SEMINARS I N NEURO1,OGY-VOLUME
10, N O . 3
SEPTEMBER 1990
The Brain in Schizophrenia
Schizophrenia rarely has been of interest as a clinical entity in neurology, primarily for two reasons. First, since the clinical manifestations of schizophrenia are almost exclusively behavioral, they are not easily translatable into traditional neurologic terms. Second, the neurobiologic basis of schizophrenia has remained elusive, despite decades of intensive investigation by many disciplines within the neurosciences. During the first half of this century, most of the neurobiologic research on schizophrenia focused on finding a pathognomonic lesion in the brain. T h e effort was notoriously unsuccessful and encouraged speculation about a psychogenic etiology of schizophrenia. However, the studies from the first half of this century were methodologically limited in a number of respects. Few of then1 were adequately controlled. Most of then1 failed to examine the same brain areas systematically. Few studies considered sites outside of the neocortex. Perhaps most important, the effort assumed that the illness is a singular pathologic entity, rather than a variety of disorders with common clinical features. As a result, investigators tended to dismiss nonspecific and inconsistent findings. Since the diagnosis of schizophrenia is made on purely clinical grounds, the disorder could conceivably include phenotypically similar illnesses with diff'ering pathophysiologic bases. Another problem with older studies involved the lack of diagnostic reliability in psychiatry and the multiple classification systems that had been used for schizophrenia. This problem made comparisons between studies dif'f'icult and the need for standardized diagnostic criteria essential.
The widespread acceptance, in 1980, of explicit diagnostic criteria for most psychiatric disorders, analogous to those used in the clinical diagnosis of neurologic disorders such as multiple sclerosis and Alzheimer's disease, represents one of the most important developments of this century in schizophrenia research and in the clinical practice of' psychiatry. T h e classification system of the Diagnostic and Statistical Manual (DSM, now the DSM-111-K[evised]) has dramatically improved the reliability of psychiatric diagnosis and has made it possible to select more homogeneous research cohorts.' Without this dramatic development in diagnostic nosology, the consistent neurobiologic data base that has begun to emerge from research on schizophrenia would not have been possible. T h e classic approach in clinical neurology focuses on lesion localization in nervous system disorders before considering the etiology and pathophysiology of the lesion. Kecent studies have begun to localize the lesion or lesions underlying schizophrenia. This article will review those studies and their implications for central nervous system function in patients with this disorder.
NEUROLOGIC SIGNS The clinical neurologic examination of' patients with schizophrenia yields very few consistent findings. Unusual neurologic signs in medicationfree patients have been noted since the end of the 19th century, including bizarre posturing, mannerisms, stereotypies, peculiarities of gait, and other difficult-to-characterize abnormal movements.'
*Director of Consultation Neurology, Clinical Brain Disorders Branch, National Institute of Mental Health, Neuroscience Center at St. Elizabeth's Hospital, Washington, D.C. ?Chief, Clinical Brain Disorders Branch, National Institute of Mental Health, Neuroscience Center at St. Elizabeth Hospital, Washington, D.C. Reprint requests: Dr. Weinberger, Clinical Brain Disorders Branch, National Institute o f Mental Health, Neuroscience Center at St. Elizabeth Ilospital, Washington, D.C. 20032
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Copyright 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Thomas M . Hyde, M.D., Ph.D., * and Daniel K. Weinberger, M.D. f
NEUROPSYCHOLOGY Neuropsychologic testing can be used to identify and quantify focal deficits in central nervous system function. While schizophrenia has been the subject of neuropsychologic investigation for over 50 years, until recently this effort did little to amplify our understanding of this disorder. Most studies have addressed the question of whether patients with schizophrenia appeared "organic" in their neuropsychologic testing profile. The results, though fairly consistent in demonstrating that the
patients do score in the organically impaired range, were in general dismissed as being epiphenomena of psychosis and not representative of a valid cognitive incapacity. Even consistently observed deficits, such as poor performance on tests of sustained attention, are difficult to interpret in neurologic terms, because the role of purposeful behavioral factors is not easily controlled. T h e nature of the cognitive deficits observed is illustrated by a recent controlled study of monozygotic twins discordant for schizophrenia.12 Goldberg and colleagues" found that general cognitive performance was worse on almost every scale of measurement, including tests of general intelligence, memory, abstract reasoning, and attention, when comparing the twin with schizophrenia to the unaffected cotwin. These results suggest fairly widespread cortical dysfunction. However, the magnitude of the deficits was mild in most instances. On many of the tests, the perfbrmance of the affected twin was still within the broad range of normal, even though it was poorer than the score of the cotwin. If the cotwins had not been available for comparison, the existence of reduced performance in the affected twins would not have been appreciated in many cases. This underscores the subtle nature of the neuropsychologic deficits in schizophrenia. In addition, fbcal cognitive deficits have been explored in studies using focused neuropsychologic batteries.".'"mpaired verbal recall has been consistently replicated, though the magnitude of the deficit is mild compared with patients with amnestic disorders. 'Ihis deficit may be the functional correlate of the structural abnormalities noted in the temporal lobe, and the hippocampus in particular, in both neuropathologic and neuroimaging studies (which will be elaborated in subsequent sections). However, it is important to note that similar memory impairment occurs with lesions of the frontal lobe,14.'%nd that some of the medications used to treat patients with schizophrenia can impair memory function. Another line of neuropsychologic evidence suggests that the dorsolateral prefrontal cortex may be dysfunctional in patients with schizophrenia. The dorsolateral prefrontal cortex mediates numerous complex behaviors, including the abilities to associate knowledge with action, to establish abstract sets, and to change them when appropriate, to filter or suppress memories, to monitor personal behavior, and to provide drive and goaldirected thinking.lWany of these abilities appear to be impaired in patients with schizophrenia. T h e Wisconsin Card Sort (WCS) test, a relatively simple neuropsychologic task which requires
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Rather than being classified as movement disorders or abnormal involuntary movements, they usually have been dismissed as a manifestation of the primary mental disturbance. It is possible, however, that these movements have a pathophysiologic substrate in abnormal function of the basal ganglia. They may correlate with pathologic findings in the basal ganglia, as will be described."-" More study needs to be devoted to the abnormal involuntary movements in schizophrenia. T h e most consistent neurologic finding in patients with schizophrenia has been an impairment of smooth pursuit eye movement^.^,^ This finding is probably present in the majority of patients with chronic schizophrenia and in a significant proportion of their first-degree relatives. It does not appear to be the result of medical treatment. Smooth pursuit is defective because of the intrusion of saccades. Localization of the region accounting for this defect is unknown. T h e frontal cortex, basal ganglia, and cerebellum all play a role in suppressing saccadic intrusions into smooth pursuit eye movements. A complex attentional defect, secondary to frontal lobe dysfunction, is believed by some to be the cause of abnormal smooth pursuit in ~chizophrenia.~ This abnormality may relate to other evidence of frontal lobe dysfunction, as discussed later. T h e prevalence of neurologic "soft signs," including such findings as primitive reflexes and poor coordination, is higher in patients with schizophrenia than in patients with affective disorders%r "neurotics."1° It has been suggested that the presence of soft signs is indicative of subcortical"' andlor frontal pathologic lesions." However, these findings, by their character, do not indicate a clearly localizable lesion of the central nervous system. As later sections will establish, abnormalities have been found in both subcortical and frontal structures, perhaps correlating at least circumstantially with the high prevalence of soft signs in patients with schizophrenia.
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abstract set formation and set shifting, is particularly sensitive to dorsolateral prefrontal cortex dysfunction. Patients with schizophrenia perform poorly on the WCS.17 This poor performance does not necessarily reflect a generalized inability or unwillingness to perform cognitive tasks. On tasks that utilize primarily posterior cortical regions, such as block design, patients with schizophrenia tend to perform n ~ r r n a l l y . ~ ~ ~ ' ~ T h e so-called negative or deficit symptoms of schizophrenia include impaired motivation, shallow affect, paucity of thought, and cognitive deficits. A popular hypothesis holds that these "negative" symptoms may be attributable to a functional lesion of the prefrontal cortex. Neuropathologic evidence of injury to the prefrontal cortex, though not negligible, is Language function has been the subject of numerous studies in schizophrenia, but no consistent results have Though the language of patients with this disorder is sometimes bizarre and disorganized, it is not easily characterized in the lexicon of aphasiology. A popular but weakly supported hypothesis is that dominant hemisphere dysfunction, in temporal, parietal, or inferior frontal regions, may underlie the putative language dysfunction in schizophrenia.
