H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner and M.G.P.Feenstra (Eds.)

Progress in Brain Research, Vol. 85 0 1990 Elsevier Science Publishas B.V. (Biomedical Division)

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CHAPTER 26

The prefrontal cortex in schizophrenia and other neuropsychiatric diseases: in vivo physiological correlates of cognitive deficits Karen Faith Berman and Daniel R. Weinberger Clinical Brain Disorders Branch, National Institute of Mental Health, NIMH Neurosciences Center at St. Elizabeths, Washington, DC 20032, USA

Introduction

The prefrontal cortex in human behavior and cognition The role of the prefrontal cortex has intrigued students of human behavior for many years. Galen, in the second century, believed that the seat of the soul resided in this part of the brain. Albertus Magnus in the twelfth century insightfully foreshadowed modern thinking that the frontal lobes were necessary for problem solving and planning (McHenry, 1969). However, even in more recent times unraveling the functions of the prefrontal cortex remained an elusive goal. In fact, for many years the human prefrontal cortex was viewed as a physiologically “silent area” and was thought to contribute little if anything to human behavior and cognition. This misconception stemmed in part from inadequate definitions of what constitutes cognition and from the relative insensitivity of standard tests of intelligence (on which patients with frontal lobe lesions are often unimpaired) in measuring so-called “executive functions”. Correspondence:K.F. Berman, M.D., Clinical Brain Disorders Branch, National Institute of Mental Health, NIMH Neurosciences Center at St. Elizabeths, Washington, DC 20032, USA.

New approaches to studying the human brain, including neuropsychological tests devised to measure aspects of cognition such as mental flexibility and concept formation, suggest that, far from being a silent, redundant area, the prefrontal cortex may be at the core of that which is most human, shaping our attitudes and organizing our cognitive repertoire to produce the highest order goal-directed behaviors. Through the formation and execution of long- and short-term plans, the internal manipulation of representational systems, and the use of complex sequencing, the prefrontal cortex appears to play a fundamental role in the hierarchical organization of cognitive control and, indeed, in human consciousness (Perecman, 1987).

Methods for studying prefrontal function in man Implications of prefrontal lesions The importance of the prefrontal cortex in higher human cognition and behavior has been elucidated by observations of patients with focal cortical lesions. Published case reports of such patients first appeared in the nineteenth century. One of the earliest well-observed and well-documented cases of prefrontal damage was that of Phineas Gage in whom behavioral and personality changes were described following the accidental destruction

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of a portion of his frontal lobes that occurred while he was employed as a railway worker (Harlow, 1868, as cited in Fuster, 1989). Since then, studies of patients with prefrontal traumatic injury, including several large series of war veterans (Salazar et al., 1986), as well as those with stroke, or surgical resection of tumors or of epileptic foci have firmly established that damage to the prefrontal cortex in humans results in a syndrome of complex and often subtle signs and symptoms including changes in affect, social behavior, and cognition. Some investigators have delineated distinct behavioral syndromes associated with orbitomedial and dorsolateral lesions. One problem with making general inferences about human frontal lobe function from observations of patients with gross frontal lobe lesions is that naturally or iatrogenically occurring prefrontal lesions are not well controlled in extent or location. In fact, few pathological lesions exclusively damage dorsolateral prefrontal cortex. Another problem is that in patients with tumors or epilepsy it is not clear whether the remaining brain tissue is actually normal. Similar concerns apply to patients with stroke or trauma where there may be sequelae that are distant to the prefrontal lesions themselves. In vivo brain imaging An alternative approach has recently become available through the advent of in vivo functional brain imaging techniques that allow the study of the normal living, working, human brain. These include 33Xe inhalation regional cortical blood flow (rCBF) measurements, single photon emission computed tomography (SPECT), and positron emission tomography (PET), all of which involve relatively non-invasive regional imaging and quantification of various parameters of local brain activity such as cerebral blood flow, glucose metabolism, and receptor occupancy and density. These techniques have allowed direct investigation of prefrontal cortical function during various cognitive and other conditions, and they have proven extremely useful for investigating brain func-

tion in disease states in which the prefrontal cortex has been implicated. Observations of similar patterns of cognitive deficits on neuropsychological tests that are sensitive to prefrontal lobe damage and of behavioral abnormalities that are common both in patients with known frontal lobe lesions and those with other neuropsychiatric diseases have raised the possibility that the prefrontal cortex may play a role in a diverse spectrum of illnesses including schizophrenia, Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, Alzheimer’s disease, and others. Since gross structural frontal lobe pathology is not a prominent feature of the brains of most patients with these illnesses (with the exception of Alzheimer’s disease), a mechanism other than a disordered prefrontal cortex per se must be postulated. This paper explores the concept that disruption at any site along the rich and complex circuits interconnecting the prefrontal cortex with other cortical and subcortical structures can result in the clinical “frontal lobe syndrome” and that measuring brain physiology during specific behaviors can help to delineate at what level such a disruption occurs. In this chapter we describe the use of in vivo functional brain imaging, via the 133Xeinhalation method for measuring rCBF, to study frontal lobe function in a variety of neuropsychiatric disorders that may be related to prefrontal dysfunction. We will focus on schizophrenia, an illness in which prefrontal cortex is of considerable heuristic interest and has long been impugned. Investigations of schizophrenia exemplify the potential power of such studies to elucidate pathophysiological mechanisms underlying diseases in which there are few clues. Despite nearlya century of post-mortem anatomical investigations of the brains of patients with schizophrenia, no consistent pathological lesion has been uncovered in this illness, and the anatomical basis for the brain functional abnormalities has remained unclear (Kirch and Weinberger, 1986). Comparing the results of blood flow studies in schizophreniawith those of patients with diseases such as Parkinson’s disease, Huntington’s

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disease, and Alzheimer’s disease, all of which involve behavioral alterations thought to reflect dysfunction of prefrontal cortex, but in which the pathological substrates are better understood than are those underlying schizophrenia, may provide clues about the pathophysiological mechanism in the latter illness.

