventriclebecameswollen,the one that still containedthe choroidplexus. Dandyconcludedthat the water in the ventriclesthat caused hydrocephalus camefrom the choroidplexus.It appearedto him that water was continuallycomingfrom the choroidplexusand neededto get out of the brain. If it couldnot passthroughthe outlets,the brain wouldswelllike a ballootr,in every way like the stomachandthe bladder. Dandywasassumingthat the water in the brainwasnot important. His focuson intraventricularwater was in keepingwith the times:everyoneassumedthat the brainwas drivenby electricity. Physics,not chemistry,was importantto the brain.In lookingat the insideof the brain as a balloon,Dandywas ableto eschewall chemicalconsiderations andbasehis paradigmon physicsand,in this instance,on the laws of fluid mechanics.His paradigmwas basedon the premisethat the waterin the ventricleshadno chemical relationshipto the electricallydrivensurroundingbrain. Next Dandyasked,'Wheredoesthe water go onceit leavesthe brain?'To find out; he openedup boththe right andleft sideof the skull,lifted up both the left andthe right hemispheres of the brain and passeda gauzestrip aroundthe mid brain. He had hopedto demonstratethat this rnanoeuvrealsocausedhydrocephalus. But it didn't. After this procedure,the ventricleswere normalin size. He repeatedthe experiment,but onthis secondoccasionhe soaked the gauzestrips in tincture of iodineto inducea scar.After this procedure,the ventricleswere indeedlarger thanbefore. Fromthesethreesetsof experiments, Dandyconcluded that the choroidplexuswasthe sourceof ventricularwater; that ventricular water passedout of the brain;andthat onceoutsidethe brain, ventricularwater flowedaroundthe brainto the veinsat the top of the skull where it re-enteredthe circulation.Theseexperiments gavebirth to the Dandyparadigm. Very quicklyDandygavehis experimentsclinicalsignificance. He concludedthat there were two kinds of hydrocephalus. One kindresultedfrom blockadeof the aqueduct:fluidcouldnot get out of the ventricle.For suchpatientshe proposeda divertingoperation that allowedthe fluid producedin the choroidplexusto leak out of the brain througha new surgicallyconstructedhole in the

WHYIS THE BRAINHOLLOW?

129

floor of the third ventricle. This operationbecameknown as a 'third ventriculostomy' (seeFig. 13.4). resultedfrom infectiouspostThe secondkindof hydrocephalus meningiticscarsaroundthe surfaceof the brain. Fluid couldget out of the brain,but it couldnot makeits wayto the veinsat the top of the head.For suchpatients,Dandyproposedanotherkind of operation:removalof the choroidplexus,the sourceof the offending fluid(seeFig. 13.5). Dandydid many of these operationson patients,and for two other surgeonsall overthe worldfollowedin hisfootsteps. decades But a host of retrospectivestatisticalanalysesof theseoperations demonstratethat neither choroidplexectomynor third ventriculostomywasan effectivetreatmentfor hydrocephalus. With the developmentof malleableplasticsin World War II, 'shunts'of manytypeswere developed, andnowhundredsof these operationsare performed daily throughoutthe world to treat The uppertip of the shuntis typicallyplacedin the hydrocephalus. ventricle, usuallythe right, and the distal end is placedin the

Fig. 13.4 lf waterwas trapped in the brain,Dr Dandymade a hole in the back of the third 'thirdventriculostomy', doesn'twork ventricle.This cleveroperation,

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THE FABRICOF MIND

abdomen;this allows fluid from the ventricle to drain into the abdomen(seeFig. 13.6). There are many technicalproblemswith shunts:children may outgrowthem,the tubingmay kink, break,twist, becomeplugged with debris or becomeinfected.But the operationis one that is generallyquite successful;it has madehydrocephalusa manageabledisease. Shuntproceduresare the mostnumerousoperationsperformed today,andsurgeonsinsert thesedevicesin the by neurosurgeons beliefthat the successof their surgicalwizardryvalidatesDandy's dictumthat water flowsfrom the insideof the brain to the outside. But do thesesuccessfuloperationsprove Dandyto be right? Carbondioxide,a gas,comesout of the hollowlungs,but it is not producedthere; it comesfrom cellsall over the body.No physician would assign carbon dioxide production to the lungs simply becausean endotrachealtube allowscarbondioxideto leave the lungs. Urine comesout of the hollow bladder,but it is not produced there;it comesfrom the kidneyssomedistanceaway.No physician wouldassignurineproductionto the bladdersimplybecausea bladder catheterdrainsurine away.

Alligotorforcepsremovingchoroidplexus

pathway',Dandy Fig. 13.5 For patientswith meningitiswho developeda'blocked sub-arachnoid proposedthe heroicbut unsuccessfufoperationof choroidplexusremoval,thinkingwronglythat the flow of water into the ventriclewould be reducedby this procedure

WHYIS THE BRAINHOLLOW?

131

Fig. 13.6Shuntsare tunnelledunderthe skinto drainexcessfluidfromthe brainto the abdomen

But physicians,chiefly neurosurgeons,drain spinal fluid from the hollow brain and jump to the conclusionthat the fluid is producedin the ventricle by the choroidplexus,as Dandytaught. If ventricular water movedin exactly the oppositedirection,if the choroidplexuswere the majorpathwayfor water to leavethe brain, not enter it, ventricle shunts would work just as effectively. hasled my The successof ventricularshuntingin hydrocephalus to believein Dandy'sparadigmas neurosurgeons, busycolleagues, a fundamentalfact of physiology,?shavephysiciansandscientists of all kinds.Who,after all, knew the most aboutthe hollowbrain? Without doubt,the neurosurgeons. Dandy'sexperimentswere donein the fast lane of science,the Hunterianlaboratoryof JohnsHopkins.Only three years before, the scientific,laboratory-based the Flexnerreport hadchampioned practised at JohnsHopkinsas the modelthat all medicinethat was other medicalschoolsshouldcopy. It was that report that triggeredthe decisionof the HarvardMedicalSchoolto constructthe PeterBent BrighamHospitalandto recruit Cushingto run it. The Hunterianlaboratoryhadseenthe revolutionarypituitary experimentsof Cushing;indeed,Dandyhad beenthere to see someof them himself,and Dandymust havefelt the pressureto produce

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THEFABRICOF MIND

that permeatesthe competitiveinstitutionsthat wish to stay not only in the fast lanebut alsoat the headof the pack. Dandy'sexperiments were performedwith no controlanimals, with no record of the numberof animalsoperatedotr, with no regard for inter-speciesvariability,with no record of the time base,with no histologicalcorrelation,with no attemptto quantify andwith no involvementof a neutralscientist.He the differences did them essentiallyalone without any experiencedscientific colleagues;William Blackfan, who joined him, was equally But the lackof controls,the absenceof numbers, inexperienced. the disregardfor brainchemistry,the beliefthat braintissuewas of the interpretationof asinert asa rubberballoon,the narrowness data, the quick transferenceof the laboratoryresults to the that the operations operatingroomandthe refusalto acknowledge didn't work are the mostdistressingfeatures. One of Dandy'sexperiments,cursorilydescribeda few pages ?go, revealshow wrong his investigationswere. Surgeonswho havelivedin the daysof the 'iodineprep',a methodof skincleansing that was employeddecadesago to sterilize surgicalfields, repeatedlywitnessedsevere burns of the back from excessive iodineappliedin a sloppywayto the abdomen.Someof theseburns resultedin a full thicknessskin loss.This substancewouldbe the lastthing on the labshelfthat anexperienced surgeonwouldput in the brain.A destructivechemical'burn' of the brain'scortexmany inchesaway would be assuredby the migration of the iodine. Dandy,with no surgicalexperienceto guidehim, employediodine to makea 'scar' aroundthe mid brain,but the experienced eyesees in hisownphotographs the telltalesignsof corticaldestruction;the enlargedventricleshe describedas 'hydrocephalus' are impossible to distinguishfrom the brain atrophy that attends nerve cell destruction.Dandyperformedthis experimenton oneanimal,yet it becamea keystoneto his argument.Whatis more remarkableis the uncriticalacclaimthis experimentreceived. Dandywasso convincedthat his 1911experimentshadyielded the 'truth' that he ceasedaskingquestionsaboutthe hollowbrain andvacatedthe experimentalanimallaboratory. Flushedby his laboratorysuccesses and the acclaimthey had receiv€d,Dandyinjectedair into the ventriclesof humans;air did not pass into the brain but remained in the ventricles. This supportedhis notionthat brain tissuewasinert andwouldbehave exactlyas a rubber balloon.Moreover,air couldbe manipulated over the outsideof the brain alongthe pathwayfor water that he thought he had demonstratedthere. These splendidpictures

WHY/S IHE BRAINHOLLOW?

133

cementedDandy'sparadigmin the minds of brain scientistsfar morethanhisanimalstudieshaddone.The radiologysuitebecame the experimentallaboratoryfor brain water, and thousandsof humanX-raysseemedto proveDandyto becorrect.Nowit is clear that arr injectedinto the brain doesnot behaveat all like brain water; it followsvery differentpathways. Almostas soonas they were performed,Dandy'sexperiments had were heraldedall over the world.Hopkins,andneurosurgery, doneit again.As Cushinghaddiscoveredthe raison d'ltre for the Dandy,haddiscovered pituitaryin that institution,his successor, the raison d'Atrefor the hollowventriclesof the brain.The world 'truth' about the pathway that acceptedthat Dandy found the water took throughthe brain. He wasjoinedby a broadgroup of supportersfrom both scienceand medicineto claim that he had madesenseof ventricularanatomy,describedthe physiologyof the ventricular system,explainedventricularpathology,that is, developeddiagnostictests for ventriculardisease hydrocephalus, anddesignedandperformedcuresfor ventriculardiseases. Look carefullyat that list. It includeseverythingthat is pertinent to the hollowbrain:the anatomy,the physiology,the pathology,the diagnosisandthe cure. Dandy'sparadigmwas much like Galen's.He skeweredmany different facets of the ventricle to form a paradigmthat almost defiedattack.He hadcoveredeverybase.Moreover,asGalenhad built hisparadigmon fuistotle's holypneuma,Dandybuilt hisparadigm on the holiest conceptin medicine- circulation.His third circulationof brain water gainedattentionandrespectbecauseit so closelyresembledthe first circulationof Harvey(blood)andthe secondcirculationof Hunter (lymph). My criticismsare these. First, neither choroidplexectomynor third ventriculostomyis If Dandy'sparadigmwere effectivetherapy for hydrocephalus. correct,theseoperationswouldbe effective. Second,there is solidevidencethat the choroidplexusabsorbs water; the amountof water that it secretesand the amountof water it absorbsare difficult to determine.There are regional differencesin the lining of the ventricleandalsoin the functionof the choroidplexusand it is quite possiblethat the choroidmay handlewater like the kidneydoes;it mayreleasewater in oneplace andabsorbit in another. Third, the ventriclesare not the impermeablerubber balloons that Dandy assumed.Althoughair may not passinto the brain, water in the ventriclecertainlydoes.Muchlargermolecules,such

THE FABBICOF MIND

134

peroxidase,20,000timeslarger than the sizeof a as horseradish water molecule,readily passfrom the ventricle into the brain itself. Fourth, if special'fishingnets' are cast into the watersof the ventricle,at least317 separatekindsof peptidescanberecovered. gel elecThe 'net' that doesthis is a simpletest: two-dimensional trophoresis.Suchgelsmovemoleculesat differentrates because of electrical chargesand molecularweights. One tiny drop of ventricularfluid wouldproduce317 differentspotson sucha gel. Yet if this samenet is castoutsidethe brain,just at the outletof the ventricularsystem,there are only 309 differentspots.The lackof an increasein thesespotsat the outlet of the ventricledamnsthe Dandyparadigm.The accumulationof more peptidesin the ventricle suggeststhat water may be movingin a directionprecisely oppositeto that preachedby Dandy:towardsthe choroidplexus. The 'sewer-like'functionthat Dandyascribedto the ventricles gel data (seeFig. cannotbe supportedby thesetwo-dimensional 13.7). Fifth, if syntheticbrainhormonesthat havea powerfuleffecton the endocrineglandsof the bodyare placedin the ventricle,they

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WHY/S IHE BRAINHOLLOW?

735

mayhaveno effectwhatsoeveron theseglands.By Dandy'sparadigm,thesesubstances shouldbe washedout of the brainandinto the bloodstreamwherethey couldexert their action. Sixth,if the powerfulhormonevasopressin, or ADH, is injected into the blood,the bodywill retain water. If ADH is injectedinto the ventriclethe oppositehappens:the body loseswater. This demonstrates that this substancedoesnot leavethe brain along Dandy'stime-honouredpathway.For whateverreason,the brain 'traps'ADH in the ventricleor, possibly,thereis a currentof water that flowstowardsthe choroidplexus. Seventh,in an earlier day when the hazardsof radioisotopes were not so well knowtr,radioactivesubstances were put in the ventriclesof humans.The isotopesappearedin the bloodalmost instantly,within the first minute,but did not appearoutsidethe ventricleuntil muchlater, proof that they hadnot travelledto the bloodstreamalongDandy'spathway. Theseare only sevenobservationsthat do not fit with Dandy's notionson brainwater; there are manymore. Dandy's paradigm is a mismeme that ranks with that of Aristotle's hollow, ptreuma-filledarteries and Galen's four humours.If the evidenceagainstDandyis so certain,why is his paradigmstill includedin the leadingjournalsas a basic'truth'? Why is it still acceptedby the best educatedpsychiatrists,neurologists and neurosurgeonsand the brightest neuroanatomists, neurophysiologists andneurochemists? First andforemost,nearlyall of thesegroupsare contentwith Dandy'sanswerto the questioo,'Why is the brain hollow?'For their own reasons,they see no substancein the questionnowhere that its answer could lead. Neurosurgeons,watching everydaythe successof shuntsbaseduponDandy'sparadigm,see no reasonto askthe question.The intellectualsecuritythat neurosurgeonsgainedfrom the Dandyparadigmnot onlyfor their hydrocephalusoperations but also for most of their intracranial proceduresis well known.AlthoughDandy'sexplanationmay be wrong, they basemuchof what they do on the simplethesisthat big ventriclesare unhealthy;shunts,andventriculardrains,yield smallerventriclesandhealthierpatients.Their functioningshunts couldmeanthat brain water leavesthe brain throughthe choroid plexus;for the diseases neurosurgeons dealwith it makesno differparadigm ence,the works.The acceptance of the Dandyparadigm makesit easierfor everyoneto work with the paradigmof the electricallydrivenbrain. Most scientiststodayare reductionists.To challengeDandy's

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THEFABRICOF MIND

paradigmrequiresa holisticapproachto the brain.Thoseat the top in brainsciencegainedtheir pedestalsby knowingmore andmore aboutlessand less.To challengethe Dandyparadigmrequiresa knowledgeof brain anatomy,physiology,pathology,radiologyand surgery.Very few of today'sscientistswouldclaimto havea sound graspof eachof thesedisciplines. Informationoverloadis a major contributorto the longevityof Dandy'smismeme.Dandy'sparadigmhasbeenquotedby somany scientificauthorsin so manydifferentwaysandfor so manydifferent reasonsthat it runs like a goldenthread from publicationto publication.In a tug-of-warbetweenone new referenceand a million old references,the battle wouldresemblean ant trying to outpullan elephant. Many decadesago, Cushingraised seriousquestionsabout Dandy'sparadigm.Tom Milhorat,a neurosurgeon in New York, raisedsimilarquestionsin a well-reasoned articlewritten in L975. Thosecriticismswere publishedwhenthe paradigmof an electrically driven brain was in vogue and there was no urgencyto in the Dandyparadigm. confrontthe manyobviousinconsistencies But if oneacceptsthe notionthat the brainis a hormonallymodulatedgland,thenthe questior,'Whyis the brainhollow?',loomsas central. of distant Billionsof dollarshavebeenspentto takephotographs planets,to pilfer a few stonesfrom the gulliesof the moonandto shovelinto the surfaceof Mars to see scratcha remote-controlled if it containedlife. While this fantasticeffort to understandmore aboutthe surfacesof distantplanetshasbeengoingotr,the inside surfaceof the humanbrain hasremainedlargelyunexplored.The photographicexplorationof its inner surfacehasbeenmuchmore haphazard than that of the planets,few moleculeshave been pilferedfrom betweenthe cilia of the ventricleand no remotecontrolshovelshavebeensentinto the brainto tell us moreabout life on the surfaceof the ventricle. The ventricles of the brain are much more than fluid-filled andfootballgamesgo better. cushionsthat makeyour somersaults Althoughthese spacesappearat first glanceto be the cleanest spacesin the body,they containa treasuryof endocrineinformation aboutthe brain that is unattainableanywhereelse.It seems certainthat only by tappinginto this treasuryof hormoneswill the mysteriesof the hollowbrainglandbe revealed. More andmore evidencesuggeststhat the brain was givenits hollowform to fulfil endocrinefunctions.The humanventricleis the bestplace,perhapsthe only reliableplace,to searchfor corre-

WHYIS THE BRAINHOLLOVI?

lationsbetweenhumanbehaviourandbrainhormones. Dandy,without doubt, achievedgreatness.He boldly charged into the no-man'slandof the brain'sventricle,bothin the operating room andin the laboratory,andshowedto the world that it was a spacethat surgeonscouldenter.He did for the insideof mankind's microcosmwhatNeil Armstrongdidfor mankind'smacrocosm. He physician,an wasalsoateacherof highstandards, a compassionate inventivesurgeon,and a good writer; to this day his book The Brain is the best singlevolumein the field of neurosurgery. Like many young academicphysiciansbefore and after him, Dandywas askedby his institutionto do resedrchto obtainnew informationaboutthe mysteriesof the body.But Dandy,like many before and after him, was also askedto care for the sick, to be involvedwith their anxietiesandtheir diseases, to careand,sometimes,to cure. He fell into the trap that befallsmost young peoplewho are askedto partake of this schizophrenia: he spokeas a research physicians. But whenaskedto addressscienscientistto his fellow tists, he spokeof diseaselike a pastor. Modernbrain scientistsuseDandy'smismemeto protect their beliefthat electricityis the stuffof thought;it combinesventricular anatomy,physiology,pathology,diagnosisandtherapyin a strong paradigm,which virtually defiesattack. As long as it is in place, physiologists do not needto explorethe 'wetness'of the brain.

of Wonder Shoreline

The questiotr,'Why is the brainhollow?',may be the most important unansweredquestionaboutthe brain.Sincethe humanbrain hasbeenthe shapingforce of our civilization,this questionmight be regardedas one of the most importantbiologicalquestionsof our times. Why is this questionso important? Look backat the ageof Galen.The hollownessof the heart had been establishedby other anatomists;Galenhad assignedfunctions to eachof its chambers.The right heart allowedthe liver to pump bloodthrough it into veins;the left heart allowedthe toand-fromovementof pneumaandsanquine.Galenevenfabricated a hollownessthat wasn't there. He placedhollow pores in the

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THE FABRICOF MIND

'sootystuff' to movefrom the venous heart'sseptumthat allowed bloodinto the arterialblood. As long as Galen'serrors about the heart remainedunquestioned,all other portionsof his philosophycouldremainin place. Vesaliusfirst questionedthe existenceof Galen'shollowporesin 'Whyis the the septum.Later WilliamHarveyaskedthe questior, heart hollow?',and togetherthesequestionsdestroyedthe grip hadheldin people'sminds. that Galen'snonsenses Few wouldhavepredictedthat the discoveryof the circulation view the world, of bloodwouldhavechangedthe way philosophers lookat the stars,yet conceiveof God,or astronomers theologians In retrospectthe questiotr,'Whyis the heart all of that happened. hollow?',changedthe courseof civilizattonas muchas any other singlequestion.If the question,'Why is the heart hollow?',hada profoundimpact on all intellectualdisciplines,would you expect anylessof the questioo,'Whyis the brainhollow?'