IN VIVO NEUROPHYSIOLOGY: REGIONAL CEREBRAL BLOOD FLOW AND POSITRON EMISSION TOMOGRAPHY STUDIES
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Both regional cerebral blood flow (rCBF) techniques and positron emission tomography (PET) have been used to measure focal activity in the central nervous system of patients with schizophrenia. They are the latest and among the most complicated techniques to study the living brain. T h e two-dimensional multiprobe rCBF technique relies on the inhalation of radioactively labeled xenon, whereas PET studies use radioactively tagged oxygen or glucose analogs. These paradigms ostensibly map regional brain activity, the "work" of the brain. They can be performed with the patient at rest and during cognitive tasks. Tasks that activate focal cortical regions have been used to test the physiologic competency of various cortical systems. The first rCBF study of patients with schizophrenia was performed in 1974 by Ingvar and F r a n ~ e nT. ~ h e~ normal resting pattern of heightened blood flow to the prefrontal cortex relative to other cortical regions ("hyperfrontality") was not seen in patients with schizophrenia." This relative "hypofrontality" was interpreted as a failure of prefrontal activating mechanisms and as a physio-
V O L U M E 10, NUMBER 3 SEPTEMBER I990
logic correlate of negative symptoms. A majority of subsequent rCBF studies have confirmed the "hypofrontality" of cortical function in schizophrenia.26This has provided physiologic confirmation of neuropsychologic studies that suggested frontal lobe dysfunction in this illness. Moreover, neuropsychologic deficits linked circumstantially to the function of the dorsolateral prefrontal cortex have recently been correlated directly with rCBF to this area. As mentioned previously, performance of the WCS is sensitive to lesions of the dorsolateral prefrontal cortex. Unlike normal individuals, medication-free as well as treated patients with schizophrenia show an inability to increase rCBF above a sensorimotor task control baseline in the dorsolateral prefrontal cortex while performing the WCSn7-(' (Fig. 1). This pathophysiologic finding has been observed in four separate studies, including a study of monozygotic twins discordant for schizophrenia. In the latter study, the affected twin consistently had less prefrontal rCBF during the WCS than did the unaffected twin. T h e physiologic deficit in the prefrontal cortex has been seen most consistently in tasks that are dependent on the function of the dorsolateral prefrontal cortex. When patients with schizophrenia have been studied during equally demanding tasks that activate posterior cortical regions, their rCBF studies are normaL3I Thus, rCBF data tend to support if not validate neuropsychologic evidence of dorsolateral prefrontal dysfunction. The finding of hypofrontality on PET studies is more equivocal than with rCBF, despite the greater anatomic resolution of the PET technique. A number of conflicting reports have been publ i ~ h e d . " - ~In~ addition, one PET study proposed that hypoparietal activity is the most significant finding," whereas another reported hyperparietal metabolism."'jThe discrepancy between rCBF and PET results, and the disparity among PET studies themselves, may be accounted for by a variety of methodologic factors.31 However, the most likely reason is that very few PET studies have involved a controlled behavioral condition. In every PET and rCBF study that has examined patients during a cognitive task that emphasized prefrontal function, patients with schizophrenia have been "hyp~frontal."~~ In addition to assaying neocortical activity, PET studies have attempted to identify other focal metablic abnormalities in the brains of patients with schizophrenia. T h e results in the temporal lobe have been contradictory. Both increase37," and decreaseJK40in metabolism have been reported. PET studies of the basal ganglia also have revealed conflicting finding^."^,^^.^' Limitations of
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SEMINARS I N NEUROLOGY
BRAIN I N SCHIZOPHRENIA-HYDE, WEINRERGER
WCS - NUMBERS PARADIGM LEFT HEMISPHERE
WCS
NUMBERS
WCS
NUMBERS
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NORMALS N=25
PATIENTS MED. FREE N=20
Figure 1. Left hemisphere rCBF landscapes in a group of normal control subjects and a group of medication-free patients with schizophrenia, during the Wisconsin Card Sort (WCS) and a number matching sensorimotor control task (NUMBERS). rCBF values are indicated by the vertical gray scale, with the darker shades depicting higher values of blood flow. The anterior pole of the hemisphere is on the left. Note that the medication-free patients with schizophrenia are unable to increase rCBF in the dorsolateral prefrontal cortex during the WCS, but appear relatively normal during the control task.
experimental design may iu part explain these discrepancies. Most PET studies involve small patient cohorts. Patient age and medication state vary between studies. Some studies are performed at rest, whereas others use cognitive tasks. The presence of these methodologic variations greatly limits comparisons between studies. Independent replication, using identical techniques and larger sample sizes, is needed to resolve the dilemmas posed by the PET studies.
NEUROANATOMY IN VIVO: CT AND MRI STUDIES Imaging studies of the central nervous system have provided the most reproducible and substantial evidence of structural abnormalities in the brains of patients with schizophrenia. The opportunity to study brain anatomy in living subjects who are relatively young obviates many of the problems inherent in studies of postmortem tissue.
Pneumoencephalography (PEG) provided the first evidence suggestive of cerebral atrophy, manifested as ventriculomegaly, in a high percentage of patients with schi~o~hrenia.~"f the many PEG studies performed over the years, most reported differences between patients and controls; the interpretation of their results is problematic. As reviewed by Weinberger et the studies were performed without well-defined diagnostic parameters for schizophrenia and without standardized methods of measurement. Computerized tomography (CT) provided more acceptable evidence of ventriculomegaly in schizophrenia. In 1976, a small cohort of elderly patients with schizophrenia was noted to have enlarged cerebral ventricles in comparison with a group of normal subjects. Ventricular size, determined quantitatively, was positively correlated with a measure of cognitive impairment.45A high prevalence of ventriculomegaly and a lesser prevalence of dilated cortical sulci were confirmed independently in a large group of younger patient^.^^,^' In a corn-
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prehensive review of 80 C I ' studies of schizophrenia, Shelton and Weinberger"' noted that 75% of' the studies found enlargement of the lateral ventricles and 80% found enlargement of the third ventricle. Similar results have emerged from more recent studies using magnetic resonance iniaging (MRI) technology (discussed later). It should be noted that in spite of the replicability of this finding, the absolute magnitude of the ventriculomegaly is usually slight. Few patients, probably less than lo%, have qualitatively large o r "abnormal" ventricles. Studies of families of patients with schizophrenia have suggested that the neuropathologic process underlying ventricular enlargement may be more prevalent than studies of unrelated individuals suggested. In studies of sibling groups, including discordant monozygotic twins, the patient with schizophrenia consistently has had the largest ventricles within the family, even if' the member who was ill had ventricles within the broader range of normal.""") While the presence of ventriculomegaly suggests that tissue loss has occurred in the brains of patients with schizophrenia, it does not identify the site o r sites o r cause of the abnormalities. T h e C T findings associated with schizophrenia were ini-
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S E P T f N B E R 1990
tially thought to be a consequence of therapy, including antipsychotic medications. In order to address this possibility, C:'T scans from untreated patients, during their first schizophreniform psychotic episode (so-called "first break" patients), have been ~ t u d i e d . " ' - ~These " controlled studies have consistently demonstrated that ventricular enlargement exists at the first episode and is not the result of chronic psychiatric treatment. This finding has stimulated speculation that ventriculomegaly actually predates the clinical onset of the illness in early adult life. A popular view is that the underlying neuropathologic process occurs long before the onset of the illness and may be developmental. T h e possibility that the findings reflect a developmental abnormality is further suggested by evidence that ventricular enlargement and cortical changes d o not progress in patients with schizophrenia scanned 7 to 9 years after their initial study.".' MRI studies have confirmed and expanded the Sindings from C T scans. A volumetric analysis of ventricular size on MKI studies in patients with schizophrenia demonstrated once again the presence of' enlarged lateral and third ventricles."Discordant monozygotic twins have been studied again in order to provide the closest possible con-
Figure 2. T I weighted MRI scan, in the coronal plane at the level of the thalamus, of monozygotic twins discordant for schizophrenia. The normal twin is depicted on the left, and the twin with schizophrenia is on the right. Note the relatively enlarged lateral and third ventricles in the twin with schizophrenia. 280
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SEMINAKS IN NEUR0I.OC;Y
NEUROPATHOLOGY Traditional anatomic neuropathologic studies have been conducted on the brains of patients with schizophrenia since at least the end of the 19th century. While a veritable cornucopia of findings has been reported, until the past 5 years, few of them have been consistently replicated. Until recently, the cerebral cortex has received most of the attention in the neuropathologic analysis of schizophrenia, probably because of the wellknown role of this structure in cognitive processes and the profound alterations of these processes in schizophrenia. In the neocortex, cerebral atrophy and cell loss have been reported on numerous occasions over the past 100 years."'~"-" 70wever, the precise characteristics and magnitude of these
