A neural plasticity hypothesis of schizophrenia

Neuroscience & BiobehavioralReviews. Vol. 8, pp. 55-71, 1984. ©Ankho InternationalInc. Printedin the U.S.A.

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A Neural Plasticity Hypothesis of Schizophrenia J O H N L. H A R A C Z

Interdepartmental N e u r o s c i e n c e Program, Brain Research Institute, 73-346 University o f California, Los Angeles, Los Angeles, CA 90024 R e c e i v e d 23 July 1982 HARACZ, J. L. A neural plasticity hypothesis of schizophrenia. NEUROSCI BIOBEHAV REV 8(1) 55-71, 1984.--An extensive research effort has failed, thus far, to conclusively identify a specific disease process (or processes) underlying the behavioral symptoms of schizophrenia. The present paper will entertain the hypothesis that the structural and functional plasticity of the brain can constitute a "nonspecific" biological etiology of schizophrenia. This plasticity need not be accompanied by infectious processes or gross alterations in neurotransmitter levels, enzyme activities, etc. that are specific to schizophrenia. The monkey isolation syndrome provides a precedent for a causal relationship between brain plasticity and pathological behavior. In a speculative manner, it will be demonstrated that neural plasticity concepts can be invoked to potentially explain several aspects of schizophrenia: the various types of behavioral symptoms exhibited by schizophrenics, the regional alterations in brain structure and function seen in chronic schizophrenics, the involvementof genetic and environmental etiological factors, the pharmacological support for the dopamine hypothesis, and the delayed onset of neuroleptic antipsychotic action. Considering the explanatory potential of neural plasticity concepts, a research program which focuses on these concepts seems warranted. Neural plasticity Schizophrenia Developmental theories Environmental enrichment and deprivation Axonal sprouting Computer-assisted quantitative histology

BIOLOGICALETIOLOGYOF SCHIZOPHRENIA

Animal models Long-term potentiation

Kindling

The dopamine hypothesis of schizophrenia receives particularly wide attention since it provides a simple and straightforward explanation for the therapeutic efficacy of neuroleptic drugs. However, an exhaustive examination of bodily tissues has not revealed compelling direct evidence of excess dopamine function in schizophrenics (for a more complete review, see [100]). Schizophrenics and controls did not differ in their CSF or postmortem brain levels of dopamine metabolites [19, 24, 50, 72, 135, 187, 268, 270]. Elevated postmortem brain concentrations of dopamine were found in schizophrenics by some laboratories [50,149], but not by others [268,270]. Schizophrenic patients reportedly have significant alterations in platelet monoamine oxidase activity and in postmortem brain neuroleptic binding, but antipsychotic drug treatment has not been ruled out as a cause of these findings [35, 56, 57, 148, 149, 163,204, 224]. Developmental theorists take a different approach in the search for an etiology of schizophrenia. Special emphasis is placed on an evolution of psychopathology which follows general rules of personality development and learning. A developmental theorist would claim that the main prognostic variables in schizophrenia are not characteristics exclusive to that disorder, but are common human traits with important developmental roots that often reach back into earliest childhood [234]. Such prognostic indicators would include family characteristics, psychodynamic conflicts, premorbid social functioning, work history, and social class [140, 233, 248]. These types of developmental variables would be not

Despite a plethora of theories and an extensive search, researchers have yet to conclusively identify a specific biological defect underlying the behavioral symptoms of schizophrenia. Extant biological theories propose a number of potential etiological agents: viruses, abnormal plasma proteins, perinatal complications, transmethylation products, autoantibodies, and excess dopaminergic activity (for reviews, see [49, 85,100, 131,156, 165,218,230,240]). Each of these theories represents an important attempt at a biological explanation of schizophrenia on the basis of a certain amount of indirect, circumstantial evidence. The theories generally have not been disproved, nor have they been compellingly supported by direct, positive evidence. For example, a viral etiology of schizophrenia is suggested by: (a) epidemiological factors [240]; (b) the presence of a cytopathic effect [5 l] and elevated cytomegalovirus antibody [241] in the cerebrospinal fluid (CSF) of some schizophrenics; and (c) the postmortem finding of subcortical gliosis in the brains of some patients [229,230]. However, attempts to transfer an infective agent by direct innoculation of brain tissue or CSF from schizophrenics into animals, tissue culture, or viral genome hybridization probes have not demonstrated the presence of a virus [51,230]. Thus, with occasional mild success, the proponents of the various biological theories continue the important search for positive evidence.

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only prognostic indicators, but also etiological agents according to developmental theory. In this view, adverse environmental factors leave the potential schizophrenic with a psychosocial deficit which eventually leads to a schizophrenic break when heightened developmental demands cannot be met. Adverse environmental factors do appear capable of exacerbating the course of schizophrenia [28, 62, 136, 179, 248, 250]. Thus, exacerbations of illness are associated with an increased incidence of stressful life events (reviewed in [62]), a high degree of emotion expressed by the patient's relatives [28, 136,248, 250], and evidence ofuncaring and overprotective parental characteristics [179]. The primary etiological importance of environmental factors is less clear, although some authors have reported abnormal communication patterns in the families of schizophrenics [15, 140, 222,272]. A controversial issue is whether or not the deviant communication patterns predate, and help to bring about, the onset of schizophrenia. Developmental theory stipulates an interaction between genetic components of vulnerability and factors in the psychosocial and physical environment. Interacting constitutional and experiential influences are said to create new biological and behavioral potentialities which help determine vulnerability to schizophrenia [271]. Similarly, several authors have proposed that emotionally stressful experiences could leave a lasting impression on neuronal circuitry and, thereby, heighten the vulnerability to future psychopathology [27, 108, 185,206]. Considering the potential etiological and/or modulatory significance of environmental factors in schizophrenia [15, 28, 62, 128, 136, 140, 179, 222,248, 250], a fruitful research concern may be the adaptation of neuronal circuitry to environmental changes. The plasticity of neuronal connections has been studied by subjecting animals to neurosurgical lesions, brain electrostimulation, and a variety of rearing environments. Each of these experimental paradigms has yielded morphological and biochemical evidence of synaptic reorganization [16, 43, 60, 79, 97, 146, 200]. Before evaluating the relevance of neural plasticity to the etiology of schizophrenia, some animal studies of environmentally-influenced plasticity will be highlighted below. E N V I R O N M E N T A L I N F L U E N C E S ON BRAIN PLASTICITY