Evidence for prefrontal involvement in schizophrenia Interest in the prefrontal cortex as a possible locus of pathology in schizophrenia dates back nearly a century. Alzheimer suggested that neuropathology in layers I1 and 111 of frontal cortex was responsible for this illness. Other pioneers in the field of schizophrenia research, notably both Kraepelin (1971) and Bleuler (1950), also considered the frontal lobes important in schizophrenia. In the first half of this century prefrontal leucotomies were performed with the notion that isolating a disordered frontal lobe from other brain areas would alleviate some of the symptoms of schizophrenia (Valenstein, 1986). However, although subtle structural changes in schizophrenia have been suggested (Benes et al., 1986), a great deal of neuropathological experimentation has failed to convincingly and consistently demonstrate gross structural damages of the prefrontal cortex. While further investigations of the gross, cellular, and even synaptic anatomy of the prefrontal cortex in schizophrenia are necessary before the case is closed on the possibility of structural pathology, evidence continues to accrue that a functional aberration of prefrontal cortex may explain some of the clinical phenomena of schizophrenia. Hallucinations and delusions may be the most dramatic clinical features of schizophrenia, but the “negative” or “defect” symptoms may be more disabling. These include flat and inappropriate affect, paucity of thought, social withdrawal, lack of initiative and motivation, poor insight and judgement - a clinical constellation reminiscent of patients with frontal lobe lesions, especially lesions of dorsolateral prefrontal cortex.

The pattern of cognitive deficits seen in schizophrenia also most consistently implicates the frontal lobes (Seidman, 1983) as do the minor or “soft” neurological signs common in schizophrenia (Quitkin et al., 1976). Of course, none of these clinical features is pathognomonic of frontal lobe disease, but methods of imaging brain function in vivo can now be applied to test the hypothesis of a dysfunction of prefrontal cortex more directly. Such studies were pioneered some 15 years ago by Ingvar and Franzen who used a relatively invasive method of measuring rCBF of one hemisphere at a time with carotid injections of 133Xe dissolved in saline. They reported that virtually all normal subjects under virtually all waking conditions exhibited relatively more blood flow to frontal cortex than to other cortical areas visible with this technique. They termed this characteristic normal pattern “hyperfrontality”. In contrast they noted that chronic schizophrenic patients were relatively “hypofrontal”, lacking the pattern of augmented anterior blood flow common to normal subjects (Ingvar and Franzen, 1974a). This intriguing finding not only revitalized interest in the role of the frontal lobes in schizophrenia, but also heralded the era of functional brain imaging techniques as applied to neuropsychiatry research. However, in the decade following the publication of this work, a number of rCBF and PET studies appeared in the literature, and the results were extremely inconsistent: while some investigators confirmed Ingvar and Franzen’s observation of hypofrontality, others did not (for reviews see Berman and Weinberger, 1986a, and Weinberger and Berman, 1988). There may be many reasons for these inconsistencies, but one of the most important probably relates to the fact that when studying brain physiology, the results depend upon how the brain is engaged while it is being studied. Measurements of cerebral blood flow or metabolism represent the sum of a complex set of cerebral physiological responses. While some of these responses reflect the illness being studied, many reflect the subject’s

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behavior and experience while the measurement is being made. It may seem obvious that the brain’s physiology may be expected to reflect and respond to its surround and internal millieu, but the implications of this fact for functional brain imaging studies, i.e. the need to control as completely as possible all sensory inputs and cognitive and motor outputs to reduce the “noise” of such measurements, may not have been fully appreciated by early investigators in this field. In fact, many of the first rCBF and PET schizophrenia studies were carried out while subjects were “atjest”, a condition during which sensory, cognitive, and motor inputs and outputs are least controlled. It has been demonstrated that resting state studies are more non-specifically variable than studies carried out during more controlled conditions (Duara et al., 1987), and it has been suggested that there may be no such thing as a “resting state” in the awake human brain (Mazziotta et al., 1982). In vivo cortical stress tests to assess prefrontal physiology An alternative approach that we have taken has been to device “cortical stress tests’’ in which rCBF is measured while subjects receive controlled sensory input and carry out specified cognitive and/or motor tasks (Berman, 1987). For example, cognitive tasks that reliably activate specific cortical areas in normal subjects can be used to test the ability of patients’ brains to physiologically respond to various cognitive or other demands. In our studies we typically make 3 rCBF measurements in each subject during 3 different conditions so that each subject can serve as his or her own control. The first of these is always a resting state study, the main purpose of which is to acclimatize subjects to the rCBF measurement procedure. The second and third of this set of measurements, taken together, have proved more informative about neuropsychiatric disorders, and schizophrenia in particular. These two procedures are usually designed such that one is a regionally and

cognitively specific task with relevance to the cortical region of interest (the stress test) and the other is a non-specific sensorimotor control task designed to be like the stress test in as many ways as possible except the cognitive processes involved. The order in which these two tasks are presented is counterbalanced across subjects to control for the possibility of an order effect. To investigate prefrontal cortex we needed a condition or cognitive test that would elevate neuronal function in prefrontal cortex above ambient levels. We chose to measure rCBF while subjects performed the Wisconsin Card Sorting test (WCS), a neuropsychological test that involves the use of feedback and working memory in the formation of conceptual sets and necessitates the shifting of these sets when appropriate. Patients with known frontal lobe pathology do poorly on this test, and Milner (1963, 1964, 1971) has shown that it is a particularly sensitive indicator of the integrity of the dorsolateral aspect of the prefrontal cortex in man. Patients with schizophrenia also consistently do poorly on the WCS (Malmo, 1974; Kolb and Whisman, 1983; Goldberg et al., 1987) and, like patients with’gross frontal lobe disease, their errors are characteristically of a perseverative nature; that is, inability to switch the conceptual set even when given feedback to do so. We also designed a sensorimotor control task during which subjects were shown slides of the numbers 1 through 4, presented in random order, which they were meant to match to 1 of 4 switches also labeled with these numbers. For this Numbers Match test, the method of presenting stimuli to the subject, the mode for the subjects’ response, and the feedback mechanism were identical to those for the WCS. Therefore, it controls for the minimal finger movement necessary to make a response, for the visual stimulation, and for the psychological experience of taking a test while having blood flow measured. Thus, blood flow measured while a subject performs the control task can be subtracted from blood flow measured while that subject performs the WCS to highlight the physiological changes related to the abstract reasoning and pro-

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blem solving aspects of the latter test. With this approach we showed (Weinberger et al., 1988a) that when normal subjects perform the WCS their dorsolateral prefrontal blood flow values are significantly elevated above levels during the Number Match control task (Figs. 1 and 2). This confirmed that it is an appropriate stress test for studying prefrontal function in neuropsychiatric patient groups.