changes have been inconsistent. No discrete finding has been consistently replicated. Several studies have observed a trend toward reduced cell number and density in the frontal lobe, particularly in the prefrontal regi~n.~~,""n addition to cell loss, thickened, densely staining dendrites and axons have been found in the cortex, again especially in the prefrontal region.jOThese findings have been difficult to interpret for a variety of reasons, including their nonspecif~icityand the possibility that they represent secondary changes. Earlier neuropathologic studies also focused on the basal ganglia, probably because of the bizarre mannerisms and catatonic posturing of some patients with schizophrenia. For unclear reasons, most of these studies have focused on the globus p a l l i d ~ sVogt . ~ and Vogt," perhaps seeking a classic clinical neuropathologic correlation, reported cell loss in this structure, especially in patients with catatonia. However, this finding has been disputed." More recently in a study relying on gross cross-sectional measurements, volume reduction has been reported in the internal segment of the globus pallidus in brains from the Vogt c ~ l l e c t i o n . ~ The cause and clinical correlates of this volume reduction have not been identified. The limbic system, with its traditional role in modulating the emotional aspects of behavior, only recently has been examined for neuropathologic changes. Nevertheless, this has clearly emerged as the most productive and informative region of the brain for finding neuropathologic changes in schizophrenia. T h e amygdala and hippocampus have come under closest scrutiny. T h e average volume of the anteromedial limbic temporal lobe (parahippocampus, hippocampus, and amygdala) appears to be reduced in patients with schizophrenia compared with control^.^ This gross morphometric finding, in one fbrm or another, has been reported by five independent groups of investigators.4,60-m F~rthermore, this postmortem abnormality correlates with MRI findings in living patients with schizophrenia.""" This degree of replication of a putative anatomic finding is unprecedented in the annals of schizophrenia research. The neuropathologic basis of the volume reduction in the amygdalar-hippocampal complex is unclear, but some provocative clues have emerged. Disarray has been reported in the arrangement of the dendrites of hippocampal pyramidal cells, j'.'" although this has not been replicated using alternative staining techniques.74A striking finding, reported by Jakob and Beckmann," is maldevelopment of the superficial layers of the entorhinal cortex. Unlike the poorly characterized morpho28 1
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trol group. T h e affected twins had significantly larger ventricles than the healthy twins. Moreover, in almost every twin pair, the affected twin had the larger ventricles, even if they seemed qualitatively 2). This result again suggests that smal15"Fig. when "ideal" controls are available, evidence of a structural neuropathologic process may be appreciated in most patients with schizophrenia. Neuroimaging studies also have been used to demonstrate focal structural abnormalities. In earlier C'I' studies, the demonstration of dilated frontal interhemispheric and sylvian fissures suggested volume loss in the frontotemporal region.4x C T studies also have reported that apparent cerebellar vermian atrophy is more prevalent in patients with schizophrenia than in controls," consistent with a recent postmortem morphometric study of the cere b e l l ~ mHowever, .~~ this finding is present in only a small fraction of patients with schizophrenia and has not been reported in first episode patients. Additionally, alcoholism was not definitively eliminated as a causative factor of vermian atrophy in either study. The most robust focal finding on MRI scans has been a reduction in the volume of temporal lobe gray matter, especially in the region containing the amygdala and hippocampus."" Moreover, the degree of reduction in temporal lobe gray matter correlates directly with the magnitude of ventricular enlargement. The specific involvement of the anterior hippocampus was further demonstrated in the MKI study of discordant monozygotic twins, in which the size of the anterior hippocampus was smaller in the affected twin in 14 of 15 pairs."" This finding correlates with postmortem analyses of the am~gdalar-hippocampal region."""-""
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metric results, this qualitative finding strongly the neuroscientific approach toward this illness. implicates an abnormality in early brain dev- Neuroleptics appear to exert their antipsychotic efelopment. Independent replications have been re- fects through their blockade of dopanline recepported but not yet published'' (Casanova MF: Per- t o r ~ . ~ T "h e popular "dopamine hypothesis" holds sonal communication). that increased dopaminergic transmission proThe nucleus accumbens, a subsection of the duces the cardinal manifestations of schizophrecorpus striatum, is considered to be a link between nia.#' Postmortem neurochemical analyses on pathe basal ganglia and the limbic system. As such, it tients with schizophrenia have focused on many has been of considerable theoretical interest in aspects of dopamine systems in the central nervous schizophrenia research. While one recent report system. Two types of dopamine receptors are present found volume reduction of this structure in patients with schizophrenia," a separate group was in the central nervous system: D, receptors are unable to confirm this finding.4 Given the strategic linked to the stimulation of adenylate cyclase, and connections of this nucleus, and its importance in D, receptors have a high affinity for "H-haloperisubcortical dopamine transmission, further study do1 and inhibit adenylate cyclase. Both receptor systems have been carefully studied in postmortem is warranted. Several reports of brainstem abnormalities tissue of patients with schizophrenia. T h e most rehave appeared, but none has been replicated. T h e producible finding has been an increase in the midbrain is the site of the primary dopaminergic density of D, receptors in the caudate, putaprojections to the limbic system, basal ganglia, and men, and nucleus a c ~ u m b e n s . ~ ~ W n f o r t u n a t e l y , cortex. In one study, the lateral substantia nigra this finding is confounded by a history of neurowas found to have decreased volume, without a loss leptic therapy in most of the patients studied. T h e of neuronal elements, suggesting a loss of neuro- results in a few patients who were said to be unpi1 in the region.'' Reports of other pathologic medicated have been inconclusive. Neuroleptic exchanges include gliosis in the periaqueductal gray posure has been shown to produce increased of D, receptors through denervation sumatter,76-77 vermian atrophy in the ~ e r e b e l l u r n , ~numbers ~ and glial nodules in the medial reticular formation persensiti~ity.~'In neuroleptic-naive patients, in of the pons.78T h e last finding, however, has been vivo quantification of D, receptor density using d i ~ p u t e d , ~ b h i the l e others have yet to be in- positron emission tomography suggested the presdependently pursued. No consistent pattern of ence of elevated receptor density in the caudate neuropathologic changes can be discerned in the nucleus in one study,'" but not in another.84 Dl receptors have not been studied as extenbrainstem. In summary, traditional neuropathologic stud- sively as D, receptors. In a recent report, decreased ies of schizophrenia have shown changes within the numbers of D, receptors and an increase in the cortex, basal ganglia, limbic system, and brainstem. DJD, receptor ratio were noted in the caudate ~~ T h e most convincing and reproducible findings nucleus of patients with s c h i z ~ p h r e n i a .Since appear to be within the region of the amygdalar- chronic neuroleptic therapy in animals does not hippocampal formation. T h e degree of replication produce analogous changes in Dl recept~rs,~Qhe that is emerging for neuropathologic changes in decreased D, receptors could be primary to schizothis region is impressive. While numerous addi- phrenia itself, rather than due to chronic neurotional sites of pathologic change have been re- leptic exposure. However, at least one report has ported, none has been replicated as frequently in failed to replicate this finding.x7 T h e mechanisms by which dopaminergic neumethodologically rigorous studies. It is notable that gliosis is not a prominent feature of the rotransmission might be excessive in schizophrenia replicable neuropathologic abnormalities. The ab- are unclear, even from a theoretical perspective. sence of significant gliotic changes, combined with Consistent with the dopamine hypothesis, it is conprovocative evidence of cytoarchitectural abnor- ceivable that a pathologic defect in schizophrenia malities, suggests that the pathologic process un- could be the abnormal production of D, receptors. derlying schizophrenia is more likely to be a devel- However, for this to result in a pathophysiologic opmental defect than an inflammatory, infectious, condition, the mechanisms of presynaptic compensation also would have to be abnormal. An alteror degenerative process. native possibility is that the increase in these receptors is secondary to other neurochemical or neuropathologic processes, with increased recepNEUROCHEMISTRY tor production being the final endpoint. NevertheT h e development of pharmacotherapy fbr less, it still remains to be proven that patients with schizophrenia in the late 1950s radically altered schizophrenia possess increased numbers of sub-
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SEMINARS I N NEUKOLOGY
BRAIN IN SCHIZOPHRENIA-HYDE, WEINBERGER
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cortical dopamine receptors in the absence of neu- in vivo neuroimaging and postmortem anatomic roleptic exposure. techniques. T h e details and etiology of temporal A pathologic increase in dopamine release also lobe-hippocampal pathologic states remain to be could account for relatively excessive dopaminer- elucidated. Neuropsychologic and cerebral blood gic transmission and the efficacy of neuroleptics. flow studies suggest that the frontal lobe is dysIncreased concentrations of dopamine and its me- functional in schizophrenics. However, there is littabolites have been found in postmortem tissue in tle known about the neuropathologic basis and only a few studies. Elevations have been found in neurochemical correlates of this deficit. the anterior perforated substance and the nucleus One of the intriguing new hypotheses about accumbens in one study,n8but not in a ~ e c o n d . ~ "the neurologic findings in schizophrenia is that Similar discrepancies have been noted in dopa- they are the result of an abnormality in the early of the brain. T h e possibility that the mine levels in the caudate and p ~ t a m e n . Ele~ ~ , ~development ~ vated dopamine levels have been detected in the clinical illness is a delayed manifestation of this left amygdala, when comparing both amygdalae process, perhaps because of an interaction between from each individual." This finding has yet to be the early developmental deficit and later maturing independently replicated, perhaps because of the functional neural systems, is a subject of speculaabsence of comparisons of right and left amygda- t i ~ n . ~ ~ While much study has been devoted to the lae from the same individuals. Many other neurotransmitters and neuropep- structural and functional abnormalities underlying tides have been examined in postmortem studies schizophrenia, much remains to be discovered. In of brain tissue from patients with schizophrenia. the past 20 years, the development and application Norepinephrine levels have been reported to be el- of new techniques, including CT, MRI, rCBF, and evated in the nucleus accumbens in one ~ t u d y , ~ 'PET, have revolutionized the study of schizophrebut not in a second." Elevated serotonin levels nia, and have produced the first consistent neurohave been noted in the putamen and globus pal- pathologic findings in this disorder. T h e pace of l i d ~ ~ . ~Decreased ~," serotonin receptor density discovery has been gradually accelerating. Applihas been reported in the frontal cortex,95." but cation of new techniques and careful use of patient selection criteria will help further decipher the this finding also has been d i ~ p u t e d . ~Glutamate, ' gamma-aminobutyric acid, cholecystokinin, neu- neurologic basis of this disorder. There is reasonrotensin, opiates, thyrotropin-releasing hormone, able hope that by the end of this century, the paand somatostatin have been assayed under a vari- thology and pathophysiology of this common but ety of paradigms. However, these findings have baffling illness will be revealed. not been replicated independently and their relationship to neuroleptic exposure remains to be determined.
