Lateralized temporal–limbic dysfunction and psychopathology

Epilepsy & Behavior Epilepsy & Behavior 4 (2003) 578–590 www.elsevier.com/locate/yebeh

Classics in Epilepsy and Behavior: 1976

Lateralized temporal–limbic dysfunction and psychopathologyq P. Flor-Henry 1 Department of Psychiatry, University of Alberta and Alberta Hospital, Edmonton, Alberta, Canada T5J 2J7

Impressed by the fact that rabies, with its predilection for hippocampal structures, presents with prominent mental symptoms: fear, terror, rage, insomnia, struck by the psychological changes accompanying tumors of the corpus callosum which encroached on the mesial aspect of the hemisphere and by the dysphoric states occurring with ischaemic lesions of the anterior cingulum, Papez,1 in 1937, stated his celebrated hypothesis. The hippocampus, fornix, mamilloanterior thalamic tract, and its projections to the cingulate gyri formed the anatomical substrate for emotion. MacLean2–4 in 1949 expanded the Papez circuit, showing that the septal nuclei, their brain stem connections via the medial forebrain bundle, the amygdaloid nuclei, and the insula were all, anatomically and functionally, part of the same complex neurophysiological system. This system he labeled ‘‘the limbic system’’ in 1952, emphasizing that the anterior cingulate and orbital-frontal components had important inhibitory functions as well as being crucial to autonomic regulation. MacLean also separated the amygdaloid subdivision of the limbic system, related to aggression and defense, from the septal subdivision, related to sexuality. Importantly, he stressed that the frontotemporal region, (posteroorbital-insulartemporopolar-pyriform-amygdaloid-rostral-hippocampal) was essentially a closed physiological system where discharges induced by electrical or strychnine stimulation tended to be confined to these limbic circuits. MacLean in 1970, because of the common symptomatology often seen in ‘‘smouldering limbic epilepsy’’

q Reprinted by permission from Ann NY Acad Sci 1976;280:777– 97. Copyright 1976 New York Academy of Sciences. 1 The neuropsychological part of this research was made possible by a grant from the Medical Services Research Foundation of Alberta.

doi:10.1016/j.yebeh.2003.07.013

and schizophrenia, concluded that perturbations of the frontotemporal limbic regions might be responsible for the affective, delusional, and perceptual abnormalities encountered in the endogenous and toxic psychoses. The critical importance of the frontotemporal areas in the organization of the limbic system has been subsequently confirmed by the studies of Jones and Powell5;6 on sensory convergence in the cerebral cortex. By neuronal degeneration techniques in the cerebral cortex, it was demonstrated in the monkeyÕs brain that the sensory areas of the neocortex establish, by an orderly step-by-step progression, reciprocal connections in the parietal and frontal cortex, finally converging in the superior temporal and orbital frontal cortex; from which they project into the cingulate gyrus, the amygdaloid, and hypothalamus. In this paper some of the evidence which suggests that the major psychopathological syndromes are the reflection of the lateralized, asymmetrical dysfunction of the anterior limbic system will be discussed, and new observations on the functional psychoses derived from neuropsychological tests and Power Spectral analysis of the EEG will be presented. Noteworthy in this context is the fact that as early as 1937 Papez quotes the earlier observations of Dandy,7 who concluded in 1931, on the basis of neurosurgical evidence, that the ‘‘seat of consciousness’’ was localized to a brain stem-left mesialfrontal-cingulate axis. Removal of the right hemisphere, of the left frontal lobe, left temporal or occipital regions were without effect on consciousness, whereas ligation of the left anterior cerebral artery produced loss of consciousness, as might brain stem injuries, but right anterior cerebral artery ligation did not influence consciousness. Papez again refers to Alford,8 who in 1933 published observations on 33 cases of left hemiplegia, not one of whom exhibited confusion and only three, emotional instability. On the other hand, 27 of 55 cases of right hemiplegia had ‘‘definite and permanent

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confusion of consciousness and emotional instability.’’ This last was essentially of the catastrophic reaction type. It is remarkable that in 1965 Serafetinides et al.,9 using the intracarotid amytal technique, made similar observations, finding in 21 patients that loss of consciousness followed only dominant injections.