Prefrontal physiology in schizophrenia Activation of prefrontal cortex in schizophrenia Using the paradigm described above we have studied patients with chronic schizophrenia and compared them with age- and sex-matched normal subjects. We demonstrated that, while betweengroup differences in prefrontal blood flow were inconsistent during resting and non-existent during simple Number Matching, robust differences could be demonstrated during the WCS (Fig. 1). Even when each subject was used as his or her own control and the differences between blood flow during the two tasks were examined, patients showed a striking failure to activate frontal cortex during the WCS, particularly the dorsolateral prefrontal cortex (Fig. 2). We have now demonstrated this basic finding of a behavior- and region-specific dysfunction of prefrontal cortex in a total of 4 different cohorts of patients, 2 who were on neuroleptics (Berman et al., 1986, 1989) and 2 who were medication free (Weinberger et al., 1986, 1988a). A consistent pattern of findings has emerged from these studies and those of other investigators using different methods (Cohen et al., 1987; Volkow et al., 1987); when schizophrenic patients are studied during rest or other non-specific conditions they may or may not appear hypofrontal, but virtually all studies carried out during prefrontal stimulation have demonstrated lower prefrontal blood flow or metabolism in schizophrenia. Thus, the bulk of the available data indicate that physiological dysfunction of the prefrontal cortex in schizophrenia, at least during physiological de-

mand, is a replicable finding. However, its interpretation must be carefully considered.

How prevalent is hypofrontality in schizophrenia? One question that has not been answered by the body of published studies of frontal lobe function in schizophrenia is: How characteristic of schizophrenic patients is hypofrontality? Is this finding a consistent characteristic of schizophrenia, or does it just affect a subgroup of patients who may have different pathophysiologies and etiologies underlying their illnesses? The approach taken by virtually all studies has been to compare the mean value for a group of patients with schizophrenia to that for an unrelated group of normal subjects. The results of such a comparison often confirm that, on the whole, patients have lower values. However, examination of the individual values typically reveals that there is a great deal of overlap between the two groups and that only a minority of patient values actually fall beyond the lower limit of the relatively wide range of normal values. One interpretation of this observation could be that only a small subgroup of patients with schizophrenia are hypofrontal. However, since we have no way of knowing what a given patient’s value would have been if he or she did not have schizophrenia, the true prevalence of hypofrontality in the schizophrenia population cannot be estimated. We had the opportunity to address this question by studying 10 pairs of monozygotic twins who were discordant for schizophrenia (Berman et al., 1989). Assuming that the rCBF measurements for the well co-twin of a monozygotic pair discordant for schizophreniamay reflect the values that would have characterized the ill twin if he or she did not have schizophrenia, the former can be used as a genetically (as well as socio-economically and environmentally) perfect control to determine the pathophysiological changes that have occurred in each patient. As in our previous studies of unrelated groups of normals and schizophrenics, when we compared

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relative prefrontal blood flow values between discordant co-twins, we found no consistent evidence of hypofrontality in the ill twins during resting or Numbers Matching. However, during the WCS in each and every case the twin with schizophrenia was more hypofrontal than his or her well co-twin (Berman et al., 1989). This suggests that in virtually every case something has happened to the brain of the schizophrenic twin to make it more hypofrontal, at least during the prefrontally linked WCS task, than it would have been without schizophrenia. It is tempting to conclude that these data confirm that there is a primary physiological impairment of prefrontal cortex in schizophrenia, that it is characteristic of the illness, and that it affects most if not all individuals who have schizophrenia. However, an alternative explanation that must be considered is that hypofrontality may not be a primary feature of schizophrenia but may rather be an epiphenomenon due to less important secondary factors. That is, is the finding related to the physiological characteristics of the region subserving the behavior - the prefrontal cortex - or does it, instead, reflect non-specific state variables. Secondary factors that may play a role in studies of schizophrenia include motivation, arousal, effort, and the effects of treatment with neuroleptic medi-

cation. Although a growing body of evidence suggests that these secondary factors do not explain hypofrontality in schizophrenia, they are important to consider.

Is hypofrontality in schizophrenia an epiphenomenon? A medication effect?

Most rCBF and PET studies have been carried out in patients who were either receiving neuroleptics at the time of the study or had been withdrawn from neuroleptics for some period of time (such as the 4-week drug-free interval in our studies). This, along with the fact that hypofrontality could not be demonstrated in several resting state PET studies of small numbers of patients who had never received neuroleptics (Early et al., 1987; Volkow et al., 1986), has suggested to some investigators that neuroleptic treatment is responsible for hypofrontality in schizophrenia. However, a growing body of evidence refutes this notion. Our own data, demonstrating WCS-related hypofrontality in 24 patients tested while on stable doses of 0.4 mg/kg/day of haloperidol (Berman et al., 1986), suggest that neuroleptic treatment or its withdrawal cannot fully explain hypofrontality. However, these results do not rule out the possibi-

Fig. 1. Lateral maps of group mean regional cerebral blood flow (rCBF) values, with the anterior pole at the left, for the left hemisphere in 25 normal controls and 20 medication-free schizophrenics during the Wisconsin Card Sorting test (WCS) and a simple Numbers Matching sensorimotor control task. Note the patients’ significantly lower prefrontal flow during the WCS. There were no between-group differences during the control task (from Weinberger et al., 1986). Fig. 2. rCBF activation maps for the same subjects as in Fig. 1. Data for the WCS are expressed as a percentage of flow during the control task. Note the significant prefrontal activation in the normal subjects and the lack of activation in the patients (from Weinberger et al., 1986). Fig. 3. rCBF maps for 18 medication-free schizophrenic patients and 17 normal control subjects during a version of the visual Continuous Performance task (CPT). Note the similar pattern in both groups. There were no significant between-group differences (from Berman et al., 1986). Fig. 4. rCBF maps for 25 medication-free schizophrenic patients and 24 normal controls. Flow values during Raven’s Progressive Matrices are expressed as a percentage of those during a simple Symbols Matching sensorimotor control task. Note the pattern of posterior activation in both groups. There were no significant between-group differences (from Berman et al., 1988a). Fig. 5 . rCBF maps for an 18-year-old patient with Moya-Moya disease and intrinsic prefrontal pathology (see text for pertinent history). Note the hypofrontal pattern during both the WCS and the Numbers Matching task.

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lity of long-term effects of neuroleptic treatment on prefrontal physiology. We studied 14 patients with Huntington’s disease, 5 of whom had been chronically maintained on neuroleptics and found no differences in prefrontal blood flow between these 5 patients and those who were neurolepticnaive (Weinberger and Berman, 1988). Moreover, our study of 8 pairs of monozygotic twins who were concordant for schizophrenia, but whose lifetime histories of neuroleptic intake differed greatly, do not support the notion of neuroleptic-mediated hypofrontality. If neuroleptics cause or exacerbate hypofrontality, it would be predicted that within each concordant twin pair the twin with the history of the most neuroleptic intake would be the more abnormal. However, we found that in 6 of the 8 concordant pairs the twin who had been exposed to more neuroleptics was the more hyperfrontal of the pair during the WCS (Berman et al., 1989). Perhaps the most direct evidence against neuroleptics as a cause of hypofrontality comes from the only study to investigate cerebral metabolism in drug naive patients during prefrontal activation. Using SPECT technology to measure rCBF, Raese et al. (1989) have recently reported that schizophrenic patients never exposed to neuroleptic medication were hypofrontal during the WCS. Taken together, these data do not support neuroleptic treatment as a major factor in hypofrontality .

