T.E. Goldberg, J.M. Gold, E.F. Torrey, and D.R. Weinberger
Am J Psychiatry 1995; 152:883-8.
OBJECTIVE: While a number of studies have suggested that women with schizophrenia have a less severe form of the disorder than men, the issue has been examined with neuropsychological measures only infrequently. METHOD: The authors compared neuropsychological test performances of men and women from four independent schizophrenic cohorts: two groups of inpatients with chronic courses at a research hospital (N = 128 and N = 63), one group of consecutive admissions to a private psychiatric hospital (N = 57), and one group of schizophrenic twins from discordant monozygotic pairs (N = 20). Nearly 100 comparisons of neuropsychological test performances were made between men and women. RESULTS: Not one comparison significantly favored women, and few were even significantly different between the sexes. CONCLUSIONS: It cannot be ruled out that the disproportionate number of men in the chronic cohorts may have reflected either more frequent intellectual deterioration in men or a bias toward more severely impaired women. Yet, men and women in all groups performed similarly, including the groups in which the sex ratios were nearly equal and were not skewed toward chronicity. These results provide little support for the hypothesis that gender is associated with a unique pathogenesis of schizophrenia or is a marker for a distinct subtype of schizophrenia, at least to the extent that cognitive impairment is a primary manifestation of the underlying disease process. However, given the lack of female patients with later ages at onset and more affective symptoms, the results in this study should be considered relevant only for chronic patients with onset of schizophrenia before age 30.
A. Hitri, M.F. Casanova, J.E. Kleinman, D.R. Weinberger, and R.J. Wyatt
Biol Psychiatry 1995; 37:175-82.
We investigated dopamine transporter receptor ligand binding in the prefrontal cortex as a function of age in schizophrenic and control postmortem brains. [3H]GBR 12935 binding constants were calculated by Scatchard analysis from the autopsied brains from 29 individuals with schizophrenia, and 28 control subjects. There were wide interindividual variations in Bmax and KD that were not related to gender, age, or postmortem interval (PMI) in controls. While there were no significant associations between gender, PMI, and Bmax, or KD in individuals with schizophrenia, there was a significant negative correlation between age and Bmax (r = -.44, p = .02). The slope of the regression lines between age and Bmax for the two groups was significantly different. The results suggest a differential effect of age, or something associated with age, on [3H]GBR 12935 binding sites in the prefrontal cortex of controls and individuals with schizophrenia.
T.M. Hyde, M.F. Egan, R.J. Brown, D.R. Weinberger, and J.E. Kleinman
Psychiatry Res 1995; 56:53-7.
Tardive dyskinesia (TD) is a common movement disorder that is associated with chronic neuroleptic exposure. To better characterize the clinical aspects of TD, we investigated the diurnal pattern of involuntary movements by blindly rating videotaped examinations of patients from the morning shortly after awakening and later in the same afternoon. In 10 patients, average TD ratings were worse in the afternoon than in the morning, especially in the case of limb- trunk dyskinesias. These findings suggest that it is important to rate patients at the same time of day in TD studies. Moreover, patients should be evaluated at least several hours after awakening.
T.M. Hyde, M.F. Egan, L.L. Wing, R.J. Wyatt, D.R. Weinberger, and J.E. Kleinman
Psychopharmacology 1995; 118:142-9.
Patients who develop persistent parkinsonism while on chronic neuroleptic therapy may be predisposed towards the development of tardive dyskinesia (TD). We investigated this issue in an animal model of TD by examining the association between catalepsy and the syndrome of neuroleptic- induced vacuous chewing movements (VCMs). VCMs were measured every 3 weeks for 33 weeks while rats received injections of haloperidol decanoate. Catalepsy was measured after the second through the seventh injections of the depot neuroleptic. There were no correlations between the severity of catalepsy scores after the second or third injections of haloperidol and the severity of the overall VCM syndrome. However, the severity of the catalepsy score following the third through seventh injections of haloperidol strongly correlated with the concurrent number of VCMs. Persistent high catalepsy scores across the six catalepsy rating sessions were strongly associated with the development of persistent severe VCMs. These findings suggest that, to the extent that persistent parkinsonian signs in humans are associated with a propensity towards the development of TD, the VCM syndrome in rats is at least a partially faithful animal model of this relationship.
T.M. Hyde, M.E. Stacey, R. Coppola, S.F. Handel, K.C. Rickler, and D.R. Weinberger
Neurology 1995; 45:1176-82.
Although the pathologic substrate of Tourette's syndrome (TS) is unknown, studies have implicated subtle changes in the basal ganglia. To further investigate structural basal ganglia pathology in TS, we performed morphometric analyses of MRIs of 10 monozygotic twin pairs discordant for severity of TS but concordant for the presence of tic disorders (mean age, 16.3 years; range, 9 to 31 years). Right caudate volume was slightly but significantly reduced in the relatively more severely affected twins as a group compared with the less affected twins (mean difference = 6%, p < 0.01). Most of this difference was attributable to volume reduction in the anterior right caudate (p < 0.02), which was smaller in the more severely affected twin in nine of 10 twin sets. The mean volume of the left lateral ventricle was 16% smaller in the more severely affected twins than in the less severely affected twins (p < 0.01). The normal asymmetry of the lateral ventricles (left greater than right) was not present in the more severely affected twins, who had a trend toward a larger right lateral ventricle. Moreover, the difference within a pair in the degree of loss of the normal ventricular asymmetry correlated with the difference within a pair in the severity of the tic disorder (r = 0.75, p < 0.02). There were no other basal ganglia, ventricular volumetric, or asymmetry abnormalities. These findings partially replicate other MRI studies and suggest that subtle structural abnormalities in the CNS, particularly in the caudate, may play a role in the pathophysiology of TS.(ABSTRACT TRUNCATED AT 250 WORDS)
T.M. Hyde, and D.R. Weinberger
Jama 1995; 273:498-501.
M.B. Knable, D.W. Jones, R. Coppola, T.M. Hyde, K.S. Lee, J. Gorey, et al.
J Nucl Med 1995; 36:1216-25.
We used equilibrium analysis of SPECT data from patients with asymmetric Parkinson's disease to determine if lateralized differences in the striatal uptake of [123I]IBZM correlate with asymmetry in clinical findings and, by inference, with lateralized differences in the concentration of extracellular dopamine. METHODS: Twelve patients with asymmetric clinical signs of idiopathic Parkinson's disease were injected with a bolus of [123I]IBZM, and multiple SPECT scans recorded the time course of radioligand uptake. The time integral method was used to estimate peak specific binding, so that a ratio of specific-to-nonspecific binding in the left and right striatum of each subject at equilibrium could be determined. Nine patients also had 99mTc-HMPAO SPECT scans which were examined for evidence of blood flow asymmetries. RESULTS: Paired t-tests comparing [123I]IBZM uptake revealed significantly greater (mean = 7.3%) availability of dopamine-D2 receptors in the basal ganglia contralateral to maximal clinical signs. Differences in receptor availability correlated significantly with differences in every measure of the clinical assessment. No significant differences in regional cerebral blood flow between the two sides were observed with 99mTc-HMPAO. CONCLUSION: These results demonstrate the ability of [123I]IBZM SPECT to reveal clinically meaningful variations in striatal dopamine receptor availability in patients with asymmetric Parkinson's disease. The equilibrium analysis technique used to determine these findings is a simple and robust method of measuring relative receptor availability and may be useful in studying other illnesses where dysfunction of dopaminergic neurotransmission is suspected.
K.J. Kotrla, and D.R. Weinberger
Annu Rev Med 1995; 46:113-22.
Neuroimaging provides an unprecedented means by which to study psychiatric disorders. Structural imaging methods, i.e. computerized tomography (CT) and magnetic resonance imaging (MRI), have revealed subtle differences in the brains of schizophrenic patients that appear to be present before symptom onset. Radionuclide functional methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have led to hypotheses about dysfunction in specific neuronal networks in schizophrenia. New advances in MRI allow functional data to be obtained noninvasively in a single individual using conventional MRI scanners. This chapter discusses the parallels between the historical technical developments in neuroimaging and the deepening understanding of the etiology and manifestations of schizophrenia.
V.S. Mattay, D.R. Weinberger, F.A. Barrios, G.S. Sobering, K.J. Kotrla, P. van Gelderen, et al.
Radiology 1995; 194:687-91.
PURPOSE: To compare directly the two most widely used methods of functional magnetic resonance (MR) imaging-- dynamic contrast material-enhanced MR imaging and blood oxygenation level- dependent (BOLD) MR imaging. MATERIALS AND METHODS: Five healthy volunteers underwent dynamic contrast-enhanced and BOLD MR imaging with a conventional 1.5-T MR unit during visual stimulation and a dark control state. BOLD studies were performed with a gradient-echo sequence, and dynamic MR imaging was performed with an echo-shifted gradient-echo sequence after intravenous administration of a bolus of gadopentetate dimeglumine. RESULTS: A significantly greater percentage signal change was found with dynamic MR imaging than with the BOLD technique. The extent of area activated was also significantly greater. CONCLUSION: With standard clinical imagers and these gradient-echo-based techniques, greater percentage activation and area of activation can be achieved with dynamic MR imaging than with BOLD MR imaging.
A.M. Murray, T.M. Hyde, M.B. Knable, M.M. Herman, L.B. Bigelow, J.M. Carter, et al.
J Neurosci 1995; 15:2186-91.
The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively motor striatum.
D.R. Weinberger, T.E. Goldberg, and C.A. Tamminga
Am J Psychiatry 1995; 152:330-1.
N.A. Breslin, R.L. Suddath, G. Bissette, C.B. Nemeroff, P. Lowrimore, and D.R. Weinberger
Schizophr Res 1994; 12:35-41.
Neurotensin (NT), a peptide which colocalizes with dopamine in some midbrain and hypothalamic neurons, has been speculated to play a role in schizophrenic illness and in the action of antipsychotic drugs. Previous work suggested a bimodal distribution of NT in patients with schizophrenia, with a subgroup having low drug-free NT concentrations which normalize with neuroleptic treatment. We studied 15 schizophrenic patients with CSF samples collected both off and on neuroleptic medication, 12 with only drug-free (DF) samples, and 10 controls. There was no significant difference in CSF NT concentrations between patients and controls, or between patients off and on medication. However, 7 patients with DFNT CSF concentrations below the patient mean showed an increase with neuroleptic treatment. Moreover, NT was significantly lower for women. Significant correlations with NT concentrations in CSF were found with deficit symptoms in patients, and with the age of the CSF sample for all subjects. There was no correlation between CSF NT concentrations and patient age, duration of illness, or levels of amine metabolites (MHPG, 5HIAA, HVA).
J.H. Duyn, V.S. Mattay, R.H. Sexton, G.S. Sobering, F.A. Barrios, G. Liu, et al.
Magn Reson Med 1994; 32:150-5.
A 3-dimensional MRI method has been developed for functional mapping of the human brain, based on blood oxygenation level dependent (BOLD) contrast mechanisms. The method uses recently introduced principles of echo-shifted FLASH to acquire a single 3D data set in 20 s. The technique was tested on a conventional 1.5 Tesla clinical scanner with a standard head coil using visual stimulation with a 8 Hz flashing white light, or a varying checkerboard pattern. Areas of increased signal intensity were identified in the visual cortex, consistent with the known functional organization.
M.F. Egan, Y. Hurd, T.M. Hyde, D.R. Weinberger, R.J. Wyatt, and J.E. Kleinman
Synapse 1994; 18:178- 89.
Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (- VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways.
J.M. Gold, B.P. Hermann, C. Randolph, A.R. Wyler, T.E. Goldberg, and D.R. Weinberger
Arch Gen Psychiatry 1994; 51:265-72.
BACKGROUND: Recent neuroimaging studies have reported structural abnormalities of mesial temporal lobe structures in schizophrenia. This study compared the neuropsychological performance of patients with schizophrenia with patients with either left or right temporal lobe epilepsy to determine if lateralized, developmental temporal lobe dysfunction provides a model of the cognitive impairments observed in schizophrenia. METHODS: A total 66 patients with schizophrenia and 101 patients with medically intractable focal temporal lobe epilepsy (48 left temporal, 53 right temporal) received a comprehensive neuropsychological battery. RESULTS: The three groups did not differ on age, years of education, or Full-Scale IQ. However, clear differences were noted in performance profiles. Patients with schizophrenia scored significantly higher than either epilepsy group on a measure of word reading thought to reflect premorbid competence. Patients with schizophrenia demonstrated greater attentional impairment and motor slowing than either epilepsy group. The patients with schizophrenia had superior semantic knowledge and verbal memory compared with the left temporal lobe group. On the Wisconsin Card Sorting Test the patients with schizophrenia obtained significantly fewer categories than either temporal lobe group, but were not significantly more perseverative. CONCLUSIONS: Data suggest lateralized temporal lobe dysfunction does not provide an adequate model of the cognitive impairments seen in schizophrenia. The disorders seem to follow different developmental paths: In early-onset epilepsy, the acquisition of cognitive skills and academic knowledge is compromised, while in schizophrenia cognitive functions are lost. Extratemporal pathologic features, most likely of the frontal lobe, are implicated in the cognitive dysfunction of schizophrenia.
T.E. Goldberg, E.F. Torrey, K.F. Berman, and D.R. Weinberger
Psychiatry Res 1994; 55:51-61.
Correlational approaches that examine the relation between neuropsychological measures and brain morphology or physiology in schizophrenia have yielded inconsistent results. This may be due in part to difficulties in ascertaining precisely to what degree each measure deviates from its genetically and environmentally determined potential level. We attempted to surmount this problem in a paradigm involving monozygotic twin pairs discordant for schizophrenia. In this paradigm, the difference score between the unaffected member and affected member of a twin pair should represent the degree of pathologic involvement irrespective of actual level. In correlating intrapair difference scores of anatomic structures measured from magnetic resonance imaging (n = 15) and prefrontal regional cerebral blood flow (rCBF) (n = 10) with cognitive abilities (after partialing IQ), we found strong associations between (1) the left hippocampus and a parameter of verbal memory, and (2) prefrontal rCBF with symptom scores and perseveration on the Wisconsin Card Sorting Test. These results support other research implicating medial temporal and prefrontal regions as important in the symptomatic expression and cognitive failures of schizophrenia. Overall, however, there was a relative paucity of significant associations between neuroanatomic and neurocognitive variables. This may have been due to the relatively restricted ranges of hippocampal size or cognitive ability found in this sample.
T.E. Goldberg, and D.R. Weinberger
Schizophr Res 1994; 11:291-6.
The question of whether and to what extent poor performance on the Wisconsin Card Sorting Test (WCST) in patients with schizophrenia can be improved with coaching has been controversial. We review relevant studies with particular reference to the following issues: (1) can improvement occur? (2) if improvement does occur, what is its significance? and (3) what is the association between performance and neurophysiology? The studies indicate that in patients with schizophrenia performance can frequently be improved, but usually remains in the abnormal range. Similar results for memory measures have been reported in patients with amnesias or dementias of known neurological origin. This suggests that simple dichotomies between neurologic and psychological explanations of cognitive impairment and potential amelioration of such impairment may be inadequate. Comparisons of the results of studies using the WCST as a clinical tool with binary cut-off scores to define normal and abnormal, as a measure of neuropsychological function along a continuum, and as an activation stimulus to probe neurophysiology suggest that absolute WCST scores may not always accurately gauge the functional integrity of neural systems dedicated to the task. This situation may arise because of individual differences in endowment and in the capacity for neuronal compensation, as well as measurement error. Given these issues, caution is advised in the interpretation of WCST scores, which are best understood as representing a final common cognitive pathway that can be the product of diverse psychological, physiological, and neuroanatomic mechanisms.
T.E. Goldberg, and D.R. Weinberger
J Clin Psychiatry 1994; 55:88-90.
Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.
T.M. Hyde, H.A. Emsellem, C. Randolph, K.C. Rickler, and D.R. Weinberger
Br J Psychiatry 1994; 164:811-7.
The association of attentional, neuropsychological, and behavioural abnormalities with Tourette's syndrome (TS) suggests that the abnormal function of the disorder extends beyond the motor circuits of the basal ganglia. To explore this possibility we studied, with conventional 18-channel electroencephalography, monozygotic twins ranging from 8 to 26 years of age, where at least one member of the twin pair suffered from TS. In nine out of the 11 twin pairs that differed in clinical severity of the tic disorder, the twin with the more severe course of illness had a significantly more abnormal electroencephalogram (EEG) by qualitative visual analysis. Most of the differences were due to excessive frontocentral theta activity, suggesting dysfunction outside the basal ganglia. There was also a significant relationship between a lower global neuropsychological testing score and a worse overall EEG. In eight of nine twin sets with different global neuropsychological testing scores, the twin with the lower score had a worse EEG. A similar relationship was found between birth weight and overall EEG quality. In the nine sets that differed in birth weight, the twin with a lower birth weight had a worse EEG in seven of the sets. The EEG findings are unlikely to be unlikely to be a medication effect because the same result was seen in the six twin pairs who had been medication-free for at least six months before entry into the study. The origin of this slowing may relate to the interaction between environmental insults to the central nervous system and the genetic component of TS, an interaction producing damage to the cortex, thalamus, or both.
T.M. Hyde, S. Nawroz, T.E. Goldberg, L.B. Bigelow, D. Strong, J.L. Ostrem, et al.
Br J Psychiatry 1994; 164:494- 500.
