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Lateralized hemispheric dysfunction in the major psychotic disorders: historical perspectives and findings from a study of motor asymmetry in older patients
SCHIZOPHRENIA RESEARCH ELSEVIER
Schizophrenia Research 27 (1997) 191--198
Lateralized hemispheric dysfunction in the major psychotic disorders: historical perspectives and findings from a study of motor asymmetry in older patients J a m e s B. L o h r
a,b,c,*,
M i c h a e l P. C a l i g i u r i a,b
a Department o f Psychiatry, University o f California, San Diego, CA, USA b Geriatric Psychiatry Clinical Research Center, San Diego, CA, USA c San Diego VA Medical Center, San Diego, CA, USA
Abstract
Differences in functioning between the two cerebral hemispheres have been reported for more than a century. In recent decades, issues related to lateralized dysfunction have been raised in psychiatric illnesses such as schizophrenia and bipolar disorder. In particular, evidence suggests that schizophrenia may be particularly associated with left hemisphere dysfunction and bipolar disorder with right hemisphere dysfunction. We discuss these issues, along with a conceptual framework for integrating hypotheses about the relationship between the major psychotic illnesses based on a two-dimensional continuum. We also present new findings from our study of motor asymmetry in older patients with psychosis that support this framework. Our results indicate that schizophrenia may be associated with left hemisphere pathology to a greater extent than right, whereas the reverse may occur in bipolar disorder. © 1997 Elsevier Science B.V.
Keywords: Bipolar disorder; Hemispheric laterality; Schizoaffective disorder; Schizophrenia 1. Introduction
Investigators have long been interested in biologic measures, including neuropathologic, imaging, psychophysiologic, and neurochemical analyses, that might help localize the sites of pathology in major psychotic illnesses. Interestingly, lateralized pathology and dysfunction are some of the most commonly reported
* Corresponding author. Present address: Psychiatry Service-116A, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel: 619-552-8585; fax: 619-642-6224. 0920-9964/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PH S0920-9964(97 ) 00062-5
localizing biologic findings in schizophrenia. In this paper, we focus on the possible importance of laterality in our understanding of schizophrenia and bipolar disorder.
2. Historical perspective
The history of hemispheric laterality and that of cerebral localizationism are intimately connected (Harrington, 1987). Before 1860, the primary protagonists of the localizationist perspective were the phrenologists, led by Franz Joseph Gall
192
J.B. Lohr, M,P, Caligiuri / Schizophrenia Research 27 (1997) 191 198
(1758-1826). Despite their avid stance that different brain functions resided within specific regions of the brain, many phrenologists, including Gall, believed essentially that the presence of two hemispheres was akin to the presence of two lungs or two kidneys--providing a buffer against injury rather than reflecting specialized functioning of the hemispheres. A dissenting opinion was offered by phrenologist Carl Spurzheim (1809 1872), a nephew of Gall, who felt that the two hemispheres must exist for some additional reason, beyond simple redundancy of function. The phrenologists' ideas were persuasive but not universally embraced. Based on studies of tissue excised from the brains of birds, Jean-Pierre-Marie Flourens (1794-1867) espoused the classic antilocalizationist perspective with his belief that the exact location of tissue excision was immaterial, but that with greater loss of tissue in general there was a correspondingly greater but diffuse reduction in brain function. The localizationist perspective, however, was greatly boosted by the studies of Paul Broca (1824-1880) on aphasia, or aphemia, as he called it. Although Broca believed that his clinical material supported the concept of localization of articulatory speech or language to the second or third frontal gyrus, he was less convinced initially of the hemispheric specificity of this localization. After several years and continuing accumulation of clinical aphasia cases, however, the notion that language is preferentially localized to the left hemisphere of the brain became widespread. John Hughlings Jackson (1835-1911) was perhaps the most thoughtful spokesperson for hemispheric lateralization of function in his time. He conceptualized brain function as consisting of a hierarchy of functions, built essentially on sensorimotor mechanisms, and ranging from the 'anterior and posterior horns of the spinal cord', through the 'ganglia of the corpus striatum', and finally to the 'highest motor centres (prae-frontal lobes)... and highest sensory centres (occipital lobes)' (Jackson, 1887, pp. 29-30). He further believed that the highest centers inhibited or controlled the lower centers, and that, with loss of function of the higher centers, the lower centers would show increased activity. He considered this loss of function of higher neurologic centers to underlie
'negative' symptoms, and the increased activity of lower centers to give rise to 'positive' symptoms. In addition to a sensorimotor distinction relating to a posterior anterior direction in the brain, Jackson also believed that there was a lateralized hemispheric, or left-right, sensorimotor distinction, in which the left hemisphere was more closely related to motor function and the right to highlevel sensory or perceptual function. The combination of these two sensorimotor gradients is related to Jackson's concept that motor function is preferentially associated with the anterior left hemisphere and perceptual function with the posterior right hemisphere. Such +quadrant' effects have been discussed more recently in terms of mood localization in the brain, in studies by Robinson et al. (1988) and Starkstein et al. (1991) and in a review of the literature from our laboratory (Jeste et al., 1988). In the early 1900s, and in particular during World War I, interest in hemispheric laterality decreased considerably. Despite Hugo Liepmann's concepts of apraxia, which supported Jackson's notions of high-level motor function being associated with the left hemisphere, many investigators of the time moved toward an antilocalizationist viewpoint. Some of this was probably due to the large number of head injuries studied during World War I, from which investigators were impressed by the capacity of the brain to assume functions initially lost as a result of trauma (Goldstein, 1939). This was considered by some to be a blow against the localizationist perspective, although in retrospect these findings were more a tribute to the plasticity of the brain+ rather than an indictment against localizationism. Hemispheric specialization received little further attention until the 1950s and 1960s, in particular with the studies by Sperry on split-brain persons who had received commissurotomies to relieve epilepsy (Sperry, 1962, 1968). In a series of elegant experiments, he demonstrated substantial differences in the way the hemispheres function, although defining these differences in terms of a single dimension has proved difficult. Since that time, numerous studies into the nature of lateralized differences have been performed, with investigators proposing a variety of distinctions relating to the nature of the functioning of the hemispheres.
,LB. Lohr, M.P. Caligiuri / Schizophrenia Research27 (1997) 191-198
Table 1 lists several of the distinctions raised between the functioning of the left and right hemispheres. From the viewpoint of psychosis, much of the current interest in hemispheric laterality can be traced back to the studies of Flor-Henry, Gruzelier, and others in the late 1960s and 1970s (Flor-Henry, 1969; Gruzelier and Flor-Henry, 1979). Flor-Henry in particular studied patients with psychomotor epilepsy and noted a relationship of schizophrenia-like symptoms with left hemisphere pathology and mood disorder symptoms with right hemisphere pathology.