REVIEW OF EVIDENCE FOR LOCALIZATION From the outset, clinical observations of certain forms of the schizophrenic syndrome emphasized the presence of language abnormalities as Kraepelin emphasized the presence of ‘‘speech confusion’’ in dementia praecox. It was Kleist who first drew attention to the localization and lateralization implications of the paragrammatical misconstructions, and of the finer disorders of speech understanding found in schizophrenia. Kleist writes in 1928,10 ‘‘we found that a defect of comprehension combined with paralogias or a defect of speech combined with paraphasic phenomena was very rare in confusional or motility psychoses. It was never absent however in the schizophrenias and was very frequently seen in catatonic and hebephrenic dementia, even in the initial stages of these two disorders.’’ In 1960, Kleist11 concluded that the linguistic formulation and understanding of abstract and insignificant thoughts, themselves connected with speech, was one of the outstanding features of schizophrenia and implied ‘‘sensory aphasic impairments similar to those found in focal brain lesions of the left temporal lobe.’’ In schizophrenia, however, higher levels of speech, those responsible for word derivations, word constructions, sentence formation, and abstract meaning of speech conceptions are perturbed — rather than more primitive levels of speech: sounds, word sequences, names, encountered with focal lesions of the left fronto-temporal regions. A number of contemporary reports have documented the presence of abnormalities and defects of speech perception in schizophrenia: Lawson et al.,12 in relation to contextual constraint, observed that schizophrenics ‘‘have a deficiency in perceiving words in meaningful relation to each other as part of an organized pattern’’ and moreover have a particular defect in auditory verbal memory; Mefferd et al.,13 comparing schizophrenics with carefully matched controls, found that the former significantly failed to reproduce stimulus words, irrespective of distractibility; Moon et al.14 noted that the ‘‘loosening of associations’’ of schizophrenia was the result of the mishearing of the stimulus words, and vanished when this was controlled for; Walker and Birch15 reported that the development of right–left preference was significantly impaired in schizophrenic children, compared to normals. Bull and Venables16 recently found impairment of speech perception in schizophrenics compared to normals and depressed pa-

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tients. This effect was independent of stimulus intensity, although with a dichotic listening paradigm they were unable to demonstrate that it was due to a left hemisphere effect. Maher17 reviewed in 1972 empirical studies on language and schizophrenia. These show that schizophrenics fail to utilize the semantic and syntactic redundancies of language, use a restricted vocabulary (hence repetitions), and also repeat at the level of syllables apparently because of an active tendency of words, or parts of words, once pronounced, to intrude again. Geschwind18 discussing mutism, akinetic mutism, echolia, palilalia and schizophrenic word salad, the socalled non-aphasic disorders of speech, considers the neurological evidence which relate this symptomatology to a disconnection of the language areas in the dominant hemisphere from the rest of the cortex, notably by large frontal or parietal lesions. He draws attention to the similarity existing between WernickeÕs fluent aphasia and schizophrenic word salad, although graphorhea, common with the latter, is almost never found in the former. It is striking that the Ônon-aphasic disorders of speechÕ are all classical symptoms of catatonic and chronic forms of schizophrenia. For several years observations derived from surprisingly diverse investigative techniques have been published, all of which demonstrate dysfunction of the dominant hemisphere in schizophrenia. It has been shown by Fitzgerald and Hallpike,19 Cawthorne et al.,20 that abnormalities of directional preponderance to caloric stimulation of the vestibular system were ipsilateral to the side of the lesioned temporal lobe. Fitzgerald and Stengel,21 studying 50 schizophrenics, found completely normal responses in 10, diminished or absent responses in 6, and 18 with abnormal directional preponderance. In 16 of these the direction of the slow nystagmic component was to the left. The remainder were normal on first, but abnormal on second examination. Monakhov,22 in the interareal analysis of in-phase alpha synchronization by toposcopic techniques, showed that normals had a preponderance of alpha synchronization on the dominant hemisphere, whereas this was reversed, or reduced in paranoid schizophrenia and in paranoid hallucinatory phases of the illness. Vinar and Skalickova,23 comparing 100 schizophrenics, 20 manic-depressives, and 220 normals, found neurological evidence implicating the dominant hemisphere in the schizophrenics. Luria and Homskaya24 published observations demonstrating that the lateral asymmetry of electrodermal responses, with attenuation or absent responses during the orienting response, were ipsilateral to lateralized frontal and/or temporal lesions. In addition, they found that nonresponders with temporal lesions might respond to signal tones, although they did not respond to neutral tones as opposed to frontal lesions, who responded neither to signal nor neutral tones. Pribram25 has provided evidence that the orienting and habituation

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characteristics of the orienting response hinge on a reciprocal hippocampal–amygdaloid interaction: amygdaloid stimulation inducing the response, hippocampal stimulation provoking its habituation. On these bases, Gruzelier and Venables26–28 reported lateralized abnormalities of the electrodermal characteristics of the orienting reflex in a large number of schizophrenics which implied dominant, or left-temporal dysfunction in this group. A smaller number of depressed patients, on the same parameters, had dysfunction of the nondominant temporal systems, whereas a group of psychopathic personality deviants showed left-sided effects. Both ophthalmodynometric29 and gamma irradiation techniques,30 with radioactive iodine, reveal that the cerebral circulation is asymmetrical and increased in the nondominant hemisphere. Nonetheless, Ingvar and Franzen,31 investigating the regional cerebral blood flow of the dominant hemisphere in 20 schizophrenics, report that, compared to normals or demented patients, although the mean cerebral blood flow is normal, there is in the schizophrenic significant hypocirculation in the left frontal and hypercirculation in the postcentral regions. This, the authors suggest, might reflect a defect in mediothalamic- fronto-cortical projection systems. In normal monozygotic twins, some 20–35% are discordant in terms of lateral preference. Gottesman and Shields32 reported that a similar proportion (2 out of 10) was found in their twins concordant for schizophrenia. However, 8 out of 11 in the pairs discordant for schizophrenia differed in laterality. This difference was statistically significant. Boklage33 has analyzed in detail this aspect of the data of Gottesman and Shields. Taking all monozygotic twins, 64% are concordant for schizophrenia. Considering dextral–dextral (MZ) pairs, 93% are concordant for schizophrenia. Of the eight dextral– dextral pairs, 7/8 are concordant, both for schizophrenia and subtype, but of the 13 sinistral–dextral pairs, only three are concordant for schizophrenia and none for subtype. In addition, the dextral–dextral pairs have the most severe illness, whereas in the sinistral–dextral grouping the sinistral twin has a more severe illness than the dextral, although still less severe than in the affected dextral–dextral pairs. The parallel with aphasia and sinistrality is striking. In strictly lateralized dextrals, damage to the dominant hemisphere induces severe dysphasic disturbances, whereas sinistrals who are more likely to have imperfect lateralization or bilateral speech representation, suffer a milder dysphasic handicap, from which they recover more rapidly after lateralized cerebral injuries. In the same manner, those twins (MZ) who are strictly lateralized, left-hemisphere dominant dextral, have the most concordant, and the most severe schizophrenia. In the mixed laterality pairs, the sinistral twin is the most likely to have the schizophrenic illness which is much more benign than in the dextral– dextral, strictly lateralized pairs, although more severe