A role for poor performance, motivation; arousal, or effort? It is well established that patients with schizophrenia score poorly on the WCS (Goldberg et al., 1987); and we have seen that this poor performance occurs in the context of a failure to activate prefrontal cortex (Weinberger et al., 1986). This raises the possibility that the patients’ poor performance is somehow responsible for the prefrontal physiological dysfunction seen during the WCS, rather than that the pathophysiology is responsible for the poor performance. For example, perhaps the patients were not even engaged in

the task, but were simply making random responses. The patterns of errors made by patients with schizophrenia does not suggest random, disinterested responses, but rather is typically one of perseveration (i.e., inability to shift the conceptual or cognitive set, even in the face of feedback to do so). Interestingly, this pattern is commonly seen in patients with known frontal lobe lesions (Milner, 1963, 1971). We have also studied other populations of patients who scored poorly on the WCS. A group of 14 patients with Huntington’s disease, who performed as poorly as our patients with schizophrenia, showed no prefrontal blood flow deficit during the WCS (Weinberger et al., 1988b); if anything they tended to have slightly higher blood flow than the normal controls. Thus, a pathophysiological mechanism for the cognitive deficits of Huntington’s disease that differs from that operating in schizophrenia is inferred (vide infra). We also used the same WCS-rCBF paradigm to study 10 mildly to moderately mentally retarded patients with Down syndrome whose performance on the WCS was considerably worse than that of either the schizophrenic or Huntington’s disease patients. Despite this poor performance, the Down syndrome patients also showed a prefrontal activation in the normal range while attempting to perform the WCS (Berman et al., 1988b). In schizophrenia we have also seen normal dorsolateral prefrontal blood flow in the face of poor performance during other tasks on which the patients perform poorly (see Fig. 3). These include an auditory discrimination task (Berman et al., 1987a) and two versions of a visual Continuous Performance task (CPT) (Berman et al., 1986), all of which require as much attention and effort as the WCS. In fact, the CPT was designed specifically as a test of attention and vigilance rather than abstract reasoning, and patients with schizophrenia characteristically perform poorly on it (Garmezy, 1978). These data suggest that poor performance per se does not indiscriminately produce hypofrontality . Additional epiphenomenological factors that are

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important to consider in studies of neuropsychiatric patients in general, and patients with schizophrenia in particular, center around motivation and interest in the task as well as attention and effort. While these factors are as difficult to measure adequately as they are to define, the fact that patients do not show deficits in dorsolateral prefrontal function during other tasks in which attention is a critical factor, even those such as the CPTs that are effortful and specifically designed to test attention and vigilance, suggests that nonspecific disturbances in attention and/or effort do not account for the WCS findings.

Is hypofrontality in schizophrenia regionally and behaviorally specific? It is worth noting that tests like the CPT may not be as specifically linked to prefrontal cortex as the WCS. The observation that in schizophrenia dorsolateral prefrontal blood flow is abnormally decreased during the prefrontally linked WCS, but is normal during non-prefrontally linked tasks such as Numbers Matching, CPTs, auditory discrimination, and resting, raises the interesting possibility that hypoprefrontality may only be manifested, or at least may be most apparent, in schizophrenia under conditions that place a regionally and cognitively specific load on the prefrontal cortex. If this conjecture were true, it would have important implications for understanding the pathophysiological mechanism, and ultimately the neural specificity, of WCS-related prefrontal failure in schizophrenia. However, the CPT, Numbers Matching, and resting conditions, unlike the WCS do not involve abstract reasoning and problem solving. An alternative hypothesis could be that schizophrenics appear hypofrontal during any and all abstract reasoning/problem solving tasks, regardless of the cortical region that subserves them. To test this hypothesis we sought to determine whether patients would appear hypoprefrontal during another abstract reasoning task, one that is not specifically linked to prefrontal cortex. Such a paradigm would also demonstrate

whether patients, if given a task that requires thought and is linked to an area other than prefrontal cortex, would fail to activate that area. To address these questions we assessed cortical function while subjects solved Raven’s Progressive Matrices (RPM), a non-verbal, abstract reasoning and problem solving test which is a well-accepted indicator of general intelligence (Burke, 1958). Subjects with postrolandic lesions are impaired on this test (Basso et al., 1973), suggesting that posterior cortical areas are critical for the cognitive functions necessary to perform it; however, there is no evidence that patients with dorsolateral prefrontal cortical lesions have particular difficulty with it. This is consistent with results of other tests of intelligence on which patients with dorsolateral prefrontal lesions are also unimpaired, and also agrees with our rCBF data showing that normal subjects activate posterior cortical areas above baseline while performing this task (Fig. 4), suggesting that it is mediated by posterior cortical areas. In contrast to the WCS, no significant activation of frontal cortical areas occurred (Berman et al., 1988a). These divergent findings in normal subjects during two different abstract reasoning tasks have implications for the role of the prefrontal cortex in normal higher cognitive function; they suggest that not all tests that require problem solving and complex higher order cognitive processing are “frontal” tasks. This notion is consistent with the perspective of many current cognitively based theories. Fuster (1989) has emphasized the role of dorsolateral prefrontal cortex in the crosstemporal integration of information (or spanning time), while Goldman-Rakic (1987) suggests that the dorsolateral prefrontal cortex functions to form “internal representations of situations or stimuli”, supporting the “ability to respond to situations on the basis of stored information, rather than on the basis of immediate stimulation”. Similarly, Ingvar (1985) proposed a primary role for this brain area in “memory of the future”, or “the production of serial action plans . . . used as templates with which is input is compared”. The