3. Studies of laterality in schizophrenia To address the issue of laterality and schizophrenia, we performed a computerized Medline review of the literature from 1980 to early 1996 (1980 marking the introduction of the DSM-III). We used the following key words in various combinations for this search: schizophrenia, bipolar disorder, schizoaffective disorder, psychosis, laterality, asymmetry, and hemispheric imbalance. We made no attempt to select specific articles based on a particular measurement domain or patient sample. Case studies were not included. Additional articles were retrieved using citations from articles identified by the computerized search. Table 1 Evolution in the conceptualization of distinctions in hemispheric function over the last 130 years Time
Left hemisphere
Right hemisphere
1860s-1910s Jackson
Language High-level motor and speech Language Verbal Analytic Analytic Serial processing Detail-oriented Propositional mind Logical Rational
Undefined High-level perception
1950s 1960s 1970s-present
Adapted from Cutting, 1990.
Spatial Nonverbal Synthetic Holistic Parallel processing Gestalt Appositional mind Creative Emotional, affective
193
Although we attempted to find as many relevant studies as possible, it is unlikely that we performed a fully comprehensive review, because there are many studies in which lateralized findings were not a primary focus of the study, and results pertaining to laterality may receive only brief mention in the results section. Thus, a fully comprehensive review would require scrutiny of thousands of controlled studies of schizophrenia over a 15-year period. Nevertheless, we believe we have captured the most important studies in which laterality issues were addressed during this period. We divided the studies into those that are strongly, partially, or not supportive of one hemisphere being more involved in schizophrenia than the other. These studies are presented in Table 2. A total of 118 articles were used to construct this table, and each study appears only once. A strongly supportive study was one in which there was a statistically significant finding between the hemispheres that the investigators attributed to pathology or dysfunction of one particular hemisphere. A partially supportive study was one in which there was a nonsignificant trend for a laterality finding or in which the laterality finding occurred only in a subgroup of the patient sample (such as only in women or only in paranoid type of schizophrenia). A nonsupportive study was one in which the issue of laterality was addressed, but no statistically significant difference between the hemispheres emerged.
3.1. Implications of laterality studies in schizophrenia Most of the studies in which the issue of laterality was addressed reported lateralized findings in schizophrenia, and most of these implicated the left hemisphere in particular. A putative hemispheric imbalance in schizophrenia in which the left hemisphere is more involved than the right has several implications regarding the pathophysiologic process or processes involved. For example, the pathophysiologic process in schizophrenia itself may cause abnormal lateralized development and function (as proposed by Crow et al., 1989). One side of the brain (mainly the left) also may be more vulnerable to the pathophysiologic processes
194
J.B. Lohr, M.P. Culigiuri " Sehizophrenia Research 27 (1997) 191 198
Table 2 N u m b e r of studies in the schizophrenia and bipolar literature since 1980 rated according to strength of support for left or right hemisphere dysfunction a Domain Schizophrenia Motor b Neuropsychologic c Functional imaging d Structural imaging d Neuropathologic and neurochemical c Overall Bipolar disorder Overall
Left strong
[,eft partial
None
Right partial
Right strong
7 18 I0 13 9 57
8 8 3 9 4 32
l 5 0 4 0 10
2 l 0 0 0 3
0 0 1 3 0 4
0
3
2
2
8
a Complete updated list of references available on request. b Consists of studies of neuroleptic-induced parkinsonism, tardive (tyskinesia. and motor control. c Consists of studies of dichotic listening, verbal and nonverbal neuropsychologic tests, and P300 and N400 responses from event-related potentials. d Consists of magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, regional cerebral blood flow, and computed tomographic studies. c Consists of postmortem studies and studies of neurotransmitter receptor densities.
involved in schizophrenia. These processes would give rise to clear-cut schizophrenic symptoms when they involve the left side of the brain. When they involve the right side of the brain, the clinical symptoms would be less clearly schizophrenic in nature. These differing explanations, and there may be others as well, are not mutually exclusive. Different processes could account for the different patients within the schizophrenia spectrum. Nevertheless, that certain pathophysiologic processes give rise to schizophrenic symptoms, primarily as an interaction between those processes and the inherent normal functions of the left hemisphere, caused us to speculate about the type of clinical picture that might result from similar processes in the right hemisphere. Because of the importance of the right hemisphere in emotions and mood (Bradshaw, 1989; Hellige, 1993), we considered that involvement of the right hemisphere might be associated with greater mood impairment, as is seen in schizoaffective or bipolar disorder, both of which can be difficult to distinguish clinically from schizophrenia. We therefore performed a similar literature search on the relationship of bipolar disorder to lateralized function and structure. Although we found fewer studies, most of these studies demon-
strated greater right than left hemisphere involvement in bipolar disorder (Table 2).
4. Caveats in laterality studies
Several important caveats must be kept in mind when evaluating the findings of any study of laterality, including ours. First, hemispheric imbalance per se does not necessarily indicate which hemisphere is predominantly involved. For example, the finding of a smaller hippocampus on the left side compared with the right side does not necessarily indicate that the left side is more pathologic, since the right side may be pathologically enlarged. The presence of a healthy comparison group can be helpful in this regard, but not completely so, for the following reason. If, in the previous hypothetical example, a healthy group had left hippocampi similar in size to those of patients with schizophrenia but their right hippocampi were larger, we might conclude that the right hippocampus is pathologically enlarged in the schizophrenic group. However, if the pathologic process in schizophrenia involved both hemispheres, perhaps only the right side was able to invoke a compensatory mechanism, involving
,L B. Lohr. M.P. Caligiuri / Schizophrenia Research 27 (1997) 191-198
enlargement, to preserve more normal hippocampal functioning. Thus what we observe not only reflects the initial pathologic processes, but also the brain's response to those processes, which could alter the interpretation of lateralized findings. A second complexity in interpreting laterality studies concerns the possibility that the hemispheres may function in a mutually inhibitory way (Kinsbourne, 1975, 1982). Therefore, finding that a certain brain region in the left hemisphere is overactive does not necessarily imply a primary pathologic process in that region, but may reflect a pathologic process in the right hemisphere, which results in insufficient inhibition of the left hemisphere. Third, language dominance and handedness may influence results. Studies, particularly functional studies in which the dependent measures involve use of language or manual dexterity, must be interpreted cautiously. Because both language and manual dexterity are associated more strongly with the left hemisphere, sorting through these issues when drawing conclusions about right hemisphere functioning is important. Thus a task designed to assess right hemisphere function, but in which the measure involves verbal communication, may introduce a left hemisphere component to the task measurement.