The issue of progressive cognitive decline in patients with schizophrenia has been debated. We performed a cross-sectional study of patients with chronic schizophrenia, aged from 18 to 69 years, in order to address this issue. The patients included in this study passed a rigorous screen for any comorbid condition with an adverse impact on central nervous system function. We assessed intellectual deterioration with a battery of neuropsychological tests known to be sensitive to cognitive impairment in progressive dementia. No evidence of accelerated intellectual decline was found. No significant differences were found between the five age-derived cohorts (18-29, 30-39, 40-49, 50-59, and 60-69 years of age) on the Mini- Mental State Examination, Dementia Rating Scale, or other tests sensitive to dementia. While performance on the Boston Naming Test significantly declined with age, this was mainly due to age rather than duration of illness. However, it is important to note that mean performances on the majority of the tests were abnormal across all cohorts studied. These results suggest that intellectual function does not markedly decline during the adulthood of patients with schizophrenia. The course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder.
G.E. Jaskiw, D.M. Juliano, T.E. Goldberg, M. Hertzman, E. Urow- Hamell, and D.R. Weinberger
Schizophr Res 1994; 14:23-8.
Ten patients, who underwent computerized tomography (CT) study during evaluation for first episode schizophreniform psychosis were restudied an average of 7 years later. Of the 10 patients, 7 were found to carry a diagnosis of schizophrenia at follow-up. In this subgroup, there was no significant change in the mean ventricular brain ratio measure of cerebral ventricular size between the index and follow-up scans. These findings are consistent with the hypothesis that ventricular enlargement is present at the onset of schizophrenia and does not progress with duration of illness or treatment.
M.B. Knable, and D.R. Weinberger
J Clin Psychiatry 1994; 55:70-3.
The mechanisms of the antipsychotic efficacy and side effect profile of clozapine are incompletely understood. In vivo pharmacologic studies suggest that while clozapine does produce D2 receptor blockade, its unusual clinical profile may relate to activity at other receptor sites and to anatomical areas outside the striatum. Rodent studies indicate that acute administration of clinical doses of antipsychotic drugs, including clozapine, induces Fos (the protein product of the immediate early gene, c-fos) in the nucleus accumbens. However, unlike typical antipsychotic drugs, clozapine does not induce Fos in the dorsal striatum and does induce Fos in medial portions of the prefrontal cortex. Clozapine seems to produce a unique signature effect on long-term neuronal metabolism in its induction of Fos in the shell of the nucleus accumbens and in the medial prefrontal cortex. Future in vivo studies of cerebral blood flow and glucose metabolism in human patients may help to elucidate the specificity and reproducibility of the effects of clozapine in the ventral striatum and prefrontal cortex.
B.S. Kolachana, R.C. Saunders, and D.R. Weinberger
J Neurosci Methods 1994; 55:1-6.
A new method was developed to carry out in vivo microdialysis experiments repetitively and routinely within an individual monkey. We designed and built a dialysis probe guide and holding device ('guide holder') which permits accurate placement of dialysis probes into cortical (e.g., prefrontal, hippocampus, and parietal cortices) and subcortical target areas (e.g., caudate nucleus, amygdala, and nucleus accumbens) of the rhesus monkey brain without extensive and repetitive surgery needed to expose a desired brain region. The guide holder is positioned, using MRI- guided coordinates, and fixed to the skull over an intended targeted region. This design provides an opportunity to conduct several experiments in a single monkey over an extended period and permits placement of several probes accurately into 'fresh' or 'experienced' tissue during repeated microdialysis experiments. In addition, during repeated dialysis experiments tissue trauma is minimized because no surgical procedure is necessary on the day of dialysate collection. This procedure can be readily adapted for use with an awake monkey.
J.J. Kulynych, K. Vladar, D.W. Jones, and D.R. Weinberger
Cereb Cortex 1994; 4:107-18.
Gender differences in hemispheric asymmetry for language functioning have been reported in the neuropsychological literature. Despite numerous reports of anatomic asymmetries in corresponding cortical regions, the possibility of gender dimorphism in the putative neuroanatomical substrate of language has not been systematically examined in vivo. We assessed asymmetry of the planum temporale (PT), a supratemporal region of auditory association cortex, in 12 normal, right-handed females and 12 age- matched right-handed males with the aid of MRI surface-rendering morphometry. Bilateral areas were also assessed for Heschl's gyrus (HG), a supratemporal region of primary auditory cortex where no asymmetry was anticipated. We found a significant interaction between gender and hemisphere for the PT, with males having significantly larger left versus right PTs. Left-right differences in PT area were not significant among females (10 of 12 males showed leftward lateralization of the PT, vs 5 of 12 females). No main effect of gender was found for total (left + right) PT area, and no asymmetries or gender effects were detected for HG. This finding of gender dimorphism in PT area is consistent with evidence for reduced asymmetry among females in the lateralization of language functions attributable to the supratemporal cortex. The implications for theories about interactions between sex hormones and the development of brain asymmetries are discussed.
B.K. Lipska, G.E. Jaskiw, and D.R. Weinberger
Pharmacol Biochem Behav 1994; 48:1053-7.
The effects of excitotoxic damage to both the medial prefrontal cortex (MPFC) and the ventral hippocampus (VH) on behaviors related to mesolimbic/nigrostriatal dopamine (DA) transmission were investigated in the rat. Locomotor activity in a novel environment, after injection of saline, and after d-amphetamine was assessed 2 and 4 weeks after ibotenic acid lesion of both MPFC and VH in adult rats. In addition, stereotypic behaviors and locomotion after apomorphine were evaluated 8 weeks after the lesion. Locomotor activity was significantly enhanced in all testing conditions in lesioned rats as compared with sham- operated animals, while oral stereotypic behaviors elicited by apomorphine were attenuated possibly because they were eclipsed by excessive locomotion. These data indicate that coexisting lesions of the MPFC and VH in adult rats produce potent and long-lasting effects on behaviors believed to be dependent primarily on the mesolimbic DA system. The profile of changes resembles more closely that observed after excitotoxic lesions of the VH alone rather than that after separate MPFC lesion.
B.K. Lipska, and D.R. Weinberger
Brain Res Dev Brain Res 1994; 78:253-8.
To explore the possibility that gonadal hormones are required for triggering the postpubertal emergence of enhanced dopamine-related behaviors in rats with neonatal excitotoxic lesions of the ventral hippocampus (VH), we assessed behavioral changes in castrated VH lesioned rats. The VH of rat pups was lesioned with ibotenic acid on day 7 after birth (PD7). Rats were castrated on PD21. Novelty- and amphetamine-induced locomotor activity were tested on PD56, and apomorphine-induced stereotypic behaviors and locomotion were evaluated on PD98. As demonstrated previously, the VH lesioned rats expressed enhanced novelty-, amphetamine- and apomorphine-induced hyperlocomotion (PD56) as well as potentiated apomorphine-induced stereotypic behaviors (PD98) in young adulthood as compared with sham-lesioned counterparts. Castration had no significant effect on novelty-induced locomotion or apomorphine-induced stereotypies but potentiated amphetamine- and apomorphine-induced hyperactivity in lesioned rats. These results indicate that the absence of gonadal hormones not only does not prevent the appearance in adulthood of behavioral disturbances linked to increased DA transmission in rats with neonatal lesions of the VH but even exaggerates those linked primarily to the mesolimbic DA system.
B.K. Lipska, and D.R. Weinberger
Neuropsychopharmacology 1994; 10:199-205.
We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mg/kg, IP), or clozapine (CLOZ) (4 mg/kg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty- and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-lesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.
L. Marsh, R.L. Suddath, N. Higgins, and D.R. Weinberger
Schizophr Res 1994; 11:225-38.
Reductions in the size of medial temporal lobe structures in schizophrenia have been demonstrated using magnetic resonance imaging. It is not clear whether these neuropathological changes are present premorbidly or if they reflect an adult-onset progressive process. In this study, quantitative measures were made of the lateral ventricles, third ventricle, amygdala, hippocampus, and cerebral hemispheres from coronal MRI images on 33 patients with schizophrenia and 41 normal controls. Images were selected a priori from the region of the temporal lobe in which we had previously demonstrated reduced volume of temporal lobe gray matter in a separate sample of patients. Results showed a decrease in amygdala, hippocampal, and amygdala-hippocampal size bilaterally and an increase in third and lateral ventricular volume. Advancing age in normals was associated with a decrease in the size of medial temporal structures and an increase in lateral ventricular size. In schizophrenia, there was a correlation between age and lateral ventricle size, but duration of illness was not associated with reductions in medial temporal tissue or ventricular enlargement. These results are consistent with prior evidence from neuroimaging and postmortem studies of medial temporal pathology in schizophrenia and support hypotheses that neuropathological changes in schizophrenia are not progressive.
C.T. Moonen, F.A. Barrios, J.R. Zigun, J. Gillen, G. Liu, G. Sobering, et al.
Magn Reson Imaging 1994; 12:379-85.
Dynamic physiological scanning, based on temporary changes in local field homogeneity during the passage of a contrast agent bolus, has been performed hitherto with echo-planar imaging (EPI) or conventional gradient- recalled techniques (FLASH). Here, it is shown that the T2* sensitivity of conventional FLASH techniques can be improved drastically on a conventional whole body instrument by delaying the gradient-echo until the subsequent TR- period without increasing total imaging time. Examples are given for a full k- space matrix (128 x 256) obtained within 2 s with a TE of 25 ms, resulting in images free of artifacts. The method is applied to bolus tracking through the brain of healthy volunteers during visual stimulation and in the dark. An average increase of regional cerebral blood volume (rCBV) in the visual cortex of 10.9% (n = 9, p = .001) was found.
B.F. Roy, C. Benkelfat, J.L. Hill, P.F. Pierce, M.M. Dauphin, T.M. Kelly, et al.
Biol Psychiatry 1994; 35:335-44.
Patients with obsessive-compulsive disorder (OCD) demonstrated significant levels of antibody for somatostatin-28, its C-terminal fragment somatostatin-14, and prodynorphin. In contrast there were lower levels of reactivity for somatostatin-28(1-14) (the N-terminal fragment of somatostatin-28) and negligible reactivity for several other peptides including beta-endorphin and corticotropin. Healthy volunteers and disease controls [schizophrenia, Alzheimer's disease, multiple sclerosis, and subjects with advanced human immunodeficiency virus (HIV) infection] exhibited negligible reactivity. These data raise the consideration of an autoimmune mechanism for some OCD.
R.C. Saunders, B.S. Kolachana, and D.R. Weinberger
Exp Brain Res 1994; 98:44-52.
The prefrontal cortex, caudate nucleus, and their dopaminergic innervations have been implicated in complex information processing. The present study utilized the in vivo microdialysis technique to characterize the extracellular dopamine levels in the prefrontal cortex and the caudate nucleus in the rhesus monkey. Basal levels of dopamine were consistently found in the caudate nucleus, while levels in the prefrontal cortex were less reliably measured. Manipulation of dopamine levels using tetrodotoxin and high potassium demonstrated that dopamine measured was dependent on neuronal firing. Administration of indirect dopamine agonists d- amphetamine and cocaine into the prefrontal cortex and the caudate nucleus increased extracellular dopamine levels 250% and 5000%, respectively. Amphetamine and cocaine had greater effects on dopamine levels in the caudate than in the prefrontal cortex. Cocaine induced increases appeared to be less than that of amphetamine and the actions of cocaine lasted longer than amphetamine. This study demonstrates the feasibility of using in vivo microdialysis in monitoring neurochemicals in different regions of the rhesus monkey brain.
D.R. Weinberger, M.S. Aloia, T.E. Goldberg, and K.F. Berman
J Neuropsychiatry Clin Neurosci 1994; 6:419-27.
Many patients with schizophrenia show clinical signs of frontal lobe dysfunction, including blunted affect, difficulty with problem solving, and impoverished thinking. The authors present cytoarchitectural, neuropsychological, and functional neuroanatomical evidence of frontal abnormalities from recent studies of frontal dysfunction in schizophrenia. It is suggested that the failure of intracortical connectivity of the prefrontal cortex accounts for both cognitive and psychotic manifestations of this illness.
S.S. Wolf, T.M. Hyde, T.W. Moody, R.C. Saunders, D.R. Weinberger, and J.E. Kleinman
Brain Res Bull 1994; 35:353-8.
The laminar and rostro-caudal distribution of 125I-neurotensin binding sites is described in human entorhinal cortex using quantitative autoradiography. Specific binding was most prominent over the cell clusters of layer II of the entorhinal cortex throughout its rostro-caudal extent. Dense binding was also observed in the adjacent presubiculum and cortical amygdaloid transition area, whereas minimal binding was detected in the hippocampus and dentate gyrus. 125I- Neurotensin may serve as a selective probe for neurotensin receptor alterations and layer II-specific cytoarchitectural disturbances in the entorhinal cortex in neuropsychiatric diseases associated with abnormalities of the mesial temporal lobe.
S.S. Wolf, T.M. Hyde, and D.R. Weinberger
J Psychiatry Neurosci 1994; 19:140-4.
Two patients with schizophrenia had markedly abnormal neuroimaging studies; one was found to have a large, cystic cavum vergae, while the other demonstrated complete agenesis of the septum pellucidum with a monoventricular system. The increased prevalence of developmental abnormalities of midline forebrain structure in patients with schizophrenia suggests that dysgenesis of these structures may be contributory to the neurobiology of schizophrenia and other psychotic disorders.
A. Abi-Dargham, M. Laruelle, B. Lipska, G.E. Jaskiw, D.T. Wong, D.W. Robertson, et al.
Brain Res 1993; 616:53-7.
Alterations in density of some serotonin receptor sites (5-HT1A receptors, 5-HT2 receptors and 5-HT uptake sites) have been reported in postmortem studies of brain obtained from subjects with schizophrenia, suggesting a disturbance in serotonergic transmission in schizophrenia. The purpose of the present study is to investigate [3H]- LY278584 binding to serotonin 5-HT3 receptors in postmortem samples of amygdala from schizophrenic and matched control subjects. As all of the schizophrenic patients but none of the controls had been treated with neuroleptics, we first investigated in rodents the effects of short-term and long- term haloperidol administration on limbic 5-HT3 receptors, and we found no effects. No differences in the maximum number of 5-HT3 binding sites (Bmax) or equilibrium dissociation constant (Kd) between schizophrenics and controls were found in amygdala. This study does not support the presence of an alteration of 5-HT3 receptors in amygdala in schizophrenic patients.
A.J. Bartley, D.W. Jones, E.F. Torrey, J.R. Zigun, and D.R. Weinberger
Biol Psychiatry 1993; 34:853-63.
To address prior reports that schizophrenia is associated with loss of normal brain asymmetry and that it might be linked to a defect of a gene controlling cerebral lateralization, we measured on three-dimensional cortical renderings from magnetic resonance imaging (MRI) scans the lengths and angles of the sylvian fissures in 10 normal monozygotic (MZ) twin pairs (n = 10 pairs) and in 10 MZ pairs discordant for schizophrenia (n = 10 pairs). We confirmed in both sets of twins the expected normal asymmetries of length and angle of the sylvian fissure. We also confirmed that the length asymmetry occurs solely in the region of the planum temporale. In the discordant twins, affected and unaffected twins did not differ in asymmetry measures, thus failing to support an association between illness per se and diminished asymmetry. Moreover, the discordant twins as a group did not differ from the normal twins as a group, thus failing to confirm the hypothesis of a genetic association with abnormal asymmetry. The implications of variations in methodology and patient samples are discussed.
A.R. Braun, G.E. Jaskiw, K. Vladar, R.H. Sexton, B.S. Kolachana, and D.R. Weinberger
Pharmacol Biochem Behav 1993; 46:51-60.
Behavioral responses to apomorphine and to the selective D1 and D2 dopamine receptor agonists SK&F38393 and quinpirole were evaluated in rats following ibotenic acid (IA) or sham lesion of the medial prefrontal cortex (MPFC). IA-lesioned rats showed an increased responsiveness to the postsynaptic effects of all of the dopamine agonists. Patterns of the responses to the selective agonists administered alone and in combination suggest that these effects might be due to selective increases in the sensitivity of postsynaptic D1 receptor-associated mechanisms. In addition, IA-lesioned rats pretreated with saline were hyperactive in comparison to sham- lesioned rats when animals were exposed to a novel open field, but spontaneous motor activity did not differ between these two groups when animals were pretreated with low doses (0.03 mg/kg) of quinpirole. The fact that hyperreactivity observed in lesioned animals is inhibited by a dose of quinpirole that is felt to act presynaptically, selectively attenuating endogenous dopaminergic tone, suggests that effects of the MPFC lesion may be mediated presynaptically as well.
M.F. Casanova, N.W. Carosella, J.M. Gold, J.E. Kleinman, D.R. Weinberger, and R.E. Powers
Psychiatry Res 1993; 49:41-62.
Neuropsychological testing of elderly schizophrenic patients reveals that a significant portion of this population exhibit varying degrees of cognitive impairment. Since Alzheimer's disease is the most common cause of dementia in geriatric patients, we investigated whether the cognitive decline observed in schizophrenia is the result of degenerative changes analogous to those characteristic of Alzheimer's disease. For this purpose, the number and distribution of senile plaques and neurofibrillary tangles were mapped in the hippocampi of 10 cognitively impaired schizophrenic patients, 10 patients with Alzheimer's disease, and 10 patients with dementia not attributed to either schizophrenia or Alzheimer's disease. In Alzheimer's disease, degenerative changes invariably predominated in the CA1 subfield, subiculum, and proisocortex. By contrast, findings characteristic of Alzheimer's disease were virtually never observed in the hippocampi of schizophrenic and other cognitively impaired patients. In some patients with Alzheimer's disease, the presence of senile plaques in the molecular layer of the dentate gyrus suggested the existence of an underlying entorhinal cortex lesion. Similar dentate gyrus pathology was never found in any of the other patients. The authors conclude that cognitive impairment in schizophrenia is not the result of degenerative changes analogous to those found in Alzheimer's disease.