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WCS and RPM differ in several critical aspects that, in light of these cognitive theories, may explain their differential effects on prefrontal cortical physiology (Berman et al., 1988a). For example, determining the proper category by which to sort a particular WCS stimulus requires that the feedback given on previous trials be considered. This may be conceptualized as the use of working memory to span time and make serial judgements. In contrast to the WCS, no previous experience is necessary to complete each RPM trial, and since all the required information is available to the subject throughout the trial, no working memory or “internal representations” are involved. Carrying out prefrontally specific cognitive operations, such as those mentioned above, may result in physiological activation of prefrontal cortex above the ambient, tonal, levels necessary to maintain wakefulness and routine neuronal homeostasis. It appears that successful performance of the prefrontally related WCS requires and results in an augmented prefrontal physiological response, while the RPM does not. In contrast to the WCS, we found that while performing RPM (an abstract reasoning test that requires at least as much attention, concentration, motivation, and mental effort as any task we have studied with rCBF - including the WCS), patients with schizophrenia did not exhibit significant differences in prefrontal rCBF compared with normal subjects (Fig. 4), and both normal subjects and patients showed similar rCBF patterns with maximal increases in parieto-occipital cortex (Berman et al., 1988a). Similar results were reported by Ingvar and Franzen (1974b). Since performance of RPM involves many of the non-specific cognitive factors also involved in the WCS (e.g. mental effort, attention, etc.), the contrasting results obtained with these two paradigms in schizophrenia probably reflect differences in the functional integrity of the regional neural systems that subserve performance of each test. These data suggest that since performance of RPM (as well as other non-prefrontally specific tests including Number Matching and the CPT)

does not require prefrontally dependent functions such as temporal integration to the same degree as the WCS, augmentation of prefrontal activity levels above baseline may not be required and the RPM challenge is more readily met by the schizophrenic prefrontal cortex than is the WCS challenge. The RPM data also suggest that patients can activate posterior cortical areas when engaged in a task is linked to these areas in normal subjects. Thus, the WCS-related prefrontal pathophysiology does not appear to be due to a generalized inatility to activate any cortical area, rather, that it is circumscribed and linked to a specific cognitive behavior. On the basis of the data outlined above what do we know about the mechanism of the pathophysiology that underlies the prefrontally linked behavioral and cognitive deficits in schizophrenia? A highly simplified scheme might consider 3 possible pathophysiological mechanisms: deefferentation of prefrontal cortex, deafferentation, and intrinsic prefrontal abnormality. While it has not been definitively delineated which of these mechanisms may play a role in the behaviorally related pathophysiology of the prefrontal cortex in this illness, some clues are offered by the collective results of these blood flow studies carried out in conjunction with a variety of cognitive conditions, and by comparing schizophrenia to other illnesses that have more clearly defined neuropathology. The following sections will consider possible roles of these 3 mechanisms in schizophrenia and other neuropsychiatric diseases. Regional cerebral blood flow in prefrontal deefferentation

One possible pathophysiological mechanism for the behavioral abnormalities in schizophrenia could be that, while the prefrontal cortex itself is intact, the pathways carrying information from prefrontal cortex to other brain areas may be aberrant. One illness in which such prefrontal deefferentation is known to occur is Huntington’s disease in which there is degeneration of one of the

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major outflow connections of the prefrontal cortex, the caudate nucleus. While widespread degenerative changes, involving cortical as well as subcortical areas, do occur in advanced cases, few if any cortical abnormalities are present in early cases (Bryn et al., 1979). However, even in early cases, a constellation of behavioral signs and symptoms as well as neuropsychological deficits characteristics of frontal lobe disease is often present (Caine et al., 1978). Because of the paucity of structural and chemical abnormalities of the cortex in such cases, and because PET studies have consistently found no alterations in cortical metabolism, Huntington’s disease is often called a “subcortical dementia”. Consistent with the observations of other investigators, we found no deficits in cortical blood flow at rest or even when patients with Huntington’s disease were engaged in cognitive tasks on which they were impaired (Weinberger et al., 1988b). In particular, unlike schizophrenic patients, the Huntington’s patients were not hypofrontal during the WCS despite similarly poor performance (Goldberg et al., 1990). This result suggests that the prefrontally related cognitive deficits in Huntington’s disease are mediated by a mechanism other than intrinsic prefrontal pathophysiology and that the mechanism is very different from that in schizophrenia. A clue to the nature of the pathophysiology in Huntington’s disease is provided by data from our study (Weinberger et al., 1988b) showing a correlation between the degree of caudate atrophy and prefrontal blood flow during the WCS. This correlation was behavior specific, occurring only during the WCS condition; thus, the effect of caudate degeneration on cortical function was most pronounced when there was heightened demand for prefrontal function. The direction of the correlation is also of interest: the smaller the caudate (i.e. the greater the caudate atrophy), the higher the prefrontal blood flow. This finding may demonstrate the normal physiological response of an intact prefrontal cortex attempting to compensate for “downstream” blockage at the head of the

caudate, the primary first order corticofugal projection site. The difference between the rCBF pattern in Huntington’s disease and that in schizophrenia suggests that prefrontal de-efferentation does not play a major role in schizophrenia.

Regional cerebral blood flow in intrinsic prefrontal pathology Intrinsic prefrontal pathology, loss of or damage to prefrontal neurons per se, offers a second pathophysiological mechanism by which prefrontal-type cognitive and behavioral deficits could occur. Such pathology is known to be present in ischemic injury, trauma, Pick’s disease, and some cases of Alzheimer’s disease. Fig. 5 shows the blood flow pattern of an 18-year-old patient with intrinsic pathology restricted mainly to the prefrontal lobe. He had presented with a clinical picture that was indistinguishable from a first episode of schizophrenia, but a CT scan revealed a frontobasilar stroke. Further work-up with cerebral angiography demonstrated vascular anomalies consistent with a diagnosis of Moya-Moya disease, a congenital condition that predisposes to infarction. Unlike patients with schizophrenia, this patient’s blood flow studies showed marked hypofrontality under all conditions, both the WCS (on which he performed poorly) and the non-prefrontally specific Numbers Matching test, and even at rest (resting data not shown). Alzheimer’s disease. Another example of intrinsic prefrontal pathology is seen in Alzheimer’s disease. Here the blood flow pattern is one of decreased prefrontal blood flow, but in the context of decreases in other cortical areas (particularly parietal and temporal cortex) as well. Like the patient with Moya-Moya disease but unlike patients with schizophrenia, patients with Alzheimer’s disease exhibit such decreases during all conditions under which they are studied (Berman and Weinberger, 1986b). Schizophrenia? As mentioned above there is very little convincing evidence for the existence of structural pathology of the prefrontal cortex in

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schizophrenia. The fact that in schizophrenia prefrontal blood flow deficits are mainly seen under conditions that impose a regionally specific physiological load or “stress” (like the WCS) not under all conditions - also tends to weigh against intrinsic prefrontal pathology. However, the possibility of subtle intrinsic pathology that‘only becomes apparent when the physiological demand placed on the frontal cortex exceeds its capacity to respond cannot be ruled out. Nonetheless, the bulk of available evidence in schizophrenia appears to be more consistent with disordered afferentation than with intrinsic frontal lobe disease or de-efferentation. Regional cerebral blood flow in prefrontal deafferentation: a possible mechanism for dysfunction in schizophrenia? Further evidence for deafferentation in schizophrenia: structural -functional relationships and limbic pathology