5. Relationship of schizophrenia and bipolar disorder The nature of the relationship between schizophrenia and bipolar disorder has been a puzzle for many years (Kerr and McClelland, 1991). Essentially, two basic hypotheses have been proposed. The first, which dates from Kraepelin (1896), forms the basis for most modern diagnostic systems, including the Diagnostic and Statistical Manual of Mental Disorders (DSM). Called the 'two-disease hypothesis', it posits that schizophrenia and bipolar disorder are separate clinical entities (Kraepelin, 1896). This approach, which is unquestionably valuable heuristically, has been criticized because of problems accounting for schizoaffective disorder, in which patients often
195
have a clinical picture somewhere between the two. The second approach, called the 'continuum hypothesis', places schizophrenia and bipolar disorder at the endpoints of a unidimensional continuum, with schizoaffective disorder representing an intermediate position (Kendell, 1991). In some cases, the continuum is extended beyond bipolar disorder to include unipolar depression. This hypothesis has also been criticized, largely because it is unclear exactly what forms the basis for this continuum. In other words, what single underlying phenomenon could possibly be involved that, when varied, can give rise to schizophrenia, schizoaffective disorder, or bipolar disorder? We have proposed that schizophrenia and bipolar disorder lie on a continuum, but in two dimensions, with psychotic symptom severity representing one axis and mood symptom severity the other axis (Fig. 1) (Lohr and Caligiuri, 1995). Schizoaffective disorder falls into an intermediate spatial region. This two-dimensional approach offers the advantage of incorporating aspects of both the two-disease and unidimensional continuum hypotheses. Additionally, it does not restrict the relationship of schizophrenia and bipolar disorder to a single varying phenomenon, since
Two-Dimensional Continuum
u)Et o.>, "om E o o
~~~
Schizophrenia
Psychotic symptoms Fig. 1. Two-dimensional continuum for major psychotic disorders, with psychotic symptom severity along the x axis and mood symptom severity along the y axis. Schizoaffective disorder tails into an intermediate spatial region. We have deliberately not drawn the boundaries between the disorders as symmetrical around the y = x line, because when psychotic symptoms are severe, they may mask mood symptoms, with the resulting condition appearing as schizophrenia even when there may be significant underlying mood involvement.
196
J. B, Lohr, M. P, Caligiuri / Schizophrenia Research 27 (1997) 191 198
two or more different processes could be at work in creating symptoms. When considered with the laterality literature discussed above, one possible explanation for the two dimensions of psychosis and mood could relate to left hemisphere and right hemisphere involvement, respectively. This is along the lines suggested by Iaccino (1993) when he stated, 'If schizophrenia has more left-hemispheric involvement (or damage), then the affective psychoses would seem to have the complementary sided asymmetry' (p. 92). Although the reasons for this are unclear, Iaccino later speculated, from an evolutionary perspective, that 'it can be reasoned that the affective psychoses developed from the schizophrenic, and eventually came to be housed in the emotional right hemisphere as the left side functionally set itself apart to regulate those linguistic components mainly associated with schizophrenia' (p. 93).
6. Instrumental motor assessment of asymmetry in the major psychoses
We have begun to assess the hypothesis that schizophrenia and bipolar disorder may be related in the sense that schizophrenia involves the left hemisphere to a greater extent than the right, while the opposite is true for bipolar disorder. In the present study, we examined a group of righthanded older patients (>45 years old) with schizophrenia, bipolar disorder, or schizoaffective disorder and compared our findings with those in healthy comparison subjects. One advantage of using a group of older patients is that there is greater diagnostic certainty than in younger patients. In addition to the above hypothesis, we also hypothesized that patients with schizoaffective disorder would not show an overall preference in the direction of abnormal laterality. 6.1. Methods
Sixty-five patients and 30 healthy comparison subjects were studied. Their demographic characteristics are listed in Table 3. Patients and controls
Table 3 Patient characteristics for the study of m o t o r asymmetry Diagnosis
n
Age
Schizophrenia Mania Schizoaffective Normal
49 6 10 30
57,0 61.5 58.7 60.7
(1.3) (3.6) (3.4) (2.1)
Illness duration
Sex (male:female)
26.7 (1.7) 26.0 (5.2) 27.3 (4.6) --
34:15 6:0 10:0 20:10
Data are means (standard errors).
were recruited for this study as part of their participation in ongoing research within our Geriatric Psychiatry Clinical Research Center. Patients were maintained on stable dosages of neuroleptic medication for at least 3 months before their motor assessment. The use of neuroleptics, mood stabilizers, or antiparkinsonian medications varied widely across patients and was not controlled for in this study. All subjects were right-handed. Patients met DSM-IV criteria for paranoid type of schizophrenia, schizoaffective disorder, or manic episode of bipolar disorder. There were no significant differences between the patient groups in age or illness duration. As in our previous studies of motor asymmetry, we used a measure of hand force instability. A patient is instructed to press and hold a stable level of force with their index finger placed on a strain gauge, while following a stable target representing that force on a computer monitor. The amount of variation around that target over time represents the degree of hand force instability. Force instability, reported as percent error, is computed by obtaining the mean and standard deviation of the points of the waveform over a 15-s interval and computing the coefficient of variation by dividing the standard deviation by the mean. An asymmetry score is computed by subtracting the force error score of the right hand from that of the left hand. Using this technique, we previously found significantly greater rightthan left-hand force instability in a group of right-handed patients with schizophrenia and significantly greater left- than right-hand force instability in a group of right-handed patients with bipolar disorder. The healthy control sample
J.B. Lohr, M.P. Caligiuri / Schizophrenia Research 2 7 (1997) 191-198
showed no lateralized difference (Lohr Caligiuri, 1995).
and
197
and patients with schizophrenia (p=0.007 and p=0.0003, respectively). Other comparisons were not significant.