T.E. Goldberg, J.M. Gold, R. Greenberg, S. Griffin, S.C. Schulz, D. Pickar, et al.
Am J Psychiatry 1993; 150:1355-62.
OBJECTIVE: This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. METHOD: Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N = 57), unipolar depression (N = 29), and bipolar disorder (N = 16). RESULTS: The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test--Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. CONCLUSIONS: These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.
T.E. Goldberg, T.M. Hyde, J.E. Kleinman, and D.R. Weinberger
Schizophr Bull 1993; 19:797-804.
The course of cognitive function in schizophrenia has often been debated. In one view, it is thought to be akin to that of a progressive dementia with relentless cognitive decline. In another view, the deficits are thought to remain relatively stable, analogous to those of a static encephalopathy. Review of longitudinal and cross-sectional studies strongly supports the latter interpretation. In particular, we present data from a recent cross-sectional study in which cohorts of patients in their third, fourth, fifth, sixth, and seventh decades of life were administered a battery of tests known to be sensitive to progressive dementing diseases. All patients were carefully screened to exclude those with neurologic, systemic, or psychiatric comorbid conditions, and cohorts were matched on estimated premorbid intellectual capacity. Although scores on most tests were impaired, no evidence of decline across groups was observed. These results are also consistent with neuroimaging and neuropathological studies in that no evidence for an active degenerative process has been discovered.
J.J. Kulynych, K. Vladar, D.W. Jones, and D.R. Weinberger
J Comput Assist Tomogr 1993; 17:529-35.
OBJECTIVE: The emergence of methodologies for accurately rendering cortical surfaces suggests possible quantitative applications of surface rendering to morphometry of the cerebral cortex. We examined this novel use of surface renderings in a study of the planum temporale, a neuroanatomical structure exhibiting well-documented normal asymmetry previously visible only in postmortem studies. MATERIALS AND METHODS: With the aid of three-dimensional renderings of the supratemporal cortex, the area of the planum temporal was analyzed in the volume MRIs of seven normal, strongly right-handed males. RESULTS: In comparison with areas derived from conventional measurements of serial MRI sections, planum temporale areas derived from supratemporal surface renderings offered far greater interrater reliability, and presumably improved validity as reflected by more consistent evidence of the anticipated planum asymmetry. CONCLUSION: Morphometry of the supratemporal cortex is enhanced by the use of three-dimensional surface renderings. Application of surface-rendering techniques to morphometry of other cortical regions is discussed.
M. Laruelle, A. Abi-Dargham, M.F. Casanova, R. Toti, D.R. Weinberger, and J.E. Kleinman
Arch Gen Psychiatry 1993; 50:810-8.
BACKGROUND: This study investigates serotonergic receptors in prefrontal cortex of patients with schizophrenia. METHODS: We measured serotonin 2 receptors and serotonin uptake sites in prefrontal and occipital cortex of schizophrenics, patients with chronic schizoaffective disorders, nonpsychotic suicides, and controls. Diagnoses were established according to DSM-III-R criteria from medical chart reviews. RESULTS: In prefrontal cortex, serotonin 2 density was decreased in chronic psychotics dying of natural causes, as opposed to psychotics dying of suicide, controls, and nonpsychotic suicide victims. Serotonin uptake sites were decreased in prefrontal cortex of schizophrenics and nonpsychotic suicides, but not in patients with schizoaffective disorder. None of the observed differences were clearly related to antemortem pharmacological treatments. In the occipital pole, no differences were found among the groups. CONCLUSIONS: Selective prefrontal alterations of both presynaptic and postsynaptic serotonin receptor densities are present in at least some schizophrenic patients.
B.K. Lipska, G.E. Jaskiw, and D.R. Weinberger
Neuropsychopharmacology 1993; 9:67-75.
The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implications of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.
B.K. Lipska, and D.R. Weinberger
Brain Res Dev Brain Res 1993; 75:213-22.
The developmental effects of neonatal excitotoxic ventral hippocampal (VH) damage on behaviors related to dopaminergic (DA) transmission in the basal ganglia were investigated in the rat. Ibotenic acid (in Lesion) or artificial cerebrospinal fluid (in Sham) was infused into the VH of 7-day-old (PD7) rat pups. Haloperidol-induced (1 mg/kg, i.p.) catalepsy and apomorphine-induced (0.75 mg/kg, s.c.) stereotypic behaviors as well as locomotion were assessed in Sham and Lesion rats prior to (PD35) and after puberty (PD56). On PD35, Lesion and Sham animals did not differ in induced catalepsy or stereotypy. On PD56, however, Lesion animals were less cataleptic following haloperidol injection and manifested supersensitivity to apomorphine as compared to Sham rats. At both, PD35 and PD56, locomotor activity after apomorphine was significantly increased in Lesion animals as compared with controls. These results indicate that the neonatal excitotoxic VH lesion results in a unique time- dependent pattern of behavioral changes related to striatal DA transmission. Moreover, the response to apomorphine differs qualitatively from that previously reported after the analogous lesion induced in adult animals in which stereotypy was reduced. These findings suggest that early hippocampal deafferentation affects the development of other brain regions, such as the medial prefrontal cortex, that are also involved in the regulation of striatal DA function.
S. Marenco, R. Coppola, D.G. Daniel, J.R. Zigun, and D.R. Weinberger
Psychiatry Res 1993; 50:177-92.
We studied regional cerebral blood flow (rCBF) by xenon-133 dynamic single photon emission computed tomography (SPECT) in 17 normal volunteers who were performing the Wisconsin Card Sorting Test (WCST), a task that is particularly sensitive to disturbance of the prefrontal cortex, and a simple matching-to-sample task (BAR) as a sensorimotor control. Three methods for statistical analysis of regional subtraction data were used: absolute rCBF values, percent distribution values, and means adjusted for global CBF changes (covariance analysis). The absolute values had high variance, due to the combination of interindividual differences in global flow and intra-individual variation, and showed no statistically significant regional changes. This variation was greatly reduced by percent values and covariance analysis, which had quite similar outcomes. With both methods, significant increases of rCBF during the WCST as compared with the BAR were seen in the right anterior dorsolateral prefrontal and left occipital cortices, and reduction of rCBF in the left pararolandic region. Moreover, significant correlations with performance were found in the medial regions of the frontal lobes, with opposite trends for the right and left hemisphere. The posterior dorsolateral prefrontal region showed a negative correlation with sensory-motor frequency, an index related to the task's difficulty. These results are consistent with previous findings using other rCBF techniques and confirm the statistical advantage of normalization and covariance methods, which yield practically identical results, at least in this analysis based on regions of interest.
C. Randolph, J.M. Gold, C.J. Carpenter, T.E. Goldberg, and D.R. Weinberger
J Clin Exp Neuropsychol 1993; 15:853-66.
Two experiments employing a stem-completion priming paradigm are reported. The first of these compared patients with schizophrenia (SC) to normal controls and demonstrated impaired implicit memory in the SC patients under task conditions identical to those used previously with other patient groups. The second experiment was designed to examine the effects of implicit task demands and stimulus selection upon susceptibility to priming, with a second group of SC patients and normal controls. Results indicated that the ability to carry out the task demands of the implicit condition (i.e., generate completions for word-stems) was inversely related to susceptibility to priming in both the SC patients and controls. In addition, the baseline probability of specific completions was found to be correlated with the ease of priming those completions, suggesting a possible mechanism for producing statistical dissociations between implicit and explicit retrieval conditions with this paradigm. These findings suggest that certain implicit tasks may be susceptible to nonmemory psychological influences that have not been adequately investigated to date; these may be responsible for normalizing the performance of amnesic patients as well as producing statistical dissociations from explicit memory tasks.
C. Randolph, T.M. Hyde, J.M. Gold, T.E. Goldberg, and D.R. Weinberger
Arch Neurol 1993; 50:725-8.
OBJECTIVE--To determine whether there is a relationship between tic severity and neuropsychological function in Tourette's syndrome (TS). DESIGN--The study employed a case-control series involving monozygotic twin pairs, divided into more severe and less severe groups based on tic severity and tested with a neuropsychological battery of tests. SETTING--Twin pairs were recruited nationwide and evaluated in the National Institute of Mental Health Neuropsychiatric Research Hospital. PATIENTS--Twelve twin pairs (mean age, 10.5 years; range, 8 to 16 years) in which at least one member met criteria for a diagnosis of TS. RESULTS--Global neuropsychological performance was significantly worse in the twins with more severe tic symptoms, with significant differences emerging on individual tests of attention, visuospatial perception, and motor function. In each twin pair, the twin with more severe tics had poorer global neuropsychological function. CONCLUSIONS--The results suggest that the nongenetic factors that influence tic severity in TS exert a similar effect on neuropsychological function, and that these two clinical manifestations of TS may share a common pathophysiologic state.
D.R. Weinberger
J Neuropsychiatry Clin Neurosci 1993; 5:241-53.
Recent data from studies of the prefrontal cortex (PFC) in humans and laboratory animals are reviewed with particular reference to the anatomical substrates of prefrontal neuropsychological function in health and disease. The PFC has been shown to have a unique pattern of supramodal connectivity with intracortical and subcortical circuits that place the PFC in an anatomical position to subserve executive cognitive functions and modulate limbic information to relate to basal ganglia circuits in a highly specific manner and to uniquely control the neurochemical elements of attention and reward. PFC connectivity is also consistent with current hypotheses about prefrontal neuropsychology, which emphasize conscious, goal-directed behavior guided by past experience. PFC connectivity explains the frequency with which prefrontal dysfunction is seen in disease states, which, on the basis of neuroimaging and neuropathology data, can be categorized as either intrinsic or dysconnection disorders.
D.R. Weinberger
J Clin Psychiatry 1993; 54:3-5.
Positron emission tomography (PET) and single photon emission computed tomography (SPECT) use advanced computer image construction techniques to illustrate regional cerebral function, metabolism, and chemistry. Although the resolution of PET is higher than that of SPECT, and the technical development of SPECT has lagged behind that of PET, SPECT has recently enjoyed increasingly widespread use, particularly because its costs and technology are within the reach of all clinical nuclear medicine facilities. SPECT imaging agents have greater half-lives than those used with PET, thereby permitting longer and more detailed neurochemistry study than is possible with PET. The research value of both methods has unique potential compared with computed tomography (CT) and magnetic resonance imaging (MRI), which traditionally have provided a static image of the brain's structure or anatomy.
K.F. Berman, E.F. Torrey, D.G. Daniel, and D.R. Weinberger
Arch Gen Psychiatry 1992; 49:927-34.
We addressed several questions regarding hypofunction of the prefrontal cortex (hypofrontality) in schizophrenia by measuring regional cerebral blood flow during three different cognitive conditions in monozygotic twins who were discordant or concordant for schizophrenia or who were both normal. These questions included the prevalence of hypofrontality, the importance of genetic predisposition, and the role of long-term neuroleptic treatment. Significant differences between affected and unaffected discordant twins were found only during a task linked to the prefrontal cortex, the Wisconsin Card Sorting Test. During this condition, all of the twins with schizophrenia were hypofrontal compared with their unaffected co-twins, suggesting that, if appropriate cognitive conditions and control groups are used, hypofrontality can be demonstrated in the majority of, if not all, patients with schizophrenia. When unaffected co-twins of patients with schizophrenia were compared with twins who were both normal, no differences were observed, suggesting that nongenetic factors are important in the cause of the prefrontal physiologic deficit that appears to characterize schizophrenia. When concordant twins with a high- vs a low-dose lifetime history of neuroleptic treatment were compared, the twin receiving the higher dose was more hyperfrontal in six of eight pairs, suggesting that long-term neuroleptic treatment does not play a major role in hypofrontality.
A. Abi-Dargham, G. Jaskiw, R.L. Suddath, and D.R. Weinberger
Schizophr Res 1991; 5:210.
D.G. Daniel, T.E. Goldberg, R.D. Gibbons, and D.R. Weinberger
Biol Psychiatry 1991; 30:887-903.
The finding of clinical and laboratory differences between schizophrenic patients with large and small cerebral ventricles has led to the widespread assumption that large ventricles are a marker that characterizes a subgroup of patients with schizophrenia. We reviewed all published English language ventricle-to-brain ratio (VBR) studies in which individual data points were available (schizophrenics: n = 691, medical controls; n = 205, normal volunteers: n = 160). Using a univariate normal mixture model to examine the distribution of ventricular size in each group, we found no evidence of a mixture of Gaussian distributions (i.e., bimodality) within any of the three groups. The same analysis was then performed on the combined sample of schizophrenic patients and normal and medical controls, respectively. In each case the improvement in fit of a mixture of normal distributions compared to a single component normal distribution was significant. The data do not support the notion that ventricular enlargement is a discontinuous marker of a subtype of schizophrenia.
D.G. Daniel, E. Kim, D. Kostianovsky, T.E. Goldberg, M.F. Casanova, D. Pickar, et al.
Biol Psychiatry 1991; 29:745-56.
Although previous studies have reported differences in computed tomography (CT) scan attenuation values between patients with schizophrenia and controls, interpretation of these findings has been hindered by methodological shortcomings such as the failure to control for head size, scanner calibration differences, and other confounding variables. In the present study of CT attenuation values in multiple brain regions in 20 patients with chronic schizophrenia and an equal number of age- and sex- matched normal subjects we controlled for head size and normalized the attenuation values for each scan to an internal standard. No significant differences emerged between the patients with schizophrenia and the controls. However, in the controls only, the mean density of white matter in the left frontal area was significantly higher (t = -2.83, p = 0.01) than that in the right. The results, although possibly suggestive of deviant lateralization in schizophrenia, raise questions about the sensitivity and validity of regional CT attenuation values in detecting subtle anatomic abnormalities in patients with this illness.
D.G. Daniel, D.R. Weinberger, D.W. Jones, J.R. Zigun, R. Coppola, S. Handel, et al.
J Neurosci 1991; 11:1907-17.
To explore the role of monoamines on cerebral function during specific prefrontal cognitive activation, we conducted a double-blind placebo-controlled crossover study of the effects of 0.25 mg/kg oral dextroamphetamine on regional cerebral blood flow (rCBF) as determined by 133Xe dynamic single-photon emission- computed tomography (SPECT) during performance of the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task. Ten patients with chronic schizophrenia who had been stabilized for at least 6 weeks on 0.4 mg/kg haloperidol participated. Amphetamine produced a modest, nonsignificant, task-independent, global reduction in rCBF. However, the effect of amphetamine on task-dependent activation of rCBF (i.e., WCST minus control task) was striking. Whereas on placebo no significant activation of rCBF was seen during the WCST compared with the control task, on amphetamine significant activation of the left dorsolateral prefrontal cortex (DLPFC) occurred (p = 0.0006). Both the mean number of correct responses and the mean conceptual level increased (p less than 0.05) with amphetamine relative to placebo. In addition, with amphetamine, but not with placebo, a significant correlation (p = -0.71; p less than 0.05) emerged between activation of DLPFC rCBF and performance of the WCST task. These findings are consistent with animal models in which mesocortical catecholaminergic activity modulates and enhances the signal-to-noise ratio of evoked cortical activity.
T.E. Goldberg, L.B. Bigelow, D.R. Weinberger, D.G. Daniel, and J.E. Kleinman
Am J Psychiatry 1991; 148:78-84.
OBJECTIVE: The authors sought to determine if an acute dose of dextroamphetamine might have positive effects on affect and cognition in schizophrenic patients maintained on a regimen of haloperidol and, if so, what variables might predict such improvements. METHOD: Twenty-one patients with chronic schizophrenia who were hospitalized on a research ward received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind, placebo- controlled, crossover study. All patients were receiving 0.4 mg/kg per day of haloperidol. Cognitive tests, motor tests, global ratings, mood ratings, and videotape ratings were used to determine the effect of the coadministration of these drugs. Ventricle-brain ratios derived from CT scans were used to predict response to the coadministration of these drugs. RESULTS: Amphetamine improved performance on a measure of concept formation on the Wisconsin Card Sorting Test but did not result in changes in performance on tests of memory or attention. As a group, the patients were more active and performed psychomotor tests more quickly while receiving amphetamine. Six patients were judged by clinical raters to have improved in terms of affect, cooperation, and engagement with the environment. Improvement was associated with enlarged cerebral ventricles and increases in blink rate from the placebo to the active drug condition. No patient unequivocally worsened. CONCLUSIONS: These results may be consistent with the theory that coadministration of amphetamine and haloperidol produces relatively selective enhancement of cortical dopaminergic activity. However, because of the acute nature of the trial and the specialized research environment in which it was conducted, the authors do not advocate amphetamine as a routine clinical treatment of schizophrenia.
G.E. Jaskiw, D.R. Weinberger, and J.N. Crawley
Biol Psychiatry 1991; 29:703-6.
M. Laruelle, A. Sidhu, M.F. Casanova, D.R. Weinberger, and J.E. Kleinman
Neurosci Lett 1991; 131:273-6.
We studied binding of [125I]SCH 23982 in two regions of human brain, the caudate and the dorsolateral prefrontal cortex. Binding characteristics of [125I]SCH 23982 and of the non-iodinated tritiated analogue, [3H]SCH 23390, were compared. In caudate, binding of [125I]SCH 23982 was consistent with binding to D1 dopamine receptors while in frontal cortex, [125I]SCH 23982 bound mostly to serotonergic 5HT2 receptors. In contrast to [3H]SCH 23390, no evidence of binding of [125I]SCH 23982 to D1 receptors could be found in human frontal cortex. This indicates that iodination of SCH 23390 induces a decrease in its relative D1 versus 5HT2 selectivity that prohibits the use of [125I]SCH 23982 to label D1 receptors in human cortex.