REFERENCES SUMMARY Schizophren~ahas been the subject of intensive neuropsychologic, neuroradiologic, neuropathologic, and neurochemical investigations. T h e most consistent and reproducible result from all this effort has been the demonstration of a mild degree of enlargement of' the cerebral ventricles. The existence of this finding is no longer a subject of controversy, and it clearly occurs independently of psychiatric treatment and chronicity of disease. This finding represents the strongest evidence to date that a structural lesion of the central nervous system underlies schizophrenia. The localization of the lesion responsible for ventricular enlargement and for the clinical findings in schizophrenia is not as clear. Pathologic alterations in the anteriomedial temporal lobe, particularly in the hippocampus, have been independently identified by several groups, using both
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other affective disorders. Arch (;en Psychiatry 1981; 38: 1355 Kennard M. Value of equivocal signs in neurologic diagnosis. Neurology (Minneap) 1960; 10:753 Cadet JL, Rickler KC, Weinberger DR. T h e clinical neurologic examination in schizophrenia. I n : Nasrallah HA, Weinberger DR, eds. Handbook of schizophrenia, vol. 1: the neurology of schizophrenia. Amsterdam: Elsevier, 1986; 1-47 Goldberg T E , Ragland JD, Gold J , et al. Neuropsychological assessment of monozygotic twins discordant for schizophrenia (Submitted for publication). Calev A, Venables P H , Monk AF. Evidence for distinct verbal memory pathologies in severely and mildly disturbed schizophrenics. Schizophr Bull 1983;9: 247-64 Grafman J , Vance SC, Weingartner H. T h e effects of lateralized frontal lesions on mood regulation. Brain 1986;109:1127-48 Freedman M, Oscar-Berman M. Bilateral frontal lobe disease and selective delayed response deficits in humans. Behav Neurosci. 1986; 100:337-42 Stuss DT, Benson DF. Neuropsychological studies o f t h e frontal lobes. Psychol Bull 1984;95:3-28 Goldberg'I'E, Weinberger DK, Berman KE', et al. Further evidence for dementia of the prefrontal type in schizophrenia. Arch Gen Psychiatry 1987;44: 1008-14 Goldberg T E , Weinberger DR. Probing prefrontal function in schizophrenia with neuropsychological paradigms. Schizophr Bull. In press Goldberg 'I'E, St Cyr JA, Weinberger DR. Procedural learning in schizophrenic patients. (Submitted for review). Benes FM, Bird ED. An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients. Arch Gen Psychiatry 1987;44:608-16 Jakob H , Beckmann H. Gross and histological criteria for developmental disorders in brains of schizophrenics. J R Soc Med 1989;82:466-9 Silverberg-Shalev R , Gordon HW, Bentin S, Aranson A. Selective language deterioration in chronic schirophrenia. J Neurol Neurosurg Psychiatry 1981;44:547-51 Kolb B, Whishaw IQ. Performance of schizophrenic patients o n tests sensitive to left o r right frontal, temporal, o r parietal function in neurological patients. J Nerv Ment Dis 1983;171:435-43 Faber R, Reichstein MR. Language dysfunction in schizophrenia. Br J Psychiatry 1981;139:519-22 Ingvar DH, Franzen G. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr Scand 1974;50:425-62 Berman KF, Weinberger DR. Cerebral blood flow studies in schizophrenia. In: Nasrallah H , Weinberger DK, eds. T h e neurology of schizophrenia. Amsterdam: Elsevier, 1986:277-307 Weinberger DR, Berman KF, Zec KF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 1986;43: 114-24 Berman KF, Zcc RF, Weinberger DR. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. 11. T h e role of medication, attention, a n d mental effort. Arch Gen Psychiatry 1986;43: 126-35 Weinberger DR, Berman KF, lllowsky BP. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. 111. A new cohort and evidence for a monoaminergic mechanism. Arch (;en Psychiatry 1988; 45:609-15 Berman KF, .rorrey EF, Daniel DG, Weinberger DR. Prefrontal cortical blood flow in monozygotic twins concordant a n d discordant for schizophrenia. Soc Neurosci Abstr 1989; 15:699 Weinberger DR, Berman KF. Speculation o n the mean-
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ing o f cerebral metabolic hypofrontality i r i schizophrenia. Schizophr Bull 1988; 14: 157-68 Kling AS, Metter E J , Riege WH, Kuhl DE. Comparison of PET measurement of local brain glucose metabolism a n d C.4'1' measurement of brain atrophv in chronic schizophrenia and dcprcssion. Am J Psyt hiatry 1986; 143: 175-80 Volkow ND, Wolf AP, Van Gelder P, et al. Phenomenological correlates of metabolic activity iu 18 patients with chronic schizophrenia. Am .J Psychiatry 1987; 144: 151-8 Wolkin A, Jaeger J , Brodie J l ) , et al. Persistence of cerebral metabolic abnormalities in chronic schizophrenia as determined by positron emission ton~ography.Am J Psychiatry 1985; 142:564-7 1 Cleghorn J M , Garnett ES, Nahmias, ct 211. Increased frontal and reduced parietal glucose metabolisrn in acute untreated schizophrenia. Psychiatry Res. 1989; 28:ll9-33 Shcppard G, Manchancla R, Gruzelier J , et al. "0 positron emission tomographic scanning in predominantly never-treated acute schizophrenic patients. Lancet 1983; 2: 1448-52 Jernigan I'L, Sargerit T 111, Pfefferbaum A, et al. 'Vhorodeoxyglucose PE'I' in schizophrenia. Psychiatry Res 1985; 16:317-30 DeI.isi I,E, Ruchsbaum MS, Holcomb H l I , et al. Increased temporal lobe glucose use in chronic schizophrenic patients. Biol Psychiatry l989;25:835-51 Wolkin A, Blornquist G, Greitz T, et al. PET studies of glucose metabolism in patients with schizophrenia. A,jNR 1983;4:550-1 G u r RE, Resnick SM, G u r RC, et al. Region;tl brain function in schizophrenia. 11. Repeated evaluation with positron emission tomography. Arch Gcn Psychiatry l987;44: 1 19 Buchsbau~nMS, Wu J C , DeLisi LE, et al. Positron ernission tomography studies of basal ganglia and somatosensory cortex neuroleptic d r u g effects: differences between normal controls and schizophrenic patients. Biol Psych 1987;22:479-94 Early TS, R c i n ~ a nEM, Raichle ME, Spitznagel EL. Left globus pallidus abnorn~alityin never-medicated patients with schizophrenia. Proc Natl Acad Sci USA 1987;84:561-3 Lemke R. Untersuchungen uber die soziale Prognose d e r Schizophrenie unter besonderer Berucksichrigung des encephalographischen Befuncles. Arch Psychiatr Nervenkr 1935;104:89-136 Weinberger DK, Wagner RI., Wyatt R.J. Neuropathological studies of schizophrenia: a selective review. Schizophr Bull 1983;9: 193-2 12 Johnstone EC, Crow '11, Frith CD, et al. (:erebra1 ventricular size and cognitive impairment in chronic schizophrenia. Lancet 1976;2:924-6 Weinberger DR. Torrey EF, Neophytides AN, Wyatt RJ. Lateral cerebral ventricular e n l a r g e n ~ e n in t chronic schizophrenia. Arch Gen Psychiatry 1979;36: 735-9 Weinberger DK, .li>rrey EF, Neophylidelr AN, Wyatt R.J. Structural abnorn~alitiesof the cerebral cortex in chronic schizophrenia. Arch Gen Psychi;itry 1979;36: 935-9 Shelton KC, Weinberger 1)K. X-ray computerized tornography studies in schizophrenia: a review a n d synthesis. In: Nasrallah HA, Weinberger DK, eds. Ilandbook of' schizophrenia, vol. 1: the neurology of schizophrenia. Amsterdam: Elsevier, 1986;207-50 Weinberger DK, DeLisi LE, Neophytides AN, Wyatt RJ. Farnilial aspects of C T scan abnormalities in chronic schizophrenic patients. Psychiatry Res 1981;4:65-71 Keveley AM, Reveley MA, Clifford CA, Murray RM. Cerebral ventricular size in twins discordant for schizophrenia. Lancet 1982;2:540-1
