Biomedical subjects

D R Weinberger

Publications and source records attributed to D R Weinberger.

At least 19 recordsLinked to original sources

PubMed1999

Neuropsychological performance of monozygotic twins discordant for bipolar disorder.

BACKGROUND: A paradigm that involves cognitive assessment of monozygotic (MZ) twins discordant for a neuropsychiatric disorder (here bipolar illness) allows for the examination of both disease-specific impairments (in the comparison of affected to unaffected twins) and risk factors (in the comparison of unaffected twins to normal twins). METHODS: Neuropsychological functions were evaluated in seven MZ twin pairs discordant for bipolar illness and seven pairs of normal MZ twins in an attempt to highlight cognitive abilities associated with manifestations of disease and genetic risk factors. At the time of testing, 3 of the affected twins were euthymic, 2 had depressive symptoms, and 2 had manic symptoms; all were receiving medication. All twins receive neuropsychological tests to evaluate intelligence, attention, visuospatial skills, language, learning and memory, and problem solving. RESULTS: Statistical analyses revealed that the affected twins were significantly impaired as compared to the unaffected (and normal) twins on some measures of visuospatial functioning and some verbal memory measures. In contrast to a sample of MZ twins discordant for schizophrenia studied previously, the cognitive impairments we observed in bipolar twins were mild in nature and fairly circumscribed. The unaffected twins performed significantly worse than normal controls on a Brown-Petersen memory task, verbal list learning, and overall Wechsler Memory Quotient. CONCLUSIONS: These data suggest that while some visuospatial deficits and verbal memory deficits may be features of bipolar disorder related to disease parameters, mild attenuations in overall memory or retrieval function may be related to genetic factors associated with the illness.

Adult↗

PubMed1999

Cell biology of the hippocampal formation in schizophrenia.

The hippocampal formation (HF) has been a centerpiece of neuropathologic investigations of schizophrenia. Numerous MRI studies have demonstrated a slight bilateral reduction in HF volume. Reports of reduced N-acetyl aspartate measured with in vivo proton spectroscopy suggest that neuronal pathology exists. However, morphometric data from postmortem studies have not revealed a clear change in HF size, and recent studies of neuronal number and of cytoarchitecture have been largely negative. Evidence of glial proliferation is consistently absent. The most reproducible positive anatomic finding in postmortem HF has been reduced size of neuronal cell bodies. Studies of gene transcription have provided replicable evidence of decreased expression of mRNAs for synaptophysin, GAP-43, cholecystokinin, and non-NMDA glutamate receptor subunits (GLU R 1 and 2), particularly in CA 3-4. These data about the cellular and molecular biology of the HF in schizophrenia are different from that found in a number of conditions associated with hippocampal damage, including excitotoxicity, epilepsy, alcoholism, Alzheimer's disease, steroid neurotoxicity, and normal aging. Notwithstanding the real possibility that the data are epiphenomena of chronic illness, the findings may implicate a unique cellular defect in schizophrenia--a genetic variation affecting the plasticity of HF circuitry and connectivity. Directions for further research are proposed.

Hippocampus↗

PubMed1999

Hemispheric and sex-linked differences in Sylvian fissure morphology: a quantitative approach using volumetric magnetic resonance imaging.

OBJECTIVE: In a sample of right-handed adults, volumetric magnetic resonance imaging (MRI) was used to reinvestigate hemispheric and sex-linked differences in Sylvian fissure (SF) morphology. BACKGROUND: Asymmetries of the SF exist with a predominant leftward asymmetry consistently reported in postmortem studies. These anatomic asymmetries may reflect asymmetric allocation of adjacent opercula, with some investigators positing a relationship with planum temporale asymmetries, as the postcentral SF is more asymmetric than the anterior segment. Sex-related differences have also been reported with reduced asymmetries in women relative to men. METHOD: Using in vivo MRI surface renderings, SF asymmetries were studied in a group of consistently right-handed men (n = 12) and women (n = 12). Anterior and postcentral SF lengths were measured. RESULTS: Overall, there was a significant leftward asymmetry of the horizontal SF (anterior and postcentral) in men and women. Whereas there was a significant leftward asymmetry of the postcentral SF, there was no significant asymmetry of the anterior SF. There was an increase in the parietal operculum anterior to the posterior ascending ramus (PAR) in the left hemisphere and posterior to the PAR in the right hemisphere when SF asymmetries were leftward, with the length of the anterior parietal operculum positively correlated with postcentral SF length. CONCLUSIONS: These findings demonstrate that the SF is asymmetric but that clear sex-related effects do not exist in consistently right-handed subjects.

