28424ournal ofNeurology, , and 1995;58:284-292

SPECIAL LECTURE J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from

Psychiatry and neuropathology: the maturing of a relationship

W A Lishman

I am grateful for the invitation to deliver this work of Kraepelin at the turn of the present third David Oppenheimer lecture. It presents century. an opportunity to explore the relationships The third is "inquirie which is made by between the disciplines of psychiatry and Anatomie.... And as for the footesteps of neuropathology, and also of course to con- , and their devastations of the inward sider , which is closely related to parts ... they ought to have beene exactly both. observed by multitude of Anatomies." Bacon, And I am pleased that the lecture is in is referring, of course, to the need for clinico- honour of the memory of David pathological correlations-one of the main Oppenheimer, who introduced me to the spurs to neurology's progress but, as we shall mysteries of neuropathology when I worked see, a less straightforward issue for psychiatry. in neurology in Oxford some 35 years ago. The fourth area points directly towards Later at the Maudsley Hospital and Institute what we would today call social psychiatry: of Psychiatry I met Peter Daniels and Sabina "Humane Philosophy or Humanitie . . . hath Strich, David's predecessors at Oxford. The two parts. The one considereth Man segre- Maudsley Hospital had valued neuro- gate, or distributively: The other congregate from the time it was founded. or in societie". This brings us to the central theme of It was almost a century after this was writ- my talk, and the conundrum with which ten that responsibility for the care of the psychiatry has wrestled for the past two insane passed finally into medical hands. centuries or more-the complex, tantalising, Before this theologians and philosophers had relationship between disorders of the mind had most to say about mental illness, and and identifiable disorder of the , in effect mystical conceptions had been dominant- the relationship between psychiatry and some sufferers were esteemed and venerated,

neuropathology. others persecuted as demoniacally possessed. http://jnnp.bmj.com/ The medical profession then began to hazard an interest. Its early formulations were often Historical development bizarre and naive, sometimes focusing on the Some regard history as a rather sterile exer- brain but just as often on the uterus or gas- cise where science is concerned. But without trointestinal tract. Psychological causes also a glance at the past it is hard to appreciate the came to be championed by way of disturbed richness of the present day scene. It may emotions or "passions". In this manner the therefore be useful to sketch in something of stage was set for the great divisions of opinion on October 2, 2021 by guest. Protected copyright. the evolution of the current status quo. which have characterised psychiatry ever We start with a remarkable man who was since. Psychiatry's muddles and uncertainties not involved with himself-Francis were still rife in the 19th century, when they Bacon, philosopher and Lord Chancellor of stood in sharp contrast to the evolving disci- England. What he wrote about mental dis- pline of neurology. Neurology and knowledge orders in 16051 is more astonishing each time of the brain grew up hand in hand together. we read it. In effect he set out detailed pre- Each advance in the understanding of brain scriptions for research which were to unfold anatomy and physiology led to applications in slowly over the next 350 years. He recom- the clinical field, with clinical observation mended four lines of enquiry, each of which feeding constantly back to refine understand- has borne fruit in different ways: the first, to ing of the brain. And neurology's ally from Institute of consider "the Seates, and Domiciles which the start was neuropathology. Abercrombie's Psychiatry, De the severall faculties of the minde doe take work in 18282 rested on clinicopathological Crespigny Park, and occupate in the Organs of the bodie" correlations on a large series of carefully stud- London SE5 8AF, UK ied cases. Here was the start of a more W A Lishman, Emeritus began with phrenology some 200 years later, Professor of and has continued as the cornerstone of rewarding set of enterprises than confronted . research in . those, such as John Haslam at Bethlem, who The third David His second "to set downe a Narrative of were looking to brain pathology for clarifying Oppenheimer Lecture, the speciall cases of his patientes, and how mental illness. The more that was learned delivered at the Radcliffe Infirmary, Oxford, they proceeded" forms the basis of psychiatric about the nervous system, the more could 17 June 1994. nosology, which reached its height with the neurological illnesses be explained. The Psychiatry and neuropathology: the maturing ofa relationship 285