Environmentally-influenced brain plasticity has been most frequently studied by restricting the visual or general sensory environments of animals. For example, when monkeys are raised with one eyelid sutured shut, a marked imbalance develops in the afferents from the lateral geniculate nucleus to the visual cortex. Autoradiographic labelling of axonally-transported protein reveals that the geniculocortical projection corresponding to the open eye predominates over that of the closed eye [110]. This study, and the studies reviewed below, tend to support the suggestions of Lund [143] and Singer [223] that environmentally-activated pathways form more synapses or undergo a consolidation of transmission efficiency while inactive pathways may lose synapses or efficiency. Both monocular and binocular visual deprivation produces deficits in the density of visual conical synapses and dendritic spines [45, 46, 75, 76, 78, 180, 201,202]. Accompanying the neural changes are aberrations in visual acuity and visuomotor behavior [69, 168, 192, 213,236, 245, 252]. Physiological, anatomical, and behavioral studies indicate that the neuronal connectivity of the visual system is

highly susceptible to deprivation effects only during a critical period in development [59, 109, 20l, 274]. Even in adulthood, though, visual deprivation can induce gross decreases in the volume of the lateral geniculate nucleus and the thickness of the visual cortex, as well as alterations in the physiological responsiveness of visual cortical cells [48, 77, 223]. Different levels of general sensory stimulation can also have striking effects on brain development. In order to control the complexity of the general sensory environment, rats are raised under so-called "enriched" (EC), "impoverished" (IC), or "standard" conditions (SC) [200]. EC rats are grouped in a large cage containing a variety of toys and other objects while small groups of SC rats are housed in plain cages. Each IC rat is isolated in a small, plain cage and is not allowed to see or touch another animal, though auditory and olfactory cues may still be present. The environmental separation is usually begun at weaning and maintained for 30 to 160 days. Among the many effects, EC rats significantly exceeded IC animals in the following parameters: cerebral conical weight and depth, dendritic branching complexity and spine frequency, neuronal nuclear volume, RNA/DNA ratio, RNA diversity, and brain-specific protein concentrations [60, 97, 98, 200]. The neural changes appear to be behaviorally relevant since the EC animals excel in a variety of tasks (for reviews, see [97,121 ]). In general, the EC/IC differences are most apparent in the visual cortex [18,61]. From birth through old age, the later the EC/IC separation is begun the less the brain responds to the differential environments [61, 74, 152, 194]. However, environmental separation commenced in adulthood can still lead to significant differences in cerebral cortical weight and thickness, dendritic length and spine density, total dendritic material per neuron, acetylcholinesterase activity, RNA/DNA ratio, and mazelearning ability [18, 34, 3%40, 52, 61, 96, 194, 243, 244]. These results suggest that some brain neurons retain a significant degree of structural plasticity well into adulthood [96]. Underlying mechanisms are still unclear, but the EC/IC findings have been interpreted to suggest that IC rats exhibit delayed development of environment-dependent neurons [122]. EC rats might benefit from a prolonged neurological activation which stimulates a number of metabolic processes [256,257]. Whatever the mechanisms may be, it seems clear that both visual experience and general environmental complexity can influence the structural and functional plasticity of the brain. Environmental influences on structural brain plasticity are also seen in monkeys raised in social isolation. These monkeys develop a variety of abnormal behaviors including self-clasping and biting, retarded motor activity, avoidance of social contact, fearfulness, and a lack of appropriate sexual behavior [81, 102, 159, 195, 214, 228]. Light microscopic examination of the brains of isolated monkeys reveals dendritic branching deficits in cells of the cerebral and cerebellar cortices [81, 195, 196, 228, 235]. Compared to sociallyraised controls, 6- to 8-month-old deprived monkeys show a significant decrease in the dendritic branching of cerebellar Purkinje cells [81] and layer-IV cerebral conical stellate cells [195, 196, 228, 235]. Since the dendrites of these cell types normally receive a rich innervation, it is quite possible that the altered dendritic branching reflects an altered synaptic organization. It also seems possible that the decreased dendritic branching was a response to the relatively diminished opportunity for motor activity, general somatosensory stimulation,

N E U R A L PLASTICITY AND SCHIZOPHRENIA and social interaction (or any combination of these factors) provided by the rearing environment of the isolated monkeys. Although it is difficult to determine which aspects of the isolation environment are related to the dendritic changes, recent studies are beginning to distinguish between the effects of social and sensorimotor deprivation [196,228]. This distinction was made by raising some monkeys in the usual social-isolation condition, but with the added presence of a trapeze, ladders, and play objects. Such sensorimotor enrichment did not prevent the development of typical isolation syndrome behaviors. At an anatomical level, the additional sensorimotor stimulation prevented the dendritic branching deficits in layer-IV stellate cells of the primary somatosensory and motor cortices, but not the secondary motor cortex. The dendritic branching indices (number of branches for each branch order, ratio of dendritic tips to primary dendrites) in the visual, prefrontal, and secondary somatosensory cortices were insignificantly affected by social deprivation with or without sensorimotor enrichment. Thus, it appears that monkey isolation syndrome behaviors are specifically a consequence of social isolation, and are correlated with dendritic branching deficits in the secondary motor cortex (also referred to as the "supplementary motor area" or SMA [182,269]). The SMA in man and monkey occupies the medial surface of the superior frontal gyrus rostral to the primary motor cortex. On the basis of previous theories of brain plasticity [143,223], the SMA dendritic deficits could be interpreted to reflect a chronically decreased activation of SMA neurons by social stimuli. The above results indicate that social deprivation, like visual and general sensory deprivation, can induce structural deficits that are manifestations of structural brain plasticity. Social deprivation effects were most apparent in the SMA of isolated monkeys, although behaviorally-relevant structural changes might have also existed in other unexamined brain areas (e.g., the limbic system [195]). Interestingly, Buchsbaum et al. [31] noted that schizophrenic patients exhibit deficits in cerebral blood flow and glucose use which tend to be focused in the vicinity of the SMA. Taken together, these results may be indicative of a chronically decreased activation of SMA neurons in schizophrenic patients and in an animal model of psychopathology. The SMA appears to function in the programming of voluntary motor behaviors in monkeys and man [26, 177, 198]. Based on the correlation between SMA dendritic deficits and monkey isolation syndrome behaviors, the SMA might also facilitate the development of normal social behaviors. Thus, it can be hypothesized that an SMA dysfunction underlies the deficits in social behaviors seen in human and monkey pathological behavior syndromes. The above evidence of SMA dysfunctions in isolated monkeys and schizophrenic patients seems interesting enough to stimulate a further comparison between isolated monkeys and schizophrenics with regard to biological substrates of behavior. In this theoretical exercise, it is not assumed that isolated monkeys and schizophrenic patients exhibit closely similar behavioral states. It is assumed, instead, that the social isolation of monkeys can provide a model of the biological mechanisms that underlie environmentally-induced psychopathology. Similar biological mechanisms may underlie the modulatory, or even primary etiological, influences of environmental factors in schizophrenia [15, 28, 62, 136, 140, 179, 222, 248, 250, 271, 272]. The comparative discussion below will demonstrate that the structual and functional plasticity of the brain may constitute