Adult↗

PubMed1998

Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype.

BACKGROUND: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. RESULTS: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable. CONCLUSIONS: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.

Adult↗

PubMed1998

MRI asymmetries of Broca's area: the pars triangularis and pars opercularis.

Broca's area, which includes the pars triangularis (PTR) and pars opercularis (POP), is a neuroanatomic region important in speech-language production. Previous data demonstrated that PTR asymmetries are highly correlated with language dominance determined by selective hemispheric anesthesia or Wada testing, suggesting that asymmetries of the PTR may, in part, predict language dominance. The POP, however, has not been measured on volumetric magnetic resonance imaging (MRI), and therefore, it is unclear whether morphological asymmetries of the POP exist, and whether these asymmetries differ in right- and left-handers. The purpose of this study was to determine if measurable asymmetries of the POP exist on MRI, and whether the direction of the asymmetries differ in right- and left-handers. The PTR and POP were measured on volumetric MRI scans of 16 right-handers and 16 left-handers matched for age and gender. There was a significant leftward asymmetry of the PTR in right- and left-handers, although the asymmetry was reduced in the left-handers. In contrast, there was a leftward asymmetry of the POP in right-handers, and a rightward asymmetry in the left-handers. Handedness, derived from a handedness inventory, was positively correlated with POP asymmetry.

Adult↗

PubMed1998

Hemispheric control of motor function: a whole brain echo planar fMRI study.

The aim of this study was to explore whether recruitment of the ipsilateral motor cortex during non-dominant motor movement reflects left hemispheric control of motor function or simply the greater complexity or unfamiliarity of the motor task. BOLD fMRI was performed in normal right-handers during two motor tasks: (1) sequential finger movements (SM task) with the right or left hand; and (2) random finger movements (RM task) with the right hand. In all subjects, activation was predominantly in the contralateral motor areas (primary sensorimotor, lateral premotor, parietal and supplementary motor regions) and ipsilateral cerebellum. While the ipsilateral motor areas were also activated, single subject analysis revealed these areas to be more extensive and to be seen in more subjects during the non-dominant hand SM task and dominant hand RM task than during the more familiar dominant hand SM task. Similarly, group analysis also revealed ipsilateral activation in the primary sensorimotor and lateral premotor areas, but only during the non-dominant SM task and the dominant hand RM task. Non-dominant hand movements, perhaps because they are less 'automatic', appear to require more cortical activity similar to complex tasks with the dominant hand, and result in greater recruitment of ipsilateral cortical motor areas and striatum. The study also illustrates how potentially meaningful subtleties seen on individual maps may be obscured with group averaging approaches.

Adult↗

PubMed1998

Changing patterns of brain activation during maze learning.

Recent research has found that patterns of brain activation involving the frontal cortex during novel task performance change dramatically following practice and repeat performance. Evidence for differential left vs. right frontal lobe activation, respectively, during episodic memory encoding and retrieval has also been reported. To examine these potentially related issues regional cerebral blood flow (rCBF) was measured in 15 normal volunteers using positron emission tomography (PET) during the naive and practiced performance of a maze task paradigm. SPM analysis indicated a largely right-sided, frontal lobe activation during naive performance. Following training and practice, performance of the same maze task elicited a more posterior pattern of rCBF activation involving posterior cingulate and precuneus. The change in the pattern of rCBF activation between novel and practiced task conditions agrees with results found in previous studies using repeat task methodology, and indicates that the neural circuitry required for encoding novel task information differs from that required when the same task has become familiar and information is being recalled. The right-sided preponderance of activation during naive performance may relate to task novelty and the spatially-based nature of the stimuli, whereas posterior areas activated during repeat performance are those previously found to be associated with visuospatial memory recall. Activation of these areas, however, does not agree with previously reported findings of left-sided activation during verbal episodic memory encoding and right-sided activation during retrieval, suggesting different neural substrates for verbal and visuospatial processing within memory.