As reviewed above, the pathophysiological model that appears to best fit the pattern of cortical blood flow abnormalities in schizophrenia is that of a decoupling of prefrontal cortex from the afferenting pathways that provide information to it. While such prefrontal deafferentation has yet to be directly demonstrated in schizophrenia, a number of observations support this concept. One finding that is consistent with this line of thinking concerns a relationship between prefrontal blood flow and subcortical brain structures. One of the most reproducible and time-tested findings reported in the schizophrenia literature is that, on the average, the lateral ventricles of patients with schizophrenia are larger than those of the normal populace (Shelton and Weinberger, 1986). We found a behavior-specific inverse correlation between relative prefrontal blood flow and lateral ventricular size as measured with X-ray computerized tomography (CT); this correlation was seen during the WCS but not during the non-specific Numbers Matching task (Berman et al., 1987b). One possi-

ble interpretation of this result is that there is structural pathology of diencephalic and limbic periventricular structures and that this may somehow be responsible for impaired prefrontal activation during the WCS. Since increased lateral ventricle size is a non-specific finding that could reflect pathology anywhere in the brain and since CT is not able to distinguish between soft tissue features of similar densities (such as gray and white matter), the exact structures involved could not be ascertained in this study. Using magnetic resonance imaging, which offers an anatomically clearer picture of brain structures, Suddath et al. (1989) reported a 20% reduction in temporal lobe gray matter (particularly in the portion of the temporal lobe containing the amygdala and hippocampus) in schizophrenia, a finding that was correlated with ventricular size. Preliminary evidence from our study of monozygotic twins discordant for schizophrenia suggests a further refinement of the structural - functional relationship posited above, that a link between the hippocampus and the prefrontal cortex may play a role in the WCS-related cognitive and physiological deficits in schizophrenia. This observation is particularly intriguing in light of recent demonstrations in the monkey of direct projections from the hippocampus to the prefrontal cortex and metabolic coupling of prefrontal cortex, hippocampus, and medial thalamus during working memory tasks (Friedman and Goldman-Rakic, 1988). While such indirect evidence implicating these structures in the cognitive impairments characteristics of schizophrenia continues to accrue, the exact nature of such a putative deafferentation remains unknown. However, a neurochemical role for dopamine warrants further examination. The role of dopamine

Although a clear picture of the role of the dopaminergic systems in human higher functions is just beginning to emerge, considerable work in non-human primates has demonstrated that path-

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ways providing dopaminergic innervation to prefrontal cortex are important for cognition. Brozowski et al. (1979) provided compelling evidence that dopaminergic activity in prefrontal cortex is involved in the expression of prefrontally mediated cognition in monkeys. Those investigators found that chemical lesioning of dorsolateral prefrontal cortex (sulcus principalis) with 6hydroxydopamine, producing depletion of prefrontal dopamine, resulted in a decrement in performance of prefrontally linked cognitive tasks similar to that caused by surgical ablation. It is easy to hypothesize from this work that a disorder of prefrontal dopamine may play a role in prefrontally linked cognitive and physiological deficits in humans. Evidence for such a situation, and particularly for the involvement of the mesocortical dopamine system, comes from clinical and pharmacological studies. Parkinson’s disease. Parkinson’s disease is characterized by a loss of nigrostriatal as well as mesocortical dopamine circuits and thus represents a known situation of deafferentation of the prefrontal cortex. In this illness physiological findings that are consistent with such a dopamine deafferentation have been demonstrated and may have a counterpart in schizophrenia. For 10 nondemented patients with mildly to moderately severe Parkinson’s disease (Weinberger et al., 1988c) prefrontal blood flow values during the WCS correlated with stage of illness as well as with bradykinesia and rigidity, which are clinical measures traditionally thought to be linked to dopaminergic function. Prefrontal blood flow did not correlate with degree of tremor, which is less associated with the dopamine system. There was also a robust inverse correlation between prefrontal blood flow and performance on the WCS. It is interesting that the direction of this correlation (i.e. poorer performance in the context of lower prefrontal rCBF) is the same as that observed in schizophrenia (Weinberger et al., 1986). In both illnesses the degree to which these patients can activate prefrontal cortex during the card sort relates to how successfully they perform the task. This

raises the possibility that there may be some common mechanisms underlying prefrontal defects in schizophrenia and Parkinson’s disease. Schizophrenia. As in Parkinson’s disease, the neurochemical system that has traditonally been most implicated’ in schizophrenia is dopamine. However, the two illnesses are usually thought to have few similarities and, in fact, are often conceptualized as being at opposite extremes of the spectrum of dopamine disorders. Based on the observation that neuroleptics can ameliorate the positive symptoms of schizophrenia while dopamine agonists can exacerbate them, the “dopamine hypothesis” of schizophrenia, in its classical form, postulates a relative overabundance or overactivity of dopamine, while the hallmark of Parkinson’s disease is dopamine depletion. Nonetheless, there are a number of clinical and experimental observations suggesting that there may be some common mechanisms in these two patient populations. For example, both groups share the so-called deficit symptoms of flat affect, decreased motivation, amotivation, and specific cognitive deficits (which are not ameliorated by neuroleptics) described above for patients with intrinsic frontal lobe disease. In Parkinson’s disease these symptoms have been attributed to decreased dopaminergic activity in prefrontal cortex. There is increasing evidence that a similar mechanism may play a role in the manifestation of these clinical phenomena in schizophrenia. The first lines of evidence linking Parkinson’s disease and schizophrenia are the correlations and clinical features enumerated above. A corollary line of evidence implicating a deficient dopamine system in schizophrenia stems from measurements of cerebrospinal fluid (CSF) monoaminergic metabolites. We found a relationship between CSF levels of the dopamine metabolite homovanillic acid (HVA) and the degree of WCS-related prefrontal activation. Higher HVA levels correlated with higher relative prefrontal flow in the patients (Weinberger et al., 1988a). This relationship was found only for blood flow measured during the WCS and not for that during the non-specific

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number matching task or other non-prefrontal tasks (Berman et al., 1988a). This pattern of a behavior-specific relationship is remarkably similar to that of the correlations we saw between WCS prefrontal blood flow and lateral ventricular size. Since data from monkeys suggest that CSF HVA levels reflect HVA concentrations in prefrontal cortex (Ellsworth et al., 1987), these observations provide further evidence that the mesocortical dopamine system, perhaps through a structural neuropathological abnormality (reflected by enlargement of the lateral ventricles), is involved in the prefrontal pathophysiology of schizophrenia. Can the notion of hypodopaminergic function be reconciled with the hypothesis of hyperdopaminergic function that has held sway in schizophrenia for many years? The exact pathways have yet to be completely traced in humans, but it is clear that complex feedback circuits connect the prefrontal and subcortical dopamine systems in the normal brain. For example, mesocortical dopamine neurons appear to affect prefrontal cortical neurons that in turn exert feedback control over mesolimbic activity (Thierry et al., 1984). Pycock et al. (1980) demonstrated in the rat that a disruption of this system at the level of the prefrontal cortex can result in a functional hyperactivity of basal ganglia and limbic dopamine. It is possible that a similar dysregulation of the dopamine systems may exist in schizophrenia (Weinberger, 1987). If hypodopaminergic function does exist and if it underlies prefrontal pathophysiology in schizophrenia, hypofrontality should be reversible with dopamine agonists. To test this hypothesis we studied the effects of the dopamine agonist apomorphine on WCS-related rCBF in a small group of chronically psychotic subjects. In each of the patients with schizophrenia hypofrontality during the WCS was ameliorated to some degree following a subcutaneous dose of apomorphine (Daniel et al., 1989a). This result is supported by a subsequent study using SPECT technology to measure the effects of amphetamine on rCBF