than if the mixed laterality dextral twin is affected. It would appear that similar laws govern left-hemisphere speech specialization, dextrality, mixed laterality and dysphasia, on the one hand, and lateral preference, dextrality–sinistrality, concordance for, and severity of schizophrenia, on the other. Posttraumatic Psychoses Hillbom and Kaila34 extracted 81 cases of psychosis from 1,821 brain-injured soldiers. Of these, 20 were schizophrenic-paranoid psychoses. 17/20 had temporal lesions, with a significant excess on the left side. Subsequently, Hillbom,35 having expanded his series to 3,552 cases, took a random sample ðn ¼ 415Þ and established a temporal localization and a left-sided association with psychosis. In cases without psychiatric disabilities the incidence of right and left wounds was comparable, but as psychiatric disability increased, there was a regular trend by which left-sided wounds outnumbered right-sided injuries; this became significant when left temporal lesions alone were considered. Remarkably similar were the findings of Lishman,36 who studied 670 patients with penetrating head injuries, extracted from an initial cohort of 1,024 on the basis of documentation for adequate analysis. Psychiatric disability and intellectual disorders correlated with brain damage and involvement of the left hemisphere but was independent of generalized intellectual impairment, physical disability, posttraumatic amnesia, and posttraumatic epilepsy. Left temporal lesions showed a strong association with psychiatric disability. Affective disorders were associated with right-hemisphere damage and there was a trend for right frontal lesions to lead to the ‘‘post-traumatic syndrome’’ and left frontal lesions to sexual and psychopathic changes. Davison and Bagley37 selected 40 cases of schizophrenic psychoses associated with closed head injuries and with skull fracture from the international literature, on the basis of adequacy of information provided. They found significant associations between temporal lesions, left-hemisphere injuries, closed head injuries, and unconsciousness of more than 24 hours. Cerebral Tumors Bingley,38 studying mental symptoms in temporal lobe gliomas, reported that in 198 dextral patients there was a moderate association between mental symptoms and papilloedema. If the lobes were considered separately, however, there was no association with the dominant, but a marked association between papilloedema, mental symptoms, and the nondominant lobe. Furthermore, with dominant lesions mental symptoms occurred before the appearance of papilloedema, and in cases without papilloedema dominant gliomas had more psychic symptoms. Also, blunting of affect was strongly associated with dominant gliomas. These remarkable

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relationships again emphasize the importance of dominant temporal pathology in the genesis of psychiatric symptomatology. Davison and Bagley37 culled 77 cases of schizophrenic psychoses associated with cerebral tumors and found that, compared to unselected series of cerebral tumors, the tumor site in the psychotic group had a temporal localization ðp < :001Þ. In a correlational analysis made between individual symptoms and lesion site in 80 cases with circumscribed lesions, the most significant statistical relationships that emerged related primary delusions and catatonic symptomatology to left hemisphere, particularly left temporal localization ðp < :001Þ. Temporal Lobe Epilepsy The study of psychopathological manifestations encountered in temporal lobe epilepsy, as this writer has already extensively discussed,39–42 demonstrates very significant laterality effects with respect to psychosis, psychopathic personality deviation, and affective disturbances. There is a very strong association linking dominant temporal epilepsy with schizophrenic and paranoid psychoses and with psychopathy. There is a weaker, but nevertheless quite definite, relationship between nondominant temporal epilepsy and manic-depressive psychoses, and, more generally, with dysphoric states of neurotic type. Interestingly, Mnoukhine and Dinabourg,43 investigating 139 children with cerebral palsy, hemiparesis, and epilepsy, observed that cerebral insult lateralized to the dominant hemisphere produced profound intellectual retardation and blunting of affectivity, whereas lateralization to the nondominant hemisphere led to ‘‘distinct intensification of emotional manifestations, abrupt excitability, melancholic depressions.’’ Neuropsychological Investigation of Psychopathy and Depression Dr. L.T. Yeudall and this writer have reported44 evidence derived from 70 patients: depressed (neurotic, psychotic, with and without structural brain damage) and psychopaths (primary and ‘‘neurotic’’ criminals) chosen simply because they had, consecutively, been referred for neuropsychological testing. Hence, in this respect, it was a biased sample. They were subjected to a neuropsychological test battery, organized by Yeudall and consisting of 25 indicators of localized and lateralized cerebral dysfunction, evaluating frontal, temporal, and parietal functions. Blind neuropsychological interpretations showed that psychopathy was related to dominant and depression to nondominant frontotemporal dysfunction (r ¼ :76; p < :001). What is more, for the depressed patients the nondominant lateralization held irrespective of the presence, or absence, of brain damage. It was noteworthy that primary psychopaths alone exhibited dominant effects, the ‘‘neurotic’’ crimi-