closer neurological manifestations could be sis. Here was a conspicuous and common J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from delineated, the greater the impetus for patho- mental disorder with, at last, a firm pathologi- logical examination of the brain after death. cal basis. Pick's and Alzheimer's diseases Psychiatry watched from the sidelines and were to follow later under the influence of envied this success. But its attempts to follow such an approach. But this left the great suit were bedevilled by errors and false starts. mass of other psychiatric illness-the major One of the more remarkable was the upsurge psychoses, the neuroses, and the personality of phrenology from the teaching of Gall and disorders-still far removed from a neuro- his disciples. Franz Joseph Gall was a talented pathological explanation. neuroanatomist who made major discoveries And here it was that the pendulum took a for his time. But in addition he made far- massive swing. As a curious and fascinating fetched claims which caught the public imagi- consequence of the earlier debates between nation. He insisted that the mind could be Charcot and Bernheim, dynamic psychiatry analysed into independent faculties, each with was born. The young visited its seat in the cortex, and-the fatal flaw- both contestants and decided firmly in favour that the size of each "cerebral organ" of psychological systems of explanation. He matched its functional capacity and could be commenced his own studies of hysteria and determined by inspecting the contours of the developed his own astounding edifice of skull. Gall's system challenged the prevalent psychodynamic theory. A new model of the notion of holistic brain function and provided mind, no less, was born, with entirely new a powerful impetus to neurology, but when systems of explanation for mental illness. venturing into the psychological field it over- From that point onwards a dichotomy was reached and discredited itself. established and was to become deeply Another reverse followed later in the cen- entrenched. As we entered the 20th century, tury when Charcot began his studies of hyste- "mind science" was pitted against "brain ria at the Salpetriere. He developed theories science" as the way forward for clarifying of hysteria and of hypnotism which postu- mental derangement. The schism has lated disordered cerebral function. To plagued us (and in some ways benefited us) Charcot the stages of hypnotism were the ever since. outward signs, reflecting physiological changes in the nervous system indicative of hysteria. A clash of opinion followed when The schism Liebeault and Bernheim claimed the converse I do want to emphasise that this division of view-that psychological factors were responsi- opinion has had beneficial as well as adverse ble for the induction of hypnosis, and that the influences. It has broadened the outlook of "aptitude to transform an idea into an act" psychiatry in very important ways. To have was possessed, not by hysterics alone, but by aped neurology too closely would have everyone in varying degree. The second view impeded progress disastrously. Psychiatry, by of course prevailed. A psychological concep- standing back from the brain and the neuro- tion won over a physiological model of a sciences for a while, recruited to its ranks complex mental phenomenon. those who concentrated on other methods

Throughout the 19th century, neverthe- for understanding mental illness. Psycho- http://jnnp.bmj.com/ less, psychiatrists continued to look towards dynamics, although often claiming more neuropathology. The main focus of activity than its just deserts, has enriched our know- passed to Germany, where psychiatrists of ledge enormously. Developments in clinical this period were almost without exception psychology, in particular learning theory, good neurologists and neuropathologists. The have brought new approaches to treatment in formidable figure of Wilhelm Griesinger in the fields of depression and the neuroses. Berlin proclaimed that "mental diseases are And the study of social processes has been brain diseases". Before his death in 1868 he rewarding both in theory and in practice. on October 2, 2021 by guest. Protected copyright. had written: "Psychiatry and neuropathology "Mind science" has deserved and amply are not merely two closely related fields; repaid its place in the armamentarium of they are but one field in which only one psychiatry. To have pursued a headlong language is spoken and the same laws rule."3 search for tissue pathology alone would have Heinroth, who held the Chair at Liepzig, eclipsed much that is valuable, particularly in was alarmed at so "somatic" a view-the the treatment domain. richness of mental life was being viewed too The downside of the situation has been the narrowly: "Soul! The great most meaningful split that emerged between neurology and word! The only treasure of man, the very psychiatry. Instead of a close continuing dia- being of the self. How they drag you down logue, with mutual enrichment, during most by making you the slave of the body! Yes, of this century neurologists and psychiatrists they drag you down when they look upon have tended to drift apart. And neuropatho- you as a cadaver which one could cut to logists, not surprisingly, have found their pieces with a knife, or as a chemical com- closest allegiance with neurology. There they pound which could be broken down into have had a central role, an equal partnership elements, or as a mechanical contraption the in unravelling "the footesteps of diseases and workings of which one could calculate with their devastations of the inward parts". mathematics."'4 Neuropathology has often taken the lead in Griesinger's position was reinforced by the the demarcation of neurological enti- success achieved in relation to general pare- ties, in refining their categories, and perform- 286 Lishman