57 a biological mechanism that mediates environmentallyinduced pathological behavior in monkeys and man. In the case of isolated monkeys, structural and functional brain plasticity seems to provide the most plausible biological explanation for the bizarre isolation syndrome behaviors. Isolated and socially-raised monkeys differed experimentally only in their rearing environments. Therefore, enduring environmentally-induced changes in brain structure and function must underlie the enduring behavioral abnormalities of isolated monkeys. One such structural change may already have been identified, namely the SMA dendritic deficits. It seems unlikely that the isolation syndrome behaviors were secondary to a viral infection, perinatal complications, or an inherited biochemical defect. As pointed out previously, these types of specific biological factors have been hypothesized, but not conclusively identified, as causes of schizophrenia. Could it be, then, that there are no specific biological causes of schizophrenia? It is conceivable that schizophrenic symptoms, like monkey isolation syndrome behaviors, are end products of structural and functional brain plasticity. This plasticity could be a "nonspecific" biological etiology of schizophrenia in the sense that it need not be accompanied by infectious processes or gross alterations in neurotransmitter levels, enzyme activities, etc. that are specific to schizophrenia. A neural plasticity hypothesis of schizophrenia would seem to necessarily impart environmental factors with primary etiological significance. Some authors have, in fact, reported abnormal communication patterns in the families of schizophrenics [15, 140, 222, 272], but others found that a global assessment of parent-child relationships was only very weakly associated with psychopathological disorders in the child [199]. Even if deviant communication could be conclusively identified, the deviance may have been a response to, rather than a cause of, the child's schizophrenic behavior. Thus, a role for deviant communication, or any other specific psychosocial factor, in the genesis of schizophrenia remains to be unequivocally demonstrated [129]. The importance of schizophrenogenic factors in the environment could be estimated by examining the biological and adoptive siblings of schizophrenic adoptees. If schizophrenogenic rearing factors were significant influences one would expect the adoptive siblings reared by the same parents to show some increase in risk for schizophrenia, whereas the biological siblings reared in a different family should show a diminished risk [129]. This prediction was contradicted by two studies which found that the biological siblings had a much higher risk for schizophrenia than did the adoptive siblings [125, 129, 130]. The prevalence of schizophrenia and "schizophrenia spectrum disorders" in the adoptive relatives of the schizophrenic adoptees was not significantly different from that in the adoptive relatives of nonschizophrenic control adoptees [130]. The prevalence in both of these two groups of adoptive relatives was in accord with the rate that would be expected in the general population. These findings tend to assign primary etiological significance to genetic factors. However, the approximately 5 0 - % discordance for schizophrenia in monozygotic twins constitutes clear evidence that environmental factors must operate in the development of schizophrenia [95,130]. Taken together, the above data permit the conclusion that environmental factors usually operate on a genetically transmitted vulnerability [130]. From the above discussion, the present state of schizophrenia research can be summarized as follows: (a) an im-

58 pressive accumulation o f data has not compellingly linked any specific biological disease process or specific environmental factor to the etiology of schizophrenia; (b) to the extent that environmental factors are etiologically important, they probably interact with a genetically transmitted vulnerability. Although the failure to find specific etiological factors does not preclude the future identification of such factors, this essay will consider the parsimonious assumption that there are no specific biological or environmental causes of schizophrenia. This view assigns etiological importance to a disharmony of nonspecific biological and environmental factors that, individually, are associated with relatively large segments of the general population. Thus, no single factor could be described as a specific etiology of schizophrenia since each factor will also be associated with some nonschizophrenic individuals. In accord with the above, Ciompi [36] described neural plasticity as providing a bridge between biological and psychosocial variables in a multi-causal concept of schizophrenia. Similarly, van Kammen and co-workers proposed that environmental stressors may bring on psychotic decompensation in vulnerable individuals by altering dopaminergic activity [246] or patterns of synapse formation, including the extent and location of axonal and dendritic arborizations [123]--although the same stressors may be innocuous for non-predisposed persons. In summary, nonspecific genetic factors may predispose the schizophrenic to produce abnormal plastic responses to nonspecific stresses that typically occur in the lives of many schizophrenic and nonschizophrenic individuals. A genetically-heightened neural responsivity to stress could help to explain the relative rareness of schizophrenia with respect to the commonness of nonspecific stress. Neural responsivity here refers to the tendency to produce biochemical changes in the brain, alterations in brain structure or the size of individual neurons, and changes in transsynaptic physiological connectivity (e.g., "synaptic potentiation" as discussed in the section below entitled "Neural plasticity and catecholamine systems"). Jacobson [115] suggested that the responsivity of neurons to the environment could show genetic variation within a given species. Thus, different human genotypes may respond to environmental stressors with different degrees of alterations in neuronal connectivity and behavior. Nonspecific genetic factors could heighten the tendency of schizophrenics to produce a wide variety of stress-induced brain changes that are individually exhibited by some nonschizophrenics. In this view, what is " a b n o r m a l " or "specific" about the biology of schizophrenia would be the overall conglomeration of stress-induced changes. The neural plasticity hypothesis just outlined is quite consistent with theoretical conceptualizations already in the literature. M. Bleuler has drawn attention to nonspecific hereditary and experiential factors: " a disharmony among individually healthy traits may constitute the hereditary disposition for the schizophrenic illnesses" (M. Bleuler [21], p. 4%). Furthermore, " t h e most diverse types of psychic traumas play a role in the genesis of the schizophrenias. Countless people who never become schizophrenic are also exposed to all the psychotraumatic effects that are found in the premorbid histories o f schizophrenics" (M. Bleuler [21], pp. 478-479). Meehl [161] postulated that anhedonia, cognitive slippage, interpersonal aversiveness, and ambivalence are the behavioral expressions of the genetic factors predisposing to schizophrenia. These traits were described as the core features of the personality which becomes clinically