Adult↗

PubMed1998

Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine.

The effects of early brain damage are often, but not always, milder than the effects of comparable damage in adults, depending on the age at which injury occurred, the region of the brain damaged, and the brain functions involved. Studies of the impact of early brain damage have generally focused on functions primarily associated with the neural structures injured, even though the development and function of distant but interconnected neural systems might also show effects. Here we examine the regulation of striatal dopamine by the dorsolateral prefrontal cortex, in adult monkeys that had had either neonatal or adult lesions of the medial-temporal lobe and in normal animals. We use microdialysis to measure the dopamine response in the caudate nucleus after the infusion of amphetamine into the dorsolateral prefrontal cortex. Normal animals and those with adult lesions showed a reduction in dopamine overflow; in contrast, monkeys with neonatal lesions showed increased dopamine release. Thus, early injury to the primate medial-temporal lobe disrupts the normal regulation of striatal dopamine activity by the dorsolateral prefrontal cortex during adulthood. Early focal lesions may have substantial and long-lasting impacts on the function of a distant neural system.

Animals↗

PubMed1998

Psychomotor slowing, negative symptoms and dopamine receptor availability--an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients.

Anhedonia and psychomotor slowing in schizophrenia have been attributed to a dysfunction of dopaminergic neurotransmission. To differentiate between disease and drug-induced negative symptoms, we examined eight drug-free and eight neuroleptic-treated schizophrenic patients. Positive and negative symptoms and extrapyramidal side effects were assessed using standardized rating scales (PSAS, AMDP, SANS). 'Reaction time' and 'motor speed' were measured using a computer-aided system and striatal dopamine D2/D3 receptor availability was assessed using [I-123]IBZM SPECT. Psychomotor reaction time, parkinsonism, affective flattening and avolition were increased in treated patients relative to the untreated cohort and were negatively correlated with dopamine D2/D3 receptor availability. Significant positive correlations were found between parkinsonism and affective flattening and between psychomotor slowing and avolition. Positive symptoms were not significantly associated with striatal IBZM binding. These findings support the hypothesis that neuroleptic-induced dopamine D2/D3 blockade in the striatum can mimic certain negative symptoms, such as affective flattening and avolition, and indicates that psychomotor testing may be helpful in differentiating between disease and drug-induced negative symptoms.

Acute Disease↗

PubMed1998

Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study.

BACKGROUND: Proton magnetic resonance spectroscopic imaging (1H-MRSI) studies have reported reductions of N-acetyl aspartate (NAA), a marker of neuronal integrity, in the hippocampal region (HIPPO) and dorsolateral prefrontal cortex (DLPFC) of pharmacologically treated patients with schizophrenia. The purpose of the present study was twofold: to exclude drug treatment as a source of the previous findings and to examine NAA relative concentrations in a unique sample of chronically untreated patients. METHODS: We studied 12 medication-free patients, 5 of whom were "drug naive" and symptomatic for a mean of 12 years, and 12 control subjects. Ratios of areas under the metabolite peaks of the proton spectra were determined [i.e., NAA/creatine (CRE), NAA/choline (CHO), CHO/CRE] for multiple cortical and subcortical regions. Hippocampal formation and frontal lobe volumes were also measured to test for correlations with 1H-MRSI data. RESULTS: Significant reductions of NAA/CRE and NAA/CHO were found bilaterally in HIPPO and DLPFC. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. No significant correlation was found between metabolite ratios, length of illness, and volumes of the hippocampal region and frontal lobe. Mean ratios and effect sizes were not different in chronically ill but still medication-naive patients in comparison with subacute patients and previously studied chronic patients receiving medications. CONCLUSIONS: Bilateral reductions of NAA ratios in HIPPO and DLPFC are reliable findings. The findings implicate a relatively localized pattern of neurochemical pathology that does not appear to change with prolonged illness whether medicated or unmedicated.