ing the role of arbiter when diagnosis is in research. During the middle part of the cen- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from doubt. tury this came to illuminate behaviour. An Equally unsurprising has been neu- enlarging body of evidence pointed to systems ropathology's disenchantment with psychia- of the brain which dealt with the ground stuff try. It has often not known where to look for of psychiatry-with the regulation of higher the supposed nugget of brain pathology; or it order functions and of emotion. Just as dis- has suspected that the brain malfunction coveries in the previous century had been of must be infinitely diffused. And apart from a benefit to neurology, so now it was found that handful of disorders inherited from the turn discrete brain lesions could affect the control of the century it mostly looked in vain. It of aggression and other complex behaviours. found psychiatric nosology in disarray. Lesions in the hypothalamus and temporal Amorphous and ill defined samples of lobe were found to alter fear and aggression.7 8 patients usually yielded equally amorphous Cingulectomy in monkeys led to inquisitive- findings. The relationship between psychiatry ness, loss of shyness for humans, and loss of and neuropathology has often tended to be "social conscience" in interaction with other one of frustration bordering on despair. monkeys.910 Olds and Milner1' demonstrated centres governing reward and aversion in the hypothalamus and rhinencephalon. On stim- Resurrection ulation these could lead to fruitless repetitive And yet, as with most relationships hope has behaviours similar to those seen with stereo- sprung eternal. And throughout the present typies and compulsions. With certain elec- century there has been a periodic fanning of trode placements these could persist without the flame. satiation. Analogies with obsessive-compul- First we return to general paralysis of the sive disorder and addictive behaviour seemed insane. Early in the century the syphilitic aeti- obvious. Delgado's'2 work was particularly ology of general paresis was decisively proved impressive in demonstrating the close interac- when Noguchi and Moore demonstrated the tion between intracerebral and social-environ- Treponema pallidum within the brain in 1913.5 mental factors in governing behaviour. This ended disputes about the cause of the Radiostimulation of discrete areas of the condition, which are nowadays hard to imag- brain in monkeys could lead to aggressive ine. A relationship between syphilis and threatening displays, but only in certain con- insanity had long been recognised, but until texts namely, when the animal was in an the organism itself was revealed in the brain appropriate hierarchical relationship to its aetiological importance continued to be given immediate peers. Here, then, was work in the to hereditary factors, alcohol consumption, laboratory which mimicked the sophistication and even sexual excess. of psychiatry. In the wake of the first world war there was Throughout all this, neuropsychology grew an explosive "experiment of nature" in the in stature, increasing its yield of relevant form of epidemics of encephalitis lethargica information. The study of brain damaged that swept across Europe. Attacks could be patients was adding to knowledge, not only of accompanied by marked psychiatric distur- cognitive processes, narrowly defined, but of

bances, clearly resulting from brain malfunc- such matters as the neural substrates of emo- http://jnnp.bmj.com/ tion. Conditions resembling the catatonia of tion and of body image disturbances. The schizophrenia, or states of hallucinatory immense importance of the prefrontal cortex excitement and terror, could be observed in relation to key aspects of social functioning from the outset. Among the long term seque- became increasingly clear. lae were numerous phenomena which had In the 1950s and 1960s, with an abrupt- previously been explained in "functional" ness that could scarcely have been predicted, terms-tics, torticollis, compulsions, pro- we saw the upsurge of . found disturbances of will, and far reaching What was striking was the undoubted efficacy on October 2, 2021 by guest. Protected copyright. changes of personality. of drugs, not in the organic psychiatric Thus a great variety of psychopathological domain but in relation to the socalled "func- phenomena could be ascribed to pathological tional" psychiatric disorders. This was changes in the brain, and this focused atten- immensely impressive, both to neurologists tion on the relationship between mental and psychiatrists. Medications could alleviate symptoms and brain structure as never depression, calm mania, even abolish the hal- before. Von Economo wrote in 1929: "just as lucinations of schizophrenia. These disorders, we find it hard today to follow up the trend of too, must surely have a cerebral basis. thought of our scientific predecessors for With this there developed a joint and esca- whom bacteriology and the lore of brain- lating interest, by neurologists and psychia- localisation did not exist, future generations trists alike, in the fundamentals of brain will hardly be able to appreciate our pre- biochemistry. During the past three decades encephalitic neurological and psychiatric con- there has been an explosive advance in under- ceptions, particularly with regard to socalled standing how the brain works at the cellular functional disturbances."6 Unfortunately, level. Here is the long awaited justification for however, as encephalitis died away, so in Haslam, Griesinger, and others who main- large measure did the lessons to be learned tained that the brain was central to mental from it. disorder after all. Another pointer to the promise of neu- As a final strand woven into the tapestry ropathology came from experimental brain we come to brain imaging. This has been a Psychiatry and neuropathology: the maturing of a relationship 287