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nals showing nondominant dysfunction. Systematic analysis of the verbal and performance scales of the Wechsler (W.A.I.S.), confirmed these laterality effects, the psychopaths exhibiting a decrement of verbal, over performance I.Q. and the depressed a decrement of performance over verbal I.Q. scores. It is well established that the vocabulary and similarities subtests of the WAIS are sensitive indicators of dominant hemispheric dysfunction, and the object assembly and block design subtests, of dysfunction of the nondominant hemisphere. These observations are in agreement with a large body of psychometrical data on psychopathy and depression. It is suggested, however, that it is not because they ‘‘act out’’ that psychopaths have a diminished verbal I.Q. and that it is not ‘‘because they are depressed’’ that affective patients have a lowered performance I.Q., but rather that these lateralized decrements and the corresponding psychopathological states are different reflections of underlying lateralized cerebral disorganization.

NEUROPSYCHOLOGICAL AND POWER SPECTRAL EEG ANALYSIS OF THE FUNCTIONAL PSYCHOSES Neuropsychological Investigation Method Consecutive patients ðn ¼ 114Þ who fulfilled our research criteria for schizophrenia, mania, hypomania or depression (unipolar and bipolar) were subjected to neuropsychological testing, under blind conditions. The criteria for schizophrenia were strict, following Schneiderian, rather than Bleulerian formulations. Two or more Schneiderian symptoms of the first rank had to be present, in a setting of clear consciousness, without a history of exogenous factors, in the absence of structural disease of the Central Nervous System and where the abnormal mental symptoms could not be understood as being derivative of an underlying morbid mood. When the above constellation appeared to be reactive to adverse life events and showed a well-marked affective coloring, they were classified as ‘‘schizophreniform.’’ Acute psychoses, even if thought disordered, hallucinatory, and with florid symptoms of the first rank which were periodic in course, and which exhibited either at the time of examination or in previous episodes definite clinical depression or mania, were labeled ‘‘schizo-affective’’ and classified with the affective psychoses. The affective syndrome of depression was characterized by dysphoric mood, present for at least two weeks, with subjective sadness, anorexia, loss of weight, insomnia, or hypersomnia, loss of energy, diminished libido, impaired concentration and delusions of unworthiness. The diagnosis of mania, or hypomania, was established when

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euphoria or irritability was found, accompanied by motor overactivity, pressure of speech, flight of ideas, delusional grandiosity, distractability and diminished sleep requirements. The diagnostic criteria were related to those advocated by Feighner et al.45 The mental state was documented by the Present State Examination Schedule, developed by Wing et al.,46 which was also completed by a second psychiatrist* to allow for the reliability of the psychiatric symptomatology elicited and for a subsequent correlational analysis between psychic symptoms and neuropsychological variables. Approximately half the schizophrenia series belonged to the nuclear syndrome and half to the ‘‘schizophreniform’’ variety. Ninety percent of the nuclear group satisfied the criteria of Feighner et al. There was 90% agreement on subdiagnosis between the two psychiatrists. The average duration of illness was nine years. Including the ‘‘schizophreniform’’ class the agreement on diagnosis fell to 50%, 64% being Feighner positive. The distinction between the nuclear and schizophreniform varieties was made retrospectively. Similarly the agreement on diagnosis for the affective psychoses was 78%, 75% fulfilling the criteria of Feighner.45 The patients were then tested, under blind conditions, with the ‘‘laterality’’ neuropsychological test battery, devised by Yeudall.  In addition, the Wechsler Adult Intelligence Scale was administered (WAIS). In about half the series the testing was carried out before the administration of psychotropic drugs. Because the psychopathological syndromes selected were severe, the testing, undertaken by a specially trained assistant,   took on the average five to eight hours, but not infrequently had to be done over two days, taking 13–16 hours. The neuropsychological ‘‘pattern’’ analysis was interpreted under double blind conditions at the end of the two years of study by two neuropsychologists§ to permit an interreliability assessment. Neither the tester, nor the neuropsychologists knew the patients nor their diagnosis. Results The psychotic series consisted of schizophrenia ðn ¼ 54Þ and affective psychoses ðn ¼ 60Þ. The two * Dr. B. Howarth, Consultant Psychiatrist, Alberta Hospital, Edmonton, Canada.   The ‘‘Laterality’’ neuropsychological battery consists of 27 variables which were derived from the following tests: Wepman–Jones Aphasia Screening Test, Trail-Making A and B, sensory–perceptual integration: auditory, visual, somesthesic, and visual fields, Dynanometer, Seashore Speech Sounds, Graham–Kendal Memory for Designs, RavenÕs Colored Progressive Matrices, Organic Integrity Test, FingerOscillation, Oral Word-Fluency, Purdue-Pegboard, Tactual Formboard astereognosis, Seashore Rhythm, Finger localization, and WilliamÕs clinical memory evaluating both verbal and nonverbal learning.    Mr. W. Stefanyk, Psychologist, Alberta Hospital, Edmonton, Canada. § Dr. L.T. Yeudall and Mr. D. Faux.