Adult↗

PubMed1998

Types and characteristics of remote memory impairment in schizophrenia.

Remote memory, as the term is used in the present study, refers to semantic information or autobiographical information for events and facts that are thought to be stored in the neocortex. In schizophrenia, findings of abnormalities in remote memory have been reported. However, it is unclear whether these are due to retrieval factors or other factors (e.g. paucity of information, disorganized lexicosemantic representations). Furthermore, it is unclear whether there is a temporal gradient in remote memory. In the first study, we utilized a cueing procedure for semantic fluency in order to determine whether retrieval factors play a marked role in impairments. In comparing patients with schizophrenia to patients with affective disorder and normal controls, we found that cueing had an equivalent effect upon all groups, suggesting that marked retrieval deficits were not the primary determinant of poor performance in fluency. Furthermore, we found that semantic fluency was disproportionately impaired vis-a-vis phonologic fluency, suggesting that abnormalities may be greater in storage areas presumed to be in temporal parietal cortex rather than in prefrontal cortex (which has been associated with retrieval deficits). In the second study, we examined the temporal gradient of autobiographical memory in patients with schizophrenia and normal controls. Whereas normal controls exhibited high and equivalent performance across childhood, early adult, and recent memories, patients with schizophrenia exhibited a u-shaped profile perhaps unique in the neuropsychiatric literature. This may reflect a combination of secondary memory impairments which effect the acquisition of new information coupled to very mildly accelerated rate of forgetting, 'recency' effects, and/or inefficient encoding. Taken together, these studies provide further support for the notion that schizophrenia has a relatively unique pattern of neuropsychological deficit based on neocortical dysfunction that includes, though is not restricted to, temporoparietal regions.

Adult↗

PubMed1998

Operant conditioning and the orbitofrontal cortex in schizophrenic patients: unexpected evidence for intact functioning.

Neuroimaging and neuropsychological studies have consistently implicated dorsolateral prefrontal cortex as abnormal in schizophrenia. However, other areas of frontal cortex have received far less attention. In particular, few studies have examined orbital frontal regions with other than olfactory tests. In the present study we wished to assess the functional capability of orbital frontal cortex using a test developed by Bechara et al. (1994) that assesses a subject's capacity to acquire a preference through reward and punishment, using a gambling task that involved gains and losses of play money. Thirty normal subjects and 12 patients with schizophrenia (three undifferentiated, eight paranoid, one schizoaffective) comprised the sample in the present study. We found that patients with schizophrenia exhibited a pattern of findings similar to that of normals and dissimilar to that of patients with known orbital frontal damage. In our study, both normal subjects and schizophrenic patients chose most frequently from decks of cards in which there were frequent rewards and infrequent penalties, as might be expected on the basis of operant conditioning literature. We also found that performance on this task was not correlated with tests of working memory or long-term memory, suggesting that the development of a preference may occur implicitly. Our findings also argue against a general deficit in schizophrenia, as performance on the gambling task appeared relatively uncompromised.

Adolescent↗

PubMed1998

Uncoupling cognitive workload and prefrontal cortical physiology: a PET rCBF study.

Working memory is a fundamental cognitive building block involved in the short-term maintenance and transformation of information. In neuropsychological studies, working memory has been shown to be of limited capacity; however, the neurophysiological concomitants of this capacity limitation have not been explored. In this study we used the [15O] water PET rCBF technique and statistical parametric mapping to examine normal subjects while they performed two cognitive tasks, both individually and simultaneously. One task was the Wisconsin Card Sorting Test, a complex reasoning task involving working memory, and the other was a rapidly paced auditory verbal shadowing task. When both tasks were performed simultaneously, there were significant decrements in performance compared with the individual task performance scores, indicating that cognitive workload had been increased. Analysis of the rCBF maps showed that when the two tasks were performed together, in contrast to when they were performed separately, there was less prefrontal activation. These results suggest that increases in cognitive workload do not necessarily recruit and then sustain cortical neurophysiological resources to a maximum, but rather may actually be accompanied by a diminution in cortical activity.