golden thread indeed. With the stage well set, the story. New findings are emerging in rela- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from it was natural that this new window into brain tion to vascular disturbance and changes in abnormality should be vigorously applied to white matter in Alzheimer's dementia. Indeed mental disorder. As we shall see such ven- its distinction from vascular dementia is tures have been rewarding. But they can eas- under reappraisal once again. This story ily run into trouble without a firm backing begins with brain imaging, when it was found from neuropathology. For psychiatry as well that some demented patients showed low as for neurology, neuropathology is the final attenuation in the white matter, especially in arbiter, the definitive yardstick, against which the periventricular regions.23-25 At first this new discoveries need to be compared. was thought to be rare, perhaps a reflection of Binswanger's disease-a rather esoteric vari- ant of vascular dementia. But as scanning The present scene techniques improved the incidence steadily So much for history and matters that have rose. It was rechristened "leukoaraiosis",26 come to shape the present day scene. We can and found in up to a third of patients with turn now to aspects of current progress which Alzheimer's disease.2' Ivan Janota had already illustrate the benefits of a close, continuing drawn attention to changes in white matter at relationship between psychiatry and neu- necropsy in certain patients who seemed to ropathology. Three common psychiatric con- have Alzheimer's disease.28 And Brun and ditions will be considered-disorders which Englund have now reported them in well over absorb an immense share of the facilities, half.29 When present the changes show dis- finances, and energies available-dementia, tinct associations with vascular risk factors,30 alcoholism, and schizophrenia. In all three and are thought to reflect hypoperfusion in neuropathology is steadily refining, some- the territories involved. Amyloid deposition times redefining our understanding at a fun- in blood vessels could be aetiologically rele- damental level. vant. Thus the situation regarding white matter lucency in dementia has altered considerably, The dementias from a suspected marker of Binswanger's dis- The principal forms of dementia were ease, through something that is seen in most described at the turn of the century. But this multi-infarct dementias, to something affect- did not mean that they were properly under- ing a substantial proportion of patients with stood. Alzheimer's disease. It seems as though vas- The commonest form-Alzheimer's dis- cular factors and Alzheimer changes may ease-was characterised by plaques and tan- commonly reinforce one another. The tradi- gles, obvious on histology. It became clear tional distinction between parenchymatous that this was a unitary disease whether affect- and vascular dementia is becoming to some ing the middle aged or elderly. But it extent blurred, and another view of the remained uncertain how far such features pathogenesis of Alzheimer's dementia may be accounted for the mental failure. Could their opening up. role be subsidiary, even epiphenomenal, to Next we come to the frontal lobe demen- the core disease process? Plaques could, after tias. Independently of one another, Brun31 all, be found in considerable numbers in and Gustafson32 in Sweden, and Neary et al in http://jnnp.bmj.com/ mentally well preserved elderly people who Manchester,33 have drawn attention to a size- had died from other causes. able group of patients whose dementia pre- Psychiatrists, with their aptitude for alter- sents with social breakdown rather than overt native explanations, sometimes wondered cognitive failure. These are of great impor- whether the symptoms of dementia might tance to psychiatry. Such patients are not depend, not directly on the brain pathology, infrequently misdiagnosed for some consider-

but on the nature of the patient's "reaction" able time-as hypomania, alcoholism, or per- on October 2, 2021 by guest. Protected copyright. to the ageing processes within his brain.'3 It is sonality disorder. Some have presented as not difficult to see how far this line of obsessional disorder, even responding at first argument might have been destined to run. to treatment for this. The importance of the But neuropathological studies were to get the group lies in its frequency and in the chal- matter back on course. Corsellis at Runwell'4 lenge it presents for neuropathology. It has and Tomlinson, Roth, and Blessed in been estimated to account for up to 10% of Newcastle'5-'8 were able to show that the cases of dementia,34 especially those setting in severity of the pathological changes was in the presenile period. There is also a dis- indeed related to the severity of the clinical tinct familial incidence. picture. Wilcock and Esiri in Oxford showed And what of the neuropathological basis? this very clearly indeed where neurofibrillary Some cases seem to represent classical Pick's tangles were concerned.19 Moreover tangle disease, but, and this is the important discov- counts correlated with the severity of choline ery, the great majority do not. Some 80% of acetyl transferase reductions in the brain.20 them lack all evidence of Pick's or of This has led to an intensive study of the com- Alzheimer's pathology.34 They show fron- position and genesis of the tangles them- totemporal degenerative changes of an ill selves, with the finding that they consist of defined nature, with mild loss of neurons, microtubule derived tau protein in altered and slight gliosis and spongiosis. Very occa- conformation.22 sionally the same clinical picture, and the his- And of course this is far from the end of tology, is seen in patients with amyotrophic 288 Lishman