14 /ssuesForThoseWhoAre Well

lato,committedto the perfectionof the sphere,postulateda soul-forcethat came from a sphericaluniverse into the sphericalcranium.Aristotle,led astrayby air-filledarteries, concludedthat heaven-sentpneumaempowereda rational soul residingin the heart. Galen'sbelief in humoursled him to think the soul-force- animalspirit - was storedin the ventricles. Descarteswas more specific:he concludedthat the pinealgland wasthe seatof the soul.The group-thinkerswho followedGalvani haveplacedthe soulin the left brainandmadebrainelectricityits helmsman.In the pastdecade,as regulatinghormoneshavebeen foundthroughoutthe body,the soul has lost its home.It is scattered everywhere- in the brain,the gut, the ovary,the pituitary are correct,everycell contains andthe adrenal;if paracrinologists moleculesthat give life to the soulandguidance the well-chiselled to the mind. Three laboratorytechniques- electronmicroscopy, immunohistochemistry and hybridization histochemistry- have allowed scientiststo peekinto cellsto seethis new soulandmindessence (seeFig. 14.1). Whenthe soulwasin the sphericalhead,the hollowheart,the ventricles,the pineal,or the left brain,philosophers andscientists who were interestedin such things could keep one force- one 'reduction'- centralto their thoughts.Modern thinkersaboutthe soul must contemplatea plethoraof regulatinghormones,each with a long Latin name.Table 14.1 illustratesthe abbreviations that can more easilydescribethe numerous,ubiquitousguiding forcesthat whirl aboutinsidethe body. Most, if not all, of these substancesare not foundonly in the brain.They areproducedin manyremoteglandsandorgans.Table I4.2 showstheir sitesof productionoutsidethe brain.

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Table14.1 BRAINHORMONES Hormone Regulatory

Abbreviation

ACh Acetylcholine EPI Adrenalin NE Norepinephrine Serotonin 5-HT H Histamine Dopamine DA Gamma aminobutyrate GABA Glutamate GLU GLY Glycine Melatonin MEL Nuerophysin NP(Mus) Muscarinic Nicotinic Neurophysin NP(Nic) Vasopressin Arginine AVP LysineVasopressin LVP Angiotensin A2 Thyroid Hormone TH Thyroid Releasing Hormone TRH Hormone Luteinizing LH Releasing Hormone GNRH Gonadotropin GrowthHormone GH Releasing Hormone GrowthHormone GHRH Somatostatin SRIF Releasing Hormone CRH Corticotropin Prolactin PRL Substance'P SUB.P Neurotensin NTSN Intestinal VIP Vasoactive Peptide GAST Gastrin Cholecystokinen CCK Bombesin BOMB ACTH Adrenocorticotropin Pro-opiomelanocortin 31-K LPH Lipotropin ENDO Endorphin DYN Dynorphin ENK Enkephalin Hormone MSH Melanotropin Stimulating INS Insulin

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Table14.2 SITESOF HORMONE PRODUCTION OUTSIDE THE BRAIN Regulatory Hormone

OtherOrganSites Brain Pituitary Adrenal Gut Gonads

Acetylcholine Adrenalin Noradrenalin Serotonin Histamine Dopamine GABA Glutamate Glycine Melatonin Muscarinic NP Nicotinic NP AVP LVP Angiotensin Thyroid Hormone TRH LH GNRH GrowthHormone GHRH SRIF CRH Prolactin P Substance Neurotensin VIP Gastrin Cholecystokinen Bombesin ACTH 31-K Lipotropin Endorphin Dynorphin Enkephalin MSH Insulin

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Table 14.3 showsthe kinds of behaviourthat are modifiedby regulatorybrainhormones.Noneof the hormonesis linkedspecithe opporfically to a behaviourin this table, but it emphasizes tunity for correlating certain kinds of behaviourwith certain hormones. ANDBEHAVIOUR HORMONES 14.3 REGULATORY Table Hormone Regulatory

Behaviour

Acetylcholine Adrenalin Noradrenalin

Memory

Serotonin GABA Dopamine Neurophysin Muscurinic Neurophysin Nicotinic Vasopressin Angiotensin Hormone Thyroid Hormone Releasing Thyroid Hormone Luteinizing Hormone Releasing Gonadotropin GrowthHormone

Joy

Somatostatin Hormone Releasing Corticotropin

Addiction

Prolactin P Substance

Opiateoverdose

Neurotensin Peptide Intestinal Vasoactive

Sorrow

Gastrin Cholecystokinen Bombesin ACTH Pro-opiomelanocortin Lipotropin Endorphin Dynorphin Enkephalin Hormone Stimulating Melanotropin

Rage

lnsulin

Pain

Thirst Hunger Satiation Orgasm Sleep

Depression Suicide Fear Peace

/SSUESFORTHOSEWHOAREWELL

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Table I4.4 lists the many different bodily functionsthat are influencedby regulatoryhormones.In this table,specificcorrelations are not made,but the needfor suchconnections is apparent. BY REGULATORY Table14.4 BODILY FUNCTIONS INFLUENCED HORMONES Hormone Regulatory

BodyFunction

Acetylcholine Adrenalin Noradrenalin Serotonin GABA Dopamine Neurophysin Muscarinic Nicotinic Neurophysin Vasopressin

Sleep

Angiotensin Thyroid Hormone Thyroid Hormone Releasing Hormone Luteinizing Releasing Hormone Gonadotropin GrowthHormone Somatostatin Releasing Hormone Corticotropin Prolactin P Substance Neurotensin Vasoactive lntestinal Peptide Gastrin Cholecystokinen Bombesin ACTH Pro-opiomelanocortin Lipotropin Endorphin Dynorphin Enkephalin Melanotropin Hormone Stimulating lnsulin

Bloodcoagulation

Pain Bloodpressure Digestion

lmmunity function Sexual Reproduction Temperature control Bowelmotility Gastricacidity Skinrashes Asthma Ageing Obesity Arthritic stiffness

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To demonstratecorrelations,linesmust be drawnbetweenthe different hormonesand the different brain behavioursor body might functions.Table14.5showshowonehormotr€,vasopressin, influenceseveraldifferentkindsof behaviour.

AND VASOPRESSIN BETWEEN Table14.5 CORRELATIONS BEHAVIOUR Acetylcholine Adrenalin Noradrenalin Serotonin GABA Dopamine Neurophysin Muscarinic Nicotinic Neurophysin Vasopressin Angiotensin Hormone Thyroid Hormone Releasing Thyroid Hormone Luteinizing Hormone Releasing Gonadotropin GrowthHormone

Memory

Somatostatin Hormone Releasing Corticotropin Prolactin P Substance Neurotensin Peptide Intestinal Vasoactive

Addiction

Gastrin Cholecystokinen Bombesin ACTH Pro-opiomelanocortin Lipotropin Endorphin Dynorphin Enkephalin Hormone Melanotropin Stimulating lnsulin

Rage

Joy Thirst Hunger Satiation Orgasm Sleep

Opiateoverdose Sorrow

Depression Suicide Fear Peace Pain

ISSUESFORIHOSEWHOAREWELL

145

Conversely,Table 14.6 showsthe possiblehormonalcorrelationsfor 'pain'. Table14.6 CORRELATIONS BETWEEN PA|NANDSEVERAL HORMONES Acetylcholine Adrenalin Noradrenalin Serotonin GABA Dopamine Muscarinic Neurophysin Nicotinic Neurophysin Vasopressin Angiotensin Thyroid Hormone Thyroid Releasing Hormone Luteinizing Hormone Gonadotropin Releasing Hormone GrowthHormone Somatostatin Corticotropin Releasing Hormone Prolactin P Substance Neurotensin Vasoactive Intestinal Peptide Gastrin Cholecystokinen Bombesin ACTH Pro-opiomelanocortin Lipotropin Endorphin Dynorphin Enkephalin Melanotropin Stimulating Hormone Insulin

Sleep

Pain Bloodpressure Digestion Bloodcoagulation lmmunity function Sexual Reproduction Temperature control Bowelmotility Gastric acidity Skinrashes Asthma Ageing Obesity Arthritic stiffness

From these tables,you would quickly decidethat one kind of behaviouror oneillnessmay be linkedto more than onehormone andthat a singlebrainhormonemaybe associated with more than oneregulatingfunction.

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No scientistknowsjust now how many regulatory hormones there are. But the question is clear: does the bodl' employ individualhormoneslike the letters of an alphabet? If it does, scientistsmay not find thousandsof individual hormones;the list may be much shorter. But the number of regulatoryhormonesin its 'alphabet'is very important.If the mind employsindividualbrain hormonesas letters of an endocrine alphabet,one extra brain hormonewould confuseevery kind of regulatingsignal. But even before the size and form of the brain's hormonal alphabetis determined,correlationsare possiblebetweencertain hormonesandcertainbodyandbrainactivities. There are severalhormonesthat are importantto memory,one ACTH and of the mind's most importantfunctions.Vasopressin, implicated in in If been learning animal experiments. have all MSH might thesehormonesareimportantto normalmemoryprocesses, they not be importantto disordersof memory?There is a silent epidernicof seniledementiain the world.If thesehormonesare as importantto humansas they are to animallearning,it is possible that the samehormonescould be important to seniledementia, indeedto all other diseasesthat causememoryloss.The question

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immediatelyarises,'Couldhormonesbe given to patientswith memory probleffis,just as insulin is given to patients with diabetes?' NormanCousins,in his book, TheAnatorn! of an lllness,sets out his experiencewith the healingpowerof joy. His severebone andjoint problemswere driven from his body by belly laughter triggered by viewing old comicmovies.Cousinspostulatedthat 'hormonesof happiness' arereleasedwhenthe dogwagshistail or whenpeopleare extremelyhappy.He foundhealingin happiness andproclaimsin a compellingway that suchhormonesmustexist. But the existenceof thesehormonesin the bloodof either animals or peopleis almostimpossible for scientiststo discern;the very act of bloodremovalcreatesstressandunhappiness. Oneof the best piecesof scientificevidenceto supportCousins'snotionthat there is a chemistryof Joy' and 'sorrow' can be foundin the chemical analysisof tears. In anyone,a stroke of goodfortune can trigger the releaseof 'happy'tears;thesehavea very differentmolecular make-upfrom 'sad'tears.The analysisof tears confirmsthat the bodyhasonechemistryfor joy andanotherfor sadness. Thirst is by far the easiestbehaviourto measurequantitatively in animalexperiments,andmore is knownaboutit than any other kindof behaviour.It is modifiedby regulatoryhormones,muchlike memoryandjoy. 'Angiotensin'is the hormonemostinvolvedin the controlof water appetite;in animalsa smallamountof it injected into the bloodvesselsgoingto the braincausesa powerfuldesireto drink. It is in the area of salt and water appetite that the importanceof brain hormoneshas becomemost obvious.Since hypertensionis so obviouslyrelated to salt and water balance, many scientistsare devoting themselvesto the study of the hormonesthat controlsalt andwater appetite,believingthat new knowledgein this areawill bring with it the control of high blood pressure. Hunger, like thirst, is controlled by regulatory hormones. Experiments in animals have linked caloric appetite to 'cholecystokinen', a hormonethat wasfoundin the intestines.Now somescientistssuggestthat more of this hormoneis producedby the brain than by the gut. Mice that have a deficiencyof this hormone in their brain, for example,have appetitesthat are insatiable.They will eat virtually anythingin sight,includingtheir cage.Conversely,sheepwho havebeengiven this hormoneinto their brain refuseto eat anything.Insulin,the hormonelinkedto diabetes,is evenmore stronglyconnectedto food hunger.Many scientistspredict that an understandingof brain hormoneswill

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allowthe ultimatein diet control;a medicationthat takesawaythe appetitefor foodbut doesnothingelse. Satiation,likethirst andhunger,is a conditionthat is determined Eachkindof appetitehasits ownsatiatingsubstance, by hormones. but most scientificinterest hasfocusedon the satiationof caloric appetite.Knowingaboutthe hormonalcontrol of satiationcould lead to the developmentof other kinds of diet-controlpills. The mysteriousdisease,anorexianervosa,stemmingfrom a feelingof continual satiatior, has been linked both to bombesin and vasopressin.New knowledgeabout the endrocrinologyof this commotr,dreadeddiseaseof youngwomenseemsto offerthe only hopefor its therapy. Sexualorgasmis at oncemysteriousandpoorlyunderstood,but most scientistsbelieveit beginsand ends in the brain, not the pelvis.The appetitefor orgasmdrivesbothmaleandfemalescientists at night, but oddly,in their daytimelives,they find very little time to study it. Many have suggestedthat the opiate-like hormonesendorphinand enkephalinare responsiblefor sexual pleasure,but the evidenceto supportthat is anythingbut certain. In many animalsthesehormoneswill trigger contractionsin the vas deferens- the tiny tube that carriessperm- and this may be the bestreasonto link thesehormonesto orgasm.Onenew brain releasinghormone',ffiayplaya key role in hormotr€,'gonadotropin maleerections,givinghopeto thosewith impotence. Sleephasbeenvery closelylinkedto brain hormones.Harvard scientistshave isolateda substancein the ventricularfluid of a sleepinggoatthat will causeanothergoatto drift off to sleep.Sleep maybe the most mysteriousthing that the braindoes:nobodyyet knowswhy we get tired, why we sleep,and what benefit sleep bringsour bodies.Yet nearlyall of the body'sendocrinerhythms arecorrelatedto sleep,andsomeof the mostmysteriousaspectsof sleep,such as rapid eye movementsleep,are directly linked to surgesin brain hormonesin the blood.Knowingwhy goatssleep, or why humansdo or do not sleepwouldhelp societyimmensely, for insomniais one of the most commoncomplaintsthat patients relateto their physicians. Addictionto opiate drugs of any kind - heroin is one kind of opiate- is governedby the interactionsof hormonesandhormone receptorsin the brain.Nature hasgiventhe brain the capacityto produceits own opiate-likedrugsandhasalsoprovidedthe brain with opiate receptorson many kinds of brain cells. Nature has establishedthis systemso that the brain can treat itself during for drug addictionrests in emergencies.One of the explanations

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the belief that injectionsof external opiatesturn off the brain machineryfor the productionof internal opiates.Eachbrain cell that normallyproducesan internalopiate- endorphin,enkephalin, or dynorphin- is turnedoff, sensingthat enoughbrainopiatesare alreadypresent.The force that comesinto an addict'slife results from a shut-downof the brain:sabilityto producebrainopiates;as long as addictscontinueto receiveexternalopiumsuchas heroin addictionwill remain.Addictionceaseswhen the brain resumes the productionof its own opiate-likehormones. Rage in animalshas been linked to the releaseof catecholamines.Manyscientistsbelievethat at the momentof extremerage - either adrenalin,norathe brain is filled with catecholamines drenalin,or serotonin.Thesein turn may trigger the releaseof many other hormones,eachof which could affect behaviourand cloudjudgement.Knowingaboutthe regulatoryhormonesresponsible for aggressivebehaviourmight reducethe numbersin our nation'sjails. Depression,especiallythe kind of depressionwhich is always 'down' and never 'up', 'unipolar depression' , cteatesimmense changesin the endocrinesystem.Thesealterationsare especially evidentin the brain/pituitaryladrenal axisandmosteasilyassessed by measuringthe amountof adrenalhormone,'cortisol',that is in the bloodstream. Typically,thosewith this kindof depression have bloodlevelsof cortisolthat arefar too highandwithoutthe typical diurnalvariation.Suchdepressedpatientsdo not suppresstheir secretionof cortisolwhengivena synthetichormonecalled'decadron', 3r indicationthat the brain has decidedto increasethe outputof hormonesfrom the pituitary andthe adrenal.Why this shouldbe is not certain,but it suggeststhat the brain may be deficientin thesehormonesor other hormonesanddirectsdistant glandsto secretemore of themto treat the deficiency. The chemicalanalysisof the brains of suicidevictims shows specialkinds of hormone profiles, very different from normal brains,indicatingthat thesepeople,who are obviouslydepressed, haveendocrineabnormalities in their brains. Fear, like rage, releases'catecholamines'. But judgingfrom manydifferentkindsof animalexperiments, manyotherhormones are alsoreleas€d,includingvasopressin, endorphinandprolactin. Many of thesehormonesare gut hormonesthat increasegastric andintestinalmotility, makingit commonfor bowelincontinence to developasa resultof fear. For centuries,Vedicpriestshavemaintainedthat meditationis the pathto peace,that there aresubstances in the bodythat canbe

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releasedby an effort of the mind that frll the mind with peace. that somesuchpeaceManyWesternscientistsnow acknowledge givinghormonesare releasedduring meditation.What they are is uncertain,but there canbe no doubtthat manyendocrinerelationshipsare changed. Pain perceptionis modifiedby many hormonesbesidesthe opiate hormones;scientistsnow acknowledgethat the greatest andtreatmentof painlies in decipherhopefor the understanding that are triggeredby pain; ing the complexendocrinerelationships growslonger and pain modulation in involved the list of hormones now includesendorphin,enkephalin,dynorphinand substanceP. which form links The stimulusof pain releasesthese substances, with the hormonereceptorsin braincells.Naturehasstoredthese hormonesin the brainfor the treatmentof pain. The correlationbetweenindividualbrain hormonesand differof ent kindsof brainandbodyactivitieshasraisedthe expectations in illnesses brain when the day They anticipate brain scientists. these humanscanbe treatedwith hormones.It wouldbe easierfor scientistsif atl animalsspokethe sameendocrinelanguagQ,for thencorrelationsmadein the laboratorycouldbe quicklymovedto the bedside.Unfortunately such is not the case. The horrnone prolactin,for example,has at least seventy-eightdifferentfunctions in seventy-eightdifferentspecies.Just as the samevowelsoundsand consonantsare useddifferentlyby differentpeoples, hormones are used by different species to convey different messages.This forces scientiststo establishfunctionalcorrelationsin the speciesof their concern. Someobservationsin animalexperimentsmay point the way, but ultimately correlationsthat will benefit mankind must be in humanstudies. established Oneproblemthat stymiesthe developmentof endocrineneurology is the 'blood-brainbarrier'. To understandthis vexingproblem, we need to look more closelyat the differencesbetween andendocrineneurology. neuroendocrinology relationships,involvesa Neuroendocrinolo {y, or brain-to-gland pyramidalhierarchy of glandswith the brain at the top. The controllingmessagesfrom the brain are amplifiedas they move down this pyramid;that is, as the hormonalmessagesmove like falling dominoes,eachmessagelasts long€r, travels further and affectsgreater numbersof other organs.Many havereferred to 'cascadinghormonalamplification'or 'hormonal this processas amplification'. All endocrineglandsexceptthe testesandthe brainhaveperme-

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able capillaries- blood vesselsare pokedfull of holes exactly as Galendescribed(seeFig. L4.z).Itis the presenceof suchcapillary poresthat allowsthe processof hormonalamplification.Hormones formed by cells in glandsfirst leak into the bloodstreamthrough theseholes,then flow throughthe bloodstreamto leak out of it in someother gland.