HARACZ schizophrenic when subjected to environmental and social stress. Meehl's [161] concept of a "schizotypic" personality resembles the DSM-III diagnostic category of "schizotypal personality disorder" which is especially prevalent among biological relatives of schizophrenics [126]. Thus, the genetic predisposition to schizophrenia seems to consist of biological factors underlying the symptoms of interpersonal dysfunction and social withdrawal [25, 126, 127]. Social dysfunction is one of several nonspecific human characteristics that significantly influence the course of schizophrenia [233,234]. These prognostic variables also include work competence, family characteristics, social class, and coping style [28, 233,234, 248]. Thus, there is good evidence that a number of widespread, nonspecific variables influence the course of schizophrenia--the evidence for etiological factors specific to schizophrenia is comparatively weak. Wynne ([271], p. 710) addressed this issue as follows: "'Because a great diversity of potent, nonspecific, or general liabilities and assets could contribute to the characteristic threshold level of vulnerability in an individual, we need to ask the question of how essential is a positive answer to the question of whether there is a spec~i~c etiologic factor for schizophrenia, or for any subgroup of schizophrenics. Perhaps we should take seriously the hypothesis of no specific etiologic factors, and try to identify the most potent constellations of general factors . . . Identification of a limited cluster of major though nonspecific environmental and genetic factors would move research, treatment, or prevention f o r w a r d . . . Another possibility that is quite conceivable is that the combinations of factors interacting with one another is what is necessary. In that sense, interaction effects may become 'specific" and more important and interesting than the major effect of any single specific factor" (italics by Wynne). As outlined above, a neural plasticity hypothesis emphasizes the interplay of nonspecific genetic and environmental factors in the genesis of schizophrenia. This emphasis on interacting processes is in line with the basic tenets of general systems theory [251] Engel [70] and Marmor [ 153] have shown how a systems approach would lead psychiatrists to seek the origins of psychopathology within the patient's total system of interrelated biological, psychosocial, economic, and cultural factors. Employing general systems theory, Scheflen [206] has argued that postnatal brain development in schizophrenics could ultimately be affected by events at the societal, familial, interpersonal, and intrapersonal (psychological) levels. This complex web of mutually interacting factors was proposed to be capable of altering dendritic proliferation and synaptogenesis with the result being an enhanced vulnerability to schizophrenia. A role for neural plasticity in the pathophysiology of schizophrenia receives some support from a recent postmortem study [217]. Non-quantitative observations suggested the presence of an increased dendritic spine density on the pyramidal cells of orbitofrontal cortex in schizophrenic patients. Scheibel and Kovelman [208] found a disorientation of hippocampal pyramidal-cell dendrite systems in schizophrenics, but this finding seemed more likely to be related to genetic or infectious processes rather than neural plasticity. Thus, the virtual absence of quantitative studies of dendritic structure in schizophrenics makes it difficult to evaluate the relevance of neural plasticity to schizophrenia, Animal studies, on the other hand, show that cerebral cortical dendrites retain a structural plasticity well into adulthood [34, 37-40, 96, 243,244]. Postmortem brain specimens from nonschizophrenic humans have shown age-related changes

N E U R A L PLASTICITY A N D S C H I Z O P H R E N I A in dendritic structure and synaptic density in neocortex and archicortex [33, 111,207, 209-211]. Correlations have been found between loss of dendritic structure and the exhibition of dementia or psychosocial deterioration before death [33, 162, 207]. Thus, alterations in dendritic branching patterns, involving both growth and degenerative processes, appear capable of affecting behavior throughout the life of man. Studies of dendritic structure in schizophrenics could be aided by computer-assisted quantitative histologic methods [157,158]. Such studies could begin to evaluate the importance of neural plasticity in the pathophysiology of schizophrenia. Although requiring quantitative confirmation, the apparently increased orbitofrontal dendritic spine density in schizophrenics may be a manifestation of structural brain plasticity. In addition to this preliminary piece of evidence, there are other theoretical and empirical considerations which indicate that neural plasticity may be involved in the biology of schizophrenia: (1) structural and functional brain plasticity may be related to the neuroradiological evidence of regionally altered brain structure and function in schizophrenics; (2) brain plasticity in schizophrenic patients might also be manifested as a stress-induced potentiation of catecholamine systems; (3) a potential role for neural plasticity in the therapeutic action of neuroleptic drugs is suggested by the delayed onset and offset of the therapeutic effect. A discussion of these topics will lead to a concluding section on proposed research directions. R E G I O N A L BRAIN STRUCTURE AND F U N C T I O N IN SCHIZOPHRENIC PATIENTS

It was concluded above that monkey isolation syndrome behaviors are end products of structural and functional brain plasticity. A logical corollary of this conclusion was also noted, namely that enduring changes in brain structure and function should be associated with the enduring behavioral abnormalities of isolated monkeys. Similar reasoning would hold that if neural plasticity plays a role in the biogenesis of schizophrenic symptoms, then schizophrenic patients should exhibit changes in brain structure and function in comparison with nonschizophrenics. This prediction will now be addressed in a review of schizophrenia research findings that relate to regional brain structure and function. Regional neuronal function in human brain can be examined with the use of neuroradiologic methods employing radioactive tracers. These methods quantify regional cerebral blood flow and glucose use in order to indirectly assess regional neuronal activity. The above quantified parameters have been found to correlate directly with neuronal activity in animals [225-227, 273]. Three laboratories have uncovered evidence of altered regional cerebral blood flow (CBF) in schizophrenic patients [11, 113, 154, 155]. Ingvar [113] found that 40 chronic schizophrenics exhibited regional CBF patterns which were related to behavioral symptom clusters. The more inactive, mute, and autistic the patients were, the lower was the flow in the frontal regions of their brains. Elevated flow in postcentral regions was significantly related to cognitive disturbances including hallucinatory activity. Each of these CBF patterns differed from the typical "hyperfrontal" circulation found in normal human subjects [112]. Mathew et al. [154,155] and Ariel et al. [11] measured regional CBF in normal controls and a total of 58 patients with subchronic to chronic schizophrenia. In contrast to the "hypofrontal"

59 CBF pattern in Ingvar's [113] patients, the more recent studies disclosed a diffuse CBF deficit present throughout widespread frontal and postcentral cortical regions in the patients. Against the background of this diffuse deficit, Mathew's patients maintained the normal relatively hyperfrontal pattern while Ariel's patients showed a diminished hyperfrontality (decreased anterior/posterior CBF ratio). Ariel et al. [1 l] found that the largest schizophrenic-normal differences in gray-matter CBF were in the anterior (largely frontal) regions. The report by Mathew et al. [154] of an inverse correlation between postcentral regional CBF and hallucinatory behavior was at variance with the previous finding of increased postcentral blood flow in hallucinating patients [113]. The contrasting results in the above studies might be explained on the basis of differing patient populations: many of Ingvar's [113] patients were permanently institutionalized and were ill for 35 or more years, whereas the patient groups of Mathew et al. [ 154] and Ariel et al. [11] had mean ages of only 26.9_+8.9 (SD) and 29.7_+10.6 years, respectively. The findings of three research groups are indicative of a diminished regional cerebral glucose use in schizophrenic patients [3 l, 32, 71,266]. In comparison with 6 normal control subjects, Buchsbaum et al. [31,32] found that 8 schizophrenics taken off neuroleptics exhibited significantly decreased glucose use in the frontal cortex and left subcortical gray matter. Widen et al. [266] reported significantly decreased frontal-to-temporal cortical ratios of glucose use in 9 schizophrenics compared to 2 control subjects. A longitudinal study of one chronic schizophrenic patient suggested that cerebral glucose use can covary over time with behavioral symptoms [71]. Prior to neuroleptic therapy the studied patient had intense auditory hallucinations and a 40-percent decrease in frontal cortical glucose use compared to normal controls. After 4 months of neuroleptic treatment, the patient underwent a moderate behavioral recovery while glucose use in the frontal cortex returned to within 25 percent of normal. Following neuroleptic withdrawal, the patient relapsed and the frontal cortical glucose use reverted to the decreased level observed prior to drug therapy. Thus, both Farkas et al. [71] and Buchsbaum et al. [31,32] found low frontal cortical glucose use in unmedicated schizophrenics, indicating that neuroleptics are not a likely cause of these findings. Golden et al. [91,92] examined brain density in 23 chronic schizophrenics and 24 normal controls by quantitating the radiolucency of brain structures as revealed in computerized tomographic (CT) scan images. Overall brain density was significantly decreased in the patients. When regional density was examined, it was found that the density deficit was concentrated primarily in the left frontal lobe of the schizophrenics [92]. These density changes were not correlated with age or lifetime neuroleptic usage [92,147]. The lack of correlation between age and density values suggests a preexistent or developmental deficit rather than a deterioration following schizophrenic onset ]l 1]. The authors speculated that the decreased brain density in schizophrenics might be accounted for by atrophied cell bodies or dendritic processes, fewer cell bodies, enlarged sulci, decreased myelinization, or decreased glial cells [92]. Largen et al. [134] failed to find any CT brain density differences between 19 normal controls and 25 schizophrenic or schizoaffective patients. However, the patient group exhibited significantly more left-right density asymmetries than did the control group. Within the patient group, but not in controls, there were