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BKAIN I N SCHIZOPHRENIA-HYDE, WEINBERGER 72. Scheibel AA, Kovelman J A . Disorientation of the hippocampal pyramidal cell and its processes in the schizophrenic patient. Biol Psychiatry 1981; 16: 101-2 73. Kovelman JA, Scheibel AB. A neurohistological correlate of schizophrenia. Biol Psychiatry 1984; 19: 1601-2 1 74. Christison GW, Casanova MF. Wcinherger DR, et al. A quantitative investlgation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry 1989;46: 1027-32 75. Bogerts B, HantschJ, Herzer M. A rnorphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. Biol. Psychiatry 1983; 18:95 1-69. 76. Nieto D, Escobar A. Major psychoses. In: Minkler J , ed. Pathology of the nervous system, vol. 3. New York: McGraw-Hill, 1972:2654-65 77. Stevens JR. Neuropathology of schizophrenia. Arch Gen Psychiatry 1982;39: 1131-9 78. Fisman M. T h e brain stem in psychosis. Br J Psychiatry 1975; l26:414-22 79. Hankoff LD, Peress NS. Neuropathology of the brain stem in psychiatric disorders. Biol Psychiatry 1981; l6:945-52 80. Seeman P, Lee T, Chau-Wong M , Wong K. Antipsychotic d r u g doses and neurolepticidopamine receptors. Nature 1976;261:717-9 81. Snyder S H , Banerjee SP, Yamamura H I , Greenberg D. Drugs, neurotransmitters, and schizophrenia. Science 1974; 184: 1243-53 82. Burt DR, Creese I , Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 1977; 1963326-8 83. Wong DF, Wagner HN Jr., Tune L, et al. Positron emission tomography reveals elevated D, dopamine receptors in drug-naive schizophrenics. Science 1986;234: 1558-63 84. Farde L, Wiesel FA, Hall H , et al. No D, receptor increase in PET study of schizophrenia. Arch Gen Psychiatry 1987;44:67 1-2 85. Hess EJ, Brancha HS, Kleinman J E , Creese I. Dopamine receptor subtype imbalance in schizophrenia. Life Sci 1987;40: 1487-97 86. Mackenzie RG, Zigrnond MJ. Chronic neuroleptic trcatment increases D-2 but not D-1 receptors in rat striatum. Eur J Pharmacol 1985; 113: 159-65 87. S e c n ~ a nP, Bzowej NH, Guan HC, ct al. Human brain D, and D, dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. Neuropsychopharrnacology 1987; 1:5-15 88. Bird ED, Spokes EGS, Iverson LL. Increased doparnine concentration in limbic areas of brain from patients dying with schizophrenia. Brain 1979; 102:347-60 89. Crow .Tj, e a k e r HF, Cross AJ, et al. Mortoamine mechanisms in chronic schizophrenia: post-mortem neurochernical findings. Br .J Psychiatry 1979;134: 249-56 90. Reynolds GP. Increased concentrations and lateral asymmetry of amygdala doparnine in schizophrenia. Nature 1983;305:527-9 91. Kleinman J E , Karoum F, Rosenblatt J E , et al. Postmortem neurochemical studies in chronic schizophrenia. In: Usdin E, Hanin I, eds. Biological markers in psychiatry and neurology. New York: Pergamon Press, 1982;67-76 92. Bird EO, Spokes EG, Iverson LL. B r a ~ nnorepinephrine and doparnine in schizophrenia. Science 1979;204: 93-4 93. Farley I J , Shannak KS, Hornykiewicz 0. Brain monoamine changes in chronic paranoid schizophrenia and their possible relation to increased dopamine receptor sensitivity. In: Pepcu G , Kuhar MJ, Enna SJ, eds. Keceptors for neurotransmitters and peptide hormones. New York: Raven Press, 1980:427-33 94. Korpi EK, Kleinman .JE, Goodman S1, et al. Serotonin
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51. Weinberger DR, DeLisi LE, Perman GP, et al. Computed tomography in schizophreniform disorder and other acute psychiatric disorders. Arch Gcn Psychiatry 1982; 39:778-83 52. Schulz SC, Koller MM, Kishore PR, et al. Ventricular enlargement in teenage patients with schizophrenia spectrum disorder. Am J Psychiatry 1983; 140: 1592-5 53. Nyback H, Wiesel FA, Berggren BM, Hindmarsh T. Computed tomography of the brain in patients with acute psychosis and in healthy volunteers. Acta Psychiatr Scand 1982;65:403-14 54. lllowsky BP, Juliano DM, Bigelow I.B, Weinberger DR. Stability of C T scan findings in schizophrenia: results of an eight year follow-up study. J Neurol Neurosurg Psychiatry 1988;51:209-13 55. Kelsoe JR, Cadet J L , Pickar D, Weinberger DR, Quantitative neuroanatomy in schizophrenia. Arch Gen Psychiatry 1988;45:533-41 56. Suddath KL, Christison GW, l'orrey EF, et al. Cerebral anaton~icalabnormalities in monozygotic twin discordant for schizophrenia. (Submitted for publication). 57. Heath RG, Franklin DE, Schraberg D. Gross pathology of the cerebellun~in patients diagnosed and treated as functional psychiatric disorders. J Nerv Ment Dis 1979; 167:585-92 58. Weinberger DR, Kleinn~an.JE, Luchins DJ, et al. Cerebellar pathology in schizophrenia: a controlled postmortem study. Am J Psychiatry 1980;137:359-61 59. Suddath KL, Casanova MF, Goldberg T E , et al. Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. Am J Psychiatry 1989; 146:464-72 60. Brown R, Colter N, Corsellis J A N , et al. Postmortcrn evidence of structural brain changes in schizophrenia. Arch Gen Psychiatry 1986;43:36-42 6 1. Jakob H, Beckmann H. Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm l986;6.!1:303-26 62. Jeste DV, Lohr JB. Hippocampal pathological findings in schizophrenia: a morphometric study. Arch
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The Brain in Schizophrenia
Schizophrenia rarely has been of interest as a clinical entity in neurology, primarily for two reasons. First, since the clinical manifestations of schizophrenia are almost exclusively behavioral, they are not easily translatable into traditional neurologic terms. Second, the neurobiologic basis of schizophrenia has remained elusive, despite decades of intensive investigation by many disciplines within the neurosciences. During the first half of this century, most of the neurobiologic research on schizophrenia focused on finding a pathognomonic lesion in the brain. T h e effort was notoriously unsuccessful and encouraged speculation about a psychogenic etiology of schizophrenia. However, the studies from the first half of this century were methodologically limited in a number of respects. Few of then1 were adequately controlled. Most of then1 failed to examine the same brain areas systematically. Few studies considered sites outside of the neocortex. Perhaps most important, the effort assumed that the illness is a singular pathologic entity, rather than a variety of disorders with common clinical features. As a result, investigators tended to dismiss nonspecific and inconsistent findings. Since the diagnosis of schizophrenia is made on purely clinical grounds, the disorder could conceivably include phenotypically similar illnesses with diff'ering pathophysiologic bases. Another problem with older studies involved the lack of diagnostic reliability in psychiatry and the multiple classification systems that had been used for schizophrenia. This problem made comparisons between studies dif'f'icult and the need for standardized diagnostic criteria essential.