Fig. 14.2Theelectronmicrograph of a capillaryof a glandshowsthe many'pores'throughwhich hormonesflow in and out of the gland Capillaries in the braindo not havesuch pores

As hormonesare carried from gland to gland by the bloodstream,excessiveor diminishedlevelsof circulatinghormonescan be establishedwith relative ease.By bloodsamples,the 'signals' passingfrom one gland to another can be intercepted.If a deficiencyis found,replacementtherapycan be given with the knowledgethat the leakycapillarieswill allow it to reachits target. The brain has all the characteristicsof a gland except one-

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leakycapillaries- and the sturdy brain capillariesare collectively calledthe 'blood-brainbarrier'. This barrier canbe easilydemonstrated by injectinga blue dye into an animal;every other organ (exceptthe testicle)turns blue,but the blood-brainbarrier keeps the brainaswhite as snow. Althoughall the hormonesin the endocrinesystemare carried by the bloodstreamto the brain, the presenceof the blood-brain barrier preventsmost hormonesfrom penetratingit. A mechanismthat might be describedas 'hormonaldeamplification' limits the effect that the endocrinesystemcan have on the nervoussystem.As hormonalamplificationis the hallmarkof all of the brain-to-glandrelationshipsof neuroendocrinology, hormonal deamplification is the hallmarkof all gland-to-brainrelationshipsof endocrineneurology.This is a fundamentaldifferencebetweenthe two sciences. Somekinds of hormones,the 'steroids', passreadily into the brain, but the 'peptide' hormonesproducedby the pituitary, the But, and any other glandsdo not easilypassthrough the wall of brain capillaries. Although the processof hormonalamplificationbeginsin the brain, the brain remainssilently separatedfrom the noisy endocrine consequences. It doesnot easilyhear the endocrinemusic producedby the other glandsof the body. Is the brainreally hormonallydeaf?As the brain'sprime function is to receive,store and sort through informationof all kinds,it is untenableto believethat it doesn'twant to hearor doesn'tneedto hearthe endocrinemusicthat it orchestrates. Sincethe discoveryof the blood-brainbarrier seventyyears?go, it hasbeenassigneda passivequality.But more evidencesupports the view that the blood-brainbarrier is active,like a sophisticated machinethat pumpssomethingsin andother thingsout. The pumpsthat residein the blood-brainbarrier are not well understood,but for one hormon€,insulin,pumpshavebeenfound that suggestthat the passageof hormonesinto the brainis determinedby a dynamicprocess.The pumpsin the blood-brainbarrier may allow the brain to pick and choosefrom the vast number of hormonesthat are continually flowing through it. As more is learnedaboutthesepumps,the endocrinesilenceof the brainlooks increasinglylike an activeprocessandonethat is asfinelytunedas the more easilystudiedprocessof cascadinghormonalamplification. The brain is not hormonallydeaf. If the blood-brainbarrier is selectivelyopenedand closed,if, hormonaldeamplificationis as

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active as hormonalamplification,a vast new areaof scienceand medicine unfolds. Many poorly understood aspects of normal behaviourmight be explainedby a dynamicallychangingbloodbrain barrier. Orgasm,for example,may result from the transient 'hormonesof happiopeningof the brain'scapillaries;blood-borne ness' may be allowedinto the brain during the brief interval that the brain's capillaries become penneable. Many behavioural diseasesmay result from a mistuned blood-brain barrier that allowsthe brain to receivetoo few or too manyhormones.Depression,for example,mayresult from capillariesthat are too tight and do not allowthe 'hormonesof happiness'into the brain.The understandingof the fine-tuning of the blood-brainbarrier would help physiciansto understanddiseasesand allow them to developnew kinds of routes by which hormonescouldbe fed to the brain. Although a dynamic, finely tuned blood-brainbarrier seems likely, there can be no escapefrom this reality: the measurement of hormonesin the bloodstreamof patients will not reflect the endocrineactivity in the brain. It is this impassethat forces me to believethat cathetersmust be placedinto the cerebralventriclesif the major diseasesof the mind are to be understood. Supposethat a brain scientist,convincedthat he or she knows 'closing gates' in animals, which hormones are responsiblefor wants to confirm this in humans. Where should the sampling needlebe placed?The blood-brainbarrier makesit unlikely that meaningfulhormonal/behaviouralcorrelationscan be established alone.Neither excessivelevelsnor diminby bloodmeasurements ished levels of brain hormoneswould be reflected in circtrlating 'hormonaldeamplification' blood. As certainly as the processof limits the flow of body hormonesinto the brain, the sameprocess limits the flow from the brain to the body. Correlationsbetweenbrain hormonesand behaviourobtained by brain biopsiesare ethicallyandmorally impossible,eventhough the measurementof brainhormonesin braintissueaffordsthe best opportunityfor suchcorrelations. Many scientists,intent on makingcorrelationsbetweenbehaviour andbrain hormones,especiallyabnormalbehaviourandbrain hormones,haveturnedto the lumbarspinalfluid for analysis.The spinalcorddoesnot extendto the endof the spinalcanalin humans, leavingalargefluid-filledspacethat canbe quiteeasilytappedwith a delicateneedlein a relativelyeasyandsafeprocedure.Lamentagel studiesdemonstratethat bly, data from the two-dimensional greatest hormones of brain array is foundin the ventricle,not the in the spinalfluid.

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Of all of the possiblesamplingsitesfor brain hormones,ventricular fluid appearsto be the best. If the brain is regardedas a gland,its hollownessmust be given a new light. It is unlikelythat the cerebralventricleshavebeenset in placesolelyfor the production and transportationof brain water. The ventricles can be regarded as centrally placedducts that contain hormones- the most brain hormonesof any singlesamplingsite. As in the hollow heart and the hollow stomach,catheters will be neededin the centre of the hollowbrain if we expectto makevalid correlations betweenbrain hormonesandbehaviour. Placing catheters in the ventricles of patients with hydrocephalus,turnoursand head trauma is done frequently and with remarkablesafety.The adventof the CAT and NMR scannersto guidecathetersinto the brain significantlyreducesthe risk of this procedure,andI predictthat in decadesto comeventricularcatheterization performed to measure hormone concentrationswill becomeas routine as the measurementof lumbar 'pressure' is today. fu understandingof the limitations of blood sampling and lumbar fluid samplingforces the conclusionthat only by placing cathetersin the cerebralventricles can the significanceof brain hormonesbe understood.Sincefew humanillnessesof the brain occur in laboratory animals, studies of human ventricular hormonesmaybe the sine qua nonof the newscienceof endocrine neurology. Becausernanyhormonesmaybe linkedto onekind of behaviour, a correlationbetweenbrain hormonesandany kind of hormonally dependentactivity must entail the measurementof not one but severalhorrnones.This amplifiesthe task considerably;a single sampleof blood or brain fluid might require forty-five separate analyticaltests. But other problemsexist. Only by timing the samplingof brain hormonespreciselywith the eventcausingpain,for example,could correlationsbe establishedthat wouldhelpour understandingof it. Quite obviously,this immenselymagnifiesthe task at hand for 'norrnal' behaviouralcorrelations. During sexual orgasffi, for example,suchcorrelationswouldhaveto be timed with exquisite e:ire,perhapsduring an interval of a few seconds.Paradoxically, correlationsof brain hormonesto 'abnormal'behaviourmight be more reliable and give scientistsbetter information.One would expect steady, long-lastingabnormalities,for example, in the disease,seniledementia;samplescouldbe obtainedat anytime.

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AlthoughI am an avowedholist,I amforcedto concedethat the majordiseasesof the brain andthe importanceof brain hormones to brain functionwill only be understoodby a very focused,very reductionisticprocedure:ventricular catheterization(see Fig. 14.3). Only by such manoeuvreswill hormone-relatedbrain illnessesbe understoodandconquered. Ifuowingthat the brain is a glandgivesthe physicianmanynew therapeuticoptions.Hormonaldiseasesof the brain,like endocrine diseasesof the body,may be brokendown into diseasesof excessive secretion- hypersecretion- and diseases of diminished secretion- hyposecretion.Physiciansmight then designtherapies that will replenisha hormone-hungrybrain anddesignother therapiesto block the effect of a hormoneexcess.But whateverthey do

Fig. 14.3 New non-invasive CAT scansallowsurgeonsto see the ventricles

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will dependon a precisemeasurementof brainhormones.It is with thesetherapeuticpossibilitiesin mindthat I advocatethe measurement of ventricularhormones. Table L4.7 lists the endocrinedisordersof other glands.It is incomplete,but it doesshowthat for eachglandthere are diseases of hyposecretionand hypersecretion.In every case where a hormonedeficiencyhasbeenidentifi€d,substitutiontherapyof the appropriatehormonehas led to cure. There is little doubt that similar 'magic'canbe performedin the humanbrain. Table14.7 ENDOGRINE DISORDERS OFGLANDS

Pituitary Thyroid Adrenal Pancreas Parathlrroids

Hypersecretion

Hyposecretion

Gigantism GravesDisease Cushing'sDisease Insulinoma Hypercalcemia

Dwarfism Hypothyroidism Addison'sDisease Diabetes Hypocalcemia

Although I can only guesswhich brain diseaseswill stem from hlposecretionof brain hormonesandwhich will stem from hypersecretion,onething is clearat the outset.If diseasesof hlposecretion canbe identified,thesediseasesmight be treatedby hormonal replacement. If deficienciesof brain hormonesare established,when and where shouldthe replacementbe given?For any suchtherapyto be effective, the timing would have to be very precise. Again, diseasesof chronic deficiencywould be most easily managed. Seniledementia,for example,might be treatedwith a chronicinfusiondevice. The site of the therapy?Hormonesgiven into the bloodstream would have no effect unless the blood-brain barrier could be opened in synchrony. Hormones given into the lumbar sack predictablywouldnot maketheir way into the brain.As the hollownessof the brain dictatesventricular cathetersfor diagnosis,the ventriclesappearto be the only feasiblesite for hormonereplacement.

of Wonder Shoreline

In L927 most of the world thought the heart was an electrical organ;the electrocardiogramhadconfirmedit. A few bravephysiciansrecognizedthat the electricalstudiesof the heart wouldlead down a dead-endstreet and attackedthe central questionof the hollowheart. The Germanphysicianwho first placeda catheterin the hollow heart was thought to be mentally unbalanced.The physician,Dr Forssmatrtr,performedthat feat by himseHand on himseH.Althoughhe wasremovedfrom his clinicalresponsibilities in 1955the world cheeredashe was for his 'mentalderangement', awardedthe NobelPrize. It was the surgical attack on the hollow heart - abhorrent, of indeed'ctary', to most- whichled to the spectacularsuccesses moderncardiology. Doubtless,physicianswere slow to placecathetersin the heart becausethey, like their patients,carrieda primevalrespectfor it. To catheterwethe heart was a desecrationof somethingholy. As the mystiquehasgonefrom the heart, its problemshavebecome muchmore tractable. There is also little to f.earin exploring the ventricles of the human brain. They are filled with hormones, and until the hormonesswimmingin theseoceansare dredgedout, countless millionsof our fellowswill remainwith brain illnessesthat canbe neither understoodnor treated. Many of their hormone-hungry brainsmay be fixed as easilyas hormone-hungrybodiesare fixed with thyroid hormoo€,insulin, oestrogenand testosterone,but that work cannot begin until cause and effect relationships between brain hormonesand brain diseaseshave been established. The next step in the effort to understandthe humanmind must be hormoneanalysisin the hollowbrainglandsof humans. It is increasinglycertainthat the two brains,the right andleft, are structurallyandchemicallydifferent.Modernday CAT scans haveconfirmedthis in humans,and endocrinestudiesof the left andright brainhaveconfirmedthis in animals. It is alsocertainthat peoplewho have'different'cerebralasymmetries- left handers- have 'different' bodies.Surprisingstructural differencesin the brains of left handersand unsuspected differencesin the bodiesof left handershavebeenconfirmedby

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NormanGeschwind, the world'sleadingauthorityon the asymmetrical structureandfunctionof the humanbrain.Countlesstimes Geschwindhasdemonstratedboth the advantages and the disadvantagesof beinga 'lefty'. The changesthat he hasfoundin the bodiesof thosewith switchedcerebralasymmetrymaybe the best evidencethat the brain mastermindsbodyfunctionsin waysthat no scientistyet understands. Geschwindbelievesit is the endocrinologyof the brain- its responseto testosterone- that beginsthis cascade. Brain/bodyrelationshipshave been more closely studied by Herbert Bensonwho, more than any other Westernscientist,has giventhe ancientwisdomof the Eastscientificvalidity.In hisbook, The Relaration Response, Bensonhas outlinedhow Westerners might take advantageof the new understandingof brain/bodyrelationships.His laboratorystudiesdemonstratethat the body can learnnew patternsof reaction;this inner wisdomcanhealdisease aseffectivelyas a doctor'sprescription. Onlyrecentlyhavethosein the Westcometo know of the benefits of meditation,but to those in the East the power of mind control is well accepted.With our knowledgeof paracrinology, storiessuchas this onetake on an excitingnew significance: Theburialaliveof the Yogi'Haridas'in 1837wasauthentically corroboratedbySir ClaudeWade,Dr JonosHoniberger andtheBritishConsulat Lahore.ReportsstatethatHaridastookonlymilkfor severaldaysbefore hisburial.Onthedayofhisburialheatenothing,butperformed theYogic internalcleansing methodof swallowing a longstripof cloth,retainingit for a whilein thestomach to absorbbile,etc.Thenheperformed another internalcleansing exercise, nauli,standing upto hisneckin warmwater andwashing outthecolon.All theopenings of hisbodywerethenstopped upwith wax.AsdomanyYogis,hehadcuttheroot of histonguesothat it couldbe rolledbackto sealthe entranceto the throat. Haridaswaswrapped in linen and placedin a box which was locked by the Maharajaof. Lahoreandkept in a summerhousewith sealeddoor andwindows.The housewas guardedday and night by the Maharaja'sbody guard. After forty daysthe box was opened.The Yogi's seryantwashedhis master with warm water, removedthe wax stoppersandput warm yeaston his scalp.He forced the teeth open with a knife and unfoldedthe tongue. Tongue and eyelidsthen were rubbed with butter. After half-an-hour Haridascameto life, seeminglynonethe worsefor his experience. Unbelievable?If the nose had been stopped with wax, yes. If not, the Yogi's burial was little different from the hibernation of animals of many kinds.

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A Western wiseman, Norman Cousins,employedthe same technique to wake and rouse his tired and painful body: I was comingunstuck.I hadconsiderabledifficultymovingmy limbs and even turning over in bed. Nodulesappearedon my body, gravel-like underthe skin, indicatingthe systemicnatureof the disease. substances At the low point of my illness,ffiy jaws almostlocked. . , I remembered havingread,ten yearsor soearlier,HansSelye'sclassicbook,The Stress of Life. With great clarity, Selyeshowedthat adrenalexhaustioncouldbe causedby emotionaltension,suchas frustration or supressedrage. He detailedthe negativeeffectsof the negativeemotionson bodychemistry. The inevitablequestionarosein my mind:what aboutpositiveemotions? If negativeemotionsproducenegativechemicalchangesin the body, wouldn't positive emotions produce positive chemicalchanges?Is it possiblethat love, hope,faith, laughter,confidence,and the will to live havetherapeuticvalue?Do chemicalchangesoccuronlyon the downside? Obviously,puttingthe positiveemotionsto work wasnothingsosimpleas turning on a gardenhose.But evena reasonabledegreeof control over my emotionsmight have a salutary physiologiceffect. . . \[e were . . . ableto get our handson someold Marx Brothersfilms. We pulleddown the blinds and turned on the machine.It worked. I made the joyous discoverythat ten minutesof belly laughterhadan anaestheticeffectand wouldgive me at leasttwo hoursof painfreesleep.Whenthe pain-killing effect of the laughterwore off, we would switch on the motion-picture projectoragain,and not infrequently,it would leadto anotherpain-free sleepinterval. And from Baghir Mostofi, the geologist from Iran who drilled the world's most productive oil well: I was on my first job to locateand drill a deep-waterwell which I hoped would prove to be artesian. The region was swampy land south of Teheran,Iran, andfull of mosquitoes.I soonfoundmyseHfeverish.My temperaturecamelike a clock,every secondday,for weeks.With each fever camechills and malaisethat sent me to my tent like a wounded hound.I knewI hadcontractedmalariabut asthe leaderof the crew and on my first assignmentno one elsewouldknow.By my interpretationof the subsurfacegeologywe were abovewater but our well was as dry as dust.Severaldayswent by. No water but manymalarialfevers.We were on the last dayof drilling aswe were reachingthe limit of our rig's capacity. I sensedI wasgoingto havea dry holeon my handsandretired to my tent with a deepfeelingof despair.An hour or so later one of the crew rousedme with the news'water'. I rushedfrom my tent andbusiedmyself with controllingthe artesianflow whichis sucha delightto watch.My joy was immense.Weeks,in fact months,went by before I realizedthat an

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externalgushofwaterhadproduced aninternalgushofjoy bywhichI was healed.I receivednoothertherapy,yet hadnot evenonemalarialfever afterthatjoyfulevent. Scientistshaveno ideawhat 'hormonesof hibernation'were activatedby the Yogi,what 'hormonesof happiness'were releasedby Cousins'sbouts of belly laughter,or what 'hormonesof healing' gushedinto Mostofi, but miraclesof inner healingare everyday occurrences. Whenscientistsbelievedthat the mindwasdrivenby electricity, they askedpriestsandmysticsto explainsuchmiracles.But now, as scientistsbeginto acknowledgethat hormonalharmoniesregulate both the brain andthe body,they look at thesemiracleswith new interest. Theseanecdotesare not religiousmyths; they are 'true' and fit the scientificfacts of the new paradigm. What are lackingare certain correlationsbetweenthe offendingillnessand the healinghormone.

15 /ssuesForIhose WhoArelll

decadeagoI wrote an article in the New England Journal 'Neurosurgery May Die'. In it I of Medicine entitled lamentedthe lack of interest in brain researchamongmy colleaguesand criticized a systemof educationthat resembleda factory that stampedout carfenders;students,like fenders,were all bent into the same shape.Many readers,especiallyneurosurgical educators,contendedthat my article overemphasized problemsand neglectedthe descriptionof opportunities.One wrote: 'Next time swingwith the sharpsideof the axe.' Now I am filled with optimismaboutthe future of my specialty, largelybecauseof the developmentof endocrineneurology.This new medicalscienceshouldbring together all those concerned with the brain in the same way that the NASA moonshotprogrammebrought together many diversegroups.But becauseof the importanceof the ventriclesto the diagnosisand therapy of may have the hormonallyrelated brain illnesses,neurosurgeons centralrole to play;they are the only peoplewho are qualifiedto placecathetersin humanbrains.Psychologists, psychiatristsand neurologistswho want to know what is wrong with their patients will need neurosurgicalhelp both to retrieve and replace the hormonesin the hollowbraingland. Young neurosurgeons,trained to believe that the operating microscopeis the be all and end all of brain surgery,may find it difficult to accept that molecules,more than microscopes,will determine their future. Yet, more than any other medical or surgicalspecialty,neurosurgerynow has the opportunityto join the revolutiongoingon in molecularbiology. This brave new world will demandthat thosemakingthe surgicaldecisionshavea thoroughknowledgeof brainendocrinology. That knowledgenow rests in the headsof thosewho live in basic sciencelaboratories,andthere will be no benefitto patientswith-

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out educationalstrategies that caffy this information into the headsof physicians;IlurS€s,administratorsand legal watchdogs. What is most important,patientsmust cometo know and believe that a boldaggressiveattackon the problemsof the mind is not a fancifulfiction but a modernreality. Very specialkinds of educational ploysmay be requiredto educatepeopleaboutthe significance of brain hormonesand the potential benefit that these substances couldbring them andtheir relatives. Before the mining and mendingof brain hormonescan begin, manyfencesmust be torn downthat separatephysicians who care for patients with brain illnesses.Similar fences existed only a decadeor two agobetweenthosewhocaredfor patientswith heart disease,yet the unprecedented co-operationbetweenall of those involved- cardiologists, radiologists,surgeons,andanaesthetists - yieldeda benefitthat hastouchedthe livesof mostof us. There canbe only one sharplyfocusedgoalfor this new effort: improvedpatientcare.For that to occurnew consortiumsmustbe developedfor those who care for patientswith hormone-related brain illnesses.Onepossiblearrangementis shownin Fig. 15.1. This flow chart demonstrateshow a patientwith a particularbrain hormoneproblemcouldhe identified,referred,diagnosed, treated and evaluated.The chart emphasizesthat no single group can begin this new effort alone; it requires co-operationfrom all involved.In the medicalcareof the brain,asin the scientificunderstandingof it, specializationcan only yield so much benefit. At somepoint thingshavegot to cometogetheragain. The starting premiseof the new knowledgethat the brain is a glandis oneof unity: the brainis onewith the body.Its finalobservation is one of harmony:hormonescome together to do the brain'sbidding. Unity must also be the starting premiseof the clinicianswho come together to developnew ways to treat those with brain But the physiciansandscientistswho focuson the brain diseases. must developmore harmoniousrelationshipswith radiologists, anaesthetists,pathologists,institutional administrators,third party insuranceagents,andthe legalprofessionbeforeanyof this canmoveforward. There aretwo majorlegalproblemssurroundingthe newopportunity to understandthe significanceof brain hormonesto brain dysfunction:patientconsentandmalpractice. Patientswith severebrain problemsare unableto sign legal documents,including consent forms for surgical procedures. Appropriately, courts protect the interests of these people

/SSUESFARTHOSEWHOAREILL Tosks

Primorycore teom

Screening

Y Medicol neurologists

b-

Exominotions

t Neurosurgeons

1-

tops Ventriculor

Y Clinicolpothologists

F

Hormoneossoys

Y Phormocologists

F

Hormonesynthesis

V Primorycore teom

Hormonedelivery ond supportivecore

Y All thoseinvolved

Doto onolysis

Fig. 15.1 A flowchartof carefor patientswith endrocrineabnormalities of the brain

becausethey are the easyprey of unscrupulous aggressors.Physicians,armedwith the mostnobleinterestsin helpingsuchpatients, may be deterredfrom simpleproceduressuchasdrawingbloodor performingspinaltaps;the court saysclearlyandcorrectly,'These patientsshallnot be guineapigs.' In this setting,the suggestionof placinga diagnosticneedleinto the centre of the brain in such patients producesa shudderin the peoplewho run psychiatric hospitals.The irony for thesepatientsis that they may be curedof the brain maladythat takesawaytheir legalindependence, but the law makesthe first stepimpossible. What is more important, perh?pS,is the threat of malpractice. The legalumbrellathat is intendedto serveandprotectthe doctorpatient relationshipnow limits everyoneconcernedwith the link between brain hormonesand behaviouralillnesses.Given the currentmalpracticeclimate,the knowledgethat mostof thosewho sit in jury boxesholdto the ancientnotionthat the brainis 'divine', andthe sinistermotivationsthat were attachedto psychosurgeons less than a decadeogo, few people are willing to take the risks ' inherentin theseexplorations.