B.K. Lipska, G.E. Jaskiw, F. Karoum, I. Phillips, J.E. Kleinman, and D.R. Weinberger
Pharmacol Biochem Behav 1991; 40:181-4.
To determine the influence of intrinsic neurons of the dorsal hippocampus on dopamine (DA) turnover in other limbic areas, DA and its metabolites were assayed in several brain areas 14 and 28 days after bilateral ibotenic acid (IA) lesions of the dorsal hippocampus in the rat. The locomotor response to d-amphetamine was also assessed. Spontaneous locomotion was increased 14 but not 28 days postoperatively. There was no change in d-amphetamine-induced locomotion at any time. Presynaptic indices of DA turnover in the medial prefrontal cortex, anteromedial striatum and nucleus accumbens were not affected by the lesion. Unlike lesions of the medial prefrontal cortex, deefferentation of the dorsal hippocampus does not increase DA turnover in the basal ganglia.
B.K. Lipska, G.E. Jaskiw, and D.R. Weinberger
Pharmacol Biochem Behav 1991; 40:169-72.
The effects of the anxiogenic beta-carboline FG-7142 (15 mg/kg IP) on exploratory locomotor activity were assessed in rats with sham or ibotenic acid (IA) lesions of the dorsal or ventral hippocampus. FG-7142 reduced exploratory activity similarly in control animals as well as in those with IA lesions of the ventral hippocampus. In contrast, FG-7142 had no effect on rats with dorsal hippocampal lesions. The results suggest that the dorsal hippocampus plays a unique role in FG-7142-mediated attenuation of locomotor exploration. Other studies suggest that serotonergic systems may mediate these properties of FG-7142.
M.S. Myslobodsky, R. Coppola, and D.R. Weinberger
Brain Topogr 1991; 3:381-90.
Bilateral EEG recording is a common practice when brain laterality needs to be assessed in cognitive neurophysiology and psychiatry research. Its precision and validity remain uncertain. With structural brain imaging methods, it is possible to examine EEG electrode placements according to the 10-20 system and the validity of inferences made on derived data. Frequent sources of placement errors are examined along with important factors that contribute to EEG imbalance. Examples are mentioned where asymmetries of EEG/ERP caused by cranial and parenchymal brain asymmetries may be mistaken for cognition- related laterality changes. Because external skull landmarks are not reliable predictors of cranial and parenchymal brain asymmetries, laterality assessment cannot be guaranteed by the 10-20 system. Consequently, a return, on a case- to-case basis, to nonstandard montages, assisted by structural brain imaging is seen as an acceptable alternative.
M.S. Myslobodsky, J. Glicksohn, R. Coppola, and D.R. Weinberger
Vision Res 1991; 31:1677-85.
The topography of visual evoked potentials (VEP) is dependent on occipital lobe morphology. Using magnetic resonance imaging we examine the sulcal pattern (the calcarine and parieto-occipital sulci), and assess the size of the cuneus and the asymmetry of the occipital lobes, computed separately for its ventral and dorsal segments. No differences were found for either the cuneus or the sulci pattern. In contrast, hemispheric asymmetry values appeared to be substantial. The predominance of the left occipital area was seen distinctly in the ventro-caudal portion of the occipital lobe. It was frequently reversed in the dorsal aspect of the lobe, notably in more rostral cuts. Such complexities may lead to ambiguities in interpreting VEP asymmetries.
D.R. Weinberger
Biol Psychiatry 1991; 29:509-11.
D.R. Weinberger, R. Gibson, R. Coppola, D.W. Jones, S. Molchan, T. Sunderland, et al.
Arch Neurol 1991; 48:169-76.
A high-affinity muscarinic receptor antagonist, 123IQNB (3- quinuclidinyl-4-iodobenzilate labeled with iodine 123), was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High- resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects, the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain, having high radioactivity counts in the basal ganglia, occipital cortex, and insular cortex, low counts in the thalamus, and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease, but further studies are needed to address questions about partial volume artifacts and receptor quantification.
D.R. Weinberger, R.L. Suddath, M.F. Casanova, E.F. Torrey, and J.E. Kleinman
Arch Gen Psychiatry 1991; 48:85-7.
K.F. Berman, and D.R. Weinberger
Prog Brain Res 1990; 85:521-36.
K.F. Berman, and D.R. Weinberger
J Neurol Neurosurg Psychiatry 1990; 53:150-60.
To assess cognitively-related regional asymmetries of brain function, regional cerebral blood flow (rCBF) was determined by the xenon inhalation method while normal subjects performed 10 different tasks and also while they were at rest. In addition to healthy subjects, patients with schizophrenia were also studied. A total of 447 rCBF studies were carried out during the following conditions: the Wisconsin Card Sort Test, a numbers matching test, a symbols matching test, Raven's Progressive Matrices, an auditory discrimination test, an auditory control task, two versions of a visual continuous performance task, line orientation, semantic classification, and resting. On the whole, those tasks that seem to require or allow for internal verbalisation resulted in the greatest activation of the left hemisphere compared with the right; right hemisphere activation predominated only in the two tasks primarily involving attention and vigilance. Furthermore, a consistent regional topography of normal cerebral functional laterality was seen: under most conditions left prefrontal cortical activity exceeded that of right prefrontal cortex; during all non-auditory tasks, parieto-occipital cortical activity had an opposite pattern-greater right than left. During most conditions the schizophrenic patients displayed the same pattern. While several cognitively specific between-group differences were found, no single cortical region was consistently implicated and no specific direction of abnormal asymmetry predominated. These data suggest that there is a predominant task-independent functional pattern of cortical activity emphasising relatively greater left anterior and right posterior activation. This pattern may reflect the verbal and attentional primacy of these areas, respectively.
M.F. Casanova, T.E. Goldberg, R.L. Suddath, D.G. Daniel, R. Rawlings, D.G. Lloyd, et al.
J Neuropsychiatry Clin Neurosci 1990; 2:363-72.
In a recent quantitative neuroimaging study, the authors reported significant reduction in the gray matter volume of both temporal lobes of schizophrenic (SC) patients. In order to better elucidate the nature of this finding (i.e., diffuse vs. focal), we analyzed the shape of the temporal lobes of 17 SC patients and an equal number of age-sex matched controls. Our shape analysis was able to discriminate between a significant number of SC and control patients based on the Fourier harmonic amplitudes of both the middle and posterior levels of the temporal lobes. These results are consistent with bilateral focal or multifocal distortions of the temporal lobes of SC patients. A similar shape analysis of the prefrontal lobes showed no significant conformational differences between the groups. The basis of this quantitative shape analysis (the Fourier expansion series) and the method by which it can be applied are explained in detail.
M.F. Casanova, C.M. Prasad, I. Waldman, B. Illowsky, B. Stein, D.R. Weinberger, et al.
Biol Psychiatry 1990; 27:138-42.
The role of iron in schizophrenia (SC) has aroused attention because of its modulatory effect on the dopamine receptor and its role as a cofactor for tyrosine hydroxylase. In addition, several postmortem studies suggest that increased mineralization (especially iron) of the basal ganglia is a possible clinicopathological correlate of schizophrenia. In order to quantitate the in vivo mineral content in the basal ganglia of patients with SC, a protocol was developed to analyze CT scans films with a LOATS computer analysis system. A total of 725 consecutive CT scans (275 SC, 450 nonSC) from a psychiatric population were reviewed. Eighteen scans (2.3%) revealed basal ganglia mineralization of which 7 cases carried a diagnosis of SC and 11 had other psychiatric disorders. All subjects had received neuroleptics, and 8 of the 11 patients in the nonschizophrenic group were demented. Both the SC and nonSC patients exhibited a prevalence (2.5%) of basal ganglia mineralization similar to that found in a postmortem series of the general population.
M.F. Casanova, R.D. Sanders, T.E. Goldberg, L.B. Bigelow, G. Christison, E.F. Torrey, et al.
J Neurol Neurosurg Psychiatry 1990; 53:416-21.
The corpus callosum (CC) has been the focus of several morphometric studies of patients with schizophrenia, but the results of these studies have been contradictory. In an attempt to improve the reliability of morphometric measurements of the corpus callosum, a computerised image analysis system was used to measure the shape, area, thickness and length of the CC on magnetic resonance imaging (MRI) in 12 pairs of monozygotic twins discordant for schizophrenia (SC). No differences in CC area (anterior, middle, posterior thirds and total), length or vertical thickness of the CC body (at three levels) were demonstrated by t test comparisons of the affected SC and unaffected twins. Statistical analysis of a Fourier expansion series suggested differences in shape between normal and SC cotwins in the second harmonic of the anterior and middle segments and effects of gender on posterior CC shape. These results fail to replicate previous findings of altered length, thickness and area in the schizophrenic CC, but implicate disease- related shape differences in the anterior and middle segment of the corpus callosum and gender-related differences in splenium shape. The disease- related shape distortion suggest ventriculomegaly rather than an intrinsic abnormality of the corpus callosum.
M.F. Casanova, M. Zito, T. Goldberg, A. Abi-Dargham, R. Sanders, L.B. Bigelow, et al.
Schizophr Res 1990; 3:155-6.
M.F. Casanova, M. Zito, T.E. Goldberg, R.L. Suddath, E.F. Torrey, L.B. Bigelow, et al.
Biol Psychiatry 1990; 28:83-4.
T.E. Goldberg, K.F. Berman, E. Mohr, and D.R. Weinberger
Arch Neurol 1990; 47:418-22.
Matching patients with etiologically distinct but clinically overlapping cognitive disorders on performance of a regionally specific neuropsychological task is a novel and potentially powerful approach to highlighting differences in the pathophysiological mechanisms of impaired cognition. We used this strategy to compare patients with Huntington's disease (HD) and schizophrenia (SC), disorders that share similarities in cognitive impairment. Patients were matched on the basis of performance on the Wisconsin Card Sorting test of prefrontal function, after which neuropsychological test data and regional cerebral blood flow data were determined while patients who performed the Wisconsin Card Sorting test were examined. Patients with HD performed worse on visuospatial tasks and recall memory than did patients with SC, although Wechsler Adult Intelligence Scales-Revised IQ and Wechsler Memory Scale memory quotients were equivalent. These differences could not be attributed to differences on the index task, the Wisconsin Card Sorting Test. Patients with HD and SC exhibited a double dissociation in regional cerebral blood flow. The patients with SC had relatively low frontal and high parietal flows, while patients with HD exhibited the reverse of this pattern. Thus, the regional cerebral blood flow and neuropsychological findings in this study appeared to demonstrate that the single final common cognitive impairment of executive function in HD and SC is associated with two markedly dissimilar pathophysiological states.
T.E. Goldberg, J.D. Ragland, E.F. Torrey, J.M. Gold, L.B. Bigelow, and D.R. Weinberger
Arch Gen Psychiatry 1990; 47:1066-72.
A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.
T.E. Goldberg, J.A. Saint-Cyr, and D.R. Weinberger
J Neuropsychiatry Clin Neurosci 1990; 2:165-73.
Two versions of the Tower of Hanoi task were used to investigate different components of learning and problem solving in schizophrenia. Prior studies have suggested that a three-disk version (Tower 3), which involves primarily problem-solving abilities and planning, is preferentially sensitive to frontal lobe lesions and that the more difficult four-disk version (Tower 4), which involves learning by doing, is sensitive to basal ganglia disease. Schizophrenic patients performed significantly worse than normal subjects on Tower 3 and Tower 4. However, they performed at least as well relatively on Tower 4 as on Tower 3, indicating that level of difficulty per se does not account for their poor performance on these tasks. Moreover, they eventually attained perfect or near- perfect performance after four days of repeated administration. Their relatively stronger performance on Tower 4 may have reflected an ability to acquire a procedure and, as such, suggests greater preservation of basal ganglia function than of prefrontal function.
R.L. Hendren, G.P. Sholevar, D.R. Weinberger, and J.M. Wiener
J Am Acad Child Adolesc Psychiatry 1990; 29:141- 8.
T.M. Hyde, and D.R. Weinberger
Semin Neurol 1990; 10:276-86.
Schizophrenia has been the subject of intensive neuropsychologic, neuroradiologic, neuropathologic, and neurochemical investigations. The 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 in vivo neuroimaging and postmortem anatomic techniques. The details and etiology of temporal lobe-hippocampal pathologic states remain to be elucidated. Neuropsychologic and cerebral blood flow studies suggest that the frontal lobe is dysfunctional in schizophrenics. However, there is little known about the neuropathologic basis and neurochemical correlates of this deficit. One of the intriguing new hypotheses about the neurologic findings in schizophrenia is that they are the result of an abnormality in the early development of the brain. The possibility that the clinical illness is a delayed manifestation of this process, perhaps because of an interaction between the early developmental deficit and later maturing functional neural systems, is a subject of speculation. While much study has been devoted to the structural and functional abnormalities underlying schizophrenia, much remains to be discovered. In the past 20 years, the development and application of new techniques, including CT, MRI, rCBF, and PET, have revolutionized the study of schizophrenia, and have produced the first consistent neuropathologic findings in this disorder. The pace of discovery has been gradually accelerating. Application of new techniques and careful use of patient selection criteria will help further decipher the neurologic basis of this disorder. There is reasonable hope that by the end of this century, the pathology and pathophysiology of this common but baffling illness will be revealed.
G.E. Jaskiw, F. Karoum, W.J. Freed, I. Phillips, J.E. Kleinman, and D.R. Weinberger
Brain Res 1990; 534:263-72.
To determine the influence of intrinsic medial prefrontal cortex (MPFC) neurons on regional brain catecholamine turnover, dopamine (DA) and its metabolites were assayed in several brain areas 14 and 28 days after bilateral ibotenic acid (IA) lesions of the MPFC in the rat. The locomotor response to D-amphetamine was also assessed. On the 14th postoperative day levels of DA, homovanillic acid concentrations and 3,4-dihydroxyphenylacetic acid were elevated in the anterior striatum of IA-lesioned animals. Spontaneous and amphetamine- induced locomotion were also increased. These changes disappeared by the 28th postoperative day. It is concluded that destruction of the efferents of the MPFC induces transient increases in DA turnover within the medial striatum and transiently increases spontaneous and amphetamine-induced locomotion.
G.E. Jaskiw, F.K. Karoum, and D.R. Weinberger
Brain Res 1990; 534:321-3.
This study assessed the possible influence of the medial prefrontal cortex (MPFC) on the response of subcortical dopamine (DA) systems to subchronic, mild stress. DA and its metabolites as well as noradrenaline were assayed in the nucleus accumbens and corpus striatum, 1 and 7 days after one week of daily intraperitoneal saline injections (Stress) or no handling (No stress), in rats with sham (Sham) or ibotenic acid (IA) lesions of the MPFC. One day after the last saline injection the level of dihydroxyphenylacetic acid (DOPAC) was elevated in the nucleus accumbens of IA/Stress rats in comparison to the Sham/No stress, Sham/Stress, and IA/No Stress groups. Levels of mesolimbic DA, DOPAC and homovanillic acid were still elevated 7 days after the last injection in IA/Stress animals in comparison to all other groups. There were no other significant differences between the groups. The data suggest that in rats with MPFC impairment, mild subchronic stress can induce alterations in mesolimbic DA activity that persist beyond the duration of the stress.
G.E. Jaskiw, and D.R. Weinberger
Pharmacol Biochem Behav 1990; 36:695-7.
Six weeks after induction of bilateral sham or ibotenic acid lesions of the medial prefrontal cortex (MPFC), groups of rats were injected with the anxiogenic beta-carboline FG-7142 (15 mg/kg IP) or vehicle (VEH) before exposure to a novel open field. The attenuation of exploratory activity by FG-7142 was markedly enhanced in the MPFC-lesioned rats. The results suggest that the behavioral effects of MPFC lesions may be amplified under stressful conditions. Secondly, the inhibition of exploratory activity by FG-7142 does not depend on its action within the MPFC.
M.S. Myslobodsky, R. Coppola, J. Bar-Ziv, and D.R. Weinberger
J Clin Neurophysiol 1990; 7:507-18.
The adequacy of the International 10-20 System is reviewed in light of demands imposed on the accuracy of lead placement by improvements in spatiotemporal brain electrical activity mapping technology. Computed tomography (CT) and magnetic resonance imaging (MRI) studies reveal that the most frequent sources of inaccuracy of electrode locations are difficulties in defining the inion, variance in the anatomy of the occipital bone, inconspicuous sagittal deformities, variance of sulcal pattern, and brain width asymmetries. Owing to these factors, electrodes placed bilaterally and equidistant from the nasion-inion line may not be homotopically located. Therefore, the authors suggest that practitioners who employ the 10-20 System in order to gain precise and more individualized laterality information do so with extreme caution until the range of placement and interpretative errors is more precisely determined using CT/MRI-assisted EEG.
C. Randolph, T.E. Goldberg, J. Gold, D.G. Daniel, and D.R. Weinberger
Am J Psychiatry 1990; 147:679-80.
R.L. Suddath, G.W. Christison, E.F. Torrey, M.F. Casanova, and D.R. Weinberger
N Engl J Med 1990; 322:789-94.