60 significantly lower densities of both gray and white matter in the left hemisphere than in the right. The results reviewed above have begun to coalesce into a pattern which suggests that chronic schizophrenia is associated with regional alterations in brain structure and function. Deficits in CBF, glucose use, and brain density were found in the frontal cortices of schizophrenics [11, 30-32, 71, 92, 113, 154]. CBF alterations were also reported in postcentral cortical regions [11, 113, 154]. Theoretically, these changes could be secondary to a regional viral infection, a regionally-expressed genetic biochemical defect, or some other specific disease process. However, regional changes in structure and function might also be derived from an inherent structural and functional brain plasticity. The latter possibility seems to be worth entertaining in view of the considerable difficulty that biological researchers have experienced in their search for specific disease processes underlying schizophrenia (proposed specific biological defects were summarized in the previous section entitled '~Biological etiology of schizophrenia"). Buchsbaum et al. [31] noted that the frontal cortical deficits in CBF and glucose use are maximal in the superior frontal-premotor cortex of schizophrenics. This cortical region is immediately adjacent to the supplementary motor area (SMA) and, indeed, a variety of physiological and anatomical evidence suggests that the premotor and supplementary motor areas are closely related functionally (for a review, see [263]). The SMA appears to function in the programming of voluntary motor behaviors in monkeys and man [26, 177, 198]. The above considerations led to the proposal that functional deficits in the vicinity of the SMA may be related to the reduced motor output and lack of goal-directed behavior that are characteristic of schizophrenia [31]. It was noted in a previous section that monkey isolation syndrome behaviors correlate with the presence of SMA dendritic deficits [196,228]. Thus, the above results may be indicative of behaviorally-relevant SMA dysfunctions in human and monkey pathological behavior syndromes. The SMA dendritic deficits in isolated monkeys were manifestations of structural brain plasticity. It is also conceivable that the SMA-related deficits in CBF and glucose use in schizophrenics are consequences of structural and functional brain plasticity. In addition to the brain density deficits described earlier, controlled CT studies have uncovered four other types of structural abnormalities in subgroups of chronic schizophrenics: enlargement of the lateral cerebral ventricles, enlargement of cerebral cortical sulci, reversal of normal neuroanatomical asymmetries, and atrophy of the cerebellar vermis [6, 93, 103, 119, 120, 142, 171,261,262, 270] (but see [117,118] for evidence of normal cerebral asymmetries and ventricular and sulcal size in a group of schizophrenic veterans). The possible functional significance of these CT findings was examined by clinically comparing subgroups of schizophrenics with clear abnormalities to subgroups with normal CT scans. In this way, it was found that the patients with CT evidence of cerebral atrophy had significantly more neuropsychological deficits and nonfocal neurological signs [262,270]. Treatment factors did not seem to be involved in the etiology of the CT abnormalities since: (a) neither ventricular nor sulcal size appeared related to the duration of hospitalization or drug treatment [261,262], and (b) significant ventricular enlargement was found in a group of young patients with first-episode schizophreniform disorder [260]. From an etiological standpoint, it is interesting that the CT

HARACZ abnormalities seemed to correlate with premorbid adjustment. Compared to schizophrenics with normal CT scans, 21 patients with cerebral atrophy had significantly poorer school and social premorbid adjustment, especially during childhood [259]. This finding led the authors to suggest that the brain structural abnormalities may be the result of early developmental defects [261,262]. In the present context, it is tempting to recall that the early development of brain structure in primates and subprimates can be altered by environmental factors (see text under "Environmental influences on brain plasticity"). Thus, the early developmental occurrence of deviant structural adaptations to the environment might be etiologically related to the CT-scan abnormalities. In summary, structural and functional brain plasticity may underlie the changes that schizophrenic patients exhibit in CBF, cerebral glucose use, and CT-scan brain structure. NEURAL PLASTICITYAND CATECHOLAMINESYSTEMS The opening section of this paper briefly summarized the major pharmacological and biochemical findings pertaining to the dopamine hypothesis of schizophrenia, viz. the pharmacological evidence for a dopaminergic hyperactivity has not been compellingly borne out by studies of dopamine function in schizophrenic subjects (reviewed in [100]). If compelling biochemical evidence for a dopaminergic dysfunction is not forthcoming, then the disparity between the pharmacological and biochemical data will require explanation. One possible resolution could be provided by the occurrence of potentiating mechanisms at dopaminergic synapses. A synapse is said to be "potentiated" if an unchanged presynaptic stimulus becomes more effective in producing a postsynaptic electrophysioiogical response. Such a potentiating process might allow a ' f u n c t i o n a l dopaminergic hyperactivity in the face of a relatively normal dopamine turnover. Post has suggested that catecholaminergic pathways in the limbic system may become potentiated following their repetitive activation by stressful events [166, 185, 188, 189]. It was further proposed that this type of potentiation could provide a mechanism by which repeated psychological stresses in man could become associated with progressive increases in psychopathology and potentially in the development of psychosis. Post's proposal will be further discussed below in light of the literature on brain potentiating mechanisms. Synaptic potentiation typically has been studied by subjecting the brains of adult animals to repetitive electrostimulation. A series of neurophysiological and behavioral events develop when certain brain sites are stimulated once daily with a brief train of electrical impulses. Initially, there is a marked potentiation of the postsynaptic electrophysiological response to a single test pulse. This phenomenon, referred to as "long-term potentiation" (LTP), is frequently discussed as an experimental model of long-term memory [22, 66, 89, 139, 144]. If the same daily electrostimulation regimen is continued, the animal eventually develops generalized motor seizures. This so-called "kindling" phenomenon has been cited as a possible model of epilepsy [4, 86, 88, 124, 160, 184, 255]. Thus, the repetitive electrostimulation paradigm is purported to have relevance to both physiological and pathological brain function. Mapping studies indicate that hippocampal pathways show the strongest and longest-lasting LTP effects, although a number of pathways throughout the limbic forebrain also exhibit LTP [190]. The enduring nature of LTP is revealed by reapplying a test pulse long after repetitive electrostimula-