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The peoplewho might backthis new endeavourlive in suchfear of the legalconsequence of a failedrisk that they refuseto participatein what couldbe oneof the most excitingandbeneficialareas in medicine.With one eye on the patient andthe other eye on the judge, they have tacitly cautionedall of those who might be involv€d, 'Accept the Dandy paradi$n: measurepressure,not peptides;manipulatebrainpressure,not brainpeptides.' Neurosurgeons will be involvedmostcloselyin the patientmanipulations neededto link brain hormonesto brain dysfunction. Consequently,the risks of these explorations,€sp€cially the malpracticerisks,will fall very squarelyuponour shoulders.These risks are not insurmountable,and I live with the belief that our society,onceenlightened,will supportthe explorationof the mind andthe risks entailed,as they havesupportedthe explorationand the risks that astronautshavetakenasthey movedour societyinto space. the oneshownin Considerhow a new consortiumof physicians, 'Nellie'. Fig. 15.1,might handlethe problemsof your aunt,called Younotethat Nellieis not rememberingthingsvery well; shedoes well with the remote memoriesof her childhood,but her shortterm memoryis very bad.The first time you take Nellie to her physician,heexaminesher andsaysthat sheis ageingmorerapidly thanmost.In the weeksthat followher memorybecomesworse, so muchworsethat you seekmedicalattentionagain.On this visit the physicianagreesthat Nellie, zt fifty-six, is in trouble and testing. suggestsshehavepsychological testssuggestthat Nelliehasanorganicbrain The psychologist's problem;sheneedsa neurologist,you are told. After a more detailed examination,both a CAT scan and an 'preseniledemenNMR scan,the neurologistsaysthat Nellie has tia'; thereis nothingthat canbedone,youaretold,andasyouleave the office you are assuredthat she will not comprehendher suffering. If this fate shouldbefallNellie this year,the neurologistwould humanelysuggestthat you put both your anxietiesand Nellie away. If the disastershouldbefall Nellie in a year or two, I havelittle of ventridoubtthat the neurologistwill pushfor the measurement tap. a ventricular have peptides, will Nellie and cular performventriculartapswith great frequency. Neurosurgeons In childrenwith large ventriclesthis is easilydone,but in adults with smallerventriclesthe target is smallerandit is more difficult to tap the ventricle with confidencethat the needlewill pass

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directly into the ventricle.But the CAT scannercan guide the placementof the needle directly into the ventricle with little chanceof error. Sucha procedureis doneunderlocalanaesthesia, requiresonlya tiny incisionanda drill holeinto the skullto allowa delicateneedleto be guidedthroughthe silent portion of the right brain into the right lateral ventricle.Whilethis is not somethingto be done lightly, the risks are no greater than those for cardiac catheterization. Twenty years from now, the disease,'preseniledementia'will be understoodas well as diabetesis today. An insulin lack is presumed,thoughoftennot measured,in patientswith diabetes.In decadesto come,the confidenceof the doctorslookingafter those like Nellie might grow to such an extent that they can predict Nellie's molecularproblem.But for the next few years,until the molecular correlations are fully understood,the fluid removed from Nellie's brain will be sent to a laboratoryfor analysis. Two kindsof testswill be performedon Nellie'sbrainfluid. The first will involve a screening test; at present the best such procedureis the two-dimensionalgel study that separatesmolecules accordingto their electrical chargesand their molecular weight. This test can count the numberof different moleculesin the fluid, but cannotdeterminethe quantityof any of them. A singledropof Nellie'sventricularfluidis all that is requiredfor this test, yet it might yield a picture like that in Fig. L3.7. The pathologistwho performs the two-dimensionalgel study is very excited.His practisedeye canquicklys9ethat onespotis missing in Nellie's gel study.By comparingNellie's brain fluid to that of other normal patients, the pathologist can tell precisely what substance Nellielacks;hispreviousexperiencehastaughthim that the missingspotin the two-dimensional gel is 'x' hormone. If the two-dimensionalgel study showeda lack of 'x' hormotr€, the pathologistwouldpredictablyperforma secondtest that would measurequantitativelythe amount of 'x' hormone in Nellie's ventricularfluid. This test, a'radioimmuneassay',can measure infinitesimalamountsof hormonesin blood or other fluid with great specificity. The final report might read like this: "The concentrationof 'x' hormonein the fluidis 31 nanogramsper millilitre; in normalpatientsthe concentrationof 'x' hormoneaverages 243 nanogramsper millilitre." Of course,no onehasperformedtwo-dimensional gel studieson the ventricularfluid of patientswith seniledementia.Therefore, no oneknowsfor certain that Nellie wouldhavean abnormaltwogel pattern.And it is unlikelythat suchstudieswill be dimensional

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performedin the current legalclimate.But if the memorylossof preseniledementiais causedby a hormonedeficiencyandif pathologistsin yearsto comecanverify a lackof a memoryhormonein this all-too-commondisease,an opportunityfor therapy would exist. If a 'memory peptide' could be found to be deficientin patientswith seniledementia,thesepatientscouldbe treated in the sameway that patientswith diabetesare treatedwith insulin. The molecularstructureof all of the knownbrain hormonesis established,and geneticengineersalreadyhave begunbacterial productionof most of them. Thus if a'memory hormone'were foundto be deficientin the brain of a patient suchas Nellie, the synthetichormonealreadymight be on the pharmacist'sshelf.If the memory loss of seniledementiawere linked to a new brain hormotr€,genetic engineerswould take this as a challengeand within a few monthssucha syntheticreplacementcouldbe available. In this lies muchof the excitementof the brainglandparadigm. Scientistshave masteredthe techniquesof hormone analysis, measurementandmanufacture.Whatis lackingis the correlation betweena specificbrain diseaseanda specificbrain hormone.But scientistsworkingalonecannotdo this;thesecorrelationscanonly comefrom a medicalteamof co-operatingphysicians. If we assumethat Nellie's problemwith her memory can be linked with certainty to a particular hormone deficiency- a 'memory peptide' deficiency- and that this substancehas been manufactured,how will it be givento Nellie? 'memorypeptide'for As hersis a chronicillness,shewill require a long time, perhapsfor the durationof her life, muchas diabetics do. Somemedicinecan be given daily as a pill or capsule,but if 'memory peptide' is indeeda peptideit will be digestedby the it couldbe givenbeneaththe skin,asinsulin stomach.Conceivably, is, but the presenceof the blood-brainbarrier makesit improbable that it wouldreachits target gland- the brain.Openingthe bloodbrainbarrier atthe sametime that a particulardrug is givenwould allow the drug to reachthe brain, but only injectionsgiven into veinsinfluencethe bloodvesselsof the brain.SinceNellie'sdisease is chronic,dailyintravenousinjectionsare impracticalif not impossible. Everyoneconcernedwouldbe led to the logicalconclusionthat Nellie's deficiencywould be treated most effectivelyby giving 'memorypeptide'where it is needed- in the brain itself. Again, sincehersis a chronicillness,somedeliveryroute mustbe organwed that would allow daily, perhapscontinuous,administration.

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The samelogicthat led to the placementof the samplingcatheter in the ventricle would lead to placingthe delivery devicein the ventricle,not the lumbarsac. Animalexperimentshaveconfirmedthe necessityof delivering hormonesinto the ventricle:the powerfulhormoneendorphindoes not changebehaviourif it is given intravenously;vasopressinwill improvememoryin animalsonly if it is given into the ventricles; insulingiven through the bloodstreamdoesnot control appetite but is the besthormonefor suchcontrolif giveninto the brain;and bombesin,an unusualsubstancefound in frog skin, only stops stomachulcerationif giveninto the brain. Everything we know about brain endocrinologypoints to the hollowspacesin the brain- the ventricles- as the best placefor successful therapy. A techniqueis availablethat may be usedto delivermedication chronicallyinto manyorgansof the bodyincludingthe brain; it is shownin Fig. 15.2. Chronicinfusionpumpsare usedevery day in medicalpractice,generallyin desperatesituationssuchas cancer, but increasinglyin the treatmentof diabetes.The 'tanks'of these devicesare placedbeneaththe skin,andthe long cathetertip can be tunnelledlong distancesunder the skin to the delivery site.

Pressure chamber Fig. 15.2The 'infuseaid' allowslong-term administration of drugsintodiffer.ent bodyspaces

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'tanks' in these devicesare filled Onceor twice eachmonth the simplyby stickinga delicateneedlethroughthe skin into the selfsealingrubber domeof the device. Nellie's much needed'memory peptide' could be placedinto such a chronic pump and infusedinto the ventriclesof her brain with very little technicaldifficulty. Eventhe rate of administration couldbe controlled. Two more possibilitiesrest on the shelvesof brain scientists: geneticmanipulationandcell transplantation.Either of thesecould obviatethe needfor Nellie to havea chronicpump. Geneticengineerspredictthat they soonwill be ableto manipulate the inside of humancells as easily as they now manipulate 'switching bacterialcells. Their best efforts so far have involved on' the production of specific hormoneswithin cells, thus any deficiencydiseasethat is identifiedin the brain wouldexcite their interest. Much more research must be performed in animals beforethis is begunin patients,but tremendousstrideshavebeen takenby this groupof scientistsrecently. Geneticengineersare powerlessin all of this without somecooperativeeffort from peopleworkingin alliedfields.Certaincorrelationsbetweena behaviouralabnormalitymust precedethe first andagainthe importanceof thoughtsaboutgeneticmanipulations, ventricularfluid for hormoneanalysisis apparent.It seemsdoubt'wrenches'that they employ to bend ful that the DNA-twisting genesback into shapewould be effectiveacrossthe blood-brain barrier; their manipulationsmay only be possibleif they insert their wrenchesthroughthe ventricle. Many of the best endocrinesecrets were discoveredby the simpleexpedientof movingoneendocrineglandfrom oneplaceto Whenthe brainwasthoughtof another,that is, by transplantation. as an electricallydrivencomputer,there wasno reasonto believe that the transplantationof glandulartissue into the brain itself believe would modify behaviour,but now brain endocrinologists there is. Alreadyin animals,somegland-likecellshavebeentransplanted from the adrenalglandinto the brain,wherethey not only survive but continuetheir secretions.As brain diseasesare linked more will suchtransplantations certainlyto brain hormonedeficiencies, be performedin humans.In nearly all other kinds of transplantations,donororgansor cellsfrom other humansare employed;the body's immune system recognizesthis tissue as foreign and of the body'simmunity attemptsto get rid of it. Only suppression transplants to incompatible allow will substances foreign to

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survive.Transplantinga tiny bit of a patient'sownglandinto his or her own brain sidestepsthe problems of incompatibilityand, becauseof this, glandtransplantsinto the brain are viewedwith optimismby transplantscientists(seeFig. 15.3).

D

Glond

Fig. 15.3 Transplantation of glandtissueto the brain

Cellularbiologistsinterestedin transplantationhavelearnedto harvestcells from endocrineorgansin a way that allowsa 'pure' populationof a certaincell to be extractedfrom a certain organ. The six differentkindsof cellsin the pituitary, for example,canbe separatedinto differentpopulationsandsix 'soups'prepared,each containinga live populationof onetype of cell. The samething can be donefor manyother endocrineorgans. By placingsuchcell-containing soupin bullet-shaped cell cages formedout of permeableplastics,a singlepopulationof cellr .rn b. introducedinto the brain.The cellsstay alivebecausethe needed cell-foodandlife-givingoxygenpenetratethe plasticenvelope.By the sametoken,the hormonesthat are producedby the cellsmake their way throughthe surroundingpermeablemembraneinto the

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brain.In this w?y,transplantscientistsare ableto create'artificial glands'that canbe insertedinto specificregionsof the brainwith no fear of cell migration. We haveconsidereda disease,seniledementia,whichmight be associatedwith a hormonedeficiency.But there are many other braindiseasesthat couldbe consideredin the sameway. A fellow physician,while attendinga patientwho weighedmore 'Four hundredpoundsisn't too much, than400 pounds,remarked, I once treated a man who weighed700 pounds.'To which the howcouldhe let himselfgolike lightweightreplied,'My goodness, that.' The anecdotesuggeststhat obesityis a laughingmatter,but andno cure. malignantobesityis a diseasewith dire consequences Increasingly,physiciansand surgeonshaverecommendeddrastic surgicalprocedures,but noneof theseworks very well andnoneis without severeside-effects.Malignantobesitystemsfrom a disorderedappetite,andthe best evidencesuggeststhat the control of appetite involves brain and gut hormones.Manipulatingthe appetitecontrol centre in the brain is the most logicalmethodof treatmentandis certainlybetter thanwiring the teeth togetheror re-routing the intestines.But until the hormonalcontrol of the appetite centre is understood, such therapy cannot be considered. As it is possiblethat the memory loss of seniledementiamay 'memory peptide',obesitymay result stem from a deficiencyof from the deficiencyof either bombesin,somatostatin,cholecystokineo,gastrinor insulin.As recordedin previouspages,animal studiesmaketheserelationshipsquite certain but, so far, human correlationsare not possible.Again,as the hormonesin the blood or in the lumbar fluid may not reflect what is going on insidethe brain,it seemssafeto predict that only ventricularmeasurements in humanscanleadto certaincorrelations. of thesesubstances Many patientswith schizophrenia,perhaps20 per cent, have largeventriclesthat canbe demonstratedby CAT or NMR scans. While such scansusually trigger the knee-jerk responsefor a ventricular shunt, to my knowledge shunts have not been performed for schizophrenicpatients. Moreover, despite the evidencethat ventricularhormonesdo not maketheir way out of the ventricle, the presenceof large ventricles in many schizogelsto provide phrenicpatients,andthe abilityof two-dimensional a profileof peptidesin the ventricle,not a singlecatheterhasbeen patientto measurethe placedinto the ventricleof a schizophrenic peptidesin the ventricle.This may be the most certainevidence that a legalroadblockexiststhat preventsthe studyof the relation-

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ship of brain hormonesto brain diseases,for there is no logical reasonwhy suchstudiesshouldnot havebeendonelongago. Many endocrinediseasesof the body entail the productionof 'crookedmolecules'moleculesthat are madein the wrong way by the cell.It is fairly commonfor a cancercellto beginthe production of a 'crooked'hormonethat evokesdramaticchangesin other bodyfunctions. Whetheror not schizophrenia canbe correlatedwith an excess of a hormooe, a deficiencyof a hormooe,a crookedhormotre, or no alterationin hormonesat all is uncertain.But onething is certain: as there is no animalmodelfor this disease,the answercan only comefrom humanstudies. Depression,more than any other humanbehaviouraldisorder, hasclear-cutendocrineabnormalities.As manyas one-halfof the patients with unipolar depressionhave changesin the brain/ pituitaryladrenal axis that are so dramatic that they can be measuredin the blood. Cortisol, the hormone formed by the adrenal gland after it receives a commandfrom the brain and pituitary, is typically elevatedin the bloodof thesepatients.While cortisol levelsgo up in the morninganddownin the afternoonin normalpeople,in many who have a unipolardepression,such fluctuationsare lost. If an attemptis madeto shut downcortisolsecretionby the administration of a synthetichormonecalled'decadron',it will be evidentthat the brain andpituitary are working overtimeto stimulatecortisol secretion; decadrondoesn't shut down production in a normal way. Electrocon\rulsivetherapy, or ECT, is the best therapy for unipolardepressionthat exists.It hasbeenestimatedthat 10,000 patientsstill receivethis therapyeachday despiteits bad press. Knowingthat cortisol changesare correlatedwith moodin these patientsallowsdoctorsto monitor the effectivenessof electroconvulsivetherapy;they havefoundthat the smile will return to the faceof the patienton the very samedaythat the cortisoldynamics return to normal.This newcorrelationpromisesto makethe useof electroconvulsive therapyevenmore commonplace. But why ECT is so effectiveremainsa mystery. No one knows the causeof depression,despiteits clear association with cortisol changes,but manypeoplebelievethat if the effectiveness of ECT were understood,the causeof depressionwouldbe in hand. Two things are certain: during electroconvulsivetherapy the blood-brainbarrier is openedand during the time that it remains openedthere are heroically high levels of circulating pituitary

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hormones.Thus there is every reasonto believe that this oldfashioned,poorly understood, and risky therapy is effective becauseit delivers hormonesto the brain; it opensthe brain's bloodvesselswith onehandwhile it whipsthe pituitary into action with the other. The brain under theseconditionshaslittle choice but to acceptthe hormonesthat cometo it. Opiumwasat onetime usedvery effectivelyin the treatmentof depressionand some peoplecontendthat most of the therapies that have been effective in depressionincrease brain stores of brainopiates.Knowingthat the pituitary containsgreat amountsof brainopiateshasled to the speculationthat ECT releasesopiatesendorphins- which are manufacturedin the pituitary and carried directly to the brain. Somescientistscontendthat the changesin cortisol dynamicsis evidencethat the depressedbrain is deficientin opiatehormones. They arguethat an opiate-hungrybraindemandsthat the pituitary secretemore opiate-likehormone;the cortisol excessseenin the bloodstreamis only a reflection of a brain/pituitary relationship gonewrong. Despite the effectivenessof electrocon\rulsivetherapy, an improved rationale for its effectiveness,an endocrinetest that allows physiciansto monitor its effectiveness,and convincing evidencethat ECT is giventhousandsof times daily, it may cause long-lastingproblems with short-term memory. It is this risk which prevents it from being a panaceafor those who are depressed,and it is this that has causedgroupsin our societyto protest about its continueduse. Yet despite the protests, the ability of cortisolstudiesto identify patientswho will benefitfrom ECT guaranteesthat more patientswill receiveit. The medicalcommunityin the besthospitalsin the world would not allow a diagnostic ventricular tap for patients with senile 'It is too risky,' the or depression. dementia,obesity,schizophrenia doctorswould say. But in these samehospitalsfar greater risks would be taken in patients whose epilepsyis not controlled by medications. Patients with uncontrolledepilepsy have an evaluationthat usuallybeginswith electricalstudiesof the surfaceof the brain. Thenelectrodesareplacedinto the cheekto the spacebeneaththe skullfor recordingsthere.A holeis drilledin the skull,andelectrical measurementsmadefrom within the depthsof the brain. A large flap of the skull is then lifted up, electrodesplacedon the surfaceof the brain,andthe flap sewnbackinto placeso that more electricalstudiescanbe done.

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The risks of these electrical tests are far greater than those associatedwith the ventricular taps neededfor hormonestudies, yet after this effort, andtheserisks, the team of physiciansmight sayto the patient,'We can't help.' If the teamof doctorss?y,'We canhelp',they woulddetailwhich portionsof the brain needto be excised.At operationthe areasof the brain that are sending'bad' electricalsignalswould be identified and removed.Rather large chunksof brain might be taken awayin this process. Somehowthe samenurses,physicians,administratorsandlegal ombudsmenwho preventedthe study of the ventricular fluid of a patientwith seniledementia,or obesity,or depression,or schizophrenia,becauseof the risks, will encouragediagnostictests and therapy for patientswith epilepsythat are far more destructive and immutable than the measurementand manipulationof hormonesin the ventricle. This may be one of the most glaring inconsistencies in medical practice;it is testimonyto the institutionalcommitmentto the old notion that electricity is the stuff of thought and verifiesa fear of the new paradigmfor the mind. Must a brain diseasebe verified by electrical measurements beforeit canbe rationallytreated? Is it 'legal' to acceptthe risk of a brain operationthat measures the electricalcurrentsin the brainand'illegal' to acceptthe risk of a brain operationthat measuresthe hormonesin the brain? May surgeonspermanentlymodify the structural form of the brain but not transientlymodifythe structure of its molecules? May electricitybe pumpedinto the brain during ECT knowing that it causesmemoryloss,but hormonesnot be pumpedinto the brainbecausethis therapyis too 'radical'? The scientificdiscoveriesof the pastdecademakeit crucialthat thesequestionsbe addressed; what must be doneis fairly obvious. An informedpublicwill demandfair-mindedanswersand actions from all thoseconcernedwith patient care, especiallythosewho serveas advocatesfor 'patient'srights'. It is more difficultto predict the impactof the new paradigmon other, non-medicalaspects of our society. One thing seems certain:the hormonalgeniesthat havelivedunnoticedin the brain sincehumankindbeganhaveescaped; thereis no waythat they can be put back.No onecanpredictwherethey will go andwhat they will do.