Recent neuroradiologic and neuropathological studies indicate that at least some patients with schizophrenia have slightly enlarged cerebral ventricles and subtle anatomical abnormalities in the region of the anterior hippocampus. Using magnetic resonance imaging (MRI), we studied 15 sets of monozygotic twins who were discordant for schizophrenia (age range, 25 to 44 years; 8 male and 7 female pairs). For each pair of twins, T1-weighted contiguous coronal sections (5 mm thick) were compared blindly, and quantitative measurements of brain structures were made with a computerized image-analysis system. In 12 of the 15 discordant pairs, the twin with schizophrenia was identified by visual inspection of cerebrospinal fluid spaces. In two pairs no difference could be discerned visually, and in one the twin with schizophrenia was misidentified. Quantitative analysis of sections through the level of the pes hippocampi showed the hippocampus to be smaller on the left in 14 of the 15 affected twins, as compared with their normal twins, and smaller on the right in 13 affected twins (both P less than 0.001). In the twins with schizophrenia, as compared with their normal twins, the lateral ventricles were larger on the left in 14 (P less than 0.003) and on the right in 13 (P less than 0.001). The third ventricle also was larger in 13 of the twins with schizophrenia (P less than 0.001). None of these differences were found in seven sets of monozygotic twins without schizophrenia who were studied similarly as controls. We conclude that subtle abnormalities of cerebral anatomy (namely, small anterior hippocampi and enlarged lateral and third ventricles) are consistent neuropathologic features of schizophrenia and that their cause is at least in part not genetic. Further study is required to determine whether these changes are primary or secondary to the disease.
D.R. Weinberger, U. Mann, R.E. Gibson, R. Coppola, D.W. Jones, A.R. Braun, et al.
Adv Neurol 1990; 51:147-50.
M.F. Casanova, D.G. Daniel, T.E. Goldberg, R.L. Suddath, and D.R. Weinberger
Schizophr Res 1989; 2:333-8.
Recent morphometric studies indicate that both right and left temporal lobe volumes are reduced in schizophrenic patients. Subsequent studies suggested that this volumetric reduction is the result of focal or multifocal gray matter abnormalities. Since in early life brain growth or lack thereof influences the overlying skull configuration, we attempted to elucidate the time of onset of the temporal lobe lesion in schizophrenic patients by quantifying both the volume and shape of their middle cranial fossa. Computerized tomographic scans of 17 schizophrenic patients and an equal number of age-matched controls were digitized using a LOATS image analysis system. The middle cranial fossa was manually outlined and software routines allowed the quantification of volume and shape parameters. Our results showed that no significant differences were present between schizophrenic patients and controls. If the bilateral reduction in temporal lobe volumes in schizophrenic patients is the result of an early onset (e.g., developmental) lesion, the resultant foci of gray matter abnormality may occur distant to the base of the skull. Alternatively, tissue loss may be insufficient to alter the development of the overlying skull or to be detected by our methods.
G.W. Christison, M.F. Casanova, D.R. Weinberger, R. Rawlings, and J.E. Kleinman
Arch Gen Psychiatry 1989; 46:1027-32.
Hippocampal abnormalities have been described in patients with schizophrenia, with disarray of pyramidal cells being one of the more intriguing findings. Controversy exists regarding whether disarray is present in the brains from schizophrenics in the Yakovlev collection at the Armed Forces Institute of Pathology, Washington, DC. We examined for disarray the CA1 region of the midhippocampus of 17 schizophrenics and 32 controls from this collection using computerized determination of neuronal angle and directional statistical analysis of the variability of neuronal angle. Neuronal area and shape were also assessed. We found no differences between patients and controls in these measures. Possible methodological reasons for the discrepancy between our and others' findings are discussed, as well as directions for further research into possible pathological study of the hippocampus and related structures in schizophrenia.
D.G. Daniel, K.F. Berman, and D.R. Weinberger
J Neuropsychiatry Clin Neurosci 1989; 1:377-84.
A double-blind, placebo-controlled crossover study of the effects of apomorphine on regional cerebral blood flow (rCBF) during a prefrontal cortex activation task was undertaken to explore the role of dopamine on cortical function. The subjects were eight drug-free, chronically psychotic patients; six patients had schizophrenia. In each, apomorphine increased the relative prefrontal flow. The results suggest that enhanced prefrontal dopamine activity may reverse deficits in prefrontal cortex metabolism in schizophrenia.
D.G. Daniel, M.S. Myslobodsky, L.J. Ingraham, R. Coppola, and D.R. Weinberger
Schizophr Res 1989; 2:465-72.
It has long been hypothesized, but never proven that an organic brain injury early in life predisposes to schizophrenia. Since brain and cranial development are closely linked, if such an event occurred early enough in the premorbid course of schizophrenia, it could conceivably effect skull architecture. To approach this question, the occipital bone depth and the occipitomedian angle were measured in 50 patients with chronic schizophrenia and in 35 medical controls. Strong correlations emerged between the skull asymmetry indices and the occipital and temporal lobe parenchymal asymmetry indices. There were no statistically significant differences in cranial asymmetry measures between the patients with schizophrenia and the medical controls. However, when the comparison was limited to right handed individuals with homolateral sighting dominance, a weak, but statistically significant trend was observed for more symmetrical slanting along the sagittal suture in the schizophrenic patients. In addition, cranial asymmetry was weakly predictive of increased prefrontal markings in the schizophrenic patients. The congruence of skull findings with parenchymal variables suggests that certain aspects of skull and parenchymal architecture are co-determined.
T.E. Goldberg, D.R. Weinberger, N.H. Pliskin, K.F. Berman, and M.H. Podd
Schizophr Res 1989; 2:251-7.
Patients with schizophrenia have memory deficits when compared to other neuropsychiatric and normal samples, but the mechanism by which the deficits arise is obscure. In the present study, 13 older, less educated normal subjects, and 31 inpatients with schizophrenia were administered the Selective Reminding test. In addition, the schizophrenic patients received the Mini Mental State Exam and the Brief Psychiatric Rating Scale. While normal subjects performed at a higher level on various measures of recall, a significant effect of repeated trials was present for each group for each measure, indicating that both groups learned. Normal subjects also outperformed the patients on a test of recognition memory. However, the patients exhibited a significantly greater disparity between recognition and recall than did the normal subjects, suggesting they were better able to acquire new information than to retrieve it ('forgetting to remember'). Moreover, anergia, a factor measure on the Brief Psychiatric Rating Scale, correlated significantly with recall, but not recognition memory, in the patient group. The data are suggestive of prefrontal-type cognitive and behavioral deficits in schizophrenia.
M.S. Myslobodsky, R. Coppola, J. Bar-Ziv, C. Karson, D. Daniel, H. van Praag, et al.
Brain Topogr 1989; 1:221-8.
The plagiocephaly index, an index that reflects an underlying anatomic asymmetry of the brain, was assessed in ten schizophrenic patients and its values were correlated with the lateral distribution of quantitatively evaluated EEG. The correlations between the index and alpha power at F7 were significant, positive for frontal asymmetry (frontal bulging) and negative for occipital flattening. We then studied ten normal subjects in an attempt to illuminate the contribution of several cephalic and cranial variables to the imbalance of alpha-afterdischarges (AD) of VEP recorded at O1-O2. The asymmetry index of AD was computed and correlated with asymmetries of CT-derived measures of occipital bone thickness, occipital lobe width, mastoid area, and sulcal asymmetry (the asymmetry of intraparietal sulcus location from the longitudinal fissure). With the exception of the sulcal variable all measures significantly covaried with alpha AD. These findings caution that it may be important to determine cranial and brain parenchymal asymmetries where brain laterality is pertinent to studies of EEG.
A. Reeve, D.F. Rose, and D.R. Weinberger
Arch Gen Psychiatry 1989; 46:573-6.
R.L. Suddath, M.F. Casanova, T.E. Goldberg, D.G. Daniel, J. Kelsoe Jr., and D.R. Weinberger
Am J Psychiatry 1989; 146:464-72.
Although numerous studies have confirmed the presence of larger cerebral ventricles in schizophrenia, the locus of tissue loss remains elusive. By analyzing magnetic resonance scans with computerized image analysis, the authors determined gray and white matter volumes in the temporal lobes and prefrontal regions of 17 patients with schizophrenia and 17 age- and sex-matched normal subjects. The volume of temporal lobe gray matter was 20% smaller in the patients than in the control subjects. The lateral ventricular volume was 67% larger in the patients and, when normalized for brain size, correlated inversely with the volume of temporal lobe gray matter.
J. Zohar, T.R. Insel, K.F. Berman, E.B. Foa, J.L. Hill, and D.R. Weinberger
Arch Gen Psychiatry 1989; 46:505-10.
To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.
K.F. Berman, B.P. Illowsky, and D.R. Weinberger
Arch Gen Psychiatry 1988; 45:616-22.
In previous studies we found that patients with chronic schizophrenia had lower regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) than did normal subjects during performance of the Wisconsin Card Sort Test, an abstract reasoning task linked to DLPFC function. This was not the case during less complex tasks. To examine further whether this finding represented regionally circumscribed pathophysiology or a more general correlate of abstract cognition, 24 medication-free patients and 25 age- and sex-matched normal control subjects underwent rCBF measurements with the xenon 133 technique while they performed two tasks: Raven's Progressive Matrices (RPM) and an active baseline control task. While performing RPM, normal subjects activated posterior cortical areas over baseline, but did not activate DLPFC, as had been seen during the Wisconsin Card Sort Test. Like normal subjects, patients showed maximal rCBF elevations posteriorly and, moreover, they had no significant DLPFC or other cortical deficit while performing RPM. These results suggest that DLPFC dysfunction in schizophrenia is linked to pathophysiology of a regionally specific neural system rather than to global cortical dysfunction, and that this pathophysiology is most apparent under prefrontally specific cognitive demand.
T.E. Goldberg, C.N. Karson, J.P. Leleszi, and D.R. Weinberger
Schizophr Res 1988; 1:261-6.
The relationship of cognitive impairment to the course of schizophrenia remains uncertain. By studying psychotic adolescents, 90% of whom were hospitalized for the first time, we hoped to reduce the influence of such confounding variables as lengthy disease process, neuroleptic treatment, and institutionalization. 39 psychotic adolescent subjects who fulfilled DSM-III criteria for schizophrenia, schizophreniform psychosis, paranoid schizophrenia, or atypical psychosis were compared to 41 non- psychotic adolescent psychiatric controls. Subjects were administered the Wechsler Intelligence Scale for Children-Revised, Peabody Individual Achievement tests of reading, reading comprehension, and mathematics, Bender-Gestalt, and Purdue Pegboard test within 3 weeks of admission to a psychiatric hospital. Performance IQ was significantly lower in the psychotic group (72 versus 93, P = 0.03). Thus, the IQ pattern in adolescent psychotic patients at an early stage in their illness was similar to the pattern displayed by chronic adult schizophrenic patients. Results were not consistent with theories of left hemisphere involvement in schizophrenia. Academic achievement was similar in both groups despite marked differences in performance IQ. Psychotropic medication had no significant impact on the results. In summary, deficits in processing novel material seem at the very least to be present at the onset of the psychotic disorder, though they may be non-progressive thereafter.
T.E. Goldberg, J.R. Kelsoe, D.R. Weinberger, N.H. Pliskin, P.D. Kirwin, and K.F. Berman
Int J Neurosci 1988; 42:51-8.
Though individual tests thought to assess frontal lobe function have been administered to patients with schizophrenia for many years, approaches in which a number of tests thought to tap a single function or brain region have rarely been used. Such an approach might define a critical test or a common dysfunctional cognitive process. In the present study four putative neuropsychological tests of frontal lobe integrity, namely, the Wisconsin Card Sorting Test, the Category Test, Trail Making B, and verbal fluency, were administered to 28 patients with schizophrenia. Seventy-five percent performed abnormally on at least one test. However, relationships among the test results were difficult to characterize, either by correlation or factor analysis. A hierarchical arrangement in which higher order tests proscribe performance on lower order tests did not appear to be present. Regarding sensitivity, Trails B, the only timed test, was most frequently impaired and verbal fluency was least frequently impaired. The results suggest that the tests assess somewhat different aspects of frontal lobe function, and that no single frontal lobe test is uniquely sensitive to cognitive impairment in schizophrenia.
T.E. Goldberg, J.E. Kleinman, D.G. Daniel, M.S. Myslobodsky, J.D. Ragland, and D.R. Weinberger
Br J Psychiatry 1988; 153:187-90.
Thirty-nine patients with DSM-III diagnoses of schizophrenia were examined for age disorientation, an inability to produce one's correct chronological age upon request. Six patients were age-disoriented and demented (as defined by Mini-Mental State evaluation), while two patients had delusions concerning their age, but were not demented. Age-disoriented, demented patients had very large cerebral ventricles and very low Mini-Mental State scores. This group differed on the cognitive and neuroanatomic variables from other demented, but not age-disoriented, patients, as well as from non- demented patients who were age-oriented. The age-disoriented patients appeared to be at an extreme end of the dementia spectrum in schizophrenia.
T.E. Goldberg, and D.R. Weinberger
Schizophr Bull 1988; 14:179-83.
In a recent series of studies we have attempted to clarify the nature of intellectual impairment in schizophrenia, and in particular, how patterns of dysfunction implicate specific neural systems. First, we found that acute psychotic adolescent patients displayed the same pattern of IQ scores (Performance less than Verbal) as adult chronic schizophrenic patients. We explored this deficit in problem solving by studying the performance of schizophrenic patients after receiving concrete and explicit instructions on how to do the Wisconsin Card Sorting Test, a task thought to be mediated by prefrontal cortex. We then studied the differential impact such a deficit in problem-solving strategies might have on a task thought to elicit both cognitive (prefrontal) and procedural or motor-skill (basal ganglia) processing. Procedural components appeared to be relatively more intact. We also addressed schizophrenic patients' ability to learn in other (extrafrontal) cognitive domains through verbal memory tasks and block design puzzles. Learning occurred under both conditions. We believe the overall pattern of deficit implicates primarily prefrontal neural systems, though a number of other neuropsychological functions are yet to be surveyed.
B.P. Illowsky, D.M. Juliano, L.B. Bigelow, and D.R. Weinberger
J Neurol Neurosurg Psychiatry 1988; 51:209-13.
Earlier cross-sectional studies have suggested that CT findings of ventricular enlargement and increased cortical markings in schizophrenic patients are not progressive, but individual patients have rarely been followed prospectively. Fifteen patients with chronic schizophrenia were rescanned on the same model machine after 7 to 9 years of continuous illness and, in seven cases, of continuous hospitalisation. It was not possible to demonstrate significant changes in either ventricular-brain ratio or frontal atrophy scores. These results suggest that the pathologic process responsible for CT changes in schizophrenia is static and is not affected by 8 years of neuroleptic medication and institutionalisation.
C.N. Karson, R. Coppola, D.G. Daniel, and D.R. Weinberger
Schizophr Bull 1988; 14:193-7.
Despite advances in the processing and display of electroencephalographic (EEG) data, the utility of this inexpensive and noninvasive technique in the investigation of schizophrenia has not been well established. We studied the resting EEG in 19 medication- free patients with chronic schizophrenia and 21 normal controls. Patients with schizophrenia had increased delta activity which was not specific to the frontal regions. Schizophrenic patients also had increased fast activity, and this increase was left sided for the fast beta frequency. Alpha frequency was reduced (less than 10.2 Hz) in 7 of 16 schizophrenic patients. Moreover, those patients with an alpha frequency reduction had a significantly larger mean cerebral ventricular size. These results indicate that the EEG does detect neurophysiological changes in schizophrenia. Our understanding of these changes may be enhanced by other neuroimaging techniques such as computed tomography.
C.A. Kaufmann, D.R. Weinberger, J.R. Stevens, D.M. Asher, J.E. Kleinman, M.P. Sulima, et al.
Arch Gen Psychiatry 1988; 45:648-52.
To test the possibility that some cases of schizophrenia result from infection with a transmissible slow viral agent, 57 experimental animals (six chimpanzees, 12 Old World monkeys, 17 New World monkeys, and 22 guinea pigs) were inoculated intracerebrally with brain tissue from ten patients and followed up for six years. Behavioral comparisons with control animals revealed no consistent behavioral differences. Histological, immunohistochemical, and morphometric examination of brains of animals that died revealed no specific neuropathological abnormalities. These findings do not support a role for a virus-induced slow infection in the pathogenesis of schizophrenia but must be weighed against methodological limitations in animal susceptibility, disease communicability, and assay sensitivity.
J. Kelsoe Jr., J.L. Cadet, D. Pickar, and D.R. Weinberger
Arch Gen Psychiatry 1988; 45:533-41.
Twenty-four patients with schizophrenia and 14 normal control subjects underwent magnetic resonance imaging scans using a 0.5-tesla scanner and 600-ms inversion recovery technique. A midsagittal section and twelve 1-cm coronal sections beginning at the frontal pole were obtained, and linear, area, and signal intensity measurements were made on nine brain regions. Volume estimates were made by summing consecutive sections for four of the following regions: the precallosal frontal lobes, temporal lobes, lateral ventricles, amygdala-hippocampal complexes, and cerebral hemispheres. The area of the third ventricle in its most anterior coronal slice was increased by 73% in schizophrenic subjects (0.83 +/- 0.08 cm2) in comparison with controls (0.48 +/- 0.04 cm2). Lateral ventricular volume was increased by 62% in schizophrenic subjects (24.7 +/- 2.6 mL) in comparison with controls (15.2 +/- 1.4 mL). The lateral ventricular enlargement in schizophrenic subjects was more pronounced posteriorly than anteriorly, especially at the level of the anterior thalamus and the colliculi. There were no other significant differences between schizophrenic and control groups in any other spatial or signal intensity measures. There was no brain region the size of which correlated with ventricular size. These data corroborate third and lateral ventriculomegaly in schizophrenia using magnetic resonance imaging but fail to further localize the structural abnormality.
D.G. Kirch, G. Jaskiw, M. Linnoila, D.R. Weinberger, and R.J. Wyatt
Psychiatry Res 1988; 25:233-42.