psychotic groups did not differ significantly in age (schizophrenia x ¼ 36:3; affective x ¼ 38:6Þ nor in years of education. Sixty-one percent of the schizophrenic series were male, but only 48% of the affectives. Of the total psychosis series 7.3% were sinistral or ambidextrous. This was assessed by the Marrion Annet47 questionnaire, consisting of 12 items of hand preference. Dextral choice reported on eight or more was considered dextral; similarly for sinistrality, intermediary preferences viewed as ambidexterity were allocated to the sinistral group. One-way analysis of variance, T-test analysis, multiple stepwise discriminant function analysis, and canonical variate analysis were carried out. TA B L E 1 shows the mean scores on the 75 patients who were able to complete all the neuropsychological tests. It is clear that the schizophrenics, compared to the affectives, are significantly impaired on those variables that reflect dominant frontal and temporal functions: aphasia, speech sounds, Oral Word Fluency, and TrailMaking B. Examining these variables for all patients, similar findings emerge, schizophrenics having significantly impaired scores on aphasia ðp < :04Þ, ideomotor apraxia ðp < :005Þ, Oral Word Fluency ðp < :005Þ, and Trail-Making B ðp < :01Þ. The two psychotic groups did not differ significantly from each other on Memory For Designs, Tactual Formboard, Purdue-Pegboard, and Constructional Apraxia, all tests sensitive to dysfunction of the nondominant hemisphere. It should be noted, however, that both groups, in these tests, differed from normal scores and were impaired. It was also noteworthy that bilaterally, on both fingertip writing and finger localization the schizophrenics were poorer than the affectives, but vary particularly for responses from the left hand (R. hand ¼ p < :02 vs. L. hand ¼ p < :009). The clinical memory scales, both for verbal and nonverbal, learning were similar in both categories.

TA B L E 1 ‘‘T-TE S T S ’’: SC H I Z O P H R E N I A ðn ¼ 35Þ & AF F E C T I V E ðn ¼ 40Þ
Speech Sounds Trail (A + B) Trail A Trail B Ravens, C. M. Finger Localization, Preferred Hand Finger Localization, Nonpreferred Tactual Form Board, Preferred Hand Seashore Rhythm Oral Word Fluency Aphasia Screening

x: Schiz

x: Affective

P-l-tail

12.40 284.40 66.60 217.80 10.91

6.65 184.12 46.15 137.97 7.10

0.0004 0.005 0.02 0.005 0.02

11.31

7.92

0.02

11.80

7.75

0.009

699.66 9.00 8.86 9.29

561.30 6.55 12.42 7.78

0.02 0.008 0.0004 0.05

* Subjects who Completed all tests. Means of neuropsychological variables for schizophrenia and affective psychoses.

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TA B L E 2 FR O N T O T E M P O R A L DY S F U N C T I O N
Schizophrenia: ðn ¼ 53Þ Affective: ðn ¼ 49Þ *

L

L>R

¼

R>L

R

Normal

4 0

41 0

2 3

3 41

0 4

3 1

Sinistrals excluded.

Multiple stepwise discriminant function analysis performed on the 75 patients who had completed all the tests yielded an 85% correct classification for schizophrenia and a 94% correct classification for the affective syndromes. In order of diminishing discriminatory power the variables were: (1) Speech Sound Perception; (2) Oral Word Fluency; (3) Purdue-Pegboard Assemblies; (4) Wepman–Jones Aphasia tests and (5) FingerOscillation—Preferred Hand. Interestingly, although the Full Scale WAIS I.Q. was comparable in both groups (schizophrenia x ¼ 90; affective x ¼ 94), the mean verbal I.Q. for the schizophrenics was lower (93 vs. 98, p < :07) but the mean performance I.Q. was similar with schizophrenia x ¼ 87 and affective x ¼ 89. Analysis of the subtests revealed that the schizophrenics were significantly more impaired on vocabulary ðp < :05Þ and digit span ðp < :04Þ. Curiously, a stepwise discriminant function analysis on the WAIS subtests yielded a 70% correct separation for schizophrenia and 74% for affectives. In order of diminishing importance the subtests were: (1) digit span; (2) object assembly; (3) digit symbol; (4) vocabulary, and (5) block design (MahalanobisÕ D-square-22.04, 13 d.f.; p < :05). The clinical pattern analysis (TA B L E 2) showed that both psychotic groups exhibited bilateral frontotemporal dysfunction, but that, very dramatically this was asymmetrical, predominantly left frontotemporal for schizophrenics and predominantly right frontotemporal for the affectives.– It is worth noting here that not a single case of affective or periodic schizoaffective psychosis proved to have predominantly left-hemispheric dysfunction, and that in the schizophrenias the three laterality misclassifications, all with pronounced affective features, fell into the ‘‘schizophreniform’’ variety. The three schizophrenics with normal neuropsychological profile were the only three of the series that were of superior intelligence. This is of interest in view of the recent evidence48 that intelligence and schizophrenia are independently transmitted and that high I.Q. has a favorable action on the schizophrenic process.