(Daniel et al., 1989b). Additional studies are currently being carried out to to investigate the effects of other agonist agents such as levodopa and SKF38393, a specific dopamine D1 receptor agonist . Conclusions Taken together, the studies described above demonstrate that disruption anywhere along the complex circuitry connecting prefrontal cortex with other brain areas can cause a clinically significant syndrome of abnormal behavior suggestive of prefrontal lobe dysfunction. While the final common pathway for the expression of such abnormalities (i.e. the disordered behavior and cognition) may be similar, it is clear that the prefrontal physiological repercussions, and no doubt the neurochemical concomitants, differ and reflect the underlying neural mechanism. In vivo studies of neurophysiology in conjunction with cognitive activation procedures can provide important clues about the neural mechanisms in various illnesses. Such studies may ultimately help to point the way to new treatments. Schizophrenia is a case in point. Although the agonist treatment studies mentioned above must be considered preliminary, it appears that the mystery of the prefrontal cortex, and its role in disease processes (even the relatively subtle prefrontal pathophysiology in an elusive illness like schizophrenia) is yielding to new technology, lessons from nonhuman primate models, and new pharmacological agents. A more complete picture of the primate prefrontal cortex may someday lead us to new ways to intervene and correct a primary physiological prefrontal deficit in schizophrenia and other illnesses. References Basso, A., DeRenzi, E., Faglioni, P., Scotti, G. and Spinnler, H . (1973) Neuropsychological evidence for the existence of cerebral areas critical to the performance of intelligence tasks. Brain, 96: 715-728. Benes, F.M.,Davidson, J . and Bird, E.D. (1986) Quantitative

535 cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch. Gen. Psychiat., 43: 31 - 35. Berman, K. (1987) Cortical ‘‘stress tests” in schizophrenia: regional cerbral blood flow studies. Biol. Psychiat., 22: 1304- 1326. Berman, K.F. and Weinberger, D.R. (1986a) Cerebral blood flow studies in schizophrenia. In H. Nasrallah and D.R. Weinberger (Eds.), The Neurology of Schizophrenia, Elsevier North Holland Press, Amsterdam, pp. 227 - 307. Berman, K.F. and Weinberger, D.R. (1986b) Cortical physiological activation in Alzheimer’s disease: rCBF studies during resting and cognitive states. SOC. Neurosci. Abstr., 12: 1160. Berman, K.F., Zec, R.F. and Weinberger, D.R. (1986) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. 11. Role of neuroleptic treatment, attention, and mental effort. Arch. Gen. Psychiat., 43: 126- 135. Berman, K.F., Rosenbaum, S.C.W., Brasher, C.A., Goldberg, T.E. and Weinberger, D.R. (1987a) Cortical physiology during auditory discrimination in schizophrenia: a regional cerebral blood flow study. SOC. Neurosci. Abstr., 13: 651. Berman, K.F., Weinberger, D.R., Shelton, R.C. and Zec, R.F. (1987b) A relationship between anatomical and physiological brain pathology in schizophrenia: lateral cerebral ventricular size predicts cortical blood flow. Am. J. Psychiat., 144: 1277 - 1282. Berman, K.F., Illovsky, B.P. and Weinberger, D.R. (1988a) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. IV. Further evidence for regional and behavioral specificity. Arch. Gen. Psychiat., 45: 616-622. Berman, K.F., Schapiro, M.B., Friedland, R.P., Rapoport, S.I. and Weinberger, D.R. (1988b) Cerebral function during cognition in Down syndrome. Proceedings of the I4Ist Annual Meeting of the American Psychiatric Association. Berman, K.F., Torrey, E.F., Daniel, D.G. and Weinberger, D.R. (1989) Prefrontal cortical blood flow in monozygotic twins concordant and discordant for schizophrenia. Schizophrenia Res., 2: 129. Bleuler, E. (1950) Dementia Praecox or the Group of Schizophrenias, International Press, New York, p. 467. Brozowski, T.S., Brown, R.M., Rosvold, H.E. and Goldman, P.S. (1979) Cognitive deficits caused by regional depletion of dopamine in prefrontal cortex of rhesus monkeys. Science, 929: 929 - 932. Bryn, G.W., Bots, G.Th. and Dom, R. (1979) Huntington’s chorea: Current neuropathological status. In: T.N. Chase, N.S. Wexler and A. Barbeau (Eds.), Advances in Neurology, Raven Press, New York, pp. 83 - 93. Burke, H.R. (1958) Raven’s progressive matrices: A review and critical evaluation. J. Genet. Psychol., 93: 199 - 228. Caine, E.D., Hunt, R.D., Weingarten, H. and Ebert, M.H. (1978) Huntington’s dementia: Clinical and neuropsychological features. Arch. Gen. Psychiat., 35: 377 - 384. Cohen, R.M., Semple, W.E., Gross, M., Nordahl, T.E.,

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Ingvar, D.H. and Franzen, G. (1974b) Distribution of cerebral activity in chronic schizophrenia. Lancet, 2: 1484- 1486. Kirch, D.G. and Weinberger, D.R. (1986) Post-mortem histopathological findings in schizophrenia. In: H.A. Nasrallah and D.R. Weinberger (Eds.), The Neurology of Schizophrenia, ElsevierINorth-Holland, Amsterdam, pp. 325 - 348. Kolb, B. and Whisman, I.Q. (1983) Performance of schizophrenia patients on tests sensitive to left or right frontal, temporal, and partietal function in neurologic patients. J. Nerv. Ment. Dis.. 171: 435-443. Kraepelin, E. (1971) Dementia Praecox and Paraphrenia. R.E. Krieger, New York. Malmo, H.P. (1974) On frontal lobe functions: Psychiatric patient controls. Cortex, 10: 231 - 237. Mazziotta, J.C., Phelps, M.E., Carson, R.E. and Kuhl, D.E. (1982) Tomographic mapping of human cerebral metabolism: Sensory deprivation. Ann. Neurol., 12: 435 - 444. McHenry, L.C. (1969) Garrison’s History of Neurology, Charles C. Thomas, Springfield, IL. Milner, B. (1963) Effects of different brain lesions on card sorting. Arch. Neurol., 9: 100- 110. Milner, B. (1964) Some effects of frontal lobectomy in man. In: J.M. Warren and K. Akert (Eds.), The Frontal Granular Cortex and Behavior, McGraw-Hill, New York, pp. 313 - 334.