Plasma catecholamine metabolites were measured in paired blood samples from 22 subjects with chronic schizophrenia. One sample was drawn while patients were on a stable dose of neuroleptic medication; the second was drawn 6 weeks after discontinuation of medication. In comparison with baseline values during neuroleptic treatment, there was a significant increase in the plasma concentration of the norepinephrine metabolite, 3-methoxy-4- hydroxyphenylglycol (MHPG), and a trend toward an increase in the plasma concentration of the dopamine metabolite, homovanillic acid (HVA), in the medication-free subjects. There were no significant correlations between plasma MHPG or HVA concentrations and the corresponding ratings of psychopathology for these patients.
W.B. Lawson, I.N. Waldman, and D.R. Weinberger
J Nerv Ment Dis 1988; 176:207-12.
Twenty-seven chronic schizophrenic patients and nine other psychiatric patients closely matched in education were compared on the Halstead-Reitan Battery and the Wechsler Adult Intelligence Scale (WAIS). The schizophrenic patients as a group showed significantly poorer performance on the WAIS (full scale: X +/- SD, 92.9 +/- 2.9 vs. 110.8 +/- 2.1, p less than .002) and the Halstead-Reitan Battery (HRB; Average Impairment Range = 2.1 +/- .2 vs. 1.12 +/- .06, p less than .003). In addition the schizophrenic patients did significantly worse than did nonschizophrenic patients on all WAIS subtests and scored in the impaired range on most HRB subtests. Computed axial tomography scans revealed large ventricles on nine schizophrenic patients and cortical atrophy on three others. Among schizophrenics, the enlarged ventricle group consistently scored the worst. No relationship was seen between neuropsychological test performance and degree of ongoing psychopathology as measured by the Brief Psychiatric Rating Scale. These findings are consistent with previous reports of cognitive impairment in schizophrenia and are discussed in terms of regional localization. They provide additional evidence that the impairment is related to the disease process and that structural abnormalities are associated with the more severe condition.
D. Naber, D.R. Weinberger, M. Bullinger, M. Polsby, and T.N. Chase
Compr Psychiatry 1988; 29:182-7.
R.C. Shelton, C.N. Karson, A.R. Doran, D. Pickar, L.B. Bigelow, and D.R. Weinberger
Am J Psychiatry 1988; 145:154-63.
To replicate earlier findings of central and cortical cerebral structural abnormalities and to further examine specific prefrontal cortical irregularities in schizophrenia, the authors examined computerized tomographic (CT) scans of 71 patients with chronic schizophrenia and 30 normal volunteer control subjects for ventricle-brain ratio (VBR), third ventricle width, and prominence of cortical markings in a generalized (parieto-occipital) distribution compared with the prefrontal area. Patients showed significantly larger VBRs and third ventricle widths than control subjects. Patients also showed significantly greater prefrontal markings in terms of both the number of individuals affected and the degree of difference. The relative differences on measures of VBR and prefrontal atrophy did not appear gender related, but the difference in third ventricle width between schizophrenic and control women was greater than that between schizophrenic and control men.
H. Wagner Jr., D.R. Weinberger, J.E. Kleinman, M.F. Casanova, C. Gibbs Jr., R.E. Gur, et al.
Schizophr Bull 1988; 14:383-97.
D.R. Weinberger
Lancet 1988; 2:445.
D.R. Weinberger
Trends Neurosci 1988; 11:367-70.
D.R. Weinberger, and K.F. Berman
Schizophr Bull 1988; 14:157-68.
Cerebral metabolic hypofrontality in schizophrenia is a controversial research finding. In this article we discuss some of the issues that fuel this controversy, and we speculate on the neural mechanisms that may be responsible for the finding. Most regional cerebral blood flow (rCBF) studies using radioactive xenon have found hypofrontality; the results of positron emission tomography (PET) studies have been less consistent. Several technical factors are discussed that might contribute to the inconsistencies, including airway artifacts with xenon, limitations of tomography in studying the cortex, and approaches to data analysis. The possibility that hypofrontality is a result of medication is also critically examined. The medication factor is still unclear, but most studies of patients before and after neuroleptic medication find that cerebral metabolism goes up, not down, after treatment. The role of patient behavior and experience during an rCBF or PET procedure is an important variable that has not been adequately controlled in most studies. We suggest that this has been the most important variable in interpreting cerebral metabolic data in schizophrenia. Studies of patients examined during a behavior that normally activates prefrontal cortex have consistently found hypofrontality. One theoretical mechanism that could account for hypofrontality as well as many clinical and research findings in schizophrenia is dysfunction of dopaminergic neural transmission at the level of the prefrontal cortex.
D.R. Weinberger, K.F. Berman, and T.N. Chase
Ann N Y Acad Sci 1988; 537:330-8.
In summary, we have reviewed rCBF data in humans that suggest that mesoprefrontal dopaminergic activity is involved in human cognition. In patients with Parkinson's disease and possibly in patients with schizophrenia, prefrontal physiological activation during a cognitive task that appears to depend on prefrontal neural systems correlates positively with cognitive performance on the task and with clinical signs of dopaminergic function. It may be possible in the future to examine prefrontal dopamine metabolism directly during prefrontal cognition using positron emission tomography and tracers such as F-18 DOPA.
D.R. Weinberger, K.F. Berman, M. Iadarola, N. Driesen, and R.F. Zec
J Neurol Neurosurg Psychiatry 1988; 51:94-104.
To examine the relationship between cortical physiology and dementia in Huntington's disease, rCBF during three different behavioural conditions, one of which emphasised prefrontal cognition, was determined by xenon-133 inhalation in 14 patients with Huntington's disease and in matched controls. Cortical rCBF was not reduced in Huntington's disease patients even while they manifested overt prefrontal- type cognitive deficits. Caudate atrophy on CT and rCBF were significantly correlated, but only during the prefrontal behaviour where the correlation was positive. These results suggest a qualification of the subcortical dementia concept as applied to Huntington's disease and implicate an interaction between pathology that is subcortical and cognitive function that is cortical.
D.R. Weinberger, K.F. Berman, and B.P. Illowsky
Arch Gen Psychiatry 1988; 45:609-15.
We previously reported that compared with normals, patients with chronic schizophrenia have reduced regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) during performance of the Wisconsin Card Sort Test (WCS), a DLPFC-related cognitive task, but not during nonprefrontal tasks, such as a simple number-matching (NM) test. We also found that unlike normals, patients failed to activate DLPFC during the WCS over their own baseline (NM) level. To explore the reproducibility of these findings, a new cohort of 16 medication-free patients underwent a series of xenon 133 inhalation rCBF studies under the following conditions: at rest, while performing the WCS, and while performing NM. The results confirmed our earlier findings. In addition, the concentrations in cerebrospinal fluid of homovanillic acid and 5-hydroxyindoleacetic acid correlated with prefrontal rCBF during the WCS but not during the NM test or at rest. The results show that behavior-specific hypofunction of DLPFC in schizophrenia is reproducible, and they implicate a monoaminergic mechanism.
K.F. Berman, D.R. Weinberger, R.C. Shelton, and R.F. Zec
Am J Psychiatry 1987; 144:1277-82.
The authors studied the relationship between lateral cerebral ventricular size and regional cerebral blood flow during mental activation in 30 patients with schizophrenia. Patients with large ventricles had diffusely lower cortical gray matter blood flow than patients with small ventricles. In addition, an inverse correlation between ventricular size and prefrontal blood flow was observed while patients were attempting to solve a neuropsychological test specifically related to the prefrontal cortex. These data suggest that structural brain pathology impairs prefrontal physiology in schizophrenia, implicating a neural mechanism for the intellectual deficits characteristic of this disorder.
A.R. Doran, J. Boronow, D.R. Weinberger, O.M. Wolkowitz, A. Breier, and D. Pickar
Neuropsychopharmacology 1987; 1:25-32.
Computed tomography scan analysis of 35 schizophrenic patients, 26 medical patients, and 31 normal controls revealed significantly larger ventricular brain ratios and structural changes consistent with cortical atrophy in both schizophrenic and medical patients in comparison with normal controls. The schizophrenic patients, however, differed from both control groups in terms of greater prefrontal cortical markings consistent with prefrontal atrophy, and this finding correlated inversely with levels of cerebrospinal fluid homovanillic acid. Results from this study, in addition to replicating previous findings and addressing methodologic issues concerning controls, provide new evidence implicating abnormality of the prefrontal cortex in schizophrenia and link this abnormality to central nervous system dopaminergic function.
T.E. Goldberg, D.R. Weinberger, K.F. Berman, N.H. Pliskin, and M.H. Podd
Arch Gen Psychiatry 1987; 44:1008-14.
Recent physiological and cognitive studies of schizophrenia have implicated dysfunction of prefrontal cortex as a possible explanation for some of the disabling intellectual and social aspects of the disorder. To investigate the potential reversibility of cognitive deficits and the role of state variables, eg, attention and motivation, three groups of patients with schizophrenia were administered the Wisconsin Card Sorting Test on six consecutive occasions. Two of the groups received incremental information on how to do the test, including explicit card-by-card instruction. The third group served as a control. Regardless of the degree of instruction, patients who could not do the test could not learn it. The deficit did not appear generalized, as patients were able to learn word lists on the Selective Reminding memory test and were not globally demented on the Mini-Mental State Examination. These data suggest that prefrontal-type cognitive deficits in schizophrenia may be more profound than is generally appreciated.
M.J. Jaffe, G. Bruno, G. Campbell, R.A. Lavine, C.N. Karson, and D.R. Weinberger
J Neurol Neurosurg Psychiatry 1987; 50:847- 52.
Two groups of patients with primary Parkinsonism were studied with the ganzfeld electroretinogram (ERG): seven patients who had never received dopamimetic agents, and six patients given an infusion of levodopa following a period of medication withdrawal. Patients in the first category had a subtle increase in the latency of their short-wavelength sensitive cone response recorded from the retina ipsilateral to their more symptomatic side. Most patients in the second category demonstrate an improvement in their ERG when the responses recorded following levodopa infusion were compared with baseline responses obtained during the period of medication withdrawal. These results suggest that one role of retinal dopamine may be maintenance of normal retinal responsiveness to flash stimuli.
C.N. Karson, R. Coppola, J.M. Morihisa, and D.R. Weinberger
Arch Gen Psychiatry 1987; 44:514-7.
Several topographic mapping studies of electroencephalographic (EEG) power spectra have reported increased slow (delta) activity in the frontal regions of schizophrenic patients. Using supraorbital and lateral canthus electrodes to detect eye movement, we deleted EEG epochs during eye movement in 15 medication- free patients with schizophrenia and in 13 normal control subjects. Power spectral analysis of the 28-channel EEG demonstrated a diffuse mild increase in delta activity in schizophrenic patients compared with normal control subjects but no tendency for frontal localization of this slow activity. There were no differences between schizophrenic patients and normal control subjects in other frequency bands. These results, which replicate earlier findings of increased delta activity in schizophrenia, emphasize the importance of excluding the slow activity due to eye movement in the comparisons of summed EEG spectra. This emphasis can best be ensured by equating the summed spectra from extraocular movement channels of experimental and control groups.
E.R. Korpi, C.A. Kaufmann, K.M. Marnela, and D.R. Weinberger
Psychiatry Res 1987; 20:337-45.
The concentrations of the excitatory amino acid, glutamate, the inhibitory amino acids, glycine and taurine, and the inactive amino acids, glutamine and alanine, were determined in cerebrospinal fluid samples from 12 neurological control and 17 chronic schizophrenic patients. No significant differences were observed in any amino acid between the study groups. Within the schizophrenic group, no differences were observed between paranoid and undifferentiated patients. The concentrations of these amino acids in samples obtained from six schizophrenic patients during drug-free as compared to haloperidol-treatment periods also did not differ. These results do not support the glutamate hypothesis of schizophrenia.
M.S. Myslobodsky, L.J. Ingraham, and D.R. Weinberger
Percept Mot Skills 1987; 65:415-21.
During the first two to three months after delivery infants when placed in the supine position commonly turn their heads laterally. This posture has been linked to the intrauterine orientation of the fetus. Skulls of adults were expected to bear a mark of this predominant head position in the form of occipital flattening. A blind examination of computerized axial tomography (CT) scans of 35 normal subjects assessed for handedness (20 right- and 15 mixed-handers) confirmed this prediction for the latter group only. Mixed-handers showed a slight, but reliable flattening of the right occiput. Also, there was a small but significant inverse association between the size of the petrous ridge and handedness. Examining subtle variations in skull shape of adults may provide a glimpse into some aspects of pre- and early postnatal development.
S. Raz, N. Raz, D.R. Weinberger, J. Boronow, D. Pickar, E.D. Bigler, et al.
Psychiatry Res 1987; 22:91-8.
The size of the cerebral ventricles was estimated from computed tomographic (CT) scans of 14 young patients with schizophrenia and 12 medical controls. The subjects were a representative subsample from a larger sample studied by Boronow et al. (1985). Although no CT abnormalities were detected in the psychiatric patients using traditional measures (mechanical planimetry for the lateral ventricles and a linear measure for the third ventricle), a volumetric analysis of the same 26 scans revealed enlargement of the lateral and third ventricles in the schizophrenics. The effect revealed by volumetric measures of the lateral ventricles was 58% greater than that obtained with digital planimetry and 96% greater than the effect found using mechanical planimetry. No differences were found between volumetric and digital planimetric measures of the third ventricle, but the effect revealed by the latter measure was 114% greater than that obtained by a linear index. It is suggested that volumetric measures of lateral ventricles based on information from several CT slices may be more sensitive to group differences in ventricular size than planimetry. Likewise, area measures of the third ventricle may be more sensitive to group differences than linear measures.
J.M. Rumsey, K.F. Berman, M.B. Denckla, S.D. Hamburger, M.J. Kruesi, and D.R. Weinberger
Arch Neurol 1987; 44:1144-50.
Regional cerebral blood flow was measured under three task conditions in 14 men with severe developmental dyslexia and their control subjects using a xenon 133 inhalation technique. No group differences in overall level or in pattern of gray matter flow were seen under relatively undemanding cognitive conditions. Despite minimal group differences in performance, the dyslexic group showed an increased hemispheric asymmetry (left greater than right) on a semantic classification task and a reduced anteroposterior difference on a line orientation task relative to controls. The exaggerated asymmetry suggests the possibility of less efficient information processing or inadequate bihemispheric integration. The reduced anteroposterior gradient may reflect a deficit in the ability of frontal systems to respond adequately to cognitive demands.
D.R. Weinberger
Arch Gen Psychiatry 1987; 44:660-9.
Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed lesion from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.
K.F. Berman, R.F. Zec, and D.R. Weinberger
Arch Gen Psychiatry 1986; 43:126-35.
We conducted two xenon Xe 133 inhalation regional cerebral blood flow (rCBF) studies to clarify earlier findings of dorsolateral prefrontal cortex (DLPFC) dysfunction in medication-free patients with chronic schizophrenia. In the first study, 24 neuroleptic-treated patients and 25 normal controls underwent three rCBF procedures, first while at rest, then during the Wisconsin Card Sort (WCS), which tests DLPFC cognitive function, and during a number-matching task that controlled for aspects of the WCS-rCBF experience not specifically related to DLPFC. The results were qualitatively identical to those previously reported for medication-free patients. In the second study, rCBF was determined while 18 medication-free patients and 17 normal control subjects each performed two versions of a visual continuous performance task (CPT). No differences in DLPFC blood flow between the two groups were found during either CPT condition. These data suggest that DLPFC dysfunction in schizophrenia is independent of medication status and not determined simply by state factors such as attention, mental effort, or severity of psychotic symptoms. Dysfunction of DLPFC appears to be a cognitively linked physiologic deficit in this illness.
C.L. Ludwig, D.R. Weinberger, G. Bruno, M. Gillespie, K. Bakker, P.A. LeWitt, et al.
Clin Neuropharmacol 1986; 9:373-8.
Buspirone is a novel anxiolytic whose pharmacological profile differs from that of the benzodiazepines and includes dopaminergic agonist effects. Because of these properties, buspirone's usefulness in the management of idiopathic Parkinson's disease was evaluated in a controlled study of 16 outpatients with stage I-IV disease. At doses of 10 to 60 mg/day, no significant group or individual effects could be discerned on standardized disability, dyskinesia, anxiety, or depression scales. At high dose levels (100 mg/day) however, there was a significant worsening of disability ratings and a decrease in dyskinesia scores; anxiety ratings were also significantly increased. The results indicate that buspirone is well tolerated by parkinsonian patients at conventional antianxiety doses of 10 to 40 mg. Clinical effects of high dose treatment, on the other hand, resemble those associated with a reduction in central dopamine mediated synaptic function. Since buspirone reportedly produces dose-dependent stimulation of norepinephrine containing neurons in the locus ceruleus and behavioral symptoms of such activation were observed, these clinical observations support the concept that central noradrenergic stimulation can adversely affect parkinsonian symptoms.
D.R. Weinberger, K.F. Berman, and R.F. Zec
Arch Gen Psychiatry 1986; 43:114-24.
To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC- specific cognitive test, and while performing a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.
R.F. Zec, and D.R. Weinberger
Psychiatr Clin North Am 1986; 9:49-61.
Studies relating CT abnormalities to impairments on neuropsychological tests in schizophrenic patients are critically reviewed. The overall conclusion is that there appears to be an association between CT abnormalities and neuropsychological deficits in at least some schizophrenic patient samples. It is proposed that there may be two classes of CT abnormalities in schizophrenia: incidental versus essential CT abnormalities and that neuropsychological impairment above the baseline levels found in most schizophrenic patients may be associated only with the former type. Only attempts to replicate these findings in different schizophrenic samples drawn from different settings can reveal whether this association between CT abnormalities and neuropsychological deficits is widely generalizable.