Adult↗

PubMed1998

Quantitation of regional cerebral blood flow increases in prefrontal cortex during a working memory task: a steady-state arterial spin-tagging study.

Steady-state arterial spin-tagging MRI approaches were used to quantitate regional cerebral blood flow increases in prefrontal cortex during a working memory ("two-back") task in six normal subjects. Statistically significant increases in cerebral blood flow in prefrontal cortex were observed in all six subjects: the average increase in cerebral blood flow in activated prefrontal cortex regions was 22 +/- 5 cc/100 g/min (23 +/- 7%). The results demonstrate that spin-tagging approaches can be used to follow focal activation in prefrontal cortex during cognitive tasks.

Adult↗

PubMed1998

In vivo imaging of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography.

The distribution and kinetics of 5-[123I]iodo-A-85380, a novel ligand for brain nicotinic acetylcholine receptors (nAChRs), were evaluated in the Rhesus monkey using single photon emission computed tomography (SPECT). Peak levels of radioactivity were measured in brain at 90 min after injection of the tracer. Accumulation of radioactivity was highest in the thalamus, intermediate in the frontal cortex and basal ganglia, and lowest in the cerebellum. The ratio of specific to nonspecific binding (V3") in the thalamus, estimated from the (thalamic-cerebellar)/cerebellar radioactivity ratio, reached a value of 6 at 4 h post-injection. Specific binding was reduced by subcutaneous injection of 1 mg/kg cytisine at 2.25 h after injection of radiotracer. At 2.5 h after cytisine administration, radioactivity in the thalamus was reduced by 84%, in the frontal cortex, by 76%, and in the basal ganglia, by 57% of the level measured at the time of cytisine administration, demonstrating that the binding was reversible. On the basis of these findings, together with other data indicating high affinity, receptor subtype selectivity, low nonspecific binding and lack of toxicity in animals, 5-[123I]iodo-A-85380 appears to be a promising ligand for SPECT imaging of nAChRs in the human brain.

Animals↗

PubMed1998

Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia.

Using proton magnetic resonance spectroscopic imaging (1H-MRSI) we found in a previous study a specific pattern of neuronal pathology in patients with schizophrenia as determined by relative loss of signal from N-acetyl-containing compounds (NAA). The purpose of the present study was to assess the reproducibility of the results of 1H-MRSI both in patients with schizophrenia and in normal controls. We studied twice 10 patients and 10 controls on 2 days separated by, on average, 3 months. Reproducibility was assessed with several statistical procedures including ANOVA, coefficients of variation (CVs) and intra-class correlation coefficients (ICC). Patients showed significant reductions of NAA/creatine-phosphocreatine (CRE) and NAA/choline-containing compounds (CHO) selectively in the hippocampal region (HIPPO) and in the dorsolateral prefrontal cortex (DLPFC) on both experimental days. A repeated measures ANOVA showed no effect of time on metabolite ratios in all subjects. CVs were fairly low (especially for NAA/CRE and CHO/CRE) and did not differ significantly between patients and controls. The ICCs of the ROIs reached statistical significance only in a few instances. The present multislice 1H-MRSI study shows that: (1) patients with schizophrenia, when compared as a group to normal controls, show a consistent 1H-MRSI pattern of group differences, i.e., bilateral reductions of NAA/CRE and NAA/CHO in HIPPO and DLPFC; (2)1H-MRSI data in both patients and controls do not show significant changes over this 90-day period; however, absolute metabolite ratios in individuals show low predictability over this time interval; (3) 1H-MRSI data show relatively low variability (as measured by the CVs) both in patients and normal controls, especially for NAA/CRE and CHO/CRE.

Acetylation↗

PubMed1998

Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia.

Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel "n back" working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for "activation" artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients.

Adult↗

PubMed1998

Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage.

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.

Amphetamine↗