lateral sclerosis.33 Altogether the neuropatho- fundamental to the addictive process and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from logical relationships within the group of served to perpetuate it. The alcoholic's facile, frontal dementias remain confused. Their garrulous, and unreliable behaviour was often clarification will be a necessary prelude to held to reflect such personality defects. attempts at understanding aetiology. But a careful reappraisal now suggests that Finally with the dementias we must con- a proportion of severe alcoholics may eventu- sider Lewy body disease. This has appeared ally become victims of a circular process, rather suddenly on the scene in recent whereby cerebral changes induced by their years.36 41 The Lewy body is the hallmark of heavy consumption and its attendant risks Parkinson's disease, appearing in the pig- weaken their capacity to abstain. And this mented substantia nigra and other brain stem proportion may be quite substantial.43 The nuclei. But it is now apparent that it may also refocusing of interest on the cortex came be found in considerable numbers in the largely from neuropsychological studies and cerebral cortex-socalled "diffuse Lewy body from brain imaging. Soon after computerised disease"-and that this is associated with tomography became available, it was shown dementia. Most affected patients show both that brain "shrinkage" was apparent in a half dementia and parkinsonian features, but to two thirds of cases. In comparison with some seem to show dementia alone. The controls, the ventricles of alcoholics were dementia is cortical in type, often fluctuates, enlarged by some 50%, and widening of the and tends to be accompanied by hallucina- fissures and sulci was often detectable. Such tions and behavioural disturbance. It is not findings emerged from many centres.44 infrequently diagnosed during life as multi- With abstinence there could be a gradual infarct dementia. This recent discovery is of return towards normality on the scans, but the utmost importance. It could account for this was a slow process and often the dementia encountered in a proportion of incomplete.434" Even many years later, per- patients with Parkinson's disease (up to sisting cerebral changes could be demon- 30%). It could help to explain the high inci- strated among Alcoholics Anonymous dence of extrapyramidal features in members who had abstained for a decade or Alzheimer's disease (up to 50%). And it more.47 The nature of this shrinkage and its could account in part for the repeated finding pathogenesis has remained uncertain; also the that some elderly demented patients lack processes that may permit its partial reversal. easily visible pathology (some 10%). The But neuropathological studies are bringing a Lewy body is hard to detect in the cortex with degree of clarity. Professor Clive Harper and routine stains, and much of the recent work his colleagues in Australia have made a series has made use of immunocytochemistry. Anti- of elegant studies, using quantitative methods ubiquitin antibodies provide a sensitive to help settle the matter of cortical involve- means for the detection of Lewy bodies.42 ment. On gross morphology they have found The current suggestion is that Lewy body brain weight to be slightly but significantly dementia may yet prove to be second only to reduced, and the pericerebral space over the Alzheimer's disease as a cause of dementia in hemispheres to be increased.48"4 This is seen the elderly.3833 If so we have been labouring independently of the presence or absence of too long with a severely restricted view. nutritional brain damage. The percentage of This is one of the fascinations of neu- white matter is reduced, and the enlargement http://jnnp.bmj.com/ ropathology, that the more closely you look of the ventricles (by a mean of 50%) con- the more you may find. One gets the feeling firmed.31 at times of looking for needles in a haystack, A start has been made on neuronal counts but when they are found they can revolu- in the cerebral cortex. Although such data are tionise our conceptions. sparse at present there are firm indications of a reduced neuronal population, at least in the

superior frontal cortex.3' Total counts were on October 2, 2021 by guest. Protected copyright. Alcoholic brain damage normal elsewhere, but there was shrinkage of Korsakoff is rightly famous for his description neurons in the cingulate and motor cortex as of the amnesic syndrome that bears his name. well. The 22 alcoholics involved included But it has emerged that that is not the end of some with Wemicke's encephalopathy and the story concerning brain damage in alco- some with liver cirrhosis. But almost half of holism. It now seems that many chronic alco- them had neither, and these showed equiva- holics, without this striking complication, also lent reductions. harbour brain damage of a more subtle Harper and Corbett have further attempted nature. an assessment of dendritic arborisations in a The concept of alcoholic dementia fell small group of alcoholics and controls.3' The steadily out of favour when the distinctive alcoholics showed reductions in mean den- pathology of the Wernicke-Korsakoff syn- dritic length, number of branches, and width drome was elucidated, and it became a mat- of basal dendritic fields, as measured in layer ter of controversy whether the cerebral cortex III pyramidal neurons of the superior frontal was liable to suffer. Alcoholics were said to be cortex. This last observation is interesting in prey to an "addictive process", of an ill view of certain experimental findings. defined nature, which led to their notorious McMullen et al in Toronto53 have shown that inability to benefit from attempts at treat- after five months of exposure to alcohol in the ment. Coupled to this was the idea of "pre- rat, dendritic domains are reduced in extent existing personality difficulties" which were in the hippocampus, with reduction in thick- Psychiatry and neuropathology: the maturing of a relationship 289