6.2. Results 6.3. Discussion and conclusion
The mean (standard error) motor asymmetry scores for the schizophrenic, bipolar disorder, schizoaffective, and normal comparison subjects were -1.12 (0.27), 2.86 (1.62), 1.60 (1.09), and - 0.02 (0.10), respectively. Because of nonhomogeneity of variance across the four groups for the hand force error scores, we used nonparametric tests to examine group differences in mean force error scores for the left-right ( L - R ) hand difference score. The results of a Kruskal-Wallis analysis of variance indicated a highly significant group effect for the L - R difference score ( H = 28.39; d f = 3; p<0.0001). The mean L R scores (with standard error) are shown in Fig. 2 for the four subject groups. Post-hoc Mann-Whitney tests revealed that the mean L - R score for patients with schizophrenia was significantly different from the L - R scores for patients with bipolar disorder ( p = 0.0003), patients with schizoaffective disorder (p = 0.0007) and normal comparison subjects ( p = 0.0007). Patients with bipolar disorder differed significantly from the healthy comparison subjects
® 5 O u
~4 ¢:
>,2
/i
.O
O u..
m
~'-2
SZ
BP
$A
NC
5
Fig. 2. The mean (standard error) motor asymmetry scores for the schizophrenic (SZ), bipolar disorder (BP), schizoaffective (SA), and normal comparison (NC) subjects. The schizophrenia group was significantly different from all other groups (p<0.001), and the bipolar group was significantly different from the schizophrenia and normal groups (p<0.01). The schizoaffective group was not significantly different from either the bipolar group or the normal group.
The findings from this instrumental motor assessment replicate our previous findings, indicating that schizophrenia may be associated preferentially with left hemisphere dysfunction and mania with right hemisphere dysfunction. Additionally, patients with schizoaffective disorder did not differ significantly from the healthy sample in terms of laterality, with six of the 10 patients demonstrating greater left than right hemisphere involvement, and the remaining four greater right than left involvement. These results are consistent with the conceptual framework that schizophrenia and bipolar disorder are associated with complementary hemispheric imbalance and that schizoaffecrive disorder represents an intermediate position. Also, because the findings for the older healthy comparison group in this study were similar to those of a younger group in our previous study (Lohr and Caligiuri, 1995), the effects of age on motor asymmetry may be limited. Several important considerations arise in interpreting the results of our study. First, the caveats discussed earlier regarding studies of laterality also apply in this circumstance. In particular, care must be taken, on the basis of a finding of hemisphere imbalance alone, in attributing the pathology to one or the other hemisphere. Second, the issue of mutual inhibitory function of the hemisphere may certainly play a role in the motor phenomena measured in this study. The third concern, related to language and manual dominance, is less of a problem in this study because the influence of language processing and hand preference on the force instability task is minimal. In addition to these problems, there are also concerns related to the small number of subjects in the bipolar and schizoaffective groups. Despite these caveats, we believe that current evidence supports the need to address issues of laterality in future functional and structural studies of schizophrenia and bipolar disorder. Hemispheric asymmetry may shed light on the
198 pathophysiology disorders.
J.B. Lohr, M.P. Caligiuri / Schizophrenia Research 2 7 ( 1997) 191-198 and
relationship
of these two
Acknowledgment T h i s r e s e a r c h was s u p p o r t e d in p a r t by P H S grants from the National Institute of Mental Health (R29-MH45959; P30 M H 4 9 6 7 1 ; R01 M 4 5 1 3 1 ). W e t h a n k R e b e c c a V a u g h a n a n d R o b e r t R u c k f o r a s s i s t a n c e in d a t a c o l l e c t i o n a n d analysis.
References Bradshaw, J., 1989. Hemispheric Specialization and Psychological Function. Wiley, Chichester. Crow, T.J., Ball, J., Bloom, S.R. et al., 1989. Schizophrenia as an anomaly of development of cerebral asymmetry. Arch. Gen. Psychiatry 46, 1145 1150. Cutting, J., 1990. The Right Cerebral Hemisphere and Psychiatric Disorders. Oxford University Press, Oxford. Flor-Henry, P., 1969. Psychosis and temporal lobe epilepsy: a controlled investigation. Epilepsia 10, 363-395. Goldstein, K., 1939. The Organism: A Holistic Approach to Biology Derived from Pathological Data in Man. American Book Company, New York. Gruzelier, J., Flor-Henry, P. (Eds.), 1979. Hemisphere Asymmetries of Function in Psychopathology. Elsevier/North Holland, Amsterdam. Harrington, A., 1987. Medicine, Mind, and the Double Brain. Princeton University Press, Princeton, NJ. Hellige, J.B., 1993. Hemispheric Asymmetry: What's Right and What's Left. Harvard University Press, Cambridge, MA.
laccino. J.F., 1993. Left Brain-Right Brain Differences: Inquiries, Evidence, and New Approaches. Erlbaum, Hillsdale, NJ. Jackson, J.H., 1887. Remarks on evolution and dissolution of the nervous system. J. Ment. Sci. 33, 25 48. Jeste, D.V., Lohr, J.B., Goodwin, F.K., 1988. Neuroanatomical studies of major affective disorders: a review and suggestions for further research. Br. J. Psychiatry 153, 444-459. Kendell, R.E., 1991. The major functional psychoses: are they independent entities or part of a continuum? Philosophical and conceptual issues underlying the debate. In: Kerr, A., McClelland, H. (Eds.), Concepts of Mental Disorder: A Continuing Debate. Gaskell, London, pp. 1-16. Kerr, A., McClelland, H. (Eds.), 1991. Concepts of Mental Disorder: A Continuing Debate. Gaskell, London. Kinsbourne, M., 1975. The mechanism of hemispheric control of the lateral gradient of attention, in: Rabbitt, P.M.A., Dornic, S. (Eds.), Attention and Performance, vol. 5. Academic Press, New York. Kinsbourne, M., 1982. Hemispheric specialization and the growth of human understanding. Am. Psychol. 37, 411 -420. Kraepelin, E., 1896. Psychiatrie, ein Lehrbuch fur Studierende und Arzte, 5th ed. Barth, Leipzig. Lohr, J.B., Caligiuri, M.P., 1995. Motor asymmetry, a neurobiologic abnormality in the major psychoses. Psychiatry Res. 57, 279-282. Robinson, R.G., Boston, J.D., Starkstein, S.E. et al., 1988. Comparison of mania and depression after brain injury: causal factors. Am. J. Psychiatry 145, 172-178. Sperry, R., 1962. Some general aspects of interhemispheric integration. In: Mountcastle, V.B. (Ed.), lnterhemispheric Relations and Cerebral Dominance. Johns Hopkins University Press, Baltimore, MD. Sperry, R., 1968. Hemisphere disconnection and unity in conscious awareness. Am. Psychol. 23, 723-733. Starkstein, S.E., Bryer, J.B., Berthier, M.L. et al., 1991. Depression after stroke: the importance of cerebral hemisphere asymmetries. J. Neuropsychiatr. Clin. Neurosci. 3, 276-285.