D.G. Kirch, L.B. Bigelow, D.R. Weinberger, W.B. Lawson, and R.J. Wyatt
J Clin Psychiatry 1985; 46:179-81.
The occasional presence of polydipsia in psychiatric patients, at times progressing to hyponatremia with severe medical complications, has been previously noted. The clinical history and laboratory data from eight chronically hyponatremic psychiatric inpatients were examined. Common characteristics were a diagnosis of chronic undifferentiated schizophrenia, an early age of onset of their illness, extended hospitalizations with minimal response to neuroleptic medications, heavy tobacco use, and a relatively high frequency of tardive dyskinesia and brain scan abnormalities. Water loading in three patients showed responses consistent with inappropriate secretion of antidiuretic hormone. Potential pathophysiologic mechanisms and treatment considerations are discussed.
D.G. Kirch, C.A. Kaufmann, N.M. Papadopoulos, B. Martin, and D.R. Weinberger
Biol Psychiatry 1985; 20:1039-46.
Determinations of albumin and immunoglobulin G (IgG) were performed in paired cerebrospinal fluid (CSF) and serum samples from 24 subjects with schizophrenia. These determinations allowed calculation of two indices, one that is an indicator of integrity of the blood-brain barrier and the other a measure of selective IgG production within the central nervous system (CNS). In comparison with previously determined reference values, 7 of 24 (29%) subjects showed increased blood-brain barrier permeability, and 8 of 24 (33%) demonstrated elevated endogenous CNS IgG production. One of these eight also demonstrated oligoclonal banding on high-resolution protein electrophoresis of the CSF.
J.W. Stiller, and D.R. Weinberger
Psychiatr Clin North Am 1985; 8:339-56.
A chronic, and at times, progressive neurologic syndrome associated with boxing has been recognized for some time by boxing fans and people involved with the sport. Since Martland's first description of the syndrome in 1929, there has been only one randomly selected study of ex-boxers, that of Roberts, which showed a 17 per cent prevalence of this syndrome among boxers who fought between 1929 and 1955. This syndrome can be progressive but often is not. Furthermore, the extent of occupational exposure is probably a significant risk factor. Because of this, it would be expected that the prevalance of the syndrome in the modern boxer, as well as the amateur, would be significantly less than during the first half of the century, and, indeed, several studies appear to support this. Recent studies provide evidence that brain damage does exist in modern boxers and suggests that subclinical brain damage is likely to be more prevalent than obvious clinical dysfunction. There is clearly a discrepancy between subclinical evidence of neurologic involvement (for example, an abnormal CT scan) and signs of clinical neurologic dysfunction (for example, clinical exam and neuropsychological testing). The latter tend to show less frequent and consistent evidence of brain damage in boxers than does the CT scan. Although it is tempting to assume that an abnormal CT scan presages the development of neurologic dysfunction, it is not clear that this is the case. The prevalence of the syndrome, risk for progression to functional deficit, warning signs, and the natural history cannot be defined at this time. The only way to better define these parameters would be a controlled prospective study, which has yet to be undertaken.
K.F. Berman, and D.R. Weinberger
Psychiatr Clin North Am 1984; 7:487- 501.
This article explored methods of brain imaging as they relate to the practice of psychiatry. In particular, technical aspects and clinical applications of CAT scanning are reviewed, and some neurologic conditions that may masquerade as psychiatric illness are considered. Suggested guidelines for CAT scanning in psychiatric patients are put forth, and implications of recent research findings in psychiatric disorders are discussed. In closing, we offer the following caveat: As psychiatric symptoms may be the earliest sign of structural CNS disease, the psychiatrist may be the first physician to evaluate patients with neurologic abnormalities. Because even the neurologic consultant may not be alert to the possibility of psychiatric symptoms alone heralding CNS pathology, the decision to augment the clinical impression with neuroradiologic or other brain imaging adjuncts (and to choose among them) may rest solely with the psychiatrist. Of these adjuncts, CAT scanning is almost always the most conclusive and reliable.
J.E. Kleinman, C.N. Karson, D.R. Weinberger, W.J. Freed, K.F. Berman, and R.J. Wyatt
Am J Psychiatry 1984; 141:1430-2.
Spontaneous eye-blinking, a possible measure of central dopaminergic activity, was studied in 55 drug-free chronic schizophrenic patients subdivided by cerebral ventricular size. Blink rates were higher in schizophrenic patients than in normal control subjects, regardless of cerebral ventricle size. Neuroleptics lowered blink rates in patients with normal ventricles but did not affect blink rates in patients with large ventricles. Insofar as blinking is a dopaminergic parameter, these findings suggest that the dopamine hypothesis of schizophrenia is most relevant in patients with normal ventricles.
D.R. Weinberger
J Psychiatr Res 1984; 18:477-90.
CAT scan studies linking schizophrenia to structural pathology of the brain are critically reviewed. CAT findings implicate an irreversible, static process, probably occurring early in development and resulting in a reduction of brain mass. The specificity of the process cannot be assessed from CAT images. Clinical correlations suggest that greater structural change is associated with more clinical neurological signs, suggestive of a pathological continuum rather than a sub-group concept. The CAT images are consistent with recent postmortem evidence of limbic-diencephalic pathology in schizophrenia. A structural deficit hypothesis is proposed.
D.R. Weinberger
Am J Psychiatry 1984; 141:1521-7.
Because psychiatric symptoms are frequently the earliest signs of CNS pathology, the author outlines the structural brain diseases that may underlie several psychiatric syndromes and describes the computerized axial tomographic (CAT) scan findings associated with those diseases. On the basis of an awareness of these conditions and a cost-benefit analysis, the following indications for CAT scanning of psychiatric patients are proposed: 1) confusion and/or dementia of unknown cause, 2) first episode of a psychosis of unknown etiology, 3) movement disorder of unknown etiology, 4) anorexia nervosa, 5) prolonged catatonia, and 6) first episode of major affective disorder or personality change after age 50.
D.R. Weinberger, and C. Salzman
Hosp Community Psychiatry 1984; 35:325-6.
E.I. DeLisi, C.C. Schwartz, S.D. Targum, S.M. Byrnes, E.C. Spoor, D.R. Weinberger, et al.
Psychiatry Res 1983; 9:169-71.
D.V. Jeste, S. Zalcman, D.R. Weinberger, N.R. Cutler, L.B. Bigelow, J.E. Kleinman, et al.
Prog Neuropsychopharmacol Biol Psychiatry 1983; 7:83-8.
(1) We conducted a double-blind study of acute effects of low-dose apomorphine (0.01 mg/kg) in 12 chronic schizophrenic patients. (2) Overall, there was no significant difference in therapeutic response to apomorphine versus placebo. (3) Of the individual subscales of the Brief Psychiatric Rating Scale, anxiety and depression syndromes showed significant improvement with apomorphine. (4) On dividing the schizophrenic patients into two groups on the basis of computed tomography (CT) scans, it was found that there was a significant difference in their responsiveness to apomorphine. (5) Patients with abnormal CT scans (primarily, large ventricles) tended to have improvement or no change with apomorphine, whereas those with normal CT scans tended to have worsening of symptoms. (6) Possible implications of our findings are discussed.
C.A. Kaufmann, D.R. Weinberger, R.H. Yolken, E.F. Torrey, and S.G. Pofkin
Lancet 1983; 2:1136-7.
B. Mered, P. Albrecht, E.F. Torrey, D.R. Weinberger, S.G. Potkin, and C.J. Winfrey
Lancet 1983; 2:919.
S.G. Potkin, D.R. Weinberger, M. Linnoila, and R.J. Wyatt
Am J Psychiatry 1983; 140:21-5.
The authors assayed CSF 5- hydroxyindoleacetic acid (5-HIAA) concentrations in 24 chronic schizophrenic patients, 9 of whom had enlarged cerebral ventricles according to computerized tomography scans, and in 15 control subjects with neurological disorders. Although there were no overall differences between the schizophrenic patients and the control subjects, schizophrenic patients with enlarged ventricles had significantly lower 5-HIAA concentrations. Also, ventricular size correlated inversely with 5-HIAA concentrations. The findings are consistent with other evidence that cerebral ventricular size is biologically meaningful in schizophrenic patients.
D. Reiss, C. Feinstein, D.R. Weinberger, R. King, R.J. Wyatt, and D. Brallier
Am J Psychiatry 1983; 140:453-6.
Data from adult schizophrenic patients suggest that patients with enlarged ventricles have a poorer premorbid history and may have an earlier onset of their illness than patients with ventricles of normal size. The authors examined a group of child psychiatric patients to discover whether these children at risk for major psychopathology had enlarged ventricles. Twenty psychiatric patients showed significantly enlarged ventricles compared with 19 control patients. There were no clear relationships between the children's psychiatric diagnosis and ventricular size.
R.O. Rieder, L.S. Mann, D.R. Weinberger, D.P. van Kammen, and R.M. Post
Arch Gen Psychiatry 1983; 40:735-9.
Computed tomographic (CT) scans of 28 chronic schizophrenic patients, 15 chronic schizoaffective patients, and 19 patients with bipolar affective disorder were compared on three measures: ventricular size, sulcal prominence (cortical atrophy), and cerebellar atrophy. Because the patients with bipolar disorder were older, measures were adjusted by controlling for age statistically or excluding patients over age 50 years. After age correction, there were no significant differences across diagnostic groups. Each group contained some subjects with enlarged ventricles, sulcal prominence, and/or cerebellar atrophy. The similarity of CT scan results across the three groups argues against ascribing these abnormalities to any one psychiatric disorder or to a specific drug effect. Sampling effects and the possibility of differential causes of the findings in the different diagnostic groups must be considered. Examination of the correlations of these three CT scan measures found them to be significantly related to each other. Age correlated with all measures when patients over age 50 years were included in the analysis, but not for patients aged 50 years and younger.
D. Shore, S.G. Potkin, D.R. Weinberger, E.F. Torrey, R.I. Henkin, R.P. Agarwal, et al.
Am J Psychiatry 1983; 140:754-7.
The authors used a sensitive flameless atomic absorption spectrophotometric procedure to measure CSF copper concentrations in normal controls, former heroin addicts, and unmedicated and medicated chronic schizophrenic patients and found no significant differences in CSF copper levels between these groups. Schizophrenic women had significantly lower CSF copper levels than schizophrenic men, but no significant differences were found between control men and control women. There were no differences in CSF copper levels between patient subgroups with respect to diagnostic subtype (acute versus chronic, paranoid versus chronic undifferentiated), length of hospitalization, race, medication status, platelet monoamine oxidase values, or CAT scan abnormalities.
S.D. Targum, L.N. Rosen, L.E. DeLisi, D.R. Weinberger, and C.M. Citrin
Biol Psychiatry 1983; 18:329-36.
Computerized tomograms (CT scans) and neuroendocrine challenges (TRH stimulation test and dexamethasone suppression test) were completed in 38 melancholic depressed hospitalized patients. There were no significant differences in ventricular size between delusional and nondelusional depressives. However, 5 of 20 delusional depressives (25%) in contrast to none of 18 nondelusional depressives had ventricular brain ratios greater than 2 standard deviations from the mean of 26 neurological controls. There were no demographic, clinical, or neuroendocrine differences between patients with enlarged ventricles and those with normal CT scans. Two of 5 patients with large ventricles were rehospitalized within the 1st year of ascertainment in contrast to 3 of the other 15 delusional depressed patients. The possible relevance of cerebral ventricular size for depressive disorder is discussed.
D.R. Weinberger, R.L. Wagner, and R.J. Wyatt
Schizophr Bull 1983; 9:193-212.
Over the past 20 years, there has been a relatively quiet but persistent effort to investigate anatomical neuropathology in schizophrenia. This effort has involved post- mortem histopathology using novel preparation procedures, pneumoencephalography, and computed tomography. The bulk of this research is critically reviewed here. The evidence presented suggests that the brains of schizophrenic patients frequently contain abnormalities. The limbic region is especially likely to show pathological changes. However, the changes are variable and nonspecific. The implications of these findings are discussed in terms of our limited knowledge of the clinical manifestations of subtle limbic pathology. It is concluded that pathology of limbic regions is associated with schizophrenia and that the more gross the pathology, the more neurologically impaired are the patients.
D.V. Jeste, J.E. Kleinman, S.G. Potkin, D.J. Luchins, and D.R. Weinberger
Biol Psychiatry 1982; 17:199-222.
We studied 93 chronic schizophrenic inpatients, who met the Research Diagnostic Criteria for schizophrenia. Data on a number of historical, epidemiologic, phenomenologic, biochemical, neuropathological, and treatment-response variables were analyzed, using univariate and multivariate statistical analyses. Patients were classified into pairs of subgroups, according to each of the following seven dimensions: (1) ventricle/brain ratio (VBR) assessed on computed tomography scans (normal vs. abnormal); (2) premorbid adjustment (good vs. poor); (3) therapeutic response to neuroleptics (good vs. poor); (4) platelet monoamine oxidase (MAO) activity (low vs. high); (5) paranoid features (present vs. absent); (6) tardive dyskinesia (present vs. absence); and (7) hemispheric asymmetry on computed tomography scans (normal vs. abnormal). These seven dimensions were chosen because earlier studies had shown that the variables involved were operationally definable and were of potential relevance to the subgrouping of schizophrenic patients. Our results suggested that two biological variables, viz., VBR and platelet MAO activity, might be useful in identifying two rather distinct subgroups among chronic schizophrenic patients. A subgroup with large VBR was associated with poor premorbid adjustment, neurological impairment, and poor therapeutic response to neuroleptics, while the subgroup with low platelet MAO activity was characterized by the presence of paranoid features and tardive dyskinesia. Possible explanations, implications, and limitations of our findings are discussed.
C.N. Karson, L.B. Bigelow, J.E. Kleinman, D.R. Weinberger, and R.J. Wyatt
Br J Psychiatry 1982; 140:503-7.
Spontaneous eye blink rates, psychiatric symptoms and response to neuroleptic medication may all be mediated by dopamine. Fixed doses of haloperidol, a dopamine blocking agent, were administered for six weeks to 17 chronic schizophrenic patients who had been previously withdrawn from all medications. The change in blink rates caused by haloperidol corresponded to a change in the thought disturbance syndrome which measures positive symptoms (r = .48, P less than .05). The relationship was particularly clear in patients with normal cerebral ventricles (r = .74, P less than .01).
C.N. Karson, D.R. Weinberger, L. Bigelow, and R.J. Wyatt
Am J Psychiatry 1982; 139:1627-8.
J.E. Kleinman, D.R. Weinberger, A. Rogol, D.J. Shiling, W.B. Mendelson, G.C. Davis, et al.
Psychiatry Res 1982; 7:1-7.
Naloxone produced improvement in abnormal thought content in medicated chronic schizophrenic patients, but not in drug-free patients. In contrast, drowsiness and increases in plasma prolactin concentrations were seen only in drug-free schizophrenic patients. Although growth hormone concentrations increased in drug-free and medicated schizophrenic patients, the time course was different in the two groups. Neuroleptics appear to alter naloxone's clinical and neuroendocrine effects in chronic schizophrenic patients.
J.E. Kleinman, D.R. Weinberger, A.D. Rogol, L.B. Bigelow, S.T. Klein, J.C. Gillin, et al.
Arch Gen Psychiatry 1982; 39:655-7.
Plasma prolactin concentrations in 17 drug-free chronic schizophrenic patients correlated inversely with ratings of their psychopathology. An inverse relationship between psychotic symptoms and plasma prolactin concentrations was particularly clear in patients with normal cerebral ventricular size as determined by computed tomography. The psychosis-prolactin relationship did not hold for schizophrenic patients with large ventricular size. These data suggest that the degree of psychosis is related to dopaminergic activity insofar as this is reflected by plasma prolactin concentrations, especially in schizophrenic patients with normal ventricular size. These findings lend further support to the hypothesis that ventricular size is a meaningful factor in subtyping chronic schizophrenic patients.
D.J. Luchins, D.R. Weinberger, and R.J. Wyatt
Am J Psychiatry 1982; 139:753-7.
The authors nonblindly assessed occipital cerebral asymmetry on computed tomography (CT) scans of 79 schizophrenic or schizoaffective patients and 100 neurological or medical patients. More of the schizophrenic patients had reversals of the normal asymmetry than did controls. The schizophrenics with CT evidence of brain atrophy has a higher frequency of normal asymmetrics than did controls, and the schizophrenics without atrophy had more reversed asymmetries. The schizophrenics with reversed asymmetry, compared with those with normal asymmetry, had lower verbal than performance IQ. Comparison of occipital asymmetry and lateral ventricular asymmetry indicated that reversed asymmetry in the schizophrenic patients was probably not due to localized atrophy.
S.G. Potkin, D. Shore, E.F. Torrey, D.R. Weinberger, J.C. Gillin, R.I. Henkin, et al.
Biol Psychiatry 1982; 17:1315-22.
Mean CSF zinc concentration was lower in a group of ex-heroin addicts than in groups of normal controls and neuroleptic-treated schizophrenic patients, but values were generally within the normal range of CSF zinc concentrations. There were no significant differences in mean CSF zinc concentrations between groups of drug-free schizophrenic patients, schizophrenic patients on neuroleptics, and normal controls. CSF zinc concentration may be influenced by differences in racial composition and related dietary and other habits of the groups studied.
D.R. Weinberger, L.E. DeLisi, G.P. Perman, S. Targum, and R.J. Wyatt
Arch Gen Psychiatry 1982; 39:778-83.