NEURAL PLASTICITY AND SCHIZOPHRENIA tion has ceased. In this way, potentiation of the field potential recorded from the hippocampus was shown to last at least two months after the cessation of daily entorhinal cortex stimulation [63]. Lynch et al. [145] noted that the electrostimulation parameters employed in LTP experiments resemble the natural firing patterns of neurons in behaving animals. Some cells in the hippocampus and entorhinal cortex do exhibit bursts of activity in the range of frequencies used experimentally to induce LTP [145, 167, 191]. Thus, it seems possible that the physiological repetitive firing of neurons could trigger an LTP-like process in animals not receiving electrostimulation. Accordingly, evidence of physiological LTP-like processes has been found in mice, rats, rabbits, and cats. Potentials evoked by test pulses revealed that hippocampal synaptic transmission was potentiated during the behavioral conditioning of mice, rats, and rabbits [116, 203, 238]. Synaptic potentiation was mainly confined to rats with good retention of task performance, whereas poor learners did not exhibit significant potentiation [203]. In cats, the transmission efficiencies of limbic pathways were found to vary systematically with what might be described as "personality" characteristics [1-3]. Upon singlepulse stimulation of the amygdala, the most defensive cats exhibited the greatest evoked synaptic responses in the ventromedial hypothalamus and relatively small responses in the ventral hippocampus. Perforant path stimulation also evoked relatively low ventral hippocampal synaptic responses in defensive cats. Aggressive cats showed the opposite pattern of evoked potentials in each of the three limbic pathways. These data are in logical agreement with previous electrostimulation and lesioning experiments which indicated that an amygdalo-hypothalamic pathway tonically inhibits feline aggressive behavior, while the ventral hippocampus facilitates aggression [67, 82, 219]. Thus, it appears that aggressive cats have a naturally enhanced transmission efficiency in pathways that facilitate aggression. The authors concluded that "it is likely that some form of LTP underlies naturally occurring behavioral differences between aggressive and defensive cats" ([3], p. 279). The above conclusion is supported by evidence of longlasting behavioral changes in cats induced by repetitive electrostimulation. The specific type of behavioral change may represent an enhancement of the normal function of the neural pathways activated by repetitive stimulation: lasting increases in defensiveness [1-3], aggression [1-3], food intake [54], and avoidance-withdrawal behavior [23 l] were induced by, respectively, stimulation of the amygdala, ventral hippocampus, lateral hypothalamus, and ventral tegmental area. The various behavioral changes were proposed to depend on some form of LTP in the pathways which exit from the stimulated structure [3]. Similar LTP-like processes may occur in man since enduring changes in affective behavior were observed in human subjects after repetitive amygdaloid electrostimulation [232]. Theories of stress-induced potentiation can now be approached from a perspective provided by the above brief review of the limbic potentiation literature. Post and coworkers [185, 188, 189] proposed that repetitive stressful experiences may potentiate limbic catecholaminergic pathways and, thereby, predispose an individual to future psychopathology. Stressful events later in life might trigger a psychotic episode by reactivating the potentiated pathways--albeit that the same stressors may be innocuous for non-predisposed individuals. Similarly, van Kammen et

61 al. [246] suggested that excessive aversive stimuli could lead

to increased dopaminergic activity in man and subsequently to psychotic decompensation in vulnerable individuals. The previously reviewed animal literature offers some tentative support for the concept of behaviorally-relevant catecholaminergic potentiation: (a) lasting behavioral changes are observed after the electrostimulation-induced potentiation of limbic pathways [ 1-3]; (b) naturally-occurring potentiating processes provide a potential biological explanation for individual differences in aggressiveness [1-3] and task retention [203]; (c) most limbic pathways tested have shown potentiation effects after brief repetitive stimulation [190]. Racine et al. [190] found that putative cholinergic and glutaminergic pathways exhibited potentiation, as did several other pathways which have not been neurochemically characterized. However, catecholaminergic pathways were not tested for potentiation. Thus, stimulation-induced potentiation has not been directly demonstrated in catecholaminergic systems, although Adamec and Stark-Adamec [3] have reviewed some indirect evidence suggesting that the potentiation of dopaminergic pathways may mediate stimulation-produced changes in feline defensive and avoidance behaviors. Besides the above data, the hypothesized stress-induced catecholaminergic potentiation is also consistent with four other types of experimental evidence. (1) Subjecting animals to electric foot-shocks demonstrates that mesolimbic and mesocortical dopaminergic neurons are activated by stress [20, 193,237]. (2) The repetitive administration of dopamine agonists induces a progressive disruption of behavior in animals and man: animals develop increasingly severe "stereotypic" behaviors, such as licking, gnawing, and purposeless searching movements (for a review, see [186]); normal human volunteers receiving amphetamines develop a psychosis which closely resembles the acute paranoid type of schizophrenia [8,9]. (3) Repetitive electrostimulation of mesolimbic dopaminergic neurons in cats leads to the progressive onset of a behavioral syndrome which includes fearfulness, hiding, staring, and avoidance of social contact [231]. (4) Repetitive stressful experience and amphetamine can each induce a long-lasting behavioral sensitization to the other, regardless of the order of administration [10, 68, 150]. Thus it seems possible that the repetitive activation of dopaminergic systems by either electrostimulation, pharmacological agents, or stressful events could trigger potentiating mechanisms which lead to a gradual deterioration of behavior. Post's kindling model for progressive behavioral change emphasizes a correlation between behavior and synaptic connectivity. Just as differentially aggressive cats differed naturally in the transmission efficiencies of limbic pathways [1-3], humans with psychopathology may also have alterations in the functional connectivities of some nerve tracts. According to Post's model, various psychotic symptoms may be related to potentiated pathways in different neuroanatomical areas subserving globally differing functions [185]. For example, auditory and visual hallucinations might, respectively, be associated with pathologically facilitated pathways in the temporal and occipital lobes. Motor and postural changes, such as stereotypies, waxy flexibility, and catatonia may indicate the involvement of neostriatal pathways. In this way, a wide variety of clinical phenomena potentially could be accounted for: "Thus a kindling model for the development of pathological behavior is capable of dealing with a changing symptomatology which