– The table shows the pattern analysis evaluated by the senior neuropsychologist (L.T.Y.). The second neuropsychologist (D.F.) found that 90% of the affectives had predominantly right-hemisphere dysfunction, whereas 80% of the schizophrenics had predominantly left-hemisphere dysfunction, excluding those cases with symmetrical dysfunction.

Examining the interactions existing between severity of cerebral dysfunction, laterality, lobe, and diagnosis (TA B L E S 3, 4) it is seen that mild degrees of cerebral disorganization appear to occur randomly and bilaterally in both groups. Laterality effects emerged only in the presence of severe dysfunction, and were stronger in the frontal than in the temporal regions. The strongest association was between severe left frontal dysfunction and schizophrenia. There were six affectives and two schizophrenics who proved to be sinistral. Of these, all but one (affective), on the basis of finger oscillation, dynanometric strength and preferred hand for exploration on the formboard, appeared to have remained left hemisphere dominant. On these premises, all six affectives had predominantly nondominant dysfunction, and the two schizophrenics, predominantly dominant dysfunction. In a separate analysis (Scheffes Multiple Comparisons) of the affective psychoses, the pure depressive ðn ¼ 13Þ, the pure hypomanic and manic types ðn ¼ 26Þ, the periodic schizoaffectives ðn ¼ 21Þ, the unipolar ðn ¼ 31Þ, and the bipolar cases ðn ¼ 29Þ were compared with each other. The severity of cerebral dysfunction was similar in all these subcategories, and they could not be distinguished

LA T E R A L I T Y

AND

TA B L E 3 SE V E R I T Y O F CE R E B R A L DY S F U N C T I O N

Left

Right

Frontal Schizophrenics Mild Severe

18 33

35 10

v2 ¼ 17:45 P < 0:001

Affectives Mild Severe

33 9

23 25

v2 ¼ 8:95 P < 0:01

LA T E R A L I T Y

AND

TA B L E 4 SE V E R I T Y O F CE R E B R A L DY S F U N C T I O N

Left

Right

Temporal Schizophrenics Mild Severe

26 21

28 10

v2 ¼ 3:05 n.s. (v2 ¼ 3:8, P < 0:05)

Affectives Mild Severe

22 4

19 21

Yates Corr. v2 ¼ 7:71 P < 0:01

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in terms of neuropsychological characteristics. The neuropsychological evidence presented thus suggests that the endogenous psychoses reflect lateralized, asymmetrical dysfunction of the anterior limbic structures, more particularly of the orbital frontal-anterior temporal regions, anatomically and functionally linked through the uncinate fasciculus. It is notable that a threshold effect seems to operate, milder degrees of neuropsychological dysfunction occur bilaterally in both psychoses. The schizophrenic syndrome appears to be crucially dependent on disorganization of those neuronal assemblies in the dominant frontotemporal regions that are also critical for language processes. The affective psychoses, and the periodic schizoaffective psychoses, reflect perturbation of the homologous, nondominant cerebral areas. The significance of disturbance in the anterior rather than the posterior aspects of the limbic system is further suggested by the fact that the strongest associations between diagnosis and lateralized disturbance hold in the frontal regions and are still evident in the temporal, but disappear in the parietal areas. In addition, it is perhaps worthy of emphasis that the 27 neuropsychological variables discussed, quite independently of psychic symptoms, provide an objective diagnostic technique that correctly classify the endogenous psychoses with an accuracy of the order of 90%. Power Spectral EEG Analysis This research was made possible through the collaboration of Dr. Z.J. Koles,** who was responsible for the design of the hardware and software components of the system and the analysis of the spectral data, with the technical assistance of Mr. P. Bo-Lassen.   The initial findings have been reported in an abstract.49 Twentyeight schizophrenics, 18 manic-depressive, and 19 normal controls were studied. The psychiatric groups were not medicated and had not received ECT. Needle electrodes in the right and left temporal and parietal regions were used in a unipolar montage against a vertex reference. A Tektronic type RM122 preamplifier and cascaded band pass amplifiers were also used to provide additional gain in the 3–50 Hz region. The overall amplification, determined by the 2.5 V input range of the data acquisition system ranged between 30,000 and 50,000. The data acquisition and analysis system consisted of a Hewlett–Packard 2100S minicomputer. Each subject was analyzed in ten three-minute situations: at rest, eyes open and closed, and during verbal and visu**

Dr. Z.J. Koles, Associate Professor, Division of Biomedical Engineering and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.    Mr. P. Bo-Lassen, Graduate Student, Faculty of Electrical Engineering, University of Alberta, Edmonton, Alberta, Canada.