Schizophrenia Research 27 (1997) 191--198
Lateralized hemispheric dysfunction in the major psychotic disorders: historical perspectives and findings from a study of motor asymmetry in older patients J a m e s B. L o h r
a,b,c,*,
M i c h a e l P. C a l i g i u r i a,b
a Department o f Psychiatry, University o f California, San Diego, CA, USA b Geriatric Psychiatry Clinical Research Center, San Diego, CA, USA c San Diego VA Medical Center, San Diego, CA, USA
Abstract
Differences in functioning between the two cerebral hemispheres have been reported for more than a century. In recent decades, issues related to lateralized dysfunction have been raised in psychiatric illnesses such as schizophrenia and bipolar disorder. In particular, evidence suggests that schizophrenia may be particularly associated with left hemisphere dysfunction and bipolar disorder with right hemisphere dysfunction. We discuss these issues, along with a conceptual framework for integrating hypotheses about the relationship between the major psychotic illnesses based on a two-dimensional continuum. We also present new findings from our study of motor asymmetry in older patients with psychosis that support this framework. Our results indicate that schizophrenia may be associated with left hemisphere pathology to a greater extent than right, whereas the reverse may occur in bipolar disorder. © 1997 Elsevier Science B.V.
Keywords: Bipolar disorder; Hemispheric laterality; Schizoaffective disorder; Schizophrenia 1. Introduction
Investigators have long been interested in biologic measures, including neuropathologic, imaging, psychophysiologic, and neurochemical analyses, that might help localize the sites of pathology in major psychotic illnesses. Interestingly, lateralized pathology and dysfunction are some of the most commonly reported
* Corresponding author. Present address: Psychiatry Service-116A, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel: 619-552-8585; fax: 619-642-6224. 0920-9964/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PH S0920-9964(97 ) 00062-5
localizing biologic findings in schizophrenia. In this paper, we focus on the possible importance of laterality in our understanding of schizophrenia and bipolar disorder.
2. Historical perspective
The history of hemispheric laterality and that of cerebral localizationism are intimately connected (Harrington, 1987). Before 1860, the primary protagonists of the localizationist perspective were the phrenologists, led by Franz Joseph Gall
192
J.B. Lohr, M,P, Caligiuri / Schizophrenia Research 27 (1997) 191 198
(1758-1826). Despite their avid stance that different brain functions resided within specific regions of the brain, many phrenologists, including Gall, believed essentially that the presence of two hemispheres was akin to the presence of two lungs or two kidneys--providing a buffer against injury rather than reflecting specialized functioning of the hemispheres. A dissenting opinion was offered by phrenologist Carl Spurzheim (1809 1872), a nephew of Gall, who felt that the two hemispheres must exist for some additional reason, beyond simple redundancy of function. The phrenologists' ideas were persuasive but not universally embraced. Based on studies of tissue excised from the brains of birds, Jean-Pierre-Marie Flourens (1794-1867) espoused the classic antilocalizationist perspective with his belief that the exact location of tissue excision was immaterial, but that with greater loss of tissue in general there was a correspondingly greater but diffuse reduction in brain function. The localizationist perspective, however, was greatly boosted by the studies of Paul Broca (1824-1880) on aphasia, or aphemia, as he called it. Although Broca believed that his clinical material supported the concept of localization of articulatory speech or language to the second or third frontal gyrus, he was less convinced initially of the hemispheric specificity of this localization. After several years and continuing accumulation of clinical aphasia cases, however, the notion that language is preferentially localized to the left hemisphere of the brain became widespread. John Hughlings Jackson (1835-1911) was perhaps the most thoughtful spokesperson for hemispheric lateralization of function in his time. He conceptualized brain function as consisting of a hierarchy of functions, built essentially on sensorimotor mechanisms, and ranging from the 'anterior and posterior horns of the spinal cord', through the 'ganglia of the corpus striatum', and finally to the 'highest motor centres (prae-frontal lobes)... and highest sensory centres (occipital lobes)' (Jackson, 1887, pp. 29-30). He further believed that the highest centers inhibited or controlled the lower centers, and that, with loss of function of the higher centers, the lower centers would show increased activity. He considered this loss of function of higher neurologic centers to underlie
'negative' symptoms, and the increased activity of lower centers to give rise to 'positive' symptoms. In addition to a sensorimotor distinction relating to a posterior anterior direction in the brain, Jackson also believed that there was a lateralized hemispheric, or left-right, sensorimotor distinction, in which the left hemisphere was more closely related to motor function and the right to highlevel sensory or perceptual function. The combination of these two sensorimotor gradients is related to Jackson's concept that motor function is preferentially associated with the anterior left hemisphere and perceptual function with the posterior right hemisphere. Such +quadrant' effects have been discussed more recently in terms of mood localization in the brain, in studies by Robinson et al. (1988) and Starkstein et al. (1991) and in a review of the literature from our laboratory (Jeste et al., 1988). In the early 1900s, and in particular during World War I, interest in hemispheric laterality decreased considerably. Despite Hugo Liepmann's concepts of apraxia, which supported Jackson's notions of high-level motor function being associated with the left hemisphere, many investigators of the time moved toward an antilocalizationist viewpoint. Some of this was probably due to the large number of head injuries studied during World War I, from which investigators were impressed by the capacity of the brain to assume functions initially lost as a result of trauma (Goldstein, 1939). This was considered by some to be a blow against the localizationist perspective, although in retrospect these findings were more a tribute to the plasticity of the brain+ rather than an indictment against localizationism. Hemispheric specialization received little further attention until the 1950s and 1960s, in particular with the studies by Sperry on split-brain persons who had received commissurotomies to relieve epilepsy (Sperry, 1962, 1968). In a series of elegant experiments, he demonstrated substantial differences in the way the hemispheres function, although defining these differences in terms of a single dimension has proved difficult. Since that time, numerous studies into the nature of lateralized differences have been performed, with investigators proposing a variety of distinctions relating to the nature of the functioning of the hemispheres.
,LB. Lohr, M.P. Caligiuri / Schizophrenia Research27 (1997) 191-198
Table 1 lists several of the distinctions raised between the functioning of the left and right hemispheres. From the viewpoint of psychosis, much of the current interest in hemispheric laterality can be traced back to the studies of Flor-Henry, Gruzelier, and others in the late 1960s and 1970s (Flor-Henry, 1969; Gruzelier and Flor-Henry, 1979). Flor-Henry in particular studied patients with psychomotor epilepsy and noted a relationship of schizophrenia-like symptoms with left hemisphere pathology and mood disorder symptoms with right hemisphere pathology.