Shoreline of Wonder

The new stuff of thought,brain hormones,hasa substancethat is as sturdy as the planets.The explorationof the mind may begin with electricalstudies,but electricallybasedtechnologiescannot shapethe mindanymore thanthey canshapeouter space. Spacescientistshaveendedtheir effortsto knowmoreaboutthe surfaceof the moonandarenowgettingon with the taskof shaping outer spacein a way that will benefitpeople.Brain scientistscan learnfrom this;theycanalsoput asidetheir electricalgearandget onwith the businessof shapingthe moleculesof the mind.The high priestsof brainexploration,like the high priestsof spaceexploration, may continueto pushfor more electricalmappingstudiesof boththe moonandthe brain- their livesare mademoresecureby suchstudies- but it is difficultto seehow the lot of the common manor womanis improvedby either. Is it unrealisticto believethat humankind'sinner space- the mind- can be reshapedwith the same gusto and co-operation whichled to the reshapingof earth'souter space?I think not. 'WirelessWorld' predicLook backfor a momentto the 1945 tions of Arthur C. Clarke.He foretoldthe moonshot,communicationssatellites,the explorationof far distantplanetsandthe space shuttle.Many storedhis predictionson the sameshelvesas the Buck Rogersfuturistic comics,but his notionswere the prescient predictionsfor spaceexplorations. Aristrachus,Copernicus,GalileoandKeplerwere merelyspectators of man's outer space.They used their visual senseand opticaltelescopesto makeobservationsthat were fundamentally correct;the electronicsignalsfrom our satelliteshaveshownthese ancientgeniusesto be correctin almosteveryway. Einstein,Goddard,Arthur C. ClarkeandJohnGlennwere not mere spectators;they actually reshapedpeople'souter space. They forsworethe descriptivetelescop€,either opticalor radiobased,andgrappledwith new issues- gravitationalforces,rocket propellants,the magicof the satelliteandthe Gs that the human bodycouldwithstandto placepeoplein spaceandeventuallyonthe studyof spacegavelittle benefit moon.The passivespectator-like reshapingof space- John athletic-like to mankind; the active Glenn'swillingnessto ride on a rocket, for example- provided humankindimmensebenefit.

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Brain scientistsnow standon a thresholdvery similarto that of spacescientists.They recognizethe similarities between our outer and our inner spaces;the spinningmoleculeswithin the humanmindare very muchlike the spinningplanetsthat makeup our universe.Electricallybasedstudiesmust begin eachkind of exploratoryendeavourbut, at the end,onlythe physicalreshaping of eachwill benefitmankind. Our outer macrocosmalready has been partly reshapedby satellites rocketingsmallchunksof earth- metalcommunications - into orbit. The inner microcosm- the humanmind- canalsobe reshapedby nudgingthe moleculesof the mind, brain hormones, into new orbits. But not quickly.The complexitiesof the hormonalharmonies of the mind securethe prediction whichmodulatethe mechanisms that endocrinestudiesof mind/bodycorrelationswill go on for manycenturies.The lengthycommitmentthat researchandhealth care institutionshave madeto brain electricity- a commitment that hasnot giveneither thosewho are well or thosewho are sick - shouldpallasthoseconcernedcometo see anygreatadvantages the opportunitiesthat brain hormonesbring to the understanding of normalandabnormalhumanbehaviour. 'Humanswill launchsatellites, Arthur C. Clarkesaidin 1945, they will go to the moon,and they will live in space.'His only questionwas,'When?' In 1984,parallelpredictionsare in order: physiciansandscientists will measurebrain hormones- in ventricularfluid and elseand will devisespacewhere- will link theseto specificdiseases, to restockthe mind'shormonalpantries.The only agetechniques questionis, 'When?' Thosewho care for patientswith brain illness- psychologists, psychiatrists,neurologists,neurosurgeons, andfamily physicians - suddenlyfind themselvesat the cutting edge of molecular biology.Suddenly,thesedoctorsare positionedbetweenscientists 'incurable'braindiseases. with potential'cures'andpatientswith trainingprogrammes,currentleaders Their schools,postgraduate andjournalshavenot preparedthem for this new role. but it might be the predictIn medicinethis is unprecedented, of a rapidly developingnew sciencemakingan ableconsequence impacton a broadlyeducatedpublicanda narrowlyeducatedgroup of professionals. 'Wireless In 1945 Arthur C. Clarke was forced to write his World' predictionsin a mannerandin a placethat were accessible to the public,anddecadespassedbeforethe spaceracebecamea

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reality. During that interval,most,if not all, aviatorslearnedabout spacetravel from newspapercomic strips. Before the moonshot, whole new strategiesof educationwere developedto get the young and old spaceadventurersupgradedand ready for space travel. The new knowledgeaboutbrain hormonesis in every way like the 1945 knowledgeaboutspacetravel. For mankindto benefit from this new braininformationwholenew strategiesof education must be developedto upgradethose who provide health care. Withoutthat effort,the newknowledgeaboutthe brainwill rest on laboratorybenchesandlibrary shelves. For millions who are ilI, the realizationthat the brain is a hormonally modulatedgland is revolutionary therapeutic good news. But as long as our most respectedombudsmenmaintain Plato'sbeliefin a 'divine'brain,andaslongasthat view createsthe legalclimatethat allowsphysiciansto manipulatethe pressureand electricity in the brain but not manipulateits peptidehormones, little of the potentialbenefitof the brain glandrevolutionwill be realwed. Thosewho keepthe 'truth' at the centre of the islandof knowledgemust now contemplatethe wealth of new informationabout the mindcomingfrom the 'truthfinders'at the shorelineof wonder. The new pathfindersdescribea pattern for the fabric of the mind that is wovenof manykindsof thread.They saythat a singlestrand may be pulled out, analysedand synthesized,and that such new braidsmay evenbe rewoveninto the fabric of the mind if mending is required. Truthkeepers might easily accept all of these new scientificdiscoveriesaboutbrain hormones- they involvereductions, indeedabbreviations,and left brains brought together find suchthingsboth comprehensible andteachable. But how will thosewho keepthe 'truth' dealwith the evidence that the thoughtsemergingfrom the mind spring from hormonal harmonies- from moleculesof many kinds coming together in many places?Will they recognizethe cosmicentity that orchestrates the anatomicaltrysts of the hormonesthat steer the mind? - especiallythosebandedin a group Predictably,no.Reductionists - will not seeit. Yet the pattern-discerningright brain of any individualwho takesthe time to understandthe new make-upof thoughtwill be forced to the conclusionthat the fabric of the mind is wovenby somewisecreator.Thosewho discernthe patternof the tapestry will stand in awe, knowing that its static form cannotproduce thought:molecules,somefrom the brainandothersfrom the body,

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must caresseachother - as the violinist's bow kissesthe violin strings- to createthe musicof the mind. Whatforce movesthesemolecules? Out of that questioncangrow a new beginning.

Bibliography

'Antagonismof StimulationAkil, H., May€r,D. J. andLiebeskind,J. D., producedAnalgesiaby Naloxone,a NarcoticAntagonist',Science,l9L, 96I-2,1976. lThis article waspublishedoneyear after the discovery 'gateof opiate-likehormonesin the brain and suggestedthat the control' of painwasmediatedby hormones.l Altschule,M., Origins of Conceptsin Human Behaaior,Wiley, New York, L977.[This little bookset me on the historicaltrail of the stuff of thought.J Aristotle,DePartibusAnimalium, n The WorksofAristotle[translated by W. OglelClarendonPress,London,1912. des Menschen' , Acta Noaa Berger, H.,'Das Electrenkephalogramm of the EEG.J L7opolda,6,173,1938. [Theclassicdescription Bergland,R., 'New InformationConcerningthe Irish Giant',tournal of Neurosurger!,23,265-9, 1965.[This tells how the father of general surgery,JohnHunter, and the father of neurosurg€ry,Harvey Cushing, cotlaboratedin the evaluationof the giant,CharlesO'Brien.l 'NeurosurgeryMay Die', New England Bergland,R., Journal of Medicine, 288, 1043-6, L973.[A controversialarticle espousingmy belief shouldbe more involvedin research.J that neurosurgeons 'AnatomicalVariationsin the Bergland,R., Ray, B. S. and Torack, R., HumanPituitary Gland. . . (225 autopsies),Igurnal af Neurosurgery, 28,93-9, 1968.[Itwaswhiledoingthis work that I cameto believethat pituitary hormonesmight flow 'north' to the brain.l Bergland,R. and Torack, R.,'Follicular Cellsin the HumanPituitary'; AmericanJournal of Pathologr,57, 273-98, 1969.[The first description of thesecellsin humans.] 'An Electronmicroscopic Study of the Bergland,R. and Torack, R., Zeitschriftfur Zellforschung,99,I-Lz, 1969. HumanInfundibulum', [For this work I savedbits of the pituitary stalk that I had removed during hypophysectomy.It demonstratesneurosecretorygranules producedby the brain- little 'balls'within axons.J Bergland,R., 'NeurosecretoryBodieswithin the Median Eminencein with Pituitary Tumors', Lancet,2, L270-2, L979. [The association first descriptionof this association.l

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BerglandR., andPage,R. 8., 'Canthe Pituitary SecreteDirectly to the Brain? (Affirmative Anatomical Evidenc€)', Endocrinologjt, L02, 1325-38, 1979. tBob Pageand I studiedpituitary vascularcastsin eleven species;this article pertains to the rhesusmonkeyand challengesmanyof the 'holy' conceptsin neuroendocrinology.l Bergland,R. andPage,R. B., 'Pituitary-BrainVascularRelations:a New Paradigffi', Science,204, L8-24, L979. [This article questionsthe conceptthat the pituitary glandalwayssendsits secretions'south' to the body and shows many mechanismswhich can carry hormones 'north' to the brain.I Bergland,R. M., et al, 'ACTH maybe Transporteddirectly to the Brain', Science,2L0, 541-3, 1980. [At least during ECT in sheep,this happens.l Bernard, C., 'Lecons sur la Physiologieet la pathologiedu systeme nerveux', Bailliere, Paris,1858.[The father of physiology,writing the first textbookof physiology.In it he espousesthe importanceof chemical studiesfor the body but acceptsSchwann'sview that the brain is driven by electricity.J Bernard,C., Cahier Rouge[EnglishtranslationJ,Shenkman,Cambridge, Massachusetts,1967. [In this little bedsidenotebookwe learn that Bernard thought the brain was a gland,y€t in his daytimelectures he taught the 'network theory'.J B"uqont, P.J. V. andBurrows,G. D, HandbookofPvchiatry and Endo crinologjt, Elsevier, Amsterdam, L982. [This is a good correlation betweenpsychiatricdiseasesandhormoneabnormalities.J Black,P. M., 'Neuropeptidesin CerebrospinalFluid', Neurosurgery,11, 550-5,1982. [Review.] Blakemore,C., Mechanicsof the Mind, CambridgeUniversity Press, Cambridge1977. [Certainlythe bestillustratedpopularbookaboutthe brain. It containsa gooddescriptionof Plato's zcrsmemeaboutmales andfemales.J Bloom, F. 8., 'Neuropeptid€s',&ientific American, z4s, 148-16g, 1981.[A publicationwhichexplainsall the rudimentsof brain endocrinology.l Bloom, F. 8., 'The FunctionalSignificanceof NeurotransmitterDiversity', American Journal of Physiologjt,24r, Cra l{M, rgg4. Bloom,F., et al,'Endorphins:ProfoundBehaviouralEffects,Science', 194, 630-4, 1976. [Describes'catatonia'in rats, but only after the ventricular administrationof endorphin.l Bogan,J. E., 'The Other Sideof the Brain', Buttetin of the LosAngeles NeurologicolSociety,34, 135-62, 1969.[JoeBogan,a neurosurgeon, describesthe 'corpuscallosumdivisions'that he did in patientswith epilepsy.Thesepatientswere crucialto Roger Sperry'swork on the right andleft brain.l Bradsh?w,R., 'Nerve GrowthFactor',Annual Reaiewof Biochemistry, 47, LgL-216, 1.978.[Bradshawdescribeshownerve-growthfactor can penetratecell membranesandbe carriedby retrogradeaxonalflow to the nucleusof the nerve cell.J Brightman,M. W. andReese,T. S., TunctionsbetweenApposedCellsin the Brain',fournal of CellBiology,40,648-77,1969. [Theseauthors

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showthat horseradishperoxidaseplacedinto the ventricle leaksinto the brain. If horseradishperoxidasedoesthis, water most certainly does.This challengesthe central premiseof the Dandyparadigmfor brain water which contendsthat water is madein the choroidplexus andflowsout of the ventricle.l 'CerebrospinalFluid CompartBrightman,M. W. andRosenstein,J. M., ment as Site for Neural Transplantation' , Frontiers in Hormone Research,9,36-50 , L982.[Nerve ganglia,movedinto the ventricle, lack a blood-brainbarrier, theseauthorsnote. Suchmanoeuwescould provide a 'back door' by which hormonescould be deliveredto the brain.l Bronowsky,J., The Ascent of Man, British BroadcastingCorporation, London, L973. [This famousbook detailsthe technologicalsteppingstonesof civilization'sascent.Yet the historyof mankindhasnot beena continualascent.In eo 200 it took a nosedive.Why?WhileBronowsky 'descentof man',I blameGalen(AD130bypassesthe questionof the

200).1

'ConnectionsbetweenMuscle and Brushart, T. M. and Mesulam,M., 603-5, 1980.[This article(andthe Anterior Horn Cells', Science,208, Sciencecover) show that horseradishperoxidase,injected into leg muscles,is carriedby nerve fibresinto the spinalcord.l Calvin, \[. H. and Ojemann,G. A., Inside the Brain, New American Library, New York, 1980. [This little-known book describesin lay terms what epilepsysurgeryis all about.J OpioidPeptide Cart, D., Bergland,R. M. et al.,'Endotoxin-stimulated Secretion. . . , Scrence,217,845-8 , 1982.[This studyof febrilesheep showsheroicelevationsof endorphinduring fever. This may explain illnesseswhichcauseelevatedbody the 'delirium'whichaccompanies temperature.] Coghlar,J., et al,'Hybridization Histochemistry:Use of Recombinant DNA for TissueLocalwationof SpecificMessengerRNA Populations', Clinical and Erperimental Hypertension;Theoryand Practice, 6, 63-78, 1984.[The first descriptionof this technique.] Copernicus,Nicolai, De ReaolutionibusOrbiurn Coelestium,Nuremberg, 1543.[Oneof the mostimportantbooksin the historyof thought. 'true' cosmological descriptionof our outsideworld It givesthe first of Aristotle's macrocosm.Remarkably,this waspublishedin the same year as Vesalius'sFabric of Man, which givesthe first 'true' anatomical descriptionof our inner world - of Aristotle's microcosm.] Cousins,N., The Anatorny of an lllne.s.t,Norton, New York, 1978. tA descriptionof the healingpowerof joy.l OpioidPeptides;a Guideto StructureandTermiCox,8., 'Endogenous in orderly nology',Life Sciences,3l,1645-58,L982.[Thisdocuments, fashion,the endorphinsituationas it wasin 1982.1 Cushing,Harvey, The Bio-bibliographyof AndreasVesalius,Archon, Hamden,Connecticutt,L962. [Compiledtwenty-three years after Cushing'sdeathby JohnFultonandfriends.l Cushing,H., 'Removalof a SubcorticalTumour without Anaesthesia', Journal American Medical Association,1, 847, 1908. [The first

182

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descriptionof a 'corticalmap' in a human,written two decadesbefore Penfield.l Cushing,H., The Pituitary Body and lts Disorders,Lippincott, Philadelphia,1912.lMaybethe mostimportantscientificbookwritten by a modernsurgeon.It is herethat Cushinggiveshis reasonsfor believing the pituitary is the 'conductorof the endocrineorchestra'.J Cushing,H., Studies in Intracranial Physiolog!, Oxford University Press,L926. Cushing,H., 'The Third Circulationandits Channels', Lancet,20g,851, L925. [The questionsCushingsets down here challengethe Dandy paradigmandhavenever beenanswered.] Cushing,H., 'The Reactionof PosteriorPituitary Extract when Injected into the Ventricles',Proceedingsof theNational Acadernyof Science, L7, 163-80, 239-64, 1931. [Intuitively, Cushingthought that the pituitary must secreteto the brain and performedthesebold experimentsin humans.] Dale, H., 'ChemicalTransmissionof the Effects of Nerve Impuls€s', British MedicalIournal (May issue),1934.[Notethe absenceof Feldberg's name,yet it wasFeldberg'sassaythat allowedthe work.l Dandy,\il. E. andBlackfao,K. D., 'An ExperimentalandClinicalStudyof Internal Hydrocephalus,Journal of the Arnerican Medical Association,61, 22L6, 1913. [The descriptionof the legendary'aqueductal obstruction'experiments.l Dandy, W. 8., 'Internal Hydrocephalus.An Experimental,Clinicaland PathologicalStudy', American Iournal of Diseasesof Children, 8, 406-82, 1914. [Here Walter Dandy records the results of choroid plexusremoval.l Dandy,\il. E., TheBrain[2nd edn],Prior, Hagerstown,Maryland,1g60. [In this classic,Dandydescribesthe operationshe advocatedfor the treatmentof hydrocephalus.l Dawkins,R., The SelfishGene,Oxford University Press,Oxford, 1976. [The lastchapterof this bookdescribesmemes,or ideasthat passfrom brain to brain like an infectiousvirus. My new word, 'mismemes',or 'wrong' ideasthat passfrom brain to brain, camefrom Dawkins's neologism.] de Robertis, E. D. P., 'SubmicroscopicMorphology of the Synapse', Erperimental CellResearcft, supplement5,347-69, 1958.[The-first clear-cutdemonstrationof the synapticcleft andsynapticvesicles.] de Wied, D. and van Keep, P. A., Horrnonesand the Brain; Mather Brothers;Preston,England,1980.[deWiedhasdonemore to demonstrate the importanceof peptidesto memorythan any other scientist. This reviewsthat experience.l Della-Ferra,M. 4., et al,'Peptideswith CCK-likeActivity Administered IntracraniallyElicit Satiety in Sheep', Physiologyof Behauiour, 26, - CCK- limits appetitein sheeponly 979-83, 1981.[Cholecystokinen if giveninto the ventricle.l Descartes,R., De Homine Figuris et Latinate Donatus a Florentio Schuyl,FrancesMoyard and Peter Leff, Leyden, L662. [This book demonstrates that Descarteswasnot an accurateanatomist.I

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London, of Blood Circulation, Abelard-Schuman; Doby,T., Discoaerers 1963.[Wonderfullyillustrated;the mostreadableaccountof the meme that passedfrom Vesaliusto Fabriciusto Harvey.l 'Trail of Sulfur Researchfrom Insulinto Oxytocin', du Vigneaud,V., Sciince,I23, 967, 1956.[For the work describedhere du Vigneaud won the NobelPrize.f of the Brain,McGraw-Hill;New York,' Eccles,J. C., The Understanding view that elecin this bookthe long-accepted 1973.[Ecclesarticulates hasdoneas neurophysiologist modern No of thought. stuff is the tricity 'mind' is more than the sum of the muchas Eccles.His belief that the 'holists'more parts of the brain shouldhavefuelledthe furnacesof the thanit has.l 'The Effectsof Nerve Cross-union on MuscleContraction', Eccles,J. C., Medica, in Erploratory Conceptsin Muscular Dystrophy,Excerpta 'switchingon' Amsterdam,1966.[Thisis the first descriptionof genes in responseto commandsfrom the brain.] Edwardi, B., Drawing 0n the Right Side of the Brain, Tarcher; New York, L979.[Evenbrain scientistscanlearn somethingfrom this light, well-written work of an art teacher.] 'Vagal Afferents to the Area Eng, R., Shapiro,R. and Miselis, R., of the Abstracts,8,273,L982.[A description Postrema' ,-Neuroscience vagus the through peroxidase stomach the from horseradish of flow nerve to the brain stem- an importantbut little knownnon-electrical Knowingthat the gut link betweenthe nervoussystemand the gut. 'Cangut hormonesmove question, containsbrain hormonesraisesthe to the brain via this route?'l 'Compensatory AdrenalGrowth is Engeland,W. C. andDallmar,M. F., 19, 352-62, L975. [This NeurallyModulated',Neuroendocrinologjt, reportedin 1969:there paperconfirmswhat HalaszandSzentagothai 'commands'comingfrom the brain to the endocrine arenon-electrical systemalongspecificPathways.l 'The Compound Natureof the ActionCurrent Erlang€r,J. andGasser,H., of Nerv€', American Journal of Physiolog!,70, 624-66, 1924. [For this papertheseauthorswon the NobelPrize.i e, De Venaru,rnOstiollls,L. Pasquati,Padua, Fabriciusab Aquapendent 1603.[The drawingsin this book- mirror-imagesof thoseemployedin 1628by Harvey- confirmthat it wasimportantto Harvey'sdiscovery of the circulation.l Feldberg,W. S., Fifty Years On: Looking Back On Neurohumoral Physiolog!,Liverpool University Press, 1982. [Few havedone more pioneeringwork in the nervoussystemthan Feldberg.This describes much of it. Neurosurgeonswho tinker in the posterior fossashould note this article carefully.l Feyrter, F., Ueherdie peripherenEndokrinen (Paracrinen)Druesen des Menschen,Maudrick, Wien-Duesseldorf,1953. [Feyrter first 'paracrinology' proposed'paracrine'relationsin 1938, yet the term mostby Guilleminin 1978.1 waspopularized 'Letter to PeterCollinson,Philadelphia,October79, Franklin,Benjamin,