The widespread acceptance, in 1980, of explicit diagnostic criteria for most psychiatric disorders, analogous to those used in the clinical diagnosis of neurologic disorders such as multiple sclerosis and Alzheimer's disease, represents one of the most important developments of this century in schizophrenia research and in the clinical practice of' psychiatry. T h e classification system of the Diagnostic and Statistical Manual (DSM, now the DSM-111-K[evised]) has dramatically improved the reliability of psychiatric diagnosis and has made it possible to select more homogeneous research cohorts.' Without this dramatic development in diagnostic nosology, the consistent neurobiologic data base that has begun to emerge from research on schizophrenia would not have been possible. T h e classic approach in clinical neurology focuses on lesion localization in nervous system disorders before considering the etiology and pathophysiology of the lesion. Kecent studies have begun to localize the lesion or lesions underlying schizophrenia. This article will review those studies and their implications for central nervous system function in patients with this disorder.
NEUROLOGIC SIGNS The clinical neurologic examination of' patients with schizophrenia yields very few consistent findings. Unusual neurologic signs in medicationfree patients have been noted since the end of the 19th century, including bizarre posturing, mannerisms, stereotypies, peculiarities of gait, and other difficult-to-characterize abnormal movements.'
*Director of Consultation Neurology, Clinical Brain Disorders Branch, National Institute of Mental Health, Neuroscience Center at St. Elizabeth's Hospital, Washington, D.C. ?Chief, Clinical Brain Disorders Branch, National Institute of Mental Health, Neuroscience Center at St. Elizabeth Hospital, Washington, D.C. Reprint requests: Dr. Weinberger, Clinical Brain Disorders Branch, National Institute o f Mental Health, Neuroscience Center at St. Elizabeth Ilospital, Washington, D.C. 20032
"
Copyright 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Thomas M . Hyde, M.D., Ph.D., * and Daniel K. Weinberger, M.D. f
NEUROPSYCHOLOGY Neuropsychologic testing can be used to identify and quantify focal deficits in central nervous system function. While schizophrenia has been the subject of neuropsychologic investigation for over 50 years, until recently this effort did little to amplify our understanding of this disorder. Most studies have addressed the question of whether patients with schizophrenia appeared "organic" in their neuropsychologic testing profile. The results, though fairly consistent in demonstrating that the
patients do score in the organically impaired range, were in general dismissed as being epiphenomena of psychosis and not representative of a valid cognitive incapacity. Even consistently observed deficits, such as poor performance on tests of sustained attention, are difficult to interpret in neurologic terms, because the role of purposeful behavioral factors is not easily controlled. T h e nature of the cognitive deficits observed is illustrated by a recent controlled study of monozygotic twins discordant for schizophrenia.12 Goldberg and colleagues" found that general cognitive performance was worse on almost every scale of measurement, including tests of general intelligence, memory, abstract reasoning, and attention, when comparing the twin with schizophrenia to the unaffected cotwin. These results suggest fairly widespread cortical dysfunction. However, the magnitude of the deficits was mild in most instances. On many of the tests, the perfbrmance of the affected twin was still within the broad range of normal, even though it was poorer than the score of the cotwin. If the cotwins had not been available for comparison, the existence of reduced performance in the affected twins would not have been appreciated in many cases. This underscores the subtle nature of the neuropsychologic deficits in schizophrenia. In addition, fbcal cognitive deficits have been explored in studies using focused neuropsychologic batteries.".'"mpaired verbal recall has been consistently replicated, though the magnitude of the deficit is mild compared with patients with amnestic disorders. 'Ihis deficit may be the functional correlate of the structural abnormalities noted in the temporal lobe, and the hippocampus in particular, in both neuropathologic and neuroimaging studies (which will be elaborated in subsequent sections). However, it is important to note that similar memory impairment occurs with lesions of the frontal lobe,14.'%nd that some of the medications used to treat patients with schizophrenia can impair memory function. Another line of neuropsychologic evidence suggests that the dorsolateral prefrontal cortex may be dysfunctional in patients with schizophrenia. The dorsolateral prefrontal cortex mediates numerous complex behaviors, including the abilities to associate knowledge with action, to establish abstract sets, and to change them when appropriate, to filter or suppress memories, to monitor personal behavior, and to provide drive and goaldirected thinking.lWany of these abilities appear to be impaired in patients with schizophrenia. T h e Wisconsin Card Sort (WCS) test, a relatively simple neuropsychologic task which requires
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Rather than being classified as movement disorders or abnormal involuntary movements, they usually have been dismissed as a manifestation of the primary mental disturbance. It is possible, however, that these movements have a pathophysiologic substrate in abnormal function of the basal ganglia. They may correlate with pathologic findings in the basal ganglia, as will be described."-" More study needs to be devoted to the abnormal involuntary movements in schizophrenia. T h e most consistent neurologic finding in patients with schizophrenia has been an impairment of smooth pursuit eye movement^.^,^ This finding is probably present in the majority of patients with chronic schizophrenia and in a significant proportion of their first-degree relatives. It does not appear to be the result of medical treatment. Smooth pursuit is defective because of the intrusion of saccades. Localization of the region accounting for this defect is unknown. T h e frontal cortex, basal ganglia, and cerebellum all play a role in suppressing saccadic intrusions into smooth pursuit eye movements. A complex attentional defect, secondary to frontal lobe dysfunction, is believed by some to be the cause of abnormal smooth pursuit in ~chizophrenia.~ This abnormality may relate to other evidence of frontal lobe dysfunction, as discussed later. T h e prevalence of neurologic "soft signs," including such findings as primitive reflexes and poor coordination, is higher in patients with schizophrenia than in patients with affective disorders%r "neurotics."1° It has been suggested that the presence of soft signs is indicative of subcortical"' andlor frontal pathologic lesions." However, these findings, by their character, do not indicate a clearly localizable lesion of the central nervous system. As later sections will establish, abnormalities have been found in both subcortical and frontal structures, perhaps correlating at least circumstantially with the high prevalence of soft signs in patients with schizophrenia.
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abstract set formation and set shifting, is particularly sensitive to dorsolateral prefrontal cortex dysfunction. Patients with schizophrenia perform poorly on the WCS.17 This poor performance does not necessarily reflect a generalized inability or unwillingness to perform cognitive tasks. On tasks that utilize primarily posterior cortical regions, such as block design, patients with schizophrenia tend to perform n ~ r r n a l l y . ~ ~ ~ ' ~ T h e so-called negative or deficit symptoms of schizophrenia include impaired motivation, shallow affect, paucity of thought, and cognitive deficits. A popular hypothesis holds that these "negative" symptoms may be attributable to a functional lesion of the prefrontal cortex. Neuropathologic evidence of injury to the prefrontal cortex, though not negligible, is Language function has been the subject of numerous studies in schizophrenia, but no consistent results have Though the language of patients with this disorder is sometimes bizarre and disorganized, it is not easily characterized in the lexicon of aphasiology. A popular but weakly supported hypothesis is that dominant hemisphere dysfunction, in temporal, parietal, or inferior frontal regions, may underlie the putative language dysfunction in schizophrenia.