3. Studies of laterality in schizophrenia To address the issue of laterality and schizophrenia, we performed a computerized Medline review of the literature from 1980 to early 1996 (1980 marking the introduction of the DSM-III). We used the following key words in various combinations for this search: schizophrenia, bipolar disorder, schizoaffective disorder, psychosis, laterality, asymmetry, and hemispheric imbalance. We made no attempt to select specific articles based on a particular measurement domain or patient sample. Case studies were not included. Additional articles were retrieved using citations from articles identified by the computerized search. Table 1 Evolution in the conceptualization of distinctions in hemispheric function over the last 130 years Time
Left hemisphere
Right hemisphere
1860s-1910s Jackson
Language High-level motor and speech Language Verbal Analytic Analytic Serial processing Detail-oriented Propositional mind Logical Rational
Undefined High-level perception
1950s 1960s 1970s-present
Adapted from Cutting, 1990.
Spatial Nonverbal Synthetic Holistic Parallel processing Gestalt Appositional mind Creative Emotional, affective
193
Although we attempted to find as many relevant studies as possible, it is unlikely that we performed a fully comprehensive review, because there are many studies in which lateralized findings were not a primary focus of the study, and results pertaining to laterality may receive only brief mention in the results section. Thus, a fully comprehensive review would require scrutiny of thousands of controlled studies of schizophrenia over a 15-year period. Nevertheless, we believe we have captured the most important studies in which laterality issues were addressed during this period. We divided the studies into those that are strongly, partially, or not supportive of one hemisphere being more involved in schizophrenia than the other. These studies are presented in Table 2. A total of 118 articles were used to construct this table, and each study appears only once. A strongly supportive study was one in which there was a statistically significant finding between the hemispheres that the investigators attributed to pathology or dysfunction of one particular hemisphere. A partially supportive study was one in which there was a nonsignificant trend for a laterality finding or in which the laterality finding occurred only in a subgroup of the patient sample (such as only in women or only in paranoid type of schizophrenia). A nonsupportive study was one in which the issue of laterality was addressed, but no statistically significant difference between the hemispheres emerged.
3.1. Implications of laterality studies in schizophrenia Most of the studies in which the issue of laterality was addressed reported lateralized findings in schizophrenia, and most of these implicated the left hemisphere in particular. A putative hemispheric imbalance in schizophrenia in which the left hemisphere is more involved than the right has several implications regarding the pathophysiologic process or processes involved. For example, the pathophysiologic process in schizophrenia itself may cause abnormal lateralized development and function (as proposed by Crow et al., 1989). One side of the brain (mainly the left) also may be more vulnerable to the pathophysiologic processes
194
J.B. Lohr, M.P. Culigiuri " Sehizophrenia Research 27 (1997) 191 198
Table 2 N u m b e r of studies in the schizophrenia and bipolar literature since 1980 rated according to strength of support for left or right hemisphere dysfunction a Domain Schizophrenia Motor b Neuropsychologic c Functional imaging d Structural imaging d Neuropathologic and neurochemical c Overall Bipolar disorder Overall
Left strong
[,eft partial
None
Right partial
Right strong
7 18 I0 13 9 57
8 8 3 9 4 32
l 5 0 4 0 10
2 l 0 0 0 3
0 0 1 3 0 4
0
3
2
2
8
a Complete updated list of references available on request. b Consists of studies of neuroleptic-induced parkinsonism, tardive (tyskinesia. and motor control. c Consists of studies of dichotic listening, verbal and nonverbal neuropsychologic tests, and P300 and N400 responses from event-related potentials. d Consists of magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, regional cerebral blood flow, and computed tomographic studies. c Consists of postmortem studies and studies of neurotransmitter receptor densities.
involved in schizophrenia. These processes would give rise to clear-cut schizophrenic symptoms when they involve the left side of the brain. When they involve the right side of the brain, the clinical symptoms would be less clearly schizophrenic in nature. These differing explanations, and there may be others as well, are not mutually exclusive. Different processes could account for the different patients within the schizophrenia spectrum. Nevertheless, that certain pathophysiologic processes give rise to schizophrenic symptoms, primarily as an interaction between those processes and the inherent normal functions of the left hemisphere, caused us to speculate about the type of clinical picture that might result from similar processes in the right hemisphere. Because of the importance of the right hemisphere in emotions and mood (Bradshaw, 1989; Hellige, 1993), we considered that involvement of the right hemisphere might be associated with greater mood impairment, as is seen in schizoaffective or bipolar disorder, both of which can be difficult to distinguish clinically from schizophrenia. We therefore performed a similar literature search on the relationship of bipolar disorder to lateralized function and structure. Although we found fewer studies, most of these studies demon-
strated greater right than left hemisphere involvement in bipolar disorder (Table 2).
4. Caveats in laterality studies
Several important caveats must be kept in mind when evaluating the findings of any study of laterality, including ours. First, hemispheric imbalance per se does not necessarily indicate which hemisphere is predominantly involved. For example, the finding of a smaller hippocampus on the left side compared with the right side does not necessarily indicate that the left side is more pathologic, since the right side may be pathologically enlarged. The presence of a healthy comparison group can be helpful in this regard, but not completely so, for the following reason. If, in the previous hypothetical example, a healthy group had left hippocampi similar in size to those of patients with schizophrenia but their right hippocampi were larger, we might conclude that the right hippocampus is pathologically enlarged in the schizophrenic group. However, if the pathologic process in schizophrenia involved both hemispheres, perhaps only the right side was able to invoke a compensatory mechanism, involving
,L B. Lohr. M.P. Caligiuri / Schizophrenia Research 27 (1997) 191-198
enlargement, to preserve more normal hippocampal functioning. Thus what we observe not only reflects the initial pathologic processes, but also the brain's response to those processes, which could alter the interpretation of lateralized findings. A second complexity in interpreting laterality studies concerns the possibility that the hemispheres may function in a mutually inhibitory way (Kinsbourne, 1975, 1982). Therefore, finding that a certain brain region in the left hemisphere is overactive does not necessarily imply a primary pathologic process in that region, but may reflect a pathologic process in the right hemisphere, which results in insufficient inhibition of the left hemisphere. Third, language dominance and handedness may influence results. Studies, particularly functional studies in which the dependent measures involve use of language or manual dexterity, must be interpreted cautiously. Because both language and manual dexterity are associated more strongly with the left hemisphere, sorting through these issues when drawing conclusions about right hemisphere functioning is important. Thus a task designed to assess right hemisphere function, but in which the measure involves verbal communication, may introduce a left hemisphere component to the task measurement.
