Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders.
Monte S. Buchsbaum1, Lynn E. DeLisi2, Henry H. Holcomb2, J. Cappelletti2, A C King2, Jeannette L. Johnson2, Erin A. Hazlett1, Susan Dowling-Zimmerman2, Robert M. Post2, John M. Morihisa2, William T. Carpenter3, Robert M. Cohen2, David Pickar2, Daniel R. Weinberger2, Richard Margolin2, R. M. Kessler2 •
01 Dec 1984-Archives of General Psychiatry (American Medical Association)-Vol. 41, Iss: 12, pp 1159-1166
TL;DR: Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in patients with schizophrenia and patients with affective disorder, sharing a lack of diagnostic specificity with many biologic measures.
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.
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TL;DR: 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.
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.
2,066 citations
TL;DR: The sections in this article are: Essence of Prefrontal Function: Regulation of Behavior by Representational Knowledge, Multiple Subsystems of Pre Frontal Cortex: Unity or Diversity of