IN VIVO NEUROPHYSIOLOGY: REGIONAL CEREBRAL BLOOD FLOW AND POSITRON EMISSION TOMOGRAPHY STUDIES
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Both regional cerebral blood flow (rCBF) techniques and positron emission tomography (PET) have been used to measure focal activity in the central nervous system of patients with schizophrenia. They are the latest and among the most complicated techniques to study the living brain. T h e two-dimensional multiprobe rCBF technique relies on the inhalation of radioactively labeled xenon, whereas PET studies use radioactively tagged oxygen or glucose analogs. These paradigms ostensibly map regional brain activity, the "work" of the brain. They can be performed with the patient at rest and during cognitive tasks. Tasks that activate focal cortical regions have been used to test the physiologic competency of various cortical systems. The first rCBF study of patients with schizophrenia was performed in 1974 by Ingvar and F r a n ~ e nT. ~ h e~ normal resting pattern of heightened blood flow to the prefrontal cortex relative to other cortical regions ("hyperfrontality") was not seen in patients with schizophrenia." This relative "hypofrontality" was interpreted as a failure of prefrontal activating mechanisms and as a physio-
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logic correlate of negative symptoms. A majority of subsequent rCBF studies have confirmed the "hypofrontality" of cortical function in schizophrenia.26This has provided physiologic confirmation of neuropsychologic studies that suggested frontal lobe dysfunction in this illness. Moreover, neuropsychologic deficits linked circumstantially to the function of the dorsolateral prefrontal cortex have recently been correlated directly with rCBF to this area. As mentioned previously, performance of the WCS is sensitive to lesions of the dorsolateral prefrontal cortex. Unlike normal individuals, medication-free as well as treated patients with schizophrenia show an inability to increase rCBF above a sensorimotor task control baseline in the dorsolateral prefrontal cortex while performing the WCSn7-(' (Fig. 1). This pathophysiologic finding has been observed in four separate studies, including a study of monozygotic twins discordant for schizophrenia. In the latter study, the affected twin consistently had less prefrontal rCBF during the WCS than did the unaffected twin. T h e physiologic deficit in the prefrontal cortex has been seen most consistently in tasks that are dependent on the function of the dorsolateral prefrontal cortex. When patients with schizophrenia have been studied during equally demanding tasks that activate posterior cortical regions, their rCBF studies are normaL3I Thus, rCBF data tend to support if not validate neuropsychologic evidence of dorsolateral prefrontal dysfunction. The finding of hypofrontality on PET studies is more equivocal than with rCBF, despite the greater anatomic resolution of the PET technique. A number of conflicting reports have been publ i ~ h e d . " - ~In~ addition, one PET study proposed that hypoparietal activity is the most significant finding," whereas another reported hyperparietal metabolism."'jThe discrepancy between rCBF and PET results, and the disparity among PET studies themselves, may be accounted for by a variety of methodologic factors.31 However, the most likely reason is that very few PET studies have involved a controlled behavioral condition. In every PET and rCBF study that has examined patients during a cognitive task that emphasized prefrontal function, patients with schizophrenia have been "hyp~frontal."~~ In addition to assaying neocortical activity, PET studies have attempted to identify other focal metablic abnormalities in the brains of patients with schizophrenia. T h e results in the temporal lobe have been contradictory. Both increase37," and decreaseJK40in metabolism have been reported. PET studies of the basal ganglia also have revealed conflicting finding^."^,^^.^' Limitations of
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BRAIN I N SCHIZOPHRENIA-HYDE, WEINRERGER
WCS - NUMBERS PARADIGM LEFT HEMISPHERE
WCS
NUMBERS
WCS
NUMBERS
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NORMALS N=25
PATIENTS MED. FREE N=20
Figure 1. Left hemisphere rCBF landscapes in a group of normal control subjects and a group of medication-free patients with schizophrenia, during the Wisconsin Card Sort (WCS) and a number matching sensorimotor control task (NUMBERS). rCBF values are indicated by the vertical gray scale, with the darker shades depicting higher values of blood flow. The anterior pole of the hemisphere is on the left. Note that the medication-free patients with schizophrenia are unable to increase rCBF in the dorsolateral prefrontal cortex during the WCS, but appear relatively normal during the control task.
experimental design may iu part explain these discrepancies. Most PET studies involve small patient cohorts. Patient age and medication state vary between studies. Some studies are performed at rest, whereas others use cognitive tasks. The presence of these methodologic variations greatly limits comparisons between studies. Independent replication, using identical techniques and larger sample sizes, is needed to resolve the dilemmas posed by the PET studies.
NEUROANATOMY IN VIVO: CT AND MRI STUDIES Imaging studies of the central nervous system have provided the most reproducible and substantial evidence of structural abnormalities in the brains of patients with schizophrenia. The opportunity to study brain anatomy in living subjects who are relatively young obviates many of the problems inherent in studies of postmortem tissue.
Pneumoencephalography (PEG) provided the first evidence suggestive of cerebral atrophy, manifested as ventriculomegaly, in a high percentage of patients with schi~o~hrenia.~"f the many PEG studies performed over the years, most reported differences between patients and controls; the interpretation of their results is problematic. As reviewed by Weinberger et the studies were performed without well-defined diagnostic parameters for schizophrenia and without standardized methods of measurement. Computerized tomography (CT) provided more acceptable evidence of ventriculomegaly in schizophrenia. In 1976, a small cohort of elderly patients with schizophrenia was noted to have enlarged cerebral ventricles in comparison with a group of normal subjects. Ventricular size, determined quantitatively, was positively correlated with a measure of cognitive impairment.45A high prevalence of ventriculomegaly and a lesser prevalence of dilated cortical sulci were confirmed independently in a large group of younger patient^.^^,^' In a corn-
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prehensive review of 80 C I ' studies of schizophrenia, Shelton and Weinberger"' noted that 75% of' the studies found enlargement of the lateral ventricles and 80% found enlargement of the third ventricle. Similar results have emerged from more recent studies using magnetic resonance iniaging (MRI) technology (discussed later). It should be noted that in spite of the replicability of this finding, the absolute magnitude of the ventriculomegaly is usually slight. Few patients, probably less than lo%, have qualitatively large o r "abnormal" ventricles. Studies of families of patients with schizophrenia have suggested that the neuropathologic process underlying ventricular enlargement may be more prevalent than studies of unrelated individuals suggested. In studies of sibling groups, including discordant monozygotic twins, the patient with schizophrenia consistently has had the largest ventricles within the family, even if' the member who was ill had ventricles within the broader range of normal.""") While the presence of ventriculomegaly suggests that tissue loss has occurred in the brains of patients with schizophrenia, it does not identify the site o r sites o r cause of the abnormalities. T h e C T findings associated with schizophrenia were ini-
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tially thought to be a consequence of therapy, including antipsychotic medications. In order to address this possibility, C:'T scans from untreated patients, during their first schizophreniform psychotic episode (so-called "first break" patients), have been ~ t u d i e d . " ' - ~These " controlled studies have consistently demonstrated that ventricular enlargement exists at the first episode and is not the result of chronic psychiatric treatment. This finding has stimulated speculation that ventriculomegaly actually predates the clinical onset of the illness in early adult life. A popular view is that the underlying neuropathologic process occurs long before the onset of the illness and may be developmental. T h e possibility that the findings reflect a developmental abnormality is further suggested by evidence that ventricular enlargement and cortical changes d o not progress in patients with schizophrenia scanned 7 to 9 years after their initial study.".' MRI studies have confirmed and expanded the Sindings from C T scans. A volumetric analysis of ventricular size on MKI studies in patients with schizophrenia demonstrated once again the presence of' enlarged lateral and third ventricles."Discordant monozygotic twins have been studied again in order to provide the closest possible con-
Figure 2. T I weighted MRI scan, in the coronal plane at the level of the thalamus, of monozygotic twins discordant for schizophrenia. The normal twin is depicted on the left, and the twin with schizophrenia is on the right. Note the relatively enlarged lateral and third ventricles in the twin with schizophrenia. 280
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SEMINAKS IN NEUR0I.OC;Y
NEUROPATHOLOGY Traditional anatomic neuropathologic studies have been conducted on the brains of patients with schizophrenia since at least the end of the 19th century. While a veritable cornucopia of findings has been reported, until the past 5 years, few of them have been consistently replicated. Until recently, the cerebral cortex has received most of the attention in the neuropathologic analysis of schizophrenia, probably because of the wellknown role of this structure in cognitive processes and the profound alterations of these processes in schizophrenia. In the neocortex, cerebral atrophy and cell loss have been reported on numerous occasions over the past 100 years."'~"-" 70wever, the precise characteristics and magnitude of these