5. Relationship of schizophrenia and bipolar disorder The nature of the relationship between schizophrenia and bipolar disorder has been a puzzle for many years (Kerr and McClelland, 1991). Essentially, two basic hypotheses have been proposed. The first, which dates from Kraepelin (1896), forms the basis for most modern diagnostic systems, including the Diagnostic and Statistical Manual of Mental Disorders (DSM). Called the 'two-disease hypothesis', it posits that schizophrenia and bipolar disorder are separate clinical entities (Kraepelin, 1896). This approach, which is unquestionably valuable heuristically, has been criticized because of problems accounting for schizoaffective disorder, in which patients often
195
have a clinical picture somewhere between the two. The second approach, called the 'continuum hypothesis', places schizophrenia and bipolar disorder at the endpoints of a unidimensional continuum, with schizoaffective disorder representing an intermediate position (Kendell, 1991). In some cases, the continuum is extended beyond bipolar disorder to include unipolar depression. This hypothesis has also been criticized, largely because it is unclear exactly what forms the basis for this continuum. In other words, what single underlying phenomenon could possibly be involved that, when varied, can give rise to schizophrenia, schizoaffective disorder, or bipolar disorder? We have proposed that schizophrenia and bipolar disorder lie on a continuum, but in two dimensions, with psychotic symptom severity representing one axis and mood symptom severity the other axis (Fig. 1) (Lohr and Caligiuri, 1995). Schizoaffective disorder falls into an intermediate spatial region. This two-dimensional approach offers the advantage of incorporating aspects of both the two-disease and unidimensional continuum hypotheses. Additionally, it does not restrict the relationship of schizophrenia and bipolar disorder to a single varying phenomenon, since
Two-Dimensional Continuum
u)Et o.>, "om E o o
~~~
Schizophrenia
Psychotic symptoms Fig. 1. Two-dimensional continuum for major psychotic disorders, with psychotic symptom severity along the x axis and mood symptom severity along the y axis. Schizoaffective disorder tails into an intermediate spatial region. We have deliberately not drawn the boundaries between the disorders as symmetrical around the y = x line, because when psychotic symptoms are severe, they may mask mood symptoms, with the resulting condition appearing as schizophrenia even when there may be significant underlying mood involvement.
196
J. B, Lohr, M. P, Caligiuri / Schizophrenia Research 27 (1997) 191 198
two or more different processes could be at work in creating symptoms. When considered with the laterality literature discussed above, one possible explanation for the two dimensions of psychosis and mood could relate to left hemisphere and right hemisphere involvement, respectively. This is along the lines suggested by Iaccino (1993) when he stated, 'If schizophrenia has more left-hemispheric involvement (or damage), then the affective psychoses would seem to have the complementary sided asymmetry' (p. 92). Although the reasons for this are unclear, Iaccino later speculated, from an evolutionary perspective, that 'it can be reasoned that the affective psychoses developed from the schizophrenic, and eventually came to be housed in the emotional right hemisphere as the left side functionally set itself apart to regulate those linguistic components mainly associated with schizophrenia' (p. 93).
6. Instrumental motor assessment of asymmetry in the major psychoses
We have begun to assess the hypothesis that schizophrenia and bipolar disorder may be related in the sense that schizophrenia involves the left hemisphere to a greater extent than the right, while the opposite is true for bipolar disorder. In the present study, we examined a group of righthanded older patients (>45 years old) with schizophrenia, bipolar disorder, or schizoaffective disorder and compared our findings with those in healthy comparison subjects. One advantage of using a group of older patients is that there is greater diagnostic certainty than in younger patients. In addition to the above hypothesis, we also hypothesized that patients with schizoaffective disorder would not show an overall preference in the direction of abnormal laterality. 6.1. Methods
Sixty-five patients and 30 healthy comparison subjects were studied. Their demographic characteristics are listed in Table 3. Patients and controls
Table 3 Patient characteristics for the study of m o t o r asymmetry Diagnosis
n
Age
Schizophrenia Mania Schizoaffective Normal
49 6 10 30
57,0 61.5 58.7 60.7
(1.3) (3.6) (3.4) (2.1)
Illness duration
Sex (male:female)
26.7 (1.7) 26.0 (5.2) 27.3 (4.6) --
34:15 6:0 10:0 20:10
Data are means (standard errors).
were recruited for this study as part of their participation in ongoing research within our Geriatric Psychiatry Clinical Research Center. Patients were maintained on stable dosages of neuroleptic medication for at least 3 months before their motor assessment. The use of neuroleptics, mood stabilizers, or antiparkinsonian medications varied widely across patients and was not controlled for in this study. All subjects were right-handed. Patients met DSM-IV criteria for paranoid type of schizophrenia, schizoaffective disorder, or manic episode of bipolar disorder. There were no significant differences between the patient groups in age or illness duration. As in our previous studies of motor asymmetry, we used a measure of hand force instability. A patient is instructed to press and hold a stable level of force with their index finger placed on a strain gauge, while following a stable target representing that force on a computer monitor. The amount of variation around that target over time represents the degree of hand force instability. Force instability, reported as percent error, is computed by obtaining the mean and standard deviation of the points of the waveform over a 15-s interval and computing the coefficient of variation by dividing the standard deviation by the mean. An asymmetry score is computed by subtracting the force error score of the right hand from that of the left hand. Using this technique, we previously found significantly greater rightthan left-hand force instability in a group of right-handed patients with schizophrenia and significantly greater left- than right-hand force instability in a group of right-handed patients with bipolar disorder. The healthy control sample
J.B. Lohr, M.P. Caligiuri / Schizophrenia Research 2 7 (1997) 191-198
showed no lateralized difference (Lohr Caligiuri, 1995).
and
197
and patients with schizophrenia (p=0.007 and p=0.0003, respectively). Other comparisons were not significant.