184

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L752'; Reprintedin Ben Franhlin: New WortdPhysiusf,Pergamon Press,1973.[Two pagesthat changedthe world.] Frederickson,R. C. and Geary,L. E., 'Endogenous OpioidPeptides:A Review, Progressin Neurobiologjt,19, 19-69, 1982. [This review notes that 7,500 papers pertaining to endogenousopiates were publishedbetween L976 and 1981. It contains the best endorphin/enkephalin bibliographyI haveseen.l Fulton, J. F., The Biography of Haraey Cushing, ThomasSpringfeld, 1946. [Anyonewho reads this will stand in awe of Cushingwho is without peer in the history of Americanmedicine,science,education, communicationsand patriotism. Cushingbuilt a surgical specialty- a hospineurosurgery- a fundamentalscience- neuroendocrinology tal - Peter Bent Brighamat Harvard- anda library at Yale.Yet he had time to go to war - twice - andwrite manybooks,oneof whichwon the PulitzerPrwe andseveralwhichremainclassics.l Fulton, J. F., SelectedReadings in the History of Physiologt,Thomas, Springfield,1966. [This is a model for those who write about the history of science.l Fulton, J. F., Micheal Seraetus,Humanist and Martyr, Herbert Reichner, New York, 1953. [It was John Calvin's church, not the Catholicchurch,that demandedthe deathof Servetus.l Galen,Claudius,Opera Ornnia [Twenty-two aolumesof translationJ, Nackdrunkder Ausgabe,Leipzig,L821.[Don'treadthesevolumes,just try to lift them. They are overwhelmingby weightalone,andthey held mankindin intellectualchainsfor 1,400years.l Galvani,Luigi, De Viribus Electricitatis in Motu Musculari. . . , Apud SocietemTypographic?ffi,Mutine, L79I. [The 'twitching frog legs' classic;interestinglithographs.l Garfield, E. [ed.J, Current Contents Philadelphia;publishedweekly. [Thosewhoseekto correlatehormoneswith behaviour- either normal or abnormal- can find no better guidingperiodicalthan this. Its back pageshave been computer-indexed to make it easy.Scientistsmust havethis to stay abreastof the manyrapid changesin the endocrinology of the brain.J Gazzindg?, M. S., 'The Split Brain of Man', ScientificAmerican, zLT, 24-9, L967. [In this the kindsof tests that Roger Sperry employedin his 'left brain- right brain' work are described.l Geren, B. B., 'The Formationfrom SchwannCell Surfacesof Myelin', Erperimental Cell Research,7,558-64, 1954. [In the early daysof electronmicroscopy, Gerenpublishedthis descriptionof myelinformation. Only then did scientistsrealwethat Schwanncellswere wrapped aroundnervesin Jelly-roll' fashion.l Gerendai,I., et al,'The NeuralPathwayfrom the AdrenalGlandto the Hypothalamus',Cell and Tissue Research,153, 559, L974. [The continuationof the Halaszand Szentagothaiexperimentsdonefirst in 1g5g.l Gerendai,I. andScapagnini, Lf., 'NeuralMechanismandOvarianHypertrophy', Proceedingsof theInternational Symposiumon Neuroendocrine Regulatory Mechanisms, Belgrade, 101-5, L979. [This

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describeshow non-electrical,non-pituitarycommandsfrom the brain in the ovary.l to control geneticmechanisms 'specializationof the HumanBrain', ScientificAmeriGeschwind,N., can,24L,180-99,1979. 'Left Handedness,Associationwith Geschwind,N. and Behan, F., LearningDisordQt', and Developmental ImmuneDiseases,Migraine, Proceedingsof the National Academyof Sciences,79, 5097-100, 1982.[Geschwindpostulateshere that testosteroneimbalancein the braincausesall thesethings.l 'Interactionof Morphinein Goldstein,A., Lowney,L. I. and Pal, B. K., MouseBrain', Proceedingsof the National Academyof Science,68, 'opiatereceptor' L742-9, L971.[This containsthe descriptionof the that led to the discoveryof the endorphins.l sur I'histologiedescentresnerveux',Archiaesof Golgi,C., 'Recherches Italian Biologjt,3, 285-3L7, 1883. [This containsGolgi'smismeme 'network theory' of the brain.l espousingthe 'Peptides in the brain: The New Endocrinologyof the Guillemin,R., Neuron', Science,202,390- 402,1978.[Sir IsaacNewton,in a tribute 'If to Kepler,said, I haveseenfurther, it is becauseI havestoodon the giants.' For the rest of time, all of thosewho think about shouldersof thinkingwill standon this article of Guillemin's,muchasNewtonstood on the writings of Kepler.l 'The HypothalamicHypophysioGuillemir, R., Burgus,R. and lV. Vale, Factor', Vitamins and Hormones,29, tropic ThyrotropinRealeasing ' L, L97L. [This is what Guillemin wrote about this work: . . . vt/'€ processedcloseto five million hypothalamicfragmentsfrom the brains of sheep.Sinceonesheepbrain hasa wet weight of about 100 grams, this meant handling500 tons of brain tissue. . . Finally in 1968 one milligramof a preparationof TRF wasobtained.'l Halsted,W., 'Auto and Isotransplantationof ParathyroidGlands',Iournal af Erperimental Medicine,11, L75, 1909. lHere Halstednotes that transplantedglandssurviveif the host glandsare removedbefore transplantation.This observationwas,in retrospect,the first demonstration of the 'feedbackcontrol' that underliesall endocrinerelationships.l 'HistologischerBeweiseiner Nervosen Halasz,B. and Szentagothai, J., Signalubermittlungvon der Nebennierenrinde^tm Hypothalamus', Zeitschrift fur Zellforschung,50, 2974A6, 1959. [This article will somedaybe recognisedas the keystoneto the developmentof paracrinology,for it documentsfor the first time the non-electrical,nonpituitary neural connectionsbetween the brain and the endocrine system.] Harvey, W., Exercito Anatomica de Motu Cordis et Sanguinus in Animalibus, WilliamFitzer, Frankfurt, L628.[This bookbecamethe turning point for science,medicine,philosophyand religion. Yet it addresseda simpleanatomicalquestion,'Why is the heart hollow?' Somedaysomebodywill write a similarbookwhichanswersthe simple question'Why is the brain hollow?'Will that book have the same impact?I think so.l

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Harris, G., Neural Controlof thePituitary, Arnold,London1955.[This is Harris'sfinestwritten work anda classic.] Harris, G., 'Humours and Hormones', Proceedingsof the Societyfor Endocrinology,Dalelecure,ii-xxiii, L971.[In this article Harris tells his story.] Hewitt,J., Yoga,EnglishUniversitiesPress,1960.[The quoteaboutthe hibernatingyogi on page160 camefrom this book.l Hinsey,J., 'A Searchfor the NeurologicalMechanismsof Ovulation', Proceedingsof the Societyfor Erperimental Biology and Medicine, 30, 136, 1932.[This article established that the brain controlledovulation by chemicalcommands,and not by electrical signals.It is the foundationof neuroendocrinology, accordingto MeitesandMedvei.J Hodgkin,A. L. and Huxley, A. F., 'Currents Carried by Sodiumand Potassium Ions...', Journal of Physiolog!,116: 449-72,1952.[For this discoverythe authorssharedthe NobelPrwe.f Hofstadter, D. R., Godel,Escher, Bach: An Eternal Golden Braid, HarvesterPress,London,L979. [Godelusednumbers,Escherused picturesand Bachusedmusic.But Hofstadteruseswords. All do the samething:they examinethe mysteriousmechanisms of the mind.] 'Beta-endorphin Hosubuchi, Rossier, Blooffi, F. and Guillemin, R., in J., J., VentricularFluid', Science,203,279-81,1979.[Hosubuchi, a neurosurgeon,implantedelectrodesinto the mid brains of patients with intractablepain muchas Reynolds(seebelow)did in animals.Whena current was passedthrough the electrodes,endorphinlevels rose in ventricular fluid. This is a very important observationin the understandingof the fabric of the mind.l Hughes,J., 'Isolationof an EndogenousCompoundfrom the Brain with Fropertiessimilarto Morphine,Brain Research, the Pharmacological 88, 295-308, L975. lAlthoughthis article was publishedwithout his name,Kosterlitzis regardedas the co-discovererof brain opiates.l Macmillan,Londotr,1906.[Hasanyone Huxley,T. H., CollectedEssays, written better?Or more?From Huxleycamemy quoteaboutan island of knowledge.l Huxley,T. H., 'On CertainErrors Respectingthe Heart Attributed to Aristotle', Nature, 2L, 1-5, 1880. [This article explainshow Aris'three-chambered heart, were the totle's 'hollow arteries' and his result of his insistencethat animalsbe killed by strangulation.l of Impulsesfrom Nerveto Muscle',ProceedKatz,B.,'The Transmission ings of theRoyalSocietyof London,155: 455-77, 1962.[For this Katz won the NobelPrize.l 'PituitaryCellTransplants Kelsey,M. I., Hymer,W. C. andPage,R. 8., to the CerebralVentriclesSuppressthe Pituitaty', Neuroendocrinolog!,33,3L2-I6, 1981. Knight, B., Discoaeringthe Human Body,Heinemann,London,1980. discoverythat exists.Knight [Thebestillustratedhistoryof anatomical explainsin detailthe importanceof Vesalius.l NewYork, 1960.[A very Kobler,J., TheReluctantSurgeon,Doubleduy, readableaccountof the life of JohnHunter.l Koestler, A., The Sleepwalkers,Hutchinson,London, 1959. lSlee|walkers,more than any other book,showshow a wrong view of the

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macrocosminfluencedthe courseof civilization.It stimulatedme to wonderif a wrongview of the microcosm- of the stuff of thought- has donethe same.l 'Pituitary Hormonesin Brain: Where, Kreiger, D. T. and Liotta, A. S., 1979.[Kreigerwasthe first to How andWhy', Science,205,366-72, describeACTH in the brain.Shewritesherethat sheis not convincedI am correct in stating that pituitary hormonesmay be carried to the brain.J Nature, Kreiger, D. T., et al,, 'Brain Grafts ReverseHypogonadism', 298,468-TI, 1982.[If I read the tea leavescorrectly,this will be a historicallyimportantarticle.l Tract, Lancet, Kruseman,N., et al., 'CRFin the HumanGastrointestinal 2, L245, L982.[CRFwasfoundfirst in the brain,but now it is foundin manyplaces.Kruseman'sdiscoveryof it in the gut camein the same year that Tanaka,and others, found 31-K in the gut. All kinds of evidenceshowthat CRFand31-Kare importantto thinking,especially to memory.Canthe gut think?l Kuhn, T. S., The Structure of Scientific Reaolutions,University of Chicagopress, 1962. [This book has mind-jarringinsights into the It stressesthe importhat underlienewdiscoveries. thoughtprocesses tanceof paradigmsandwas the catalystin my decisionto write about the needfor a paradigmswitch.J Lashley,K. S.,'PersistentProblemsin the Evolutionof the Mind', Quart'In Search of the erly Reaiew of Biology, 24, 28-42, 1949; and Engram', Symfosiaof theSocietyof Erperimental Biolog!, 4, 454-82, 1950.[Lashleygainedfamefor performingrat experimentsfor twenty yearssearchingfor the site of memory.He couldn'tfind it. His acknowledgementof failurewasimportantfor thosewhowouldlater claimthat memorywasa 'holographic'process.] Li, C. H., et al, 'Isolationof Lipotropinfrom SheepPituitary Glands', Nature, 208, 1093-4, 1965.[Here,ten yearsbeforethe discoveryof endorphinandenkephalin,Li describedthe giant peptidelipotropin.J 'Nerye Growth Factor: EvaluaLevi-Montalcini,R. andAngeletti, P. LJ., tion and Perspectives',In Zaimis E. (ed.) Nerae Growth Factor, Athlone,London,L972. [Whowould havethought that materialfrom the salivary gland could be important to the nervoussystem?LeviMontalcinimadethat discovery.I Lewin, R., 'The Brain's Own Opiate', New Scientist,January,L976. [Lewin, one of the world's best sciencewriters, tells in this article aboutthe serendipitousrecognitionthat the molecularsequenceof the brain hormone,enkephalinwaspresentin Li's pituitary lipotropin.l Lucion,A. B., et al, 'Intracerebroventricular Administrationof Nanogram Amounts of Endorphinor EnkephalinCauseRetrogradeAmnesia', BehauiouralBrain Research, 4,111-15, 1982.[First de Wiedandhis matessaythat oneendof the 31-K moleculesenhancesmemory. Now comes this publication,saying that the other end of 31-K limits memory.Most importantfor clinicianswho hopeto modify the endocrineenvironmentof the brain:botheffectsdependuponintraventricular, not intravascular,administration.l Lund,R. D. andHausk?,S.D., 'Transplanted NeuralTissueto Rat Brain',

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Science,193, 582-4, L976. [This is the first of many'brain transplant' articlesfrom this pace-settingSwedishgroup.l MacCullum,W.G., William StewartHalsted,Johns HopkinsPress,Baltimore, 1930. [There is a hiddensideof Halstedthat hasnot yet been written about,certainlynot here.J Mains,R. E., Eipper,B. A. andLing, N., 'CommonPrecursorto Corticotropins and Endorphins',Proceedingsof the National Academy of Sciences, T4,3014-18, 1977.IThis articledescribes31-K - the giant prohormonein the pituitary gland.J Mason,S. F., A History of the Sciences, Macmillan,New York, !962, [Certainlythe best singlesourcebook I found in my history of science research.J McComb,J. G., 'RecentResearchinto the Nature of CerebrospinalFluid Formation and Absorption',tournal of Neurosurger!, 59, 369-83, 1983.[This is an excellentreview article. It documentsthat very few scientistsin 1983 questionDandy'sparadigmfor brain water which wasadvanced in 1911.J Medawar,P. 8., Aduiceto a YoungScientlsf,Harper andRow, London, 1979.[Alsogoodadvicefor old scientists.] Medawar,P. 8., Pluto's Republrc,Odord University Press, L982.[You readit correctly:Pluto'sRepublic- a goodbookaboutthe mechanisms of discovery.l Medvei, V. C., A History of Endocrinologjt,MTP Press, Hingham, Massachusetts, 1982.[Medveiopenlyadmitsthat this compendiumis an effort to updateRolleston's1938 classic.Wonderfulreading.l Meites,J., et al, Pioneersin Neuroendocrinology, PlenumPress,New York, 1975. [In this slim volume,severalof the great pioneerswere encouragedto recall the 'incunabula'days of neuroendocrinology. Hinseywrites his story in detail in thesepages.J Melzack,R. andWall,P. D., 'PainMechanisms; A New Theory', Science, 150, 97I-9, 1965.[The first descriptionof the 'gatecontrol'theoryof pain.J Merril , C., et al, 'RegionalVariationsin CerebrospinalFluid Proteirs', Sciencq,211,1437-8, 1981.[Asa prefaceto Merril's article,readP. H. O'Farrell's article in the Journal of Biological Chemistry, 250, 4007-2L written in L975. In my discussionswith cliniciansI am surprisedhow few of them are awareof Merril's observations.If his observationsobtain in humans,we have no choice but to measure hormonesin the cerebralventricles.l Mettler, F., Personalcommunication.[Mettler and his wife co-authored an important text on the history of medicine in 1945. After her untimelydeathMettler continuedhis medicalsleuthingand haswritten, but not yet published,a bookaboutJohnHunter'sdyslexia.l Milhorat, T., 'The Third CirculationRevisit€d',tournal of Neurostlrg€r!, 42, 628-45, 1975.[This articleis the beston the question,'Why is the brain hollow?'J Milhorat, T., 'Normal Rate of CerebrospinalFormationafter Bilateral ChoroidPlexectomy' , JournalofNeurosurgery,44,735-9 , L976.[The scientificevidencethat choroidplexectomyis not effectivein hydrocephalusis presentedhere.]

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789

Milhorat,T., Mosher,M.B. andHammock,M. K., 'Evidencefor Choroid PlexusAbsorptionin Hydrocephalus' , NeutEngland Journal of Medicine, 282, 286-9, 1970. [This gives the evidencethat the choroid plexusremoveslabelledmaterialfrom the ventricle;exactlythe opposite of what WalterDandypreached.l Miller, N., 'Learningof VisceralandGlandularResponses' , Science,L63, 434-45, 1969. [A westernscientistconfirmswhat has beeneastern wisdomfor centuries.l Moniz, Egas, 'Essai d'un Traitement Chirurgical de Certaines Bulletin del'Acad4rniedeMedicine,115,385-92, L936. Psychoses', [In this, Moniz describeslobotomyfor the first time. Later the Nobel committeewould honor him, but most now regard this report as the beginningof a sadperiodin the history of neurosurgery.It is the best 'electrically-based' laboexampleof somethingthat workedwell in an ratory, but failedmiserablyat the bedside.J MontaBU,M. F., Studiesand Essaysin theHistory of Science,Schuman, New York, 1945. [In 'The BloodlettingLetter of 1539', Vesalius's discontentwith the doctrinesof Galenare bestexpressed.l Mostofi,B., Personalcommunication. Nakane,P. K., 'Classificationof Pituitary Cells by ImmunohistochemistTy', Journal of Histochentistryand Cytochemistry,18, 9, 1970. [The first descriptionof the horseradishperoxidase'sandwich'that has becomethe workhorsefor hormonelocalizationin cells.l Noda,M., et ol,'Clomingand SequenceAnalysisof AdrenalPreproenkephalin', Nature,295,202-6, 1982.lThis articledescribes50-K - the giant prohormonein the adrenalwhich containsseverallinked enkephalinfragments.l O'Malley,C. D. and Saunders,J. 8., Leonardo:On the Hurnan Body, Saunders,New York,1952. [A beautifulbook,but it showsthat Leonardowasan artist, not a scientist.l of Consciousness, Freeman,New York, Ornstein,R. E., ThePsychology L972.tof all the popularbooksaboutthe brain,I like this onethe best, eventhoughit is written by a 'soft' scientist.I Osler, William, The Eaolution of Modern Medicine, Yale University Press,New Haven,L921.lThis epicin scholarshipshowswhy Osler,a professorof medicine,wasCushing'srole model.] Pare,Ambrose,The CollectedWorks,Milford House,New York, 1968. [This book containsdescriptionsof the ventricles that had to come from Galen.The illustrationsof the ventriclesare thoseof Vesalius.l Pardridge,W., 'Brain Metabolism:A Perspectivefrom the BloodBrain Barrier', PhysiologicalReaiews,63, 1481-535, 1983. [A review article which explainswhy the blood-brainbarrier can no longer be thoughtof as a 'leadshield';it is dynamic.AlthoughPardridgedoesn't say So, the article leads me to think that many hormonally-related diseasesof the brain comefrom disordersof the blood-brainbarrier, not the brain itself.l in the AdultBrain are Paton,J. andNottebohm,F., 'NeuronesGenerated 225,1046-8,1984.lThis Recruitedinto FunctionalCircuits', Science,

190

THE FABRICOF MIND

articleshowsthat adultanimalscanproducenew nervecells;it challengesall that is 'holy'in neuroanatoffiy, especiallythe notionthat each of us suffersan irreplaceableloss of severalmillion nerve cells each day.l Paton,W., 'The Action of Morphine ... on GuineaPig lleum', British L2, 119, L957. [The tournal of Pharmacologyand Chemotherapy, first descriptionof the bio-assaythat scientistsuseroutinely to check for 'opiate-like'activity; it was this test that allowedHughesand Kosterlitzto discoverenkephalin. l Pearse,A. G. E., 'CommonCharacteristics of CellsProducingPolypeptide Hormones',Proceedings of theRoyalSocietyof London, L70,7L, 1968.[A descriptionof the APUD systemof hormoneproducingcells that is scatteredthroughoutthe body.It permeatesparacrinology.l Peterson,O. H., TheElectrophysiologof Gland Cells,AcademicPress, New York, 1980. Pickering,G., CreatiaeMalady, Nlan andUnwin, London,L974.[Read this if you doubtthat the bestkind of lateral thinkingis the conversion of problemsinto opportunities.l Plato,'The Apologyof Socratesand the Death of Socrates',in Woild Masterpieces, Norton, New York, L974. [In the Apology,Socrates's penchantfor questionsis described;in the trial that led to his deathare warningsfor all of thosewho find themselvesaskingquestionsabout new thingsinsteadof recitinganswersaboutold things.l Popa,G. T. andFielding,U., 'A Portal Circulationfrom the Pituitaryto the Hypothalamic Region', Jou,rnalof Anatomy,65,88-91, 1930.[In this, the first descriptionof the pituitary portal system,it was clearly stated that bloodmay flow from the pituitary to the brain. Although most scientistssinceWislockihavediscountedthis view, I believeit is correct.] Popper,K., TheLogic of ScientificDiscou*U,Hutchinson;London, Lg72. [In this book Popperpoints out the subtledifferencesbetweenscientific'truths' and'falsifications'.] Potts, M., Short, R. and Best, W., 'The Thread of Life', ten informal prospectusfor a televisionprogram.lFamily Health International, ResearchTrianglePark, NC, 1983.[MV statement,'As our islandof knowledgegrows,our shorelineof wondershouldexpatrd',camefrom this.l Ramony Cajal,S. Terture del sistemeneraiosodel hombrey de losaertebrados,Moya,Madrid,1899-1904.[In thesepublications, the synaptic relationships betweennervecellsare describedfor the first time.l Rapoport,S. I., BloodBrain Barrier in Physiology and Medicine,Raven Press,New York, L976.[This is a luciddescriptionof all aspectsof the bloodbrainbarrier.l Reti, L., The Unknown Leonardo,Hutchinson,London,L974. [This makesit clear that Leonardo'smirror-written words were notes to himself.l Reynolds,D. V., 'Surgery in the Rat during Electrical Anaesthesia', Science,164, 444-5, 1969. [The first descriptionof analgesiaafter electricalstimulationof the mid-brain.The studiesof Akil andHosobuchi comefrom this work.]