ospatial tasks both motor and nonmotor. During each situation three-minute recordings consisting of 10 bit samples (at a rate of 120/second), were collected simultaneously from the four electrodes. The data was analyzed with a Fast Fourier Transform in consecutive segments of 256 samples. A raw spectral estimate was obtained by averaging the transforms from all the segments, and refined spectrum by smoothing the raw estimate with a digital low pass filter. Results The schizophrenics showed significantly more power in the 20–30 Hz band in the left temporal region than normals ðp < :05Þ. Power in the right temporal region was similar in schizophrenics and normals. The schizophrenics had significantly more power in the 20–30 Hz band in the left, than in the right temporal areas ðp < :05Þ. In normals the right/left power ratios calculated in the alpha frequencies reflected the relative lateralized suppression of cerebral energy expected during verbal and spatial tasks, as originally reported by Galin and Ornstein.50 The ratios were greater during verbal than during spatial tasks. The psychotic groups showed the same effect as normals, but more weakly (p < :05 vs. p < :001, respectively), and the schizophrenics failed to show it in the parietal regions. The manic-depressives had more power in the 20–30 Hz band than normals, in both right and left temporal regions. The excess energy was however significantly greater on the right side (Left, p < :1; Right, p < :05, Mann–Whitney U-test, one tailed test). Examined at two-second intervals for three-minute periods, the time-course deviations of right/left energy ratios of both psychotic groups behaved similarly and were markedly different from normals. In normals there are frequent fluctuations of the ratios over time, above and below unity, but they are small. In both psychoses these shifts, on either side of unity, are often of much greater magnitude and of much longer duration. Conclusion These results appear to indicate bilateral, although predominantly right temporal abnormality in the affective psychoses and predominantly left temporal dysfunction in the schizophrenics. In addition the ‘‘sluggish’’ right/left energy shifts in different cognitive tasks and the abnormal time course deviations of these ratios in the psychoses suggest perhaps a defect of interhemispheric integration. Discussion It is tempting to relate the defect of interhemispheric integration to the observation that showed that the only structural difference differentiating the brains of chronic schizophrenics from normal brains was the larger width and volume of the corpus callosum in the former.51 In this perspective it is fascinating to recall that Kurt Goldstein

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in 1927,§§ describing a patient with section of the corpus callosum had the following to say on the psychopathological consequences of disturbed interhemispheric connections: ‘‘The separation of so large a part of the brain and the resulting impossibility of evaluating stimuli perceived with the right hemisphere... surely cannot be without effect on the total personality... I have pointed out the presence in my patient of a feeling of strangeness in relation to movements of the left hand, which she described with such curious expressions, (she would say someone was moving her hand and that she was not doing it herself), that she was regarded at first as a paranoiac. It appears to me not to be excluded that on this basis and under certain conditions there may develop paranoid states, perhaps also the experience of double personality and above all the experience of being influenced from without....’’

The diverse evidence reviewed and the original neuropsychological and electrophysiological data presented, shows that one of the crucial parameters leading to the schizophrenic syndrome relates to abnormal events which occur in the dominant frontotemporal circuits. Numerous studies of mean integrated amplitude in chronic schizophrenia, pioneered by Leonide Goldstein,52–55 were almost always derived from left occipital electrodes. These revealed that hypovariability was characteristic of chronic schizophrenia. More recently these workers56 found that the total integrated amplitude was higher on the left side in 173 psychiatric patients; and the anxiety and euphoriants (15 mg d-amphetamine) produced a shift to the right, whereas chlorpromazine a shift to the left, in normals. Similarly, Serafetinides57;58 reports a voltage increase, lateralized to the dominant hemisphere in schizophrenia, which correlated with improvement, spontaneous or as the result of chlorpromazine. Again recent spectral studies59;60 confirm that the abnormally high energy between 18 and 30 Hz is a striking feature of schizophrenia. The composite spectral curves averaging schizophrenics and normals (from an ongoing study) illustrate the abnormal left temporal energy in the 20– 30 Hz, characteristic of schizophrenia (FI G U R E S 1, 2). DÕElia and Perris61 have shown that integrated amplitude from parietooccipital leads is higher on the stimulated side after unilateral ECT. They also conclude62 that because of a significant increase in the variance of the amplitude on the left side, after bilateral ECT, the left hemisphere is implicated primarily in depression. It should be noted that the coefficient of variation, the more usual index of variability, did not significantly differ on the right or left in their 18 patients. Marjerrison,63 who replicated this last investigation, found a bilateral, not unilateral, increase in variance after bilateral ECT and ‘‘could not support their conclusion of more pronounced involvement of the domi-

