Richard Margolin

Bio: Richard Margolin is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Positron emission tomography & Ictal. The author has an hindex of 14, co-authored 16 publications receiving 2045 citations. Previous affiliations of Richard Margolin include University of California, Irvine.

Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders.

Abstract: • Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.

Human brain glucose utilization and cognitive function in relation to age

Abstract: Brain oxidative metabolism was examined with positron emission tomography and [18F]2-deoxy-D-glucose in 40 healthy men aged 21 to 83 years, under conditions of reduced visual and auditory stimulation. The mean cerebral metabolic rate for glucose (CMRglc) equaled 4.6 to 4.7 mg X 100 gm-1 X min-1 and did not correlate significantly with age (p greater than 0.05). Regional cerebral metabolic rates for glucose (rCMRglc) and Q ratios (rCMRglc/CMRglc), which had lower coefficients of variation than did rCMRglc, also did not correlate with age. Hyperfrontality of cerebral metabolism was absent at all ages. Age decrements were demonstrated in the error score on the Benton Revised Visual Retention Test and in the Performance Subtest scaled score of the Wechsler Adult Intelligence Scale (WAIS) but not in the Verbal Subtest scaled score of the WAIS. The cognitive test scores did not correlate with brain metabolic rates. The results indicate that brain oxidative metabolism, when measured under resting conditions with reduced sensory input, is not reduced in relation to age in healthy men. Furthermore, no significant relations between intelligence and resting cerebral metabolism are evident.

Cerebral glucose utilization, as measured with positron emission tomography in 21 resting healthy men between the ages of 21 and 83 years.

Abstract: Positron emission tomography (PET) scanning with 18F-2-deoxy-D-glucose was employed to examine hemispheric and regional rates of cerebral glucose utilization in 21 resting healthy men between the ages of 21 and 83 years. The eyes of the subjects were covered and the external auditory canals were plugged with cotton in the 45 minutes following injection of tracer. Mean hemispheric cerebral metabolic rates for glucose (CMRglc) averaged 4.3 to 4.4 mg x 100 g-1 X min-1, and mean hemispheric grey matter glucose utilization, (CMRglc)grey, averaged 5.2 to 5.3 mg x 100 g-1 X min-1. Neither parameter was correlated significantly with age, nor were their right/left ratios correlated with age (P greater than 0.05). The mean ratios, furthermore, did not differ significantly from 1. Regional cerebral metabolic rates for glucose, rCMRglc, at each of 31 identified midline and bilateral structures also were not correlated significantly with age. Mean rCMRglc ranged from 2.6 mg X 100 g-1 X min-1 at the centrum semiovale to 6.2 mg . 100 g-1 X min-1 at the precentral gyrus of the frontal lobe and precuneus of the parietal lobe. The results indicate that the cerebral metabolic rate for glucose is not correlated with age in healthy men.

[18F]fluorodeoxyglucose positron emission tomography in refractory complex partial seizures.

Abstract: Positron emission tomography with simultaneous electroencephalographic monitoring was performed with [18F]fluorodeoxyglucose in 20 patients with complex partial seizures who had normal computed tomographic scans. Seven patients had only unilateral epileptiform discharges on the electroencephalogram, 3 had predominantly unilateral discharges, and 10 had nonlocalized epileptiform abnormalities. Positron emission tomography showed a hypometabolic lesion in 16 of the 20 patients. Pathological changes in the hypometabolic region were found in postoperative specimens in 4 of 5 patients studied. Positron emission tomography was unaffected by the seizure frequency, state of alertness, or number of spike discharges during the scan. There was a tendency for patients to have higher overall metabolic rates when taking less medication. Seizures occurring during [18F]fluorodeoxyglucose uptake in 3 patients produced a hypermetabolic area at the interictal hypometabolic focus. Positron emission tomography sometimes showed more widespread hypometabolism than suspected on the basis of the scalp-recorded electroencephalogram. The frontal lobe showed a greater degree of hypometabolism than the temporal lobe in 3 patients. Focal lesions may be identified by positron emission tomography even if the electroencephalographic abnormality is not well localized.

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography.

Abstract: The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.

Abstract: • 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 peforming 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.

An application of prefrontal cortex function theory to cognitive aging.

Abstract: The purpose of this review is to extend the existing application of the frontal lobe hypothesis of cognitive aging beyond the limited work on inhibitory control (F. N. Dempster, 1992) to include memory processes supported by the prefrontal cortex. To establish a background for this analysis, I review existing models of prefrontal cortex function and present a synthesized model that includes a general function of temporal integration, supported by 4 specific processes: prospective memory, retrospective memory, interference control, and inhibition of prepotent responses. I found the frontal lobe hypothesis to perform well, with the exception of an inability to account for age-related declines in item recall and recognition memory, possibly a result of age-related declines in medial temporal function.

Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory

Abstract: The sections in this article are: 1 Essence of Prefrontal Function: Regulation of Behavior by Representational Knowledge 11 Subdivisions of Prefrontal Cortex 12 Global Nature of Prefrontal Syndrome in Humans 13 Animal Model for Prefrontal Function in Humans 14 Delayed-Response Tests and Varying Interpretations of Their Functional Significance 15 Distractability and Perseveration: Secondary Consequences of Basic Defect in Representational Memory 16 Representational Memory in Wisconsin Card Sort and Other Diagnostic Tests of Prefrontal Function in Humans 17 Localization of Delayed-Response Function: Principal Sulcus 18 Circuit Basis of Visuospatial Functions 2 Accessing and “On-Line” Processing of Representations in Visuospatial Domain: Parietal-Prefrontal Connections 21 Visuospatial Representational Memory in Humans 22 Spatial-Mnemonic Nature of Delayed-Response Deficit: Domain-Specific Memory Loss 23 Topography of Representational Memory in Prefrontal Cortex 24 Electrophysiological Evidence of Spatial-Mnemonic Processes in Principal Sulcus 25 Parietal-Prefrontal Connectivity 26 Columnar and Laminar Framework for Feedforward and Feedback Mechanisms 27 Functional Significance of Parietal-Prefrontal Collaboration 3 Long-Term Memory and “Off-Line” Processing: Prefrontal-Limbic Connections 31 Role of Hippocampus in Spatial Memory 32 Multiple Connections Between Principal Sulcus and Hippocampal Formation 33 Quadripartite Neural Network: Parietal-Temporal-Cingulate-Prefrontal Circuit 34 Limbic Contribution to Spatial Memory 4 Response Initiation and Inhibition: Projections to Striatum, Tectum, Thalamus, and Premotor Cortex 41 Motor-Control Functions of Prefrontal Cortex 42 Cortical-Striatal Pathway and Related Feedback Loops 43 Cortical-Tectal Pathway 44 Thalamic-Cortical Systems 45 Prefrontal-Premotor Connections: Anterior Supplementary Motor Cortex Relays 46 Functional Speculations 5 Modulatory Mechanisms: Brain Stem Catecholamine Projections 51 Activation of Cognitive Machinery 52 Concentration and Synthesis of Catecholamines in Primate Cortex 53 Brain Stem Innervation of Prefrontal Cortex 54 Delayed-Response Deficits and Recovery Produced by Catecholamine Loss and Replacement in Prefrontal Cortex 55 Circuit Basis for Neuromodulation in Principal Sulcus 6 Multiple Subsystems of Prefrontal Cortex: Unity or Diversity of Function 61 Unity or Diversity of Prefrontal Function 62 Frontal Eye Fields 63 Inferior Convexity 64 Orbital Prefrontal Cortices 65 Problem of Integration 7 Diseases Affecting Prefrontal Cortex 71 Schizophrenia: Loss of Corticocortical Processing and Regulation of Behavior by Representational Knowledge 72 Wernicke-Korsakoff Syndrome: Loss of Thalamocortical and Brain Stem Modulatory Mechanisms 73 Huntington's Chorea and Parkinson's Disease: Loss of Prefrontal-Striatal Mechanisms and Initiation or Inhibition of Motor Response 74 Overview of Neurobiology of Disease 8 Summary

Positron emission tomography study of human brain functional development.

Abstract: From over 100 children studied with 2-deoxy-2[18F]fluoro-D-glucose and positron emission tomography we selected 29 children (aged 5 days to 15.1 years) who had suffered transient neurological events not significantly affecting normal neurodevelopment. These 29 children were reasonably representative of normal children and provided an otherwise unobtainable population in which to study developmental changes in local cerebral metabolic rates for glucose (lCMRGlc). In infants less than 5 weeks old lCMRGlc was highest in sensorimotor cortex, thalamus, brainstem, and cerebellar vermis. By 3 months, lCMRGlc had increased in parietal, temporal, and occipital cortices; basal ganglia; and cerebellar cortex. Frontal and dorsolateral occipital cortical regions displayed a maturational rise in lCMRGlc by approximately 6 to 8 months. Absolute values of lCMRGlc for various grey matter regions were low at birth (13 to 25 mumol/min/100 gm), and rapidly rose to reach adult values (19 to 33 mumol/min/100 gm) by 2 years. lCMRGlc continued to rise until, by 3 to 4 years, it reached values of 49 to 65 mumol/min/100 gm in most regions. These high rates were maintained until approximately 9 years, when they began to decline, and reached adult rates again by the latter part of the second decade. The highest increases of lCMRGlc over adult values occurred in cerebral cortical structures; lesser increases were seen in subcortical structures and in the cerebellum. This time course of lCMRGlc changes matches that describing the process of initial overproduction and subsequent elimination of excessive neurons, synapses, and dendritic spines known to occur in the developing brain. The determination of changing metabolic patterns accompanying normal brain development is a necessary prelude to the study of abnormal brain development with positron emission tomography.

Reduction of prefrontal cortex glucose metabolism common to three types of depression.

Abstract: • Using positron emission tomography, we studied cerebral glucose metabolism in drug-free, age- and sex-matched, righthanded patients with unipolar depression (n =10), bipolar depression (n =10), obsessive-compulsive disorder (OCD) with secondary depression (n =10), OCD without major depression (n =14), and normal controls (n =12). Depressed patients were matched for depression on the Hamilton Depression Rating Scale, and subjects with OCD without depression and OCD with depression had similar levels of OCD pathology. We also studied six non—sex-matched patients with mania. Mean ( ± SD) glucose metabolic rates for the left dorsal anterolateral prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole (ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05 ±0.05; bipolar depression =1.04 ± 0.05), and were significantly lower than those in normal controls (1.12 ± 0.06) or OCD without depression (1.15 ± 0.05). Results for the right hemisphere were similar. Values in subjects with OCD with depression (1.10 0.05) were also significantly lower than in subjects with OCD without depression, and values in subjects with bipolar depression were lower than those in manic subjects (1.12 ± on this measure in the left hemisphere, although results were not significant in the right hemisphere. There was a significant correlation between the HAM-D score and the left ALPFC/hem. With medication for depression (n =12), the left ALPFC/hem increased significantly and the percentage change in the Hamilton scale score correlated with the percentage change in the left ALPFC/hem. These data support other findings that major depression is associated with a left ALPFC abnormality.