To assess whether computed tomographic findings are present at the onset of schizophrenia, we evaluated CT scans of 35 patients with first-episode schizophreniform disorder, 17 with chronic schizophrenia, 23 with affective disorders, 27 with other psychiatric disorders, and 26 controls. Both the schizophreniform and the chronic schizophrenic patients had significantly larger cerebral ventricles than did the other psychiatric or control subjects. Ventricular size in the patients with affective disorder was not significantly different than in any of the other groups. Twenty percent of the schizophreniform patients had enlarged ventricles, (ventricular-brain ratio, greater than 10). The only other subjects outside this limit were four chronic schizophrenic patients (24%). Five schizophreniform patients and three with affective disorder had evidence of mild cortical atrophy. The results suggest that, in some schizophrenic patients, ventricular enlargement and less frequently cortical atrophy predate the onset of psychoses and are not a result of psychiatric treatment.
D.R. Weinberger, D.J. Luchins, J. Morihisa, and R.J. Wyatt
Ann Neurol 1982; 11:97- 100.
The volume of a portion of the frontal and occipital lobes was measured in 40 brains in the Yakovlev Collection. In 32 cases the volume of the right frontal lobe was larger than that of the left; in the same number of cases the left occipital lobe was larger than the right (p less than 0.01). The asymmetries existed in fetal brains as early as 20 weeks of gestation. The results confirm observations made with computed tomography and indicate that this nonrandom asymmetrical pattern is an early manifestation of human brain development.
L.B. Bigelow, D.R. Weinberger, and R.J. Wyatt
Am J Psychiatry 1981; 138:81-3.
The authors describe a longitudinal, placebo- controlled study of the response to drug treatment of a 62-year-old schizoaffective patient hospitalized for 40 years. While neither lithium nor a neuroleptic drug alone was effective, both drugs administered simultaneously led to the gradual extinction of a pronounced behavioral cycle and the disappearance of manifest psychosis. The authors suggest a synergistic interaction between the two drugs and stress the need for sustained trials of the combination in patients with similar behavioral cycles.
L.E. DeLisi, L.M. Neckers, D.R. Weinberger, and R.J. Wyatt
Arch Gen Psychiatry 1981; 38:647-50.
Whole blood serotonin concentrations were studied in 33 chronic schizophrenic patients who previously had computed tomographic (CT) brain scans and in 23 healthy volunteers. The chronic schizophrenic patients had a mean serotonin concentration significantly higher than that of the controls. The patients were subcategorized into a group with abnormal CT scan findings (enlargement of cerebral ventricles, cerebral atrophy, or both) and a group with normal CT scans. The patients with abnormal CT scans had significantly higher serotonin concentrations when compared with schizophrenics with normal CT scans and with controls. The chronic schizophrenic patients with normal CT scans did not have significantly elevated serotonin concentrations compared with controls. Furthermore, ventricular size in the total group was significantly correlated with serotonin concentration.
L.E. Delisi, D.R. Weinberger, S. Potkin, L.M. Neckers, D.J. Shiling, and R.J. Wyatt
Br J Psychiatry 1981; 139:513-8.
Immunoglobulins, IgG, IgA and IgM were quantified in cerebrospinal fluid (CSF) and plasma from chronic schizophrenic patients and controls using an immunofluorescent antibody technique. A generalized reduction in immunoglobulin levels was observed in the schizophrenic patients compared with controls. While this study supports other reports of abnormal immune functioning in schizophrenia, it failed to replicate previous findings of elevations in CSF IgG and elevations in serum IgA. The aetiology and significance of these findings are hypothesized but remain elusive.
D.J. Luchins, J.C. Gillin, R.L. Wagner, L.E. DeLisi, J.M. Morihisa, D.R. Weinberger, et al.
Biol Psychiatry 1981; 16:91-5.
D.J. Luchins, J.M. Morihisa, D.R. Weinberger, and R.J. Wyatt
Am J Psychiatry 1981; 138:1501-3.
The authors examined volumetric occipital asymmetry and evidence of anterior vermian atrophy in the postmortem brains of 12 schizophrenic and 32 control subjects. Although they found no difference in the mean occipital asymmetry they found that for the schizophrenic subjects abnormal occipital asymmetry and vermian atrophy were inversely related.
D.J. Luchins, D.R. Weinberger, E.F. Torrey, A. Johnson, N. Rogentine, and R.J. Wyatt
Br J Psychiatry 1981; 138:240-3.
The frequency of HLA-A2 was examined in 32 black and 22 white schizophrenic patients separated into two groups according to whether they had normal or reversed cerebral hemisphere asymmetries as determined by computed tomography. The black patients with reversed asymmetry had a significantly greater frequency of HLA-A2 as compared to black patients with normal asymmetry and a black normal control group. There were no significant differences for any other A, B or C antigens. These findings also held when only the 22 black patients without evidence of brain atrophy were studied. The results for the white patients were in the same direction but did not reach statistical significance. These findings suggest that, at least for black schizophrenic patients, reversed cerebral asymmetry is associated with an increased frequency of HLA-A2.
D.R. Weinberger, L.B. Bigelow, S.T. Klein, and R.J. Wyatt
J Clin Psychopharmacol 1981; 1:120-3.
As a test of the hypothesis that neuroleptics can induce a psychosis secondary to dopamine receptor supersensitivity, we examined the behavioral ratings of 20 symptomatic chronic schizophrenic patients who were withdrawn from neuroleptic drugs and maintained drug free for 4 wk. We hypothesized that, if supersensitivity existed, it might be reflected in a drug-free course characterized by an initial phase of exacerbation followed by improvement (a hump). Four patients had such a course. No patient had the inverse of this hypothesized course (improvement followed by relapse). The implications of this finding and problems inherent in testing the supersensitivity psychosis hypothesis are discussed.
D.R. Weinberger, L.E. DeLisi, A.N. Neophytides, and R.J. Wyatt
Psychiatry Res 1981; 4:65-71.
To investigate the possibility that lateral cerebral ventricular size may be under genetic control, we compared the computed tomography (CT) scans of 17 healthy siblings from 7 normal sibships. The CT scans of 10 chronic schizophrenic patients and 12 of their nonschizophrenic siblings were also compared. A trend was found for a correlation of ventricular size between siblings in the healthy sibships (ICC = 0.25, p = 0.1) but not in the schizophrenic sibships (ICC = -0.05). In each sibship the schizophrenic patient had the largest ventricles; in seven cases they exceeded the normal range. Although the discordant siblings were all well within the normal range, their ventricles were larger (p = 0.001) than those of the controls. The findings suggest a genetic component to ventricular size in healthy individuals and that CT findings in schizophrenics are not coincidental familial traits but markers of the illness. The implications of the findings in the discordant siblings are discussed.
R.J. Wyatt, S.G. Potkin, J.E. Kleinman, D.R. Weinberger, D.J. Luchins, and D.V. Jeste
J Nerv Ment Dis 1981; 169:100-12.
Six biological variables- platelet monoamine oxidase activity, urine phenylethylamine concentration, brain norepinephrine concentration, abnormalities on computerized tomography, lateralization asymmetries, and the presence or absence of tardive dyskinesia-are used to discriminate possible biological groups of schizophrenic patients. All variables successfully subclassify patients, some into divisions consistent with phenomological, psychosocial, or biochemical descriptions or hypotheses of schizophrenia. None of the measures, however, has sufficiently stood the test of time to be of clinical utility.
E.F. Donnelly, I.N. Waldman, R.O. Reider, and D.R. Weinberger
Biol Psychiatry 1980; 15:649-50.
E.F. Donnelly, D.R. Weinberger, I.N. Waldman, and R.J. Wyatt
J Nerv Ment Dis 1980; 168:305-8.
The Halstead-Reitan Battery (HRB), including the Wechsler Adult Intelligence Scale, was administered to 15 young chronic schizophrenic patients in an attempt to identify blindly those patients with evidence of morphological brain abnormalities on prior computed tomography (CT). The CT scan status of 12 of 15 (80 per cent) patients was correctly identified solely on the basis of neuropsychological testing. These results supported our hypothesis that impairment on the HRB in chronic schizophrenic patients was associated with morphological abnormalities on the CT scan, and that the positive and negative CT scans of these patients could be predicted accurately.
W.J. Freed, D.R. Weinberger, L.A. Bing, and R.J. Wyatt
Psychopharmacology 1980; 71:291-7.
A variety of drugs were screened to determine which were capable of blocking the behavioral stimulation produced in mice by acute administration of phencyclidine (PCP). Chlorpromazine and clozapine blocked PCP-induced stimulation, while haloperidol, reserpine, and alpha-methyl-p-tyrosine did not. The GABA receptor agonists imidazole acetic acid and muscimol blocked PCP, but other drugs that influence GABA, such as dipropylacetic acid, baclofen, and diazepam, were ineffective. Yohimbine and methysergide also blocked PCP in high dosages, but other drugs with comparable alpha-noradrenergic and serotonergic blocking properties (phentolamine, cyproheptadine, and cinnanserin) were ineffective. Cholinergic and anticholinergic drugs, beta- noradrenergic and opiate antagonists and nonspecific sedatives and convulsants were also ineffective. These findings suggest that chlorpromazine, clozapine, yohimbine, and methysergide may share a property that is unlike their primary known modes of action on dopaminergic, alpha-noradrenergic, and serotonergic neurotransmitter systems, and that this property accounts for their ability to block PCP. However, the effectiveness of GABA agonists appears to be mediated through direct activation of GABA receptors. It is suggested that chlorpromazine and imidazole acetic acid should be considered as possible drug treatments for PCP toxicity.
D.V. Jeste, R.L. Wagner, D.R. Weinberger, K.G. Rieth, and R.J. Wyatt
Am J Psychiatry 1980; 137:247-8.
D.V. Jeste, D.R. Weinberger, S. Zalcman, and R.J. Wyatt
Br J Psychiatry 1980; 136:606-8.
D. Luchins, E.F. Torrey, D.R. Weinberger, S. Zalcman, L. Delisi, A. Johnson, et al.
Br J Psychiatry 1980; 136:243-8.
A survey of 14 published studies found no consistent association between specific HLA antigens and schizophrenia. Since these studies lacked diagnostic or biological criteria, an investigation was undertaken using recognized diagnostic criteria and CT scan findings. Typing for HLA antigens at loci A, B and C was carried out on 130 patients. Among 92 black schizophrenic patients there was an increase of HLA-A2 which remained significant even after correcting for the number of antigens studied. When the patients for whom CT scans were available were divided according to the presence or absence of evidence of brain atrophy, there was an increase of A2 in the black schizophrenic patients without evidence of atrophy, which remained significant after multiplying by the number of antigens studied. However, there was no significant increase of A2 in those with evidence of atrophy. Similar trends held for the white population but they failed to reach significance. The need for HLA studies on biologically defined groups of schizophrenic patients is stressed.
D.J. Luchins, D.R. Weinberger, J.E. Kleinman, L. Neckers, J.E. Rosenblatt, L.B. Bigelow, et al.
Am J Psychiatry 1980; 137:499-500.
H.A. Nasrallah, J.E. Kleinman, D.R. Weinberger, J.C. Gillin, and R.J. Wyatt
Arch Gen Psychiatry 1980; 37:1427.
D.R. Weinberger, L.B. Bigelow, J.E. Kleinman, S.T. Klein, J.E. Rosenblatt, and R.J. Wyatt
Arch Gen Psychiatry 1980; 37:11-3.
Response to neuroleptic drug treatment in ten chronic schizophrenic patients with enlarged cerebral ventricles was compared with ten similar patients with normal ventricles. The groups were closely matched for age, age at onset of illness, years of illness and hospitalization, drug dosage, and plasma neuroleptic concentration as measured by radioreceptor assay. Response was significantly worse in the patients with enlarged ventricles. This finding supports the notion that ventricular enlargement is clinically relevant in patients with chronic schizophrenia and that patients with this abnormality may have a biologically different illness than similar patients without it.
D.R. Weinberger, E. Cannon- Spoor, S.G. Potkin, and R.J. Wyatt
Am J Psychiatry 1980; 137:1410- 3.
The authors evaluated the premorbid adjustment of 51 chronic schizophrenic patients by retrospective chart analysis using a novel scale. Those patients with CT evidence suggestive of brain atrophy had significantly worse premorbid scores, particularly during childhood, than did the patients with normal scans. This finding provides further support for the clinical relevance of CT findings in chronic schizophrenic patients and implicates a neuropathological process that occurs early in development.
D.R. Weinberger, J.E. Kleinman, D.J. Luchins, L.B. Bigelow, and R.J. Wyatt
Am J Psychiatry 1980; 137:359-61.
In a morphometric study of the anterior cerebellar vermis of 47 brains in the Yakovlev collection, the area of the vermis of 5 of 12 brains of schizophrenic patients was smaller than that of any of 11 brains of control subjects without psychiatric or neurologic disease and 9 of 10 brains of control subjects with other psychiatric diagnoses (p less than .02). This finding confirms computerized tomography scan observations in live patients and supports the idea that some schizophrenic patients have structural abnormalities of the cerebellar vermis.
D.R. Weinberger, and R.J. Wyatt
Lancet 1980; 1:1130.
D.J. Luchins, D.R. Weinberger, and R.J. Wyatt
Arch Gen Psychiatry 1979; 36:1309-11.
Normal right-handed individuals often show neuroanatomical asymmetries of the brain on computed tomography (CT), with wider right frontal and left occipital lobes. We examined the frequency of reversals of this normal asymmetry in a group of 57 right-handed, the schizophrenic patients. Compared to 80 normal right-handeders, the schizophrenics had an increased frequency of both frontal and occipital reversals. We then divided the patients on the basis of whether they had CT evidence suggestive of brain atrophy. Those without evidence of atropy had increased frontal and occipital reversals. Those with evidence of atrophy had no increase in reversals. This suggests that reversals of neuroanatomical asymmetry, and by implication abnormalities of lateralization, are relevant to a subgroup of schizophrenic patients with otherwise normal CT scans.
D.J. Luchins, D.R. Weinberger, and R.J. Wyatt
Am J Psychiatry 1979; 136:1598-9.
D.R. Weinberger, E.F. Torrey, A.N. Neophytides, and R.J. Wyatt
Arch Gen Psychiatry 1979; 36:935-9.
Enlarged cerebral ventricles in chronic schizophrenic patients suggest a process of mild cerebral atrophy occurs in some. To see if this process involves the cerebral cortex, the widths of the Sylvian fissure, the interhemispheric fissure, and three cortical sulci were measured blindly on computerized tomography (CT) scans of 75 chronic psychiatric patients and 62 asymptomatic volunteers, all less than 50 years of age. A total of 19 of the 60 patients with chronic schizophrenia had at least one abnormality. All 15 patients with other diagnoses were within the control range. Comparing those chronic schizophrenic patients with abnormalities to those without them, there were no significant differences in age, length of illness or treatment, and length of hospitalization. From this and ventricular size data, two thirds of the chronic schizophrenics had some cerebral structural abnormality. Ventricular enlargement did not correlate significantly with cortical abnormalities. Therefore, more than one etiology may account for the structural abnormalities found in chronic schizophrenic patients.
D.R. Weinberger, E.F. Torrey, A.N. Neophytides, and R.J. Wyatt
Arch Gen Psychiatry 1979; 36:735-9.
To investigate if cerebral ventricular enlargement is associated with chronic schizophrenia, computerized tomography scans from 73 psychiatric patients were compared with 56 asymptomatic volunteers all less than 50 years old. Ventricular size was significantly greater in the subgroup of 58 chronic schizophrenic patients than in the controls. Of the chronic schizophrenic patients, 40% were outside the control range; 53% exceeded 2 SDs of the control mean. Neither duration of illness nor length of hospitalization correlated with ventricular size. The 44 chronic schizophrenic patients who had never been treated with electroshock therapy (EST) had larger ventricles than controls. A group of seven nonchronic schizophrenic patients also had enlarged ventricles; the eight patients who were either schizoaffective or nonschizophrenic did not differ from controls. This study shows that lateral cerebral ventricular enlargement is associated with chronic schizophrenia; it suggests that this is not a result of treatment.
D.R. Weinberger, E.F. Torrey, and R.J. Wyatt
Lancet 1979; 1:718-9.
J.S. Carman, J.C. Gillin, D.L. Murphy, D.R. Weinberger, J.E. Kleinman, L.B. Bigelow, et al.
Commun Psychopharmacol 1978; 2:513-23.
D.J. Greenblatt, R.I. Sahder, D.R. Weinberger, M.D. Allen, and D.S. MacLaughlin
Psychopharmacology 1978; 57:199-203.
D.R. Weinberger, and R.J. Wyatt
Jama 1978; 239.
D.R. Weinberger
Am J Psychiatry 1977; 134:1048-9.
D.R. Weinberger, and M.J. Kelly
J Nerv Ment Dis 1977; 165:263-8.
An unusual, acute extrapyramidal reaction, which resulted from treatment with haloperidol and which was unresponsive to standard anticholinergic treatment and indistinguishable on clinical grounds from acute catatonia, is described. Because the etiology of this reaction was not appreciated, progressive, life- threatening physiological deterioration ensued accompanied by unremitting neuromuscular symptoms, a clinical picture resembling both lethal catatonia and the rare neuroleptic malignant syndrome. The literature on these conditions is reviewed and various problems in differential diagnosis are discussed. It is proposed that some cases of the neuroleptic malignant syndrome and perhaps lethal catatonia may represent the evolution of severe extrapyramidal reactions.
C.E. Cherubin, S. Kane, D.R. Weinberger, E. Wolfe, and T. McGinn
Ann Intern Med 1972; 76:385-9.