ness of the corresponding dendritic strata. What clues do we have to guide us? J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from Two months of abstinence allows regrowth of Certain observations are firm-genetic liabil- dendritic branching and a return to normal ity, a tendency to appear in adolescence or thickness of the strata. This experimental early adult life, response to certain medica- work provides a tempting analogy with what is tions, and distinct associations in some cases observed on brain imaging in the human alco- with pathology in the temporal lobes and lim- holic. There is evidence that dendritic arbors bic areas. This tendency to arise with regional normally expand continuously throughout brain pathology perhaps tells neuropatholo- adult life, presumably in compensation for the gists where to look most closely. Other find- decline in neuronal numbers over the years.54 ings are almost as firm and need to be taken In the alcoholic this delicate compensatory into account-season of birth effects, vulnera- balance may be imperilled. bility to life events and to "expressed emo- It is clear from all studies that not all alco- tion" within the family, the presence of holics are equivalently at risk of cerebral antecedent impairments from childhood involvement. Such variability appears not to onwards, and a host of tantalising relation- depend on patterns of drinking, or to be ships with aspects of cerebral laterality. explained entirely by the coincident risks of So neuropathologists have been encour- cerebral anoxia, hypoglycaemia, malnutrition, aged to look at the brain anew. Bogerts and or head injury. These matters are hard to coworkers58 have reexamined the Vogts' col- evaluate with precision, but it seems likely lection of , gathered before the era of that individual susceptibility, perhaps on a neuroleptics and insulin treatment, and genetic basis, is also very important. And as showed reductions in size of the globus pal- with the liver, females appear to be at lidus and several limbic structures. Shrinkage increased risk.55 Thus some alcoholics may be of the hippocampal formation was sometimes especially vulnerable to cerebral changes obvious macroscopically. Corsellis's group59 induced by alcohol consumption, even measured a larger sample from Runwell, though they escape the development of a showing pronounced enlargement of the tem- Korsakoff syndrome. The alcoholic patient poral horns and thinning of the parahip- illustrates very well the need for continu- pocampal cortex (particularly on the left) in ing liaison between neuropathology and psy- comparison with patients with affective disor- chiatry. der. Crow et a160 have shown enlargement largely restricted to the left temporal horns- Schizophrenia that is, to that part of the brain in which And last we come to schizophrenia, perhaps anatomical asymmetries are normally present. the most baffling of all psychiatric disorders In all of these studies gliosis was conspicuous with respect to aetiology. An organic basis by its absence, suggesting a developmental has been suspected since Kraepelin's time but disturbance rather than the end result of early has remained remarkably elusive. And there damage to the brain. have been radically different ideas concerning Scheibel and coworkers6' 62 have focused on aetiology. Schizophrenia has been seen as the the hippocampus, claiming alterations in outcome of faulty psychological development, pyramidal cell orientation from orderly to dis- aided and abetted disor- by faulty parental rearing. orderly alignments, with corresponding http://jnnp.bmj.com/ The schizophrenogenic mother and the path- ganisation of their dendritic arrays. In some ogenic family have had their vogue. Social parts of the hippocampus the proportion of processes, particularly within institutions, cells rotated by 30 degrees or more was have been blamed for the "schizophrenic increased sevenfold or eightfold in compari- defect state". son with controls. The extent of the effect The development of theories which seemed to be related to the severity of the bypassed all reference to the brain is not hard clinical picture. They suggest that this may to understand. It followed in the wake of long represent the product of disturbed migration of on October 2, 2021 by guest. Protected copyright. and detailed research which failed to clarify a neurons into the primordial hippocampus dur- neuropathological basis for the disorder. The ing the second trimester of pregnancy. The Vogts56 spent a lifetime examining the brain migration and alignment of nerve cells is gov- with results that failed to gain wide accep- erned by "neuronal cell adhesion molecules", tance. In 1972 Plum57 made the peculiarly and it is suggested that these could be vulner- compelling remark that "schizophrenia is the able to maternal infection with neuraminidase graveyard of neuropathologists". Moreover bearing viruses, perhaps aided by inherited any attempt at an organic model met with defects in immunocompetence. very particular difficulties in that the strange Recent results from the studies of Akbarian phenomena of schizophrenia did not mirror and coworkers6364 are also fascinating. They the effects of known brain lesions; neurology have used histochemistry to identify a partic- was hard pressed to encompass its bizarre ular population of neurons in the grey matter manifestations. and subjacent white matter (NADPH-d neu- But the last decade or so has seen an rons). Having migrated towards the cortex upsurge of interest once again. This of course during fetal development these are normally is tempered with caution. We have lived found in greatest numbers immediately deep through too many false hopes to react with to layer VI of the cortex. In schizophrenic anything else. In particular we know that nar- brains, however, their distribution is shifted rowly conceived models of cause and effect significantly inwards and they are found in are unlikely to be upheld. deeper layers of the white matter. This is fur- 290 Lishman