6.2. Results 6.3. Discussion and conclusion
The mean (standard error) motor asymmetry scores for the schizophrenic, bipolar disorder, schizoaffective, and normal comparison subjects were -1.12 (0.27), 2.86 (1.62), 1.60 (1.09), and - 0.02 (0.10), respectively. Because of nonhomogeneity of variance across the four groups for the hand force error scores, we used nonparametric tests to examine group differences in mean force error scores for the left-right ( L - R ) hand difference score. The results of a Kruskal-Wallis analysis of variance indicated a highly significant group effect for the L - R difference score ( H = 28.39; d f = 3; p<0.0001). The mean L R scores (with standard error) are shown in Fig. 2 for the four subject groups. Post-hoc Mann-Whitney tests revealed that the mean L - R score for patients with schizophrenia was significantly different from the L - R scores for patients with bipolar disorder ( p = 0.0003), patients with schizoaffective disorder (p = 0.0007) and normal comparison subjects ( p = 0.0007). Patients with bipolar disorder differed significantly from the healthy comparison subjects
® 5 O u
~4 ¢:
>,2
/i
.O
O u..
m
~'-2
SZ
BP
$A
NC
5
Fig. 2. The mean (standard error) motor asymmetry scores for the schizophrenic (SZ), bipolar disorder (BP), schizoaffective (SA), and normal comparison (NC) subjects. The schizophrenia group was significantly different from all other groups (p<0.001), and the bipolar group was significantly different from the schizophrenia and normal groups (p<0.01). The schizoaffective group was not significantly different from either the bipolar group or the normal group.
The findings from this instrumental motor assessment replicate our previous findings, indicating that schizophrenia may be associated preferentially with left hemisphere dysfunction and mania with right hemisphere dysfunction. Additionally, patients with schizoaffective disorder did not differ significantly from the healthy sample in terms of laterality, with six of the 10 patients demonstrating greater left than right hemisphere involvement, and the remaining four greater right than left involvement. These results are consistent with the conceptual framework that schizophrenia and bipolar disorder are associated with complementary hemispheric imbalance and that schizoaffecrive disorder represents an intermediate position. Also, because the findings for the older healthy comparison group in this study were similar to those of a younger group in our previous study (Lohr and Caligiuri, 1995), the effects of age on motor asymmetry may be limited. Several important considerations arise in interpreting the results of our study. First, the caveats discussed earlier regarding studies of laterality also apply in this circumstance. In particular, care must be taken, on the basis of a finding of hemisphere imbalance alone, in attributing the pathology to one or the other hemisphere. Second, the issue of mutual inhibitory function of the hemisphere may certainly play a role in the motor phenomena measured in this study. The third concern, related to language and manual dominance, is less of a problem in this study because the influence of language processing and hand preference on the force instability task is minimal. In addition to these problems, there are also concerns related to the small number of subjects in the bipolar and schizoaffective groups. Despite these caveats, we believe that current evidence supports the need to address issues of laterality in future functional and structural studies of schizophrenia and bipolar disorder. Hemispheric asymmetry may shed light on the
198 pathophysiology disorders.
J.B. Lohr, M.P. Caligiuri / Schizophrenia Research 2 7 ( 1997) 191-198 and
relationship
of these two
Acknowledgment T h i s r e s e a r c h was s u p p o r t e d in p a r t by P H S grants from the National Institute of Mental Health (R29-MH45959; P30 M H 4 9 6 7 1 ; R01 M 4 5 1 3 1 ). W e t h a n k R e b e c c a V a u g h a n a n d R o b e r t R u c k f o r a s s i s t a n c e in d a t a c o l l e c t i o n a n d analysis.
References Bradshaw, J., 1989. Hemispheric Specialization and Psychological Function. Wiley, Chichester. Crow, T.J., Ball, J., Bloom, S.R. et al., 1989. Schizophrenia as an anomaly of development of cerebral asymmetry. Arch. Gen. Psychiatry 46, 1145 1150. Cutting, J., 1990. The Right Cerebral Hemisphere and Psychiatric Disorders. Oxford University Press, Oxford. Flor-Henry, P., 1969. Psychosis and temporal lobe epilepsy: a controlled investigation. Epilepsia 10, 363-395. Goldstein, K., 1939. The Organism: A Holistic Approach to Biology Derived from Pathological Data in Man. American Book Company, New York. Gruzelier, J., Flor-Henry, P. (Eds.), 1979. Hemisphere Asymmetries of Function in Psychopathology. Elsevier/North Holland, Amsterdam. Harrington, A., 1987. Medicine, Mind, and the Double Brain. Princeton University Press, Princeton, NJ. Hellige, J.B., 1993. Hemispheric Asymmetry: What's Right and What's Left. Harvard University Press, Cambridge, MA.
laccino. J.F., 1993. Left Brain-Right Brain Differences: Inquiries, Evidence, and New Approaches. Erlbaum, Hillsdale, NJ. Jackson, J.H., 1887. Remarks on evolution and dissolution of the nervous system. J. Ment. Sci. 33, 25 48. Jeste, D.V., Lohr, J.B., Goodwin, F.K., 1988. Neuroanatomical studies of major affective disorders: a review and suggestions for further research. Br. J. Psychiatry 153, 444-459. Kendell, R.E., 1991. The major functional psychoses: are they independent entities or part of a continuum? Philosophical and conceptual issues underlying the debate. In: Kerr, A., McClelland, H. (Eds.), Concepts of Mental Disorder: A Continuing Debate. Gaskell, London, pp. 1-16. Kerr, A., McClelland, H. (Eds.), 1991. Concepts of Mental Disorder: A Continuing Debate. Gaskell, London. Kinsbourne, M., 1975. The mechanism of hemispheric control of the lateral gradient of attention, in: Rabbitt, P.M.A., Dornic, S. (Eds.), Attention and Performance, vol. 5. Academic Press, New York. Kinsbourne, M., 1982. Hemispheric specialization and the growth of human understanding. Am. Psychol. 37, 411 -420. Kraepelin, E., 1896. Psychiatrie, ein Lehrbuch fur Studierende und Arzte, 5th ed. Barth, Leipzig. Lohr, J.B., Caligiuri, M.P., 1995. Motor asymmetry, a neurobiologic abnormality in the major psychoses. Psychiatry Res. 57, 279-282. Robinson, R.G., Boston, J.D., Starkstein, S.E. et al., 1988. Comparison of mania and depression after brain injury: causal factors. Am. J. Psychiatry 145, 172-178. Sperry, R., 1962. Some general aspects of interhemispheric integration. In: Mountcastle, V.B. (Ed.), lnterhemispheric Relations and Cerebral Dominance. Johns Hopkins University Press, Baltimore, MD. Sperry, R., 1968. Hemisphere disconnection and unity in conscious awareness. Am. Psychol. 23, 723-733. Starkstein, S.E., Bryer, J.B., Berthier, M.L. et al., 1991. Depression after stroke: the importance of cerebral hemisphere asymmetries. J. Neuropsychiatr. Clin. Neurosci. 3, 276-285.