BIBLIOGRAPHY

191

Rodgriquez,E. M., et al.,'NeuroendocrineMechanisms' , Frontiers of Hormone Research;CerebrospinalFluid and Peptide Hormones, Karger, Basel, 142-58, 1980. [A descriptionof the paradoxicalADH effect:rats were givenanti-diuretichormoneinto the ventricle and lost waterinsteadof retainingit. The Dandyparadigmwouldpredict that ADH placedinto the ventriclewouldbe carriedfirst out of the brainand then into the bloodstream.This article showsthat doesn'thappen.l Rogers, G. Brother Surgeons,Dymock's, Sydney, L957. [This book describesthe differencesbetween two brothers: John and William Hunter. William, the elder, had all the qualitiesof someonewho is left-brain dominantwhile John,a dyslexic,was clearly driven by his right brain.l Rolleston,H. D., TheEndocrine Organs in Health and Disease,Oxford University Press, 1936. [This hard-to-getbook is scholarshipat its best.This wasthe modelfor my book.l Rose,S., TheConsciousBrain, WeidenfeldandNicolson,London,L973. 'soft' scientist [If Ornstein'sbookis the best bookwritten by a about the brain,this is the best popularbookwritten by a 'hard' scientist.l Roth,1., €t al.,'The EvolutionaryOriginsof Hormones',Neu England Journal of Medicine, 306, 523, L982. [To summarrzethis article: every hormonecanbe madeeverywhereand,it would seem,by every kind of creature.l 'Intact Cerebral Rosenstein, Ventricleas a site for J. andBrighttrlan,M., Tissue Transplantatior',Nature, 275, 83-S, LgTg. tfu early and importantarticle aboutbrain transplantation.l Russell,Bertrand, A History of WesternPhilosophy,London,1946. tA well-written,well-illustratedclassiccontainingthe best descriptionof the PlatonicbodiesI haveread.J Sartan,G., Galen of Perganon, University of KansasPress,Lawrence, 1954.[This bookoutlinesthe chicaneryof Galenandhis mid-lifeswitch from 'scientist' to 'writer'. Readingit makesme believe many will comparemy similarswitchto Galen's.l Scharrer,E. andScharrer,B., Neuroendocrinologjt,Columbia University Press,New York, 1963.[The Scharrers,a husbandandwife scientifit team, outline in this bookthe fundamentalprinciplesof neuroendocrinology.J Schleiden,M. J., 'Beitrage zur Phytogenesis', Muller's Archives,1838. [This is the first descriptionof planf cells.] Schrodinger,E., Whatis Lifel, CambridgeUniversityPress,Cambridge, L967.[This famousbookcontainsthe theoretical'catin a box' experiment whichlinks the stuff of thoughtto the stuff of matter.l Schwann,T., 'MicroscopicalResearchon the Similarityin Stiucture and Growth of Animalsand Plants',Muller's Archives,1839. [The first descriptionof.animal cells.l Seelig,K., AlbertEinstein,EuropaVerlag,Zurich,1954.[Fromthis,one important Einsteinquote:'I maintainthat cosmicreligiousnessis the strongestandmost nobledriving force of scientificresearch.Only the man [sic] who canconceivethe giganticeffort andaboveall the devotion, without which original scientific thought cannot succeed,can measurethe strengthof feelingfrom which alonesuchwork. . . can

192

THE FABRICOF MIND

grow. Whata deepbeliefin the intelligenceof Creationandwhat longing for understanding,even if only of a meagre reflection in the revealedintelligenceof this world, must haveflourishedin Kepler and Newton,enablingthem aslonelymento unraveloveryearsof work the mechanismof celestialmechanics... Onlythe man[slcl who devoteshis life to suchgoalshasa living conceptionof what inspiredthesemenand gavethem strength to remainsteadfastin their aimsin spite of countlessfailures.It is cosmicreligiousnessthat bestowssuchstrength.A contemporaryhassaid,not unrightly,that the seriousresearchscholar in our generallymaterialistic age is the only deeply religious human being.'] Selverstone,8., 'Studiesof CerebrospinalFluid lin humans]usingRadioactive Tracers', Ciba Symfosium, London, L47-67, 1958. [In this, Selverstoneshowsthat a radioactivetracer placedin the ventricle is found almost instantly in the bloodstreambut doesnot appearin the cisternafor flfteen minutes.This is incompatiblewith the Dandyparadigm for brain water.l Shealy,N., et al.,'Dorsal ColumnElectroanalgesia', Journal of Neurotechnisurgery,32,560-4,1970.[The first descriptionof a space-age quethat wasthe outgrowthof the 'gate control' theory.I Sherrington,C., The Integratiae Action of the NeraousSystem,Yale University Press,New Haven,1m6. [Here Sherringtonsets in place 'hard-wired'view of an electricallydriven brain.l the essentialsof the Siegel,R. E., GalenbSysfemof Physiologjtand Medicine,Karger,Basel, 1968. Singer,C., Golenon Anatomical Procedures,Odord University Press, London,1956,andFrom Magic to Science,Benn,London, L928.[Both containdescriptionsof Galen'sprodigiousworks andwritings.J R. \il., 'Perceptionin the Absenceof NeocorticalCommissures', Sperry, in Perceptionand its Disorders,The Annual ResearchPublicationof the Associationfor Researchin NervousandMental Disease,Vol. 48, 'savant'on the left 1970. [As Sperrytaught us, we havetwo brains:a 'mystic' on the right, imbuedwith a priori who readsandwrites anda knowledge,who dreams.l 'The Divisionof the SensoryRootof Spilhr, W. G. andFrazier,C. H., lhe Trigeminus for the Relief of Tic Douloureaux,Philadelphia Medical Journal, 8, 1039- 49, 1901. [All surgicalprocedureswhich divide nervesin the nameof painrelief grow from this publication.l 'Endocrineurology',in Humoral Control of Growth and Strand, F., Dtferentiation, AcademicPress, 1973. [Many will quarrel with my 'neuroendocrinology' and'endocrineneurology'.Fleur separationof Strandsaidso first.l 'Neuropeptides: Their Distributionin the Brain', Progress Swaab,D. F., in Brain Research,55, 97-L22, L982. [The title contains the summary,yet in this rapidly changingfield eventhis recent article is now out of date.l 'Treatmentof Pain by (percutaneous) Sweet,W. H. and Wepsic,J. G., Stimulation?' , Traisactions of the American Neurological Associathat led to the useof tion, 93,103-7, 1968.[It wasthis observation percutaneous nerve stimulationin the treatmentof pain.Sweetknows more aboutpain than anyoneI know and supportsthe notion that we

BIBLIOGRAPHY

193

will treat it effectivelyonlywhenwe knowmoreaboutbrainendocrinology.I Tache, Y., et al., 'CNS Mediated Inhibition of Gastric Secretion by Bombesin',RegulatoryPeptides,3, L05-L2, 1982.[Bombesin,which was first found in frog skin, mysteriouslyquietensthe activity of the stomach.This only occurs,however,if it is placedin the ventricle. Again this demonstrateswhy the ventricle is important to hormonal therapyof the brain.l Tanaka, I. et al., 'Presence of . . . (31-K) . . . Peptides in Human Stomach',Journal of Clinical and EndocrinologicalMetabolism,54, 392-6 1982.llink this to the article of lkuseman which showsCRF, whichreleases31-K, in the gut. Then ask, 'Canthe gut think?'J Tower, D. (ed.), TheNeruousSysfamISvolsJ,RavenPress,New York, 1975.[In the yearthesevolumeswere published,enkephalinwasfound in the brain.Lookingbackat the articlesnow,lessthan a decadelater, most of them seem out of date for there is nothing about brain hormones.] Tsong,S. D., et al., 'ACTH andEndorphinare Presentin Multiple Sitesof the ReproductiveTract', Endocrinologjt,110, 2204-6, L982. [The articles of KrusemanandTanakamakeme wonderif the gut canthink. Wathesdescribesovarianvasopressin, whichalsoreleases31-K. This makesme ask, 'Canthe ovariesthink?'l Vale,\M.,et al., 'The Charaiterwationof CorticotropinReleasingFactor', Science,2L3, L394-7, 1981. [For nearly thirty years icientists searchedfor this substance,now calledCRF. This hasbeendescribed as the 'holy grail' of neuroendocrinology. Wylie Vale, the leaderof the team that foundit, hadearlier workedwith RogerGuilleminon TRF.J Vesalius,Andreas,De Humanis CorporisFabricus, Basel,1543. [This book is the Veda, Torah, Bible and Koran of medicine; its very birthright. There are many good reproductionsof it in bookstores which deserveexamination.Remarkably,the original editions were printed on such good paper that they remain in excellent condition. Harvard's CountwayLibrary has sevenfirst editions of the Fabric of Man; they are protected,but availablefor examination.J Virchow,R., Cellular Pathology,Berlin, 1858.[Virchowis the pathologist who best articulated the 'cellular theory', yet he held on to Schwann'smismemeof the 'network theory' of brain function.] Von NeumatrD, J., TheComputerand theBrain,Yale UniversityPress, New Haven,Connecticutt,1958. [The title articulatesa widely held comparison,still honouredin most academicbastions.This simplistic comparisonI eschew:the brain is more like a glandthan a computer.l 'W., Wade,N. and Broad, Betrayersof the Truth, Simonand Schuster, New York, 1983. [Tales of 'falsifications'in the laboratory,some of whichI haveseenfirst hand.l Wathes,D. C., et al., 'Neurohypophyseal Hormonesin HumanOvaty', Lancet,2,410-L2,L982.[Link thisto Tsong'sarticleto knowthat tire combinationof moleculesthat the brain employsto 'think' is foundin the ovary.]

194

THE FABRICOF MIND

'MolecularStructureof NucleicAcids', Watsotr,J. D. andCrick,F. H. C., Nature, L7L,737-8, 1953.[In Medawar'sbook,Pluto'sRepublic,this one-pagepublicationis describedas the most important scientific paperof the twentieth century.l 'The Absorptionof CerebrospinalFluid into the Venous Weed,L. H., System', ArnericanIournal of Anatorny,3l, 19I-22L, L923.[Thisis 'Paccionnian'granulationsthrough which some a descriptionof the CSFentersthe bloodstream.l 'cybernetics', Wiley,New York, 1948.[Theterm Weiner,J., Cybernetics, comesfrom the Greekword for helmsman.The notionthat reverberating, cyberneticelectricalcurrentsserveasthe helmsmenfor the mind hasbeenin voguefor severaldecades.I 'Experimentsin the Mechanismof Nerve Weiss,P. and Hiscoe,H. B., Growth',tournal of ErperirnentalZoolog!,LA7,315-93, 1948.[This 'axoplasmicflow' - the movementof was the first paper to talk about bulk material downnerve trunks.J Wells,H. G.,Mankind in theMaking,ChapmanandHall,London,1903. [It is clear to all historians,especiallyH. G. Wells,that the dark ages beganduring Galen'stime.l Whitehead,A. N., Scienceand the Modern World,Mentor, New York, the importanceof modelsfor thought in 1948. [This classic'stresses new discoveries.l HodderandStoughton,London,1980. [A splenWilson,C., Starseehers, did bookaboutcosmology.It documentshow long the mismemeof the Platonicbodiesexisted:Keplerin nn 1595concludedthat the relationships between planets correspondedto the relationshipsof the five Platonicbodies.l Wislocki,G. B. and Kng, L. S., 'A Study of the HypophysialVascular Supply',American tournal of Anatoffi!, 58, 421-72, 1936. [This is the classicdescriptionof the 'pituitary portal system'.I Wright, R. D., 'What AustralianPhysiologyOwesto AdolphHitler', Proceedingsof theAustralian PhysiologicalSociety,14, 22-7 , 1983. [Sir DouglasWright writes here aboutFeldberg's'transfer' from England to Australia.I Yates,F. E., et al., 'Potentiationby Vasopressinof CorticotropinRelease Factor', Endocrinologlt,88, 3- 15, Inducedby Corticotropin-Releasing L971. [This is the first of the many articles which confirm that ADH andCRFcometogetherasa 'hormonalharmony'to trigger the release of 31-K. My most recent work in the laboratoryhas focusedon this curioussynergism;plasmaendorphinelevationshave been observed repeatedlyin sheepthat were givenADH andCRF.I

lndex

Numbers in italics indicate illustrations. acetylcholine,70, L40,L4I Aquinas,Thomas,30 ACTH seeadrenocorticotropin addictions,4, L42,L44,148-9 Addison'sdisease,156 ADH seeanti-diuretic hormone adrenalgland, 84, 97,159,171 disorders,84, 156, hormones,101,I4L,149, 189 adrenaline,70, L40, I4L, 144 adrenocorticotropin(ACTH), 105, 140, 141,145,146 Aesculapians,37 ageing,143 seealso senile dementia air injected into brain, 132-3 Akil, Huda,102-3 Alexanderthe Great, 29, 34-5 Alexandria,30, 34-5, 37 anaesthesia,84 Anatomy of an lllness, The (Cousins),

r47 anaesthesiadolorosa,75 angiotensin,L40, l4L, I47 anorexianervosa,148 anti-diuretic hormone (ADH), 106,135, L46, 746,191,194 Apology(Plato), 17, L90 appetite, I47, L70, L82 seealso hunger; satiation,thirst argininevasopressin(AVP), 4, L40, L4L Aristotle, 16, 25,29-34, 108,139,181 on arteries,29, 34-5,38, 63, 65, 135 on the brain, 39 paradigm,31-4, 45 p n e u m a3, 1 ,3 2 , 4 0 ,4 2 , 4 4 , 6 0 ,1 3 3

quintessence, 30-1, 32,39, 40, 45,65 arteries,29,34-5, 63, 65, 135 air as contents,31-2, 34, 35, 38, 41 blood,39-40, 41,43 carotid, 37 -8. Vesalius'sdiagram,52 seealsobloodcirculation arthritis , L43 asthma,143 AVP seeargininevasopressin Axelrod, Julius, 74 axonaltransport, 90, 114 axonalflow, retrograde, 180 axoplasmicflow , L94 behaviourand hormones,4, 5, LL2,1367, I42, L44,153,163,194 Benson,Herbert, 158 Berger, Hans,71 Bernard,Claude,60, 65-6, 103 Bichat, Xavier, 111 Blackfan,William, 132 blood-brainbarrier, 150-4, 166, L7L-2, 181,189,190 blood arterial, 38-40 , 41,43 circulation,26, 3l-2,34, 46, 52, 53, 54-5,56, 133,143 pressure,143 venous,39, 41 white cells,44 blood tests for hormones,153, 154, 165, L7O,L7L bodyfunctionand hormones,L43,146 bombesin,140,I4L,I48,167,170, 193 bowelsand hormones,I43,I49

196

brain -bodyrelationships, 104-5,LL2-L3, 113,rL4, 775 cells,63-6, 118,119 controlby glands, 86,89-90,92,94, L52 controlof glands,86, 87,91-2,L0L, 104,118,171 functions,136,L52,183, endocrine 185 failure,4 119,158,193 function,28,111, andgonads,LL2-L3 grafts,187 hollow,72-3, t23-5, L26-7,133, 135,136,138-9,154,185,188 2,3, 4,82,90,96,99, hormones, L34,136, 100,104,L07,tLz,1.19, 139,140,L47,L48,t49, L57,162, 166,170,193 hormonalfunctions,86, 87-9, 104 126 andlymphatics, andproductionof semen,26-7, 27, 28 104 releaseof hormones, removingpartsof,,L73 split,L-2, A 9-10,14-15,157-8, 180,L84,L92 structure,L25 'transplant', 188,191 tumours,154 water,73, L23,L26,133,L54,188, L92 wetor dry,23,58,59,73,t02-3, L26,L37 illnesses, brain; seealsoepilepsy; of left brain;right brain;paradigms the brain;ventricles Brain, The(Dandy) , L37 b r a i na sa g l a n d2, - 3 , 4 , 6 , 2 7 , 3 9 , 4 5 , 95, 65-6,74,76,80,81-2,87-93, r74,L76, 99,100,101,1L7,L20,155, 180 Hinsey'smeme,86 150-2 lackscapillaries, axis,L49,L7L brain/pituitary/adrenal breast,9I Brown,Robert,64 Ramony, 60,65-6, 67, Cajal,Santiago 68, 68 69 permeable, L50-2, 151 capillaries, catecholamines , L49

THE FABRICOF MIND catheters in the brain, 18 65-6, 153-6, 755, 161,163,164-5, L67,L70-L,172-3 in the heart, 157 CAT scan,I54, 155,L57,165,170 CCK seecholecystokinen cellular theory of brain function, 111,193 cells brain, 64-5,66, 67, 118 continuousproduction,118 and disease,64 glandular,118 nerve, 180, 190 network theory, 66-7 Schwann,66-7 , 67,184,191 structure, 64, 66-7, 67 transplantation,168 cerebrospinalfluid (CSF),194 cholecystokinen(CCK), 4, 76, 140, L[L, 147,r70,L82 choroid plexis, L23, 724,L28, 129, 130, 131,181 function,133, 189 removal,L29,130,133,182,188 chronic infusion pumps,L67-8, 1.67 church,the, 26, 46, 54, L84 circularmovement,25-6,30, 45, 46 circulation,46, 133 brain water, 125-31,133 lymph, 125-6, 133 second,125-6 seealsoblood,circulation Clarke,Arthur C., L74, L75 cloning, 116 Coghlan,John, 117 computer,brain as a, L, 2, 3, 5, 6, 7L, 80, 193 seealsobrain,wet or dry; electricity Copernicus,26,174 cortical map, 182 corticotropin releasingfactor (CRF), 4, 194 104,105,L07,L87,193, corticotropin releasinghormone,140, L4L,145,194 cortisol,I49,I7L-2 Cousins,Normafr,4, L47, L59 CRF seecorticotropin releasingfactor Crick, Francis,15 cupping,39, 44, 45 Cushing,Harvey,69, 83, 84-6, 89, 126, 131,133,136,L79,181,r82,L84 Cushing'sdisease,84, 156 cyberneticcurrents, 71