ther evidence of disturbed migration during lesion"-that it involves systems that have yet J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.284 on 1 March 1995. Downloaded from neural development. The findings of to mature functionally. Putting it another Akbarian et al apply to the medial and the lat- way, the lesion remains largely dormant until eral temporal lobe structures, and also to the further brain maturation calls the damaged dorsolateral prefrontal cortex, which has been neuronal systems into operation. A good deal shown by techniques to be dys- of theorising centres on this aspect of the situ- functional in schizophrenia. It would seem ation.6972 It may be that the immature cir- unlikely that these cytoarchitectonic abnor- cuitry is laid bare by synaptic pruning, a malities could have arisen other than through process which in some brain areas continues some failure of cerebral development. It is into late adolescence. Or it may depend on important to note that insights at this level the maturing of cortical-subcortical relation- have become available only through the ships. The dorsolateral prefrontal cortex, for medium of neuropathology. Also that they example, is one of the last brain areas to are generated by a synthesis of clinical and myelinate, this continuing into the second neuroscientific information-that is, by ongo- and third decades of life. In animals lesions in ing dialogue between psychiatrists and neu- such a location can disturb the relationship ropathologists. between cortical and subcortical dopamine As ever, however, the mysteries of schizo- metabolism. This could be very relevant. phrenia continue to keep one step ahead. Adolescence is notably a time of stress, and This plethora of studies has focused princi- stress could tax a faulty system. pally on the temporal lobe regions, and for Thus with some ingenuity the neurodevel- very good reasons. But who knows what may opmental model can be made to encompass be waiting to be discovered elsewhere? As many aspects of what we know about schizo- other parts of the brain come under scrutiny phrenia. But caution is strongly indicated. it seems that they, too, may be affected. There is still plenty of room for debate. Zipursky and coworkers,65 for example, have recently made a detailed volumetric study of multiple brain regions, using magnetic reso- nance imaging (MRI). They find grey matter Conclusion reductions, not restricted to the temporal In conclusion, these examples amply confirm lobes, but diffusely throughout most parts of the value of a continuing relationship the cerebral cortex. Harvey, Ron, et a166 between psychiatry and neuropathology. It is working at the Institutes of Neurology and in the nature of relationships that they can be Psychiatry, have confirmed such findings, stormy, and that as they mature they pass showing, moreover, that they are specific to through various stages. In the early 19th cen- schizophrenia, at least in that they are not tury the relationship between psychiatry and found in manic-depressive psychosis.67 These neuropathology tended to be one of blind MRI findings were mirrored in an earlier faith. By the middle of the century this had postmortem investigation by Pakkenberg,68 changed to obsession and was provoking who demonstrated widespread reductions of alarm. Towards the end the focused activity both cortical and subcortical grey matter in had repaid dividends, in the delineation of schizophrenic patients. So it seems possible the major dementing illnesses, but the situa- that the cortex is diffusely affected in schizo- tion for psychiatry generally was becoming http://jnnp.bmj.com/ phrenia, in addition to any selective emphasis embroiled in doubt and conflict. on particular brain regions. This could go As we entered the 20th century psychiatry some way towards explaining the pleomor- was finding other avenues and more immedi- phic features of the disease, and perhaps its ate rewards by studying the development of variability of expression in different patients. the mind and analysing the minutiae of the Be that as it may, an accumulation of evi- patient's interactions with his world. But the

dence now points to the "neurodevelopmen- second part of the 20th century has seen a on October 2, 2021 by guest. Protected copyright. tal theory of schizophrenia".6971 It has been pronounced maturing of the relationship, and possible to sketch in only a part of the indica- such maturing has had several elements. tors in this direction. It is suggested that Mature relationships will permit areas of many schizophrenics harbour brain lesions doubt and tolerate competing points of view. which have originated very early in life, They can stand back and evaluate matters by extending back even to the intrauterine objective and realistic means. They involve a period. Such lesions predispose the person to capacity to share, and appreciate the need to develop schizophrenia later. They are of a join forces in unravelling problems. And as I subtle nature and were easily missed by ear- see it maturing of this nature has taken place lier pathologists. The anomalies concerned in both psychiatry and in neuropathology. may be the product of infection, perinatal Psychiatry has learned to be less possessive trauma, or, the now favoured theory, patterns about its unique avenues and insights into of abnormal neural migration. This last may mental disorder. As well as studying psy- be occasioned by maternal infection during chosocial forces it can prosper, like neurol- pregnancy, or may itself be inherited directly. ogy, by studying the brain. It has learned to These lesions declare themselves fully only be less jealous of neurology's allegiance with 15-20 years later, because they need to inter- neuropathology, but to join forces in this act with normal brain maturational processes alliance. It has been able to change its orien- before their impact is revealed. This is the tations where certain disorders are concerned, distinctive aspect of the "schizophrenic brain notably schizophrenia. Psychiatry and neuropathology: the maturing of a relationship 291