§§

Quoted from Geschwind, N.18

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nant hemisphere in depressive states.’’ Perris64 found further evidence for his view, reporting Visual AER, which are smaller on the left than on the right in depression, with a majority inverting after treatment. Since it has been shown that the visual AER in normals is larger over the nondominant than over the dominant hemisphere,65 this conclusion is certainly questionable, since his study lacked a normal control group. It is apparent the association between schizophrenia and the left hemisphere is more powerfully established than that of the lateralization to the right hemisphere of the affective syndromes. The problem, perhaps, is that it would seem that bifrontal and nondominant frontotemporal disorganization both may be translated into dysphoric morbid states, whereas perturbation of the dominant frontotemporal system alone modulates the schizophrenic syndrome (which may, of course, occur with bilateral disorganization). The formulation would explain why transitions from chronic manic-depressive psychosis to schizophrenia is possible, and also why the converse, chronic schizophrenic syndromes transforming themselves into manic-depressive states, never occurs. Some of the evidence that suggests that affective responses are a function of the nondominant hemisphere is as follows: 1. It is an old neurological observation that euphoric indifference is a feature of cerebral tumors of the nondominant hemisphere.66 Anosognosia for hemiplegia, found with left, but not with right, paralysis, is an analogous phenomenon. 2. Dysphoric states after penetrating head injuries are lateralized to the right,36 as are manic-depressive psychoses in temporal epilepsy.39 3. It is now accepted that unilateral nondominant ECT is as effective as bilateral ECT in certain pathological depressions. There are a number of recent studies that suggest that unilateral nondominant induction may be therapeutically more effective than bilateral.67;68 Notwithstanding, assuming bilateral and unilateral nondominant seizures to be equivalent, unilateral seizures to the dominant hemisphere are therapeutically less effective. Since the majority of unilaterally induced seizures are asymmetrically bilateral, both at the motor and neurophysiological level, and implicate more the stimulated side,61 it would follow that the nondominant hemisphere is critically involved in depression. (FI G U R E 3) 4. It has been shown69 that in normals intracarotid injection of amytal to the nondominant hemisphere produces euphoria and injections to the dominant side, depression. However, in depressed patients both dominant and nondominant injections induce euphoric responses. Further, there is an inverse relationship between speech laterality and depth of depression; the more depressed the patient, the more he appears

586

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FI G U R E 1. Composite spectrogram: 7 normals (eyes open).

to exhibit the organization of the nondominant hemisphere in both hemispheres. These findings may imply that with increasing intensity of depression the non-

dominant hemispheric dysfunction progressively leads to contralateral frontal disorganization expressed as reduced lateral specialization on that side.

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FI G U R E 2. Composite spectrogram: 11 schizophrenics (eyes open).

5. It will be recalled that observations in the thirties7;8 on hemiplegics found that emotional instability of the ‘‘catastrophic reaction’’ type was associated with

right, but not left hemiplegia; in other words, with severe insults lateralized to the dominant hemisphere. This has been confirmed by Gainotti,70 in

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FI G U R E 3. Characteristic spectral EEG found in schizophrenia.

a study of 160 lateralized cerebrovascular lesions, 80 to the left and 80 to the right hemisphere. A strong association was found between ‘‘depressive-catastrophic’’ reactions and lesions with Broca-type aphasia, i.e., dominant frontal. Abnormal mood reactions were characteristic of ischaemic lesions to the right hemisphere. It should be emphasized that ‘‘catastrophic-depressive’’ reactions are quite different from endogenous psychoses that do not occur in the wake of massive cerebral insults accompanied by hemiplegia, right or left. As dominant frontal lesions produce blunting of affect,38;43 the following hypothesis is suggested: affective responses are determined by nondominant frontotemporal limbic circuits, but are regulated by frontal mechanisms in the dominant hemisphere. With increasing intensity of depression, the frontal disorganization becomes increasingly bifrontal, and this may also modulate the schizoaffective symptomatology.71

CONCLUSION The evidence reviewed implies that the schizophrenic syndrome and psychopathy are manifestations of neuronal disorganization in the dominant orbital frontaltemporal regions. The manic-depressive syndromes reflect disorganization of the nondominant anterior limbic structures. Quite apart from the relationships existing between hemispheric dominance, language and speech abnormalities, thought disorder, and blunting of affect another association perhaps emerges. If one accepts that, for the reasons outlined earlier, subjective

‘‘consciousness’’ is a function of brain stem–mesial frontal connections on the left side, then it seems possible that the insidious feeling of personality change and ‘‘depersonalization’’ often seen in schizophrenia may also be the reflection of lateralized hemispheric dysfunction. On neuropsychological evidence the periodic schizoaffective psychoses, like the manic-depressives, have predominantly nondominant dysfunction, but some power spectral EEG data is available that shows that during the acute psychotic phase these have more extensive bitemporal involvement. How these laterality effects can be integrated with the gender-related differential hemispheric organization of the male and female brain and thus immediately account, in a developmental perspective, for the different sex incidence of the major psychopathological syndromes has been discussed elsewhere.72 Infantile autism, aggressive psychopathy, and schizophrenia are overrepresented in males, compared to females, who, on the other hand, are more liable to affective disturbances, both psychotic and neurotic. The male, whose dominant hemisphere is relatively more vulnerable, but who, compared to the female, has a more efficient nondominant hemispheric organization, will thus be more susceptible to syndromes of dominant dysfunction: autism, schizophrenia, psychopathy. The female, with relative dominant hemispheric superiority and nondominant vulnerability, will have an increased susceptibility to syndromes of nondominant dysfunction: pathological disturbances of mood. Developmental aspects are of fundamental importance, for these phenomena are most prominent early in ontogenesis and progressively diminish with maturation.

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