62 may be manifest over time in the functional psychoses and does not require a given, discrete neuroanatomical lesion to explain a variety of symptoms and syndromes" ([185], p. 37). The above discussion of Post's kindling model of psychosis indicates that the model has substantial explanatory power and a reasonable basis of support in the animal literature. Thus, it seems appropriate to ask what, if any, support for the model can be gleaned from studies of schizophrenic patients? Unfortunately, it is difficult to conceive of an ethical approach to the e x p e r i m e n t u m crucis: schizophrenics and nonschizophrenics would have to be compared with regard to the magnitude of postsynaptic responses evoked by single-pulse stimulation of limbic structures. In the absence of such an experiment one can still scan the research literature for indirect evidence of potentiating processes in schizophrenic patients. For example, four research groups have recorded abnormal limbic electrical activity, including spiking, from depth electrodes in schizophrenic patients (reviewed in [239]). Electrographic abnormalities in the septum, hippocampus, amygdala, and frontal lobes were occasionally reported to correspond precisely with the patients' ongoing psychotic behavior. Limbic spike discharges also developed in baboons subjected to repetitive electrostimulation of the amygdala [253,254]. As daily kindling trains were administered, interictal spike discharges gradually developed in the amygdala, hippocampus, mesencephalic reticular formation, and orbitofrontal cortex. The chronology and distribution of spike discharges suggested to the authors a "transsynaptic nature of functional reorganization of the brain associated with kindling." Thus, a potentiating process seems to be involved in the spread of abnormal electrical activity during repetitive electrostimulation. The presence of abnormal limbic spiking in kindled baboons, schizophrenic patients and, to be noted below, isolated monkeys [102] suggests that limbic potentiation mechanisms may be operative in each of these conditions. Bizarrely behaving isolated monkeys also exhibited sharp spiking and high-amplitude spindling in recordings obtained from the anterior septum, hippocampus, and somatosensory thalamic nuclei [102]. Such electrographic changes were not seen in socially-raised controls. These results lend some credibility to the hypothesis that stressful experience is associated with a potentiation of limbic pathways [185]. Another suggestive finding is that a subjective response to limbic or temporal lobe electrostimulation is more frequently apparent in schizophrenic and complex partial epilepsy patients than in patients with other disorders [87,104, 114, 181, 216]. This observation has been interpreted to reflect the existence of potentiated limbic pathways in schizophrenic and seizure patients [3]. Such limbic potentiation is proposed to constitute a biological substrate for the psychotic symptomatology of patients with schizophrenia or complex partial epilepsy [3, 4, 185, 186, 188, 189]. In summary, the results of both animal and human studies provide a rational ground for further investigation into the relationship between psychosis and limbic potentiation. Another form of plasticity involving catecholaminergic systems has been discussed in the schizophrenia research literature, namely post-lesional plasticity. Coyle and Johnston [44] and Hrkfelt et al. [106] suggested that a catecholaminergic hyperactivity in schizophrenia may be produced by an abnormally increased density of catecholaminergic nerve terminals in some brain areas. Each of these papers held that such a catecholaminergic hyperinnervation could have developed after a primary lesion in a nearby

HARACZ non-catecholaminergic system. A number of animal studies demonstrating this type of post-lesional plasticity have been reviewed elsewhere [43]. The hyperinnervation hypothesis receives some support from reports of elevated norepinephrine concentrations in postmortem brain samples from schizophrenics, especially those patients with paranoid features (for a review, see [270]). However, preliminary studies indicated that schizophrenics and controls did not differ in the postmortem fluorescence histochemistry of catecholamine neurons in cortical and subcortical regions [174-176]. Future tests of the hyperinnervation hypothesis may do well to include a postmortem examination of the brains of paranoid schizophrer vs with the fluorescence histochemistry technique. NEURAL PLASTICITYAND NEUROLEPTICS The present section will consider the possibility that some forms of neural plasticity mediate the antipsychotic effect of neuroleptics. Meltzer et al. [ 164] have proposed that the relatively slow onset of the therapeutic response to neuroleptics and the persistence of the therapeutic effect after neuroleptic withdrawal are both consistent with the hypothesis that neuroleptics initiate a biological process with a relatively long half-life which, in turn, initiates and maintains the antipsychotic effect. Axonal sprouting was cited as a possible example of such a process [164]. Anatomical evidence exists for axonal sprouting in response to such pharmacological agents as colchicine [94] and kainic acid [42]. A recent quantitative electron microscopic study revealed that rats chronically treated with haloperidol exhibited significantly increased numbers of axon terminals per dendrite cross section in the substantia nigra, suggesting neurolepticinduced axonal sprouting [17]. Nothing is known of the time course of this drug effect since the rats were examined only after 16 weeks of neuroleptic treatment. Further animal studies are needed to relate the time course of neurolepticinduced axonal sprouting to the time course of clinical therapeutic action. The previous section discussed the proposal that a stressinduced potentiation of catecholaminergic pathways may lead to the development of psychosis [185, 188, 189]. This proposal would assign therapeutic importance to an ability of neuroleptic drugs to counteract limbic potentiating mechanisms. Neuroleptics do, in fact, block the development of electrostimulation-induced hippocampal LTP [65, 80, 242]. However, the ability of the neuroleptics to antagonize LTP was more closely related to their ability to block calmodulin than to their relative potencies as dopamine antagonists [65]. Furthermore, neuroleptics block dopamine receptors at drug levels that are a thousand times lower than the levels needed to inhibit calmodulin or block hippocampal LTP [65]. At first glance, these findings seem to argue against LTP-blockade as a therapeutically-relevant neuroleptic action since the clinical antipsychotic activities of neuroleptics correlate closely with their dopamine-blocking potencies [47, 133,183, 215] and not with their calmodulin-inhibiting potencies [ 173]. Nevertheless, the above results are understandable since, on the basis of catecholamine-depleting treatments, dopamine and norepinephrine do not seem to be directly involved in hippocampal LTP [65]. Thus, one would not expect dopamine-receptor blockade to play an important role in antagonizing hippocampal LTP. As noted below, though, the dopamine-blocking action of neuroleptics might be expected to antagonize LTP in extra-hippocampal regions.