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Thomas Sydenham "The British Epistolaris describing smallpox, venereal dis- Hippocrates" ease, hysteria, and podagra (gout), and the celebrated Tractatus de Podagra et Hydrope, Details of Sydenham's life are few. The London 1683. These works were published Sydenhams, an ancient family were in the in Britain, Geneva, and in Amsterdam. time of King John, seated at Sydenham near There is an anecdote about him, curso- Bridgewater. Thomas was son of Mary rily dismissed by Munk as "utterly value- Geffery of Catherstone and William less": when asked why he did not write Sydenham. Little is known of his childhood. about diseases of the head, he answered In 1642 he was entered at Magdalen Hall, that he did not undertake to write upon dis- Oxford, and left shortly after for military eases that he was unable to cure. Times service as a Parliamentarian. He probably don't change. Referring to his failure to returned to Magdalen Hall in 1646, advised become a Fellow of the Royal College, by Dr Thomas Coxe (PRCP, 1682) to read Lettsom wrote in 1804: "The great medicine, taking the degree of MB in April Sydenham, for all his labours, only gained 1648. He was made a Fellow of All Souls, the sad and unjust recompense of calumny but went to Wadham as a commoner. He and ignorance . . . ". However, Munk' http://jnnp.bmj.com/ moved to Westminster, before 1661 when relates that ". . . he did not proceed doctor his earliest account of epidemics of London (MD) till after a lapse of twenty eight years were written. On 25 June 1663 he was ... he was content with the minor degree, admitted Licentiate of the College of and, as such, was, by the statutes ... inad- . missible as a Candidate, and a fortiori, as a In 1666 was published the first edition of Fellow . . . examination of the Annals Methodus Curandi Febres, propriis observa- enables me positively to assert that he never prope hunc locum sepultus est tionibus in the THOMAS SYDENHAM superstructa, Philosophical sought admission to the fellowship." on October 2, 2021 by guest. Protected copyright. Transactions, which became Transactions of Sydenham had a powerful influence on medicus in omne aevum nobilis the Royal Society, in four sections: continued contemporary medicine. Diligent and scien- natus erat AD 1624 fevers, the symptoms of continued fevers, tific in his methods, observation and prag- vixit annos 65 intermittent fever, smallpox. The dedication matism were his hallmarks. He saw himself deletis veteris monumenti vestigiis, includes a tribute to Robert Boyle. A sec- as the servant of God and nature. ne rei memoria interiret, ond edition in 1668 included a chapter on In 1689 still in practice, he was ill with hoc marmor poni jussit collegium the plague, which was epidemic in London renal stone, haematuria, and gout. He died regale medicorum londinense AD 1810 in 1645 and 1646. It contains Latin elegiacs at home in Pall Mall on 29 December 1689 optime merito revering Dr John Locke, the "founder of and was buried in the church of St James's, nearby is the burial place of analytical philosophy of the mind".' The Westminster. THOMAS SYDENHAM third edition (1676) bore the new title J M S PEARCE 304 Beverley Road, noble of the age Observationes Medicae, and was dedicated to Born AD 1624 Dr and included Anlaby, Mapletoft copious new Hull HUIO 7BG, UK He lived to 65 years material. Sydenham took the degree of age erases remnants and monuments, , not at Oxford, but at nothing in his memory will perish. Cambridge (May 17 1676), possibly This marble is placed by command of the because his son was two years earlier admit- Royal College of Physicians of London AD ted a pensioner at Pembroke College. 1 Brown J. Locke and Sydenham and other papers. 1810 in greatest merit For three months in 1677 he was laid low Edinburgh: David Douglas, 1882:33-135. by haematuria and gout, an affliction he 2 Munk W. The Roll of the Royal College of Physicians of London. 2nd ed, vol 1, 1518 to Epitaph to Thomas Sydenham first suffered in 1649. Then followed a 1700. London: published by the on the tablet erected series of College, Epistola Responsaria and Dissertatio Pall Mall East, 1878:309-14. by the College in 1810