INDEX cybernetics,194 Dale, Sir Henry, 60, 70-L,I82 Dale'slaw,70 Dandy,Walter, 72-3, L23-4, 126-33 experiments,L26-7, 727,131-3, 182 Darwin, Charles,29 da Vinci, Leonardo,L8,20,22 on brainfunction,26, 27 drawings of ventricles, 18,124,125 Dawkins,Richard,T, 46 De Bono,Edward, 55 decadron,149, 171 delirium, 181 depression,5, L42, L44, L49, L7L Descartes,Rene,61, 62,L07,108,113, L 2 5 , 1 3 91, 9 2 diabetes, L47,156, 165 digestion,143 disease,and four humours, 40 seealso illnesses DNA, 15, 116-17 dodecahedron, 72,L4,16,31, 33 dopamine,70,140,141 dorsalcolumnstimulator,79-80 dwarfism,84, 156 dynorphin, 149 dyslexia,18,19, 83-4, 188,190,191 Eastern views of the mind, 5, 108, LzL, 149-50,155 ECT seeelectroconvulsivetherapy Einstein, 59, I9L-2 electrical counterstimulation,79, 90 electricity animal,60, 61-3 brain,59, 63- 4, 65,67,68-9,70,72, 73, 97, 90, 92, 106-7,109,LL7,L20 experiments,60-1 and glands,106 and muscle,43, 61, 63, 69 and nerves,68-71 as stuffof thought,2,3, 5, 59, 67, 6 9 , 7 r , 7 2 - 3 , 9 0 - 1 ,9 2 , 9 5 , 1 9 3 electroconvulsivetherapy (ECT), 72, L7L-2,L73 (EEG), 7L-2, L7g electroencephelograph electronmicroscop€, 7L-2, 139, 146 elements,the four, L2-I3, 73,L6,30,32, 3 8 ,4 0 ,4 2 , 5 9 Empedocles, 11-13,L4,L6,28,30, 38 endocrineglands,84, 185 disorders,156,171 endocrineneurology,86, 94, 150-2, 161

197 endocrinesystem,106-7, LLL,136,150, L82 and depression,149 and brain,L52,183,185 diseases,171 endocrinology,19, 83 brain,180,184,193 and gate-control theory,l0I-2 endorphin,76, 100, 101,104,140, 141, 149,L49,L67,L72,190,191,194,195, 186, L87, Lg4 enkephalin,76, 95, 98-100, 101,104, 140,L41,145,149,149,Lg4,rg7, 1gg, 190,193 met-, 98, 99 100 leu_,98, 99 epilepsysurgery, L72-3, 181 Erasistratus,34, 39, 42, tI} Erlanger,Joseph,TL Fabricius,183 Fabric of Man, The (Vesalius),47-55, 48-53 falsification,2I, L32,190, 193 seealso intellectual institutions: truth fear,I42,I44, L49 feedbackcontrol, 185 Feldberg,Wilhelm, 70, L82, L94 fever, 181 Feytrer, Friedrich, 112 50-K, 101, 103,Lgg Florey, Howard,20 Forssmann,Dr,I57 Franklin, Benjamin,59, 60, 61 Freud, Sigmund,60, 66 Galen,Claudius,14, 94,37, 45, 47,54, 61,113,133,135,139,191,194,1gg, 191 on brain, 4L, 42, 45,L37 on heart, 4L,137-8 on liver , 4I-2, L37 on pituitary, 44 study of blood, 37 -40, 151 Galileo,26,I74 Galvani,Luigi, 60-1, 62, 63,69,70,I5, 103,139 Gasser,Herb, 60,7L gastric system,143, 149 gastrin, 140, I4I,I70 gel electrophoresis,two dimensional, r34, 134,153,165-6, 170

THE FABRICOF MIND

198 genes,7,46 and brain cells, 118 brain control of, 116-17,183 geneticengineers,166, 168 genetic manipulation,168 genetics,20, 116-17,185 genius,61, 85 Geschwind,Norman, 158 gigantism,84, 85,L26, 156 glands and electricity, 1.06 transplantation,83, 84, 168-8, 769, 185 seealsoendocrinesystem; hormones; namesof individual glands Godel,Escherand Bach (Hofstadter), 7, 186 Goldstein,Avram,97 Golgi, Camillo, 60, 66-7 gonadotropinreleasinghormone,140, 141,148 gonads,112-13,141 group mentality, 10, 15-16 growth hormone,85, 99,L26, 140, 141 Guillemin,Roger, 90, 112,185 gut, 9I, 105, 106, 107, 193 hormones,141,t47 ,I49, L70,183, 187,193 happinessandhormones,4, L22,L42, r47,153,159 Halsted,William, 83, 84, 85, 86,126-7 Harris, Geoffrey, 86, 90-1, 95, 105, Ll4 Harvey, William, 34,54-5, 56,t26,138, 183,185 healing,I47,158, 159 seealso illness,'brain;joy; patient care; therapy, and electric brain paradigm heart, 31, 138,157 and blood,Sl-2, 40 hollow, 185 and lymph, 125 as organ of thought, 32-3 see alsobloodcirculation; HarveY, William Hinsey,Joe, 86, 90, 95, 104,105,114 Hippasus,14 Hippocrates,t4, 28, 36, 44 Hofstadter,Douglas,7, 186 holism,5,77,81, 85-6, 93, 96, 108-9, r2L,136,155,176,183 see alsoreductionism,scientific

hormonalamplification,cascading, 150-1 hormonaldeamplification,152, 153 hormones,2, 3, 4,80, 140-6, 191 and behaviour,4, 5, llz, 136-7, I42, r44,153,163,184 body regulation,143,146 brain,2, 3, 82, 96, 99, 100,I04, r07, rr2, 134,136,139,140, r47 , 148,149,157,t62,166, 170,193 into brain,150-4, 183,187 control of mind, 83 deficiency,151,155-6 excess,155-6 function,I12,118, 150 4, I22, L42,147,153, of happiness, 159 and health, 2, I44, I45, 146-7 of hibernation,158-160 andpain,T6-7,I04 production,85, 99-100, 101,104-6, 106 pulsatile secretion,118 receptors,76-7, 93, 96-7, 104, 109,150 receptor blockers,96 regulating, 111,117,118 sites production,140-1, 190 structure, 89-90, 98-9 synthetic, 134 and thinking, 2, 5, 92, IL7, L74 testing,L5I-2,153, L54,165,L70, L7L see alsobrain as a gland; catheters in the brain; endocrinesystem; names of individualhormones(names listed 140-1) and glands;peptides; pituitary gland;ventricles Horsley, Victor, 66 Hughes,John,98 humours,the four, 13-14, 13,39-40, 42, 45, 135,139 hunger,I42,I44,I47-8 see alsoappetite;satiation;thirst Hunter,John,18-19,20,22,83, 84-6, L12,120-1,125-6, L79,188,191 Hunter, William, t25-6, 191 Huxley, T. H., 6 hybridizationhistochemistry,LI7, 139, 146 hydrocephalus,I27 , 727,L28-9,133,

r82 treatment,128-30, 135,154,188

INDEX hypercalcemia,156 hypersecretion,155-6 hypertension,147 seealso blood pressure hypocalcemia,156 hypogonadism,187 hyposecretion,155-6 hypothalamus,105, 185 hypothyroidism,156 idea-chord,7 illness,L44,145, L46-7 seealso epilepsy illness,brain,2-3,66, 69, 154-65,L57, 162-3, 170-3, 175,176 diagnosing,153-6, t60-7 and hormones,166, 168 treatment,2-3, 60, 66, 69, 72, 150,156 seealso epilepsy;healing; hydrocephalus;patient care immunity, 143 immunohistochemistry,139, 146, 181 impotence,148 infectious diseases,19, 83 infundibulum,126 insomnia,148 insulin,3, IL7,118, 140, t4L, I47 , L52, 165,L67,t70 insulinoma,156 intellectualinstitutions,5-6, L6, 20,2I, 35, 131-2,L93 seealso falsification; truth intuitive thought, 1 Jackson,HughliDgs,60, 66 joy andhormones,4, L22,L42,L44,L47, 153,159 Keith, Sir Arthur, 85 Kekule, August, 15 Koestler,Arthur, 85, 109 Kosterlitz, Hans, 98 Kuhn,Thomas,7 ,9, 20, 64,93 Lashley,Karl, 106 lateral thinking, 55-6, lg0 learning, t, 4,105, 146 seealsomemory;thought left brair, 1, 3, 9-10, 15-16, 18, 108, 191, 192 left-handedness,157-8, 185 Li, c. H., gg

lipotropin, 99-1A0, 700,L40,I4L, L87 liver, Galen on,4L-2 lobotomy,60, 70, 189 Loewi, Otto, 69, 70 lumbar spinalfluid, 153, I54,170 lymphatics,125-6 Marie, Pierre, 126 mechanismsof the mind: intracellular molecularevents,108-9 seealso brain as a gland; electricity; thought meditation,5, 149-50, 158 melanotropinstimulating hormone (MSH), 105, L40, l4L, 146 Melzack,Ronald,77 memes,7,L82 and culture, 7, 46 seealso mismemes;paradigmsof the brain memory, 105-6 , L82 andECT,I72 Galenon, 125 holographic,105-6, 187 and hormones,4, 105- 6, I42, L44, L46-7, 166,169,L70,Lg7 loss,4, t64-6 nature of, 120-1 site of, 187 seealso senile dementia Mendel,20 meningitis,127, 129, 730 messagesfrom the brain, 42,150-1 seealso molecular paths Mettler, Fred, 83 microtomes, 64 Milhorat, 136 mismemes,7, L82 Aristotle's,29, 34-5,38, 135,186 Dandy's, L25,L32-4,135-6,137 Golgi's,185 Plato, 26-7 Pythagoreans,13-14, L6, 25 Schwann's,63-5, 66 seealso paradigmsof the brain model verification by right brain, 15-16, 46 molecularpaths,2,90-1, 103,108-9, 113,Ll4,L20 Moniz,Egas,59, 60, 72,73 Morris, Howard, 98 Mostofi, Baghir, 159-60 MSH seemelanotropinstimulating hormone

THE FABRICOF MIND muscarinicneurophysin,140, 141,145 muscles, 42, 43, 43,61,116-17 naloxone,95, 96-7 , 96,102-3 nerve growth factor, LL4, 115 nerves,61 cutting,77,79 electrical impulses,60 fibres, 7L-2, 72 and gate-control theory, 77 -80 histology, 60 networks, 60 synapses,60, 64, 65, 68, 69-70, 74, r82 nervoussystem,34, 42,5I, 68, 111 network theory of brain function,63-6, 193 Neural Control of the Pituitary, The (Harris),9I, 97 83, 86, 87, 88-9, neuroendocrinology, 90-1, 97,93,105,113,rL4,r50-2, 180,184,186,188,191,193 neurology developmentof, 60, 66, 69 experimental,20, 68 neurones,turnover of, 118 neurosurgery, 68, 69, 7L,I32,133,135, 160,183,189 of, 60, 66,72,84, 184 development shunts,L29-3I, 135, 170 neurotensin,76, L40,I4L, t45 60, 70-2, 74, 90 neurotransmission, neurotransmitters,70, 74 new ideas,1, 6, 7, 10-11,15-16,L7, 64, 85, 125,L87 seealso questions;truth nicotinic neurophysin,140, t4L, L45 NMR scan,I54,L70 noradrenaline,70, L4I, I44 obesity,L43,I70 O'Brien,Charles,84-5, L79 observation,29, 30, 31 seealsofalsification;questions On the Motion of the Heart and Blood (Harvey), 54-5 opium,I04,172 in the brain,95, 96-8, 103,104 opiate,95, 102-3, 172, I84 addiction,148-9 blockers,96, !n,I03 in brain,96-8, 100,148-9, I79, 186,187,190

hormones,148 overdoseand hormones,I42, L44 receptors,96-7 , %,101, 148 receptorsin vas deferens,97 -8, 148 seealso endorphin;enkephalin orgasmandhormones,I42,144,148, 153 ovary,86, 90, 97,I05,106,L07,118, 185,193 oxytocin, 89 Paccioniangranulations, L23-94 pain,78,L92-3 chronic, 78 and electrical counterstimulation, 79, 186 gate-control theory, 77 -80, I0I-2 and hormones,L42,L43,L44,145, 150,159 and mid-brainstimulation,102-3, 190 operationsfor, 74-7 ,192 and opiates,96-8 pathway, 76 painkillers, 96-8 , L0L-2 producedby brain, 95, 96-8, 103, 104 seealso opiates;opium pancreas,117,156 paracrinesystem,111,LL4,LL7,118, Lzl, 139,158,183,190 paradigms developingnew, 10-11,15-16, 17, 64 maintaining,20, 35,38-9, 44, 46, 63, 66, 93 first scientific,10-11,13 seealso new ideas paradigmsof the brain,1-6 passirn,79, 45 Aristotle's,39, 45 cellulartheory, 111,193 as a computer,1, 2,3,5, 6, 71,80, 193 Dandy's, 123-4, 724,128-33, I34, 135,181,L82,188,189,191,192 electric, 2, 3, 5, 28, 59, 67, 7L,73, 77,79-80, 81, 87,107-8,113,120, L26,L28,136,175, 180,192 Galen's , 42,45-6 Harris's,9I, 97 Hippocrates's,28 Hunter's,125-6

INDEX

201

Leonardo's,26,27 Plato,L6,17, 25-6, 29, 30,38, 59, L07, network theory, 63-8 139 neurological,68-73 on the brain, 25, 26-7 , 176 Plato's,26-7,45, 180 Platonicbodies,11-14,72, 73,25,59, Schwann's,63-4, 193 194 Wislocki's,87-8, 88 140 pneuma,31,32, 40, 42, 44,60 parathyroids,156 Popa,Gregory, 86-7, 90 patientcare, 5, 74, 160-4, 172-3, LT5, portal vessels,87 189 posterior fossa,183 seeolso scientists/physiciansschism pro-hormones,100-1, 188, 189 patterns,14-15, 109 prolaction,99, L40, L4L,I45, 149,150 and new thought, 15, 20, 8b-6 preseniledementia,164, 166 recognition,14-15, 109 psychiatry,60, 66, 69, 180 and right brain, 1, 3, 14-15, 23, 28, pulsatile secretion,118 46, 95, 109 Pythagoras,10-IL, 72,16,30, 37 and senseof beauty, 56-7 Pythagoreans,10-14, 15-16, 29 seealsoright brain peaceand hormones,142, L44,149-50 questions Pearse,A. G. 8., Llz importanceof, 16, 17-18,20,2I, peptidehormones,3, 74,88,98, 152,190 22,35,39,61, 120-1,132,190 brain, 98-9, 185 storing,22 memory,3,L82 seealso new ideas: paradigms regulatory, 16 quintessence, 30-1, 32,39,40, 45, 65 peroxidase,horseradish,LL4, 775,Lgl, 183,lgg radioimmuneassay,165 phlegm,43-4 rage and hormones,L42,144, L49 physicianssespatient care; scientists/ Ray, Bronson,92 physiciansschism reductionism,scientific, t, 5, 45, 69, TT, physics,119-20 81, 95, 109,109,t2L,135-6, 155,176 pinealgland;t07,108, 125,139 reflex ovulation, 86, 90 pituitary gland,2L-3, 27, 69,84, 97,92, Relaration Response,The (Benson),158 126,169,L7L,192,196 religion,5,26,30, 45, 109,LgL-z anterior, 86, 91 reproduction,143 and brain,86-7, 88-91, L04,113-14, retrograde transport pathways,114 172,197 right brain, 1, 3, 10, 14-15, 18, 23, 4G, disorders,156 57, 108, 176,193,191,192 few veins, 92 andnew ideas,1, 15,L8,20,176 Galen on,44 seeal,sonew ideas:patterns and growth, 84-5, L26 RNA, 116-17 Harris's paradigm,9L,97 Roth, Jesse,116,117 hormones,85, 99-100, 101,10b, l4L, L4g,L7l-2,190,197 salivary glands,tL4, 115,I87 Hunter's paradigm,L25-6 satiation,L42, I44, L48 nerveless,86 Scharrer, Ernst and Berta, 90, 114 portal system,87, 88,190,lg4 schizophrenia,4, L70, I7L rhesusmonkey's,23, 180 Schleiden,Mathius, 64 stalk,179 Schrodinger,Ervin, LL9-20, IzL and third ventricle, 126 Schwann,Theodore,60, 63- 4, Go tumoursof, 85,126,I79 cells,66-7, 67, 69,7L vascularswitchyard, 87, 88, 89 on nerve connections,63-b, 65,GG Wislocki'sparadigm,113 scientists/physicians schism,3-4, b, Og, seealso gigantism; paradigmsof the 74, 90, r37, L62,t7 5, 17g, 192,lgg brain SelfishGene,The (Dawkins), Z

THEFABRICOF MIND

2A2 seniledementra,L46-7, I54, 156,166, L70 senility, 5 serotonin,70,140,141 Servetus,Michael, 26, 54, L84 sexual function, L43 Sherrington,Charles,20, 60, 67-9 shunt procedures,129-31,135, 170 skin rashes,143 sleep,L42, L43,I44, L48 Smythe,Derek, 99-100 Socrates,17-18,19, 20, 25, 28,35 somatostatin,76, t40, L4L,170 sorrow, L42, L44, L47 soul,32,40-I,45,60, 61,125,138 Sperry, Roger, 10, 15, 180, L84,L92 spinalcord, 181 surgicalremoval,75-T steroid hormones,152 Structure of ScientificReaolutions,The (Kuhn),7,64 sub-arachnoidspace,L23 substanceP, 76,L40,L4L,145,150 suicide,I42,L44,I49 surgery, 19, 84 60, 64, 65, 68, 69, 70,74,I82 synapses, Szentagothai, Janos,112-13,114 tears, 147 TENS, 79, 80 testes, 97,Llz, L50 and brain, Il2-13 testosterone,158, 185 therapy and electric brain paradigm,60, 6 6 , 7 2 , 7 4 , 7 ,78 0 , 8 1 third ventriculostomy, I29, 129,L33 thirst, L42,t44,L47 31-K,95, 100-L,702,104,105-6, 106, L07,140,L4L,L87,188,L92,L94 thought hormonesand specifickinds,L07, L87 locationof, 105-6, 187,193 and matter, 119,191 natureof, 1, 5,6-7 ,183,193 pneumatic,29,32,38 shapingof, 107,113 stuff of, 2, 3, 5, 29, 58,118,179, 186,191 seealsoelectricity;hormones;left brain; memory; patterns;right brain thyroid gland, 97,L40, t56

thyrotropin releasingfactor (TRF), 185, 193 transcutaneouselectricalnerve stimulator,T9 transversemyelitis, 7 5-7 TRF seethyrotropin releasingfactor trigeminal neur algia,76 truth, 1, 6, 9, 16,20-2, 28,35, 44, 46, L32,176,190 unifiedfield theory, 59 unifying force, 120-1 vagusnerve, 183 vasoactiveintestinalpeptide,76, 140, 141 76, 88-9, 104,105,I07, vasopressin, 135, 140, 14r, r44, t45, L46, r48, 167, 193 veins, 39, 41,53 ventriclesof the brain, 724,L25,181,189 in brain function,61, 62,L54,L61 cathetersin, I8 65-6, 153-6, 755, 161,163,164-5, L67,r70-r,L72-3 Cushing'sexperiments,89-90 Dandy'sparadigm,123-5, 724, 128-33,L34,135,189 functions,125-6,L34,136, 154 hormonesin, 3, 136,148,153,I70, 188,193 and hydrocephalus,127, 727 imagesof, 18, 78,79,124,125 and lymphatics,126 peptidesin, 134 radioisotopesin, 135 170 and schizophrenia, water in, I23, 724,125-31 water-flowpathways,123 ventricular catheterizations,153-6, 155, 161,163 Vesalius,Andrea,42, 47-55, 48-53,57, 61,62,L25,181,183,186,189,193 du Vigneaud,Vincent, 88-9, 105,114 Virchow, Rudolph,64, 65, 67 -8, 116 Volta, Allessandro,60, 63 Wall, Patrick, TT Watson,James,15 Weiner, Norbert, 71 Wislocki,George,86-9, 92, 105,113,

tr4