Milner, B. (1971) Interhemispheric differences in the localization of psychological processes in man. Br. Med. Bull., 27: 272 - 277. Pereman, E. (1987) The Frontal Lobes Revisited, IBRN Press, New York. Pycock, C.J., Kerwin, R.W. and Carter, C.J. (1980) Effects of lesions of cortical dopamine terminals on subcortical dopamine receptors in rats. Noture, 286: 74 - 77. Quitkin, F., Rifkin, A. and Klein, D. (1976) Neurologic soft signs in schizophrenia and character disorders. Arch. Gen. Psychiat., 33: 845 - 853. Raese, J.D., Paulman, R.G., Steinberg, J.L., Devous, M.D., Judd, C.R. and Gregory, R.R. (1989) Wisconsin Card Sort activated blood flow in dorsolateral frontal cortex in never medicated and previously medicated schizophrenics and normal controls. Biol. Psychiat.. 25: 100A. Salazar, A.M., Grafman, J.H., Vance, S.C., Weingarten, H., Dillon, J.D. and Ludlow, C. (1986) Consciousness and amnesia after penetrating head injury: neurology and anatomy. Neurology, 36: 178 - 187. Seidman, L.J. (1983) Schizophrenia and brain dysfunction: an integration of recent neurodiagnostic findings. Psychol. Bull., 94: 195-238. Shelton, R.C. and Weinberger, D.R. (1986) X-Ray computerized tomography studies in schizophrenia: a selective review and synthesis. In: H.A. Nasrallah and D.R. Weinberger (Ed.), The Neurology of Schizophrenia. Elsevier/North-

Holland, Amsterdam, pp. 207 - 250. Suddath, R.L., Casanova, M.F., Goldberg, T.E., Daniel, D.G., Kelsoe, J.R. and Weinberger, D.R. (1989) Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. Am. J. Psychiat., 146: 464-472. Thierry, A.-M., Tassin, J.P. and Glowinski, J. (1984) Biochemical and electrophysical studies of the mesocortical dopamine system. In: L. Descarsies, T.R. Reader and H.H. Jasper (Eds.), Monoamine Innervation of Cerebral Cortex, Alan R. Liss, New York, pp. 233-262. Valenstein, E.S. (1986) Great and Desperate Cures, Basic Books, New York. Volkow, N.D., Brodie, J.D., Wolf, A.P., Angnst, B., Russel, J. and Cancro, R. (1986) Brain metabolism in patients with schizophrenia before and after acute neuroleptic administration. J. Neurol. Neurosurg. Psychiat., 4 9 1199- 1202. Volkow, N.D., Wolf, A.P., Van Gelder, P., Brodie, J.D., Overall, J.E., Cancro, R. and Gomez-Mont, F. (1987) Phenomenological correlates of metabolic activity in 18 patients with chronic schizophrenia. Am. J. Psychiat., 144: 151 - 158. Weinberger, D.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiat., 44: 660-669. Weinberger, D.R. and Berman, K.F. (1988) Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophrenia Bu//.,1 4 157 - 168. Weinberger, D.R., Berman, K.F. and Zec, R.F. (1986) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence. Arch. Gen. Psychiat., 43: 114- 125. Weinberger, D.R., Berman, K.F. and Illowsky, B.P. (1988a) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. 111. A new cohort and evidence for a monoaminergic mechanism. Arch. Gen. Piychiat., 45: 609-615.

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Discussion J.E. Pisetsky: Schizophrenia is a heterogeneous disorder. Have

you differentiated between less regressed and more regressed patients? K.F. Berman: Patients at the NIMH tend to be a relatively homogenous group and are, therefore, not ideally suited to addressing the question of clinical correlates of hypofrontality. However, other investigators, including Dr. David Ingvar and

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colleagues over 15 years ago, have shown that those patients who are the most regressed, autistic, and “burnt out”, those who have the most severe negative symptoms are the most hypofrontal. P.R. Lowenstein: A comment - the relation between schizophrenia and dopamine is complex. William Bunney’s group showed some years ago that schizophrenic patients respond in the following wiy after administering low dosis of amphetamine: one-third get better, one-third get worse, one-third do not change. A question: Why does cerebral blood flow increase in all cortical areas? K.F. Berman: Amphetamine does not increase global blood flow. In fact global levels tend to decrease! However, dopamine agonists do appear to increase frontal flow. Furthermore, agonists seem to increase the “signal-to-noise” ratio of prefrontal flow relative to other cortical areas during prefrontally linked cognitive tasks, perhaps facilitating a more “normal” physiological response in schizophrenia. S.B. Dunnett: Is there a contradiction between your data on DA drugs, schizophrenia and parkinsonism: (a) amphetamine can induce schizophrenia-like psychosis in normals but seemed to reduce cerebrovascular pathology in your patients; (b) neuroleptics which reduce schizophrenia symptoms can induce parkinsonian side effects and, yet, your schizophrenia and Parkinson patients appeared to have deficits in frontal cerebral blood flow?

K.F. Berman: A good question. As the question implies, the dopamine theory of schizophrenia in its classical form postulates an overabundance or overactivity of dopamine in this illness. However, new methods of research on primates and new selective pharmacological agents make clear that dopamine in the brain is not a single, unitary system that is either “up” or “down”. There are complex interactions between the subcortical and cortical dopamine systems, and it has been shown in the rat that a disruption of the cortical dopamine system at the level of the prefrontal cortex acts to “take the brakes off” the subcortical dopamine system. This is one scenario by which a brain could have too much dopamine and too little dopamine at the same time. A similar scenario could be present in schizophrenia: prefrontal dopamine deficit might underly the negative symptoms of schizophrenia (which agonists help), while subcortical overactivity might explain the positive symptoms (which antagonists ameliorate). A.Y. Deutch: The convergent data suggest that the deficit may be a DA hypofunction in schizophrenia, matched by the Parkinson’s disease DA cortical hypofunction. Is the blood flow altered in progressive supranuclear palsy, in which cortical DA is not depleted? K.F. Berman: PSP is a group that we are very interested in. We have not yet studied enough subjects to draw firm conclusions.