N E U R A L PLASTICITY AND SCHIZOPHRENIA In the studies just discussed, the hippocampal LTP probably represented a potentiation of glutaminergic synapses [16, 146, 172, 264, 265]. Therefore, one would employ glutamate-blockers, and not dopamine-blockers, to test the effectiveness of postsynaptic-receptor blockade in antagonizing hippocampal LTP. Indeed, glutamate-receptor blockers markedly impair the development of hippocampal LTP [64,132]. Similarly, atropine blocks the kindling produced by repetitive carbachol administration [258] or repetitive amygdaloid electrostimulation [5,12]. These findings reinforce the concept that synaptic potentiating mechanisms require an unimpaired synaptic transmission [64,132]. It can now be recalled that Post et al. [189] specifically referred to catecholamine systems as potential sites for psychosisrelated potentiation. Based on the success of glutamateblockers in inhibiting glutaminergic potentiation [64,132], one might well expect that neuroleptics would antagonize catecholaminergic potentiation. Thus, it seems plausible that the dopamine-blocking action of neuroleptics achieves a therapeutic effect by antagonizing the potentiation of dopamine pathways. Such a proposal is supported by the demonstrated ability of neuroleptics to counteract the behavioral sensitization exhibited by animals and humans in response to repetitive dopamine-agonist administration [7, 8, 13, 23,205]. If, as proposed by Post [185], this dopaminergic behavioral sensitization reflects a "'pharmacological kindling" process, then neuroleptics might have been demonstrated to suppress behaviorally-relevant dopaminergic potentiation. The above discussion requires validation in two specific areas: (a) it remains to be electrophysiologically demonstrated that dopaminergic synapses are potentiated following their repetitive activation by electrostimulation, dopamine agonists, or stressful events (some electrophysiological evidence is indirectly suggestive of dopaminergic potentiation following repetitive dopamineagonist administration [99] and chronic social isolation [212]); (b) it must be shown that pharmacologically-relevant concentrations of neuroleptics can block the potentiation mentioned in (a). In animals, a well-documented plastic response to chronic neuroleptic administration is the development of postsynaptic dopamine-receptor supersensitivity [101, 169, 212]. However, it is difficult to fathom a therapeutic role for this form of neural plasticity. The therapeutic efficacy of neuroleptics is particularly evident in the same subgroup of schizophrenic patients that is most sensitive to the psychotogenic effect of dopamine agonists [100,246]. Thus, it seems that the neuroleptic-induced supersensitivity should tend to worsen psychotic symptoms, if it has any effect at all [247]. It may be that the postsynaptic supersensitivity is a side effect of drug treatment while some other neuroleptic action (e.g., LTPblockade, induction of axonal sprouting, etc.) produces the therapeutic effect. PROPOSEDTESTS OF SPECIFICHYPOTHESES Employing a speculative approach, this essay has shown that neural plasticity concepts can be invoked to potentially explain several aspects of schizophrenia: the various types of behavioral symptoms exhibited by schizophrenics (e.g., hallucinations, motor disorders, etc.), the pharmacological support for the dopamine hypothesis, the delayed onset and offset of neuroleptic antipsychotic action, the primary etiological and/or modulatory influences of the environment on the course of schizophrenia, and the regional alterations in brain structure and function seen in chronic schizo-

63 phrenics. Considering the explanatory potential of neural plasticity concepts, a research program which focuses on these concepts seems warranted. Such a research program need not be limited to investigating the specific forms of neural plasticity discussed in the present review. Cotman [41] has noted that we are only beginning to appreciate the structural and functional plasticity of neuronal circuitry, and that further work is needed to explore the adaptive capacities and functions of neural plasticity. In view of the nascent state of our current knowledge of neural plasticity, the present paper cannot have touched upon all of the forms of plasticity that are potentially relevant to the biology of schizophrenia. For just one example, no mention was made of the demonstrated plasticity of endogenous opioid systems in response to variations in the social environment [53,220]. Endogenous opioid peptides are also thought to interact with brain catecholamines [14,178] and the kindling phenomena [84, 137, 138]. A possible contribution of endogenous opioids to the biology of schizophrenia is suggested by the therapeutic effect of opiate agonists and antagonists in some patients (reviewed in [83]). Taken together, the above data may indicate a role for opioid peptides in a stress-induced catecholaminergic kindling process that has been proposed as a substrate of psychosis [185, 188, 189]. Instead of attempting to review every conceivable relationship between neural plasticity and schizophrenia, the present paper will conclude by listing a limited number of specific, testable hypotheses. These hypotheses are derived from a general theory relating neural plasticity to animal and human pathological behaviors. Hypothesis No. 1

Post and co-workers suggested that psychopathology results from the potentiation of catecholaminergic pathways in the limbic system following their repetitive activation by stressful events [185, 188, 189]. Animals subjected to repetitive stress could be tested for the potentiation of potentials evoked by electrostimulation of catecholaminergic pathways. The experimental procedure could be similar to that employed in studies of hippocampal potentiation during behavioral conditioning [116, 203, 238]. Post's hypothesis could be generalized to allow a search for potentiation throughout the brain, especially in view of the growing number of pathways known to support LTP [190] and the relatively widespread distribution of abnormal electrical activity recorded from depth electrodes in kindled baboons [253,254], isolated monkeys [102], and schizophrenic patients (reviewed in [239]). Hypothesis No. 2

Adaptive changes in neuronal structure contribute to the generation of animal and human pathological behaviors. Stated in terms of structure rather than function, this hypothesis is otherwise analogous to the general version of Hypothesis No. ! which proposed that neurophysiological adaptations underlie psychopathology. Altered dendritic structure has already been found in the cerebral and cerebellar cortices of isolated monkeys [81, 195, 196, 228, 235], although limbic areas have yet to be examined [195]. Quantitative studies of postmortem tissue from schizophrenics might be directed at the orbitofrontal cortex and supplementary motor area (SMA). A preliminary postmortem study suggests that schizophrenics have an increased dendritic spine density on orbitofrontal pyramidal cells [217], while in

64

HARACZ

vivo studies are suggestive of SMA deficits in glucose use and blood flow [31]. SMA dendritic deficits were found to correlate with the presence of monkey isolation syndrome behaviors [228]. Hypothesis No. 3

The density of catecholaminergic nerve terminals is abnormally increased in some schizophrenics [44,106]. This specified version of Hypothesis No. 2 could be tested by applying the postmortem fluorescence histochemistry technique [174--176]. Tissue from paranoid schizophrenics may be of special interest since members of this subtype exhibit elevated postmortem brain norepinephrine levels [270]. Also of interest would be the postmortem immunocytochemical localization of such neuropeptides as cholecystokinin, substance P, neurotensin, and the endogenous opioids [197]. These peptides appear to interact with brain catecholamines [14, 105, 107, 141, 151, 178] and may contribute to biological mechanisms underlying schizophrenia [58, 73,151,170, 267]. Hypothesis No. 4

The relationship between the CT evidence of cerebral atrophy and poor premorbid school and social adjustment led to the proposal that brain structural abnormalities in chronic schizophrenics may be the result of early developmental defects [261,262]. Since early brain development can be altered by environmental factors (see text under "Environmental

influences on brain plasticity"), it could be further hypothesized that specific environmental factors, one example being familial communication patterns [222], are etiologically related to the brain structural alterations depicted on the CT scans of some schizophrenics. This hypothesis could be tested by correlating objective indices of familial communication [29, 221, 222, 249] with CT scan results, especially those obtained from young first-episode patients [260]. These young patients have already been found to exhibit a positive relationship between cerebroventricular size and poor premorbid social adjustment [55]. Thus, it seems of interest to ask whether familial communication patterns might relate to both premorbid social adjustment and ventricular size. Hypothesis No. 5

Structural and/or functional adaptations are involved in the antipsychotic effect of neuroleptics. Neuroleptics block the development of hippocampal LTP [65, 80, 242], but it is not known if neuroleptics can antagonize LTP in extrahippocampal regions, particularly in areas of dense catecholaminergic innervation. An LTP-blocking capability would allow neuroleptics to negate the pathological potentiating mechanisms postulated in Hypothesis No. 1. Animal studies could be designed for the detection of changes in structure (i.e., axonal sprouting? [17,164]) and transmission-efficiency in various synaptic populations during neuroleptic administration.

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