changes have been inconsistent. No discrete finding has been consistently replicated. Several studies have observed a trend toward reduced cell number and density in the frontal lobe, particularly in the prefrontal regi~n.~~,""n addition to cell loss, thickened, densely staining dendrites and axons have been found in the cortex, again especially in the prefrontal region.jOThese findings have been difficult to interpret for a variety of reasons, including their nonspecif~icityand the possibility that they represent secondary changes. Earlier neuropathologic studies also focused on the basal ganglia, probably because of the bizarre mannerisms and catatonic posturing of some patients with schizophrenia. For unclear reasons, most of these studies have focused on the globus p a l l i d ~ sVogt . ~ and Vogt," perhaps seeking a classic clinical neuropathologic correlation, reported cell loss in this structure, especially in patients with catatonia. However, this finding has been disputed." More recently in a study relying on gross cross-sectional measurements, volume reduction has been reported in the internal segment of the globus pallidus in brains from the Vogt c ~ l l e c t i o n . ~ The cause and clinical correlates of this volume reduction have not been identified. The limbic system, with its traditional role in modulating the emotional aspects of behavior, only recently has been examined for neuropathologic changes. Nevertheless, this has clearly emerged as the most productive and informative region of the brain for finding neuropathologic changes in schizophrenia. T h e amygdala and hippocampus have come under closest scrutiny. T h e average volume of the anteromedial limbic temporal lobe (parahippocampus, hippocampus, and amygdala) appears to be reduced in patients with schizophrenia compared with control^.^ This gross morphometric finding, in one fbrm or another, has been reported by five independent groups of investigators.4,60-m F~rthermore, this postmortem abnormality correlates with MRI findings in living patients with schizophrenia.""" This degree of replication of a putative anatomic finding is unprecedented in the annals of schizophrenia research. The neuropathologic basis of the volume reduction in the amygdalar-hippocampal complex is unclear, but some provocative clues have emerged. Disarray has been reported in the arrangement of the dendrites of hippocampal pyramidal cells, j'.'" although this has not been replicated using alternative staining techniques.74A striking finding, reported by Jakob and Beckmann," is maldevelopment of the superficial layers of the entorhinal cortex. Unlike the poorly characterized morpho28 1
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trol group. T h e affected twins had significantly larger ventricles than the healthy twins. Moreover, in almost every twin pair, the affected twin had the larger ventricles, even if they seemed qualitatively 2). This result again suggests that smal15"Fig. when "ideal" controls are available, evidence of a structural neuropathologic process may be appreciated in most patients with schizophrenia. Neuroimaging studies also have been used to demonstrate focal structural abnormalities. In earlier C'I' studies, the demonstration of dilated frontal interhemispheric and sylvian fissures suggested volume loss in the frontotemporal region.4x C T studies also have reported that apparent cerebellar vermian atrophy is more prevalent in patients with schizophrenia than in controls," consistent with a recent postmortem morphometric study of the cere b e l l ~ mHowever, .~~ this finding is present in only a small fraction of patients with schizophrenia and has not been reported in first episode patients. Additionally, alcoholism was not definitively eliminated as a causative factor of vermian atrophy in either study. The most robust focal finding on MRI scans has been a reduction in the volume of temporal lobe gray matter, especially in the region containing the amygdala and hippocampus."" Moreover, the degree of reduction in temporal lobe gray matter correlates directly with the magnitude of ventricular enlargement. The specific involvement of the anterior hippocampus was further demonstrated in the MKI study of discordant monozygotic twins, in which the size of the anterior hippocampus was smaller in the affected twin in 14 of 15 pairs."" This finding correlates with postmortem analyses of the am~gdalar-hippocampal region."""-""
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metric results, this qualitative finding strongly the neuroscientific approach toward this illness. implicates an abnormality in early brain dev- Neuroleptics appear to exert their antipsychotic efelopment. Independent replications have been re- fects through their blockade of dopanline recepported but not yet published'' (Casanova MF: Per- t o r ~ . ~ T "h e popular "dopamine hypothesis" holds sonal communication). that increased dopaminergic transmission proThe nucleus accumbens, a subsection of the duces the cardinal manifestations of schizophrecorpus striatum, is considered to be a link between nia.#' Postmortem neurochemical analyses on pathe basal ganglia and the limbic system. As such, it tients with schizophrenia have focused on many has been of considerable theoretical interest in aspects of dopamine systems in the central nervous schizophrenia research. While one recent report system. Two types of dopamine receptors are present found volume reduction of this structure in patients with schizophrenia," a separate group was in the central nervous system: D, receptors are unable to confirm this finding.4 Given the strategic linked to the stimulation of adenylate cyclase, and connections of this nucleus, and its importance in D, receptors have a high affinity for "H-haloperisubcortical dopamine transmission, further study do1 and inhibit adenylate cyclase. Both receptor systems have been carefully studied in postmortem is warranted. Several reports of brainstem abnormalities tissue of patients with schizophrenia. T h e most rehave appeared, but none has been replicated. T h e producible finding has been an increase in the midbrain is the site of the primary dopaminergic density of D, receptors in the caudate, putaprojections to the limbic system, basal ganglia, and men, and nucleus a c ~ u m b e n s . ~ ~ W n f o r t u n a t e l y , cortex. In one study, the lateral substantia nigra this finding is confounded by a history of neurowas found to have decreased volume, without a loss leptic therapy in most of the patients studied. T h e of neuronal elements, suggesting a loss of neuro- results in a few patients who were said to be unpi1 in the region.'' Reports of other pathologic medicated have been inconclusive. Neuroleptic exchanges include gliosis in the periaqueductal gray posure has been shown to produce increased of D, receptors through denervation sumatter,76-77 vermian atrophy in the ~ e r e b e l l u r n , ~numbers ~ and glial nodules in the medial reticular formation persensiti~ity.~'In neuroleptic-naive patients, in of the pons.78T h e last finding, however, has been vivo quantification of D, receptor density using d i ~ p u t e d , ~ b h i the l e others have yet to be in- positron emission tomography suggested the presdependently pursued. No consistent pattern of ence of elevated receptor density in the caudate neuropathologic changes can be discerned in the nucleus in one study,'" but not in another.84 Dl receptors have not been studied as extenbrainstem. In summary, traditional neuropathologic stud- sively as D, receptors. In a recent report, decreased ies of schizophrenia have shown changes within the numbers of D, receptors and an increase in the cortex, basal ganglia, limbic system, and brainstem. DJD, receptor ratio were noted in the caudate ~~ T h e most convincing and reproducible findings nucleus of patients with s c h i z ~ p h r e n i a .Since appear to be within the region of the amygdalar- chronic neuroleptic therapy in animals does not hippocampal formation. T h e degree of replication produce analogous changes in Dl recept~rs,~Qhe that is emerging for neuropathologic changes in decreased D, receptors could be primary to schizothis region is impressive. While numerous addi- phrenia itself, rather than due to chronic neurotional sites of pathologic change have been re- leptic exposure. However, at least one report has ported, none has been replicated as frequently in failed to replicate this finding.x7 T h e mechanisms by which dopaminergic neumethodologically rigorous studies. It is notable that gliosis is not a prominent feature of the rotransmission might be excessive in schizophrenia replicable neuropathologic abnormalities. The ab- are unclear, even from a theoretical perspective. sence of significant gliotic changes, combined with Consistent with the dopamine hypothesis, it is conprovocative evidence of cytoarchitectural abnor- ceivable that a pathologic defect in schizophrenia malities, suggests that the pathologic process un- could be the abnormal production of D, receptors. derlying schizophrenia is more likely to be a devel- However, for this to result in a pathophysiologic opmental defect than an inflammatory, infectious, condition, the mechanisms of presynaptic compensation also would have to be abnormal. An alteror degenerative process. native possibility is that the increase in these receptors is secondary to other neurochemical or neuropathologic processes, with increased recepNEUROCHEMISTRY tor production being the final endpoint. NevertheT h e development of pharmacotherapy fbr less, it still remains to be proven that patients with schizophrenia in the late 1950s radically altered schizophrenia possess increased numbers of sub-
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SEMINARS I N NEUKOLOGY
BRAIN IN SCHIZOPHRENIA-HYDE, WEINBERGER
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cortical dopamine receptors in the absence of neu- in vivo neuroimaging and postmortem anatomic roleptic exposure. techniques. T h e details and etiology of temporal A pathologic increase in dopamine release also lobe-hippocampal pathologic states remain to be could account for relatively excessive dopaminer- elucidated. Neuropsychologic and cerebral blood gic transmission and the efficacy of neuroleptics. flow studies suggest that the frontal lobe is dysIncreased concentrations of dopamine and its me- functional in schizophrenics. However, there is littabolites have been found in postmortem tissue in tle known about the neuropathologic basis and only a few studies. Elevations have been found in neurochemical correlates of this deficit. the anterior perforated substance and the nucleus One of the intriguing new hypotheses about accumbens in one study,n8but not in a ~ e c o n d . ~ "the neurologic findings in schizophrenia is that Similar discrepancies have been noted in dopa- they are the result of an abnormality in the early of the brain. T h e possibility that the mine levels in the caudate and p ~ t a m e n . Ele~ ~ , ~development ~ vated dopamine levels have been detected in the clinical illness is a delayed manifestation of this left amygdala, when comparing both amygdalae process, perhaps because of an interaction between from each individual." This finding has yet to be the early developmental deficit and later maturing independently replicated, perhaps because of the functional neural systems, is a subject of speculaabsence of comparisons of right and left amygda- t i ~ n . ~ ~ While much study has been devoted to the lae from the same individuals. Many other neurotransmitters and neuropep- structural and functional abnormalities underlying tides have been examined in postmortem studies schizophrenia, much remains to be discovered. In of brain tissue from patients with schizophrenia. the past 20 years, the development and application Norepinephrine levels have been reported to be el- of new techniques, including CT, MRI, rCBF, and evated in the nucleus accumbens in one ~ t u d y , ~ 'PET, have revolutionized the study of schizophrebut not in a second." Elevated serotonin levels nia, and have produced the first consistent neurohave been noted in the putamen and globus pal- pathologic findings in this disorder. T h e pace of l i d ~ ~ . ~Decreased ~," serotonin receptor density discovery has been gradually accelerating. Applihas been reported in the frontal cortex,95." but cation of new techniques and careful use of patient selection criteria will help further decipher the this finding also has been d i ~ p u t e d . ~Glutamate, ' gamma-aminobutyric acid, cholecystokinin, neu- neurologic basis of this disorder. There is reasonrotensin, opiates, thyrotropin-releasing hormone, able hope that by the end of this century, the paand somatostatin have been assayed under a vari- thology and pathophysiology of this common but ety of paradigms. However, these findings have baffling illness will be revealed. not been replicated independently and their relationship to neuroleptic exposure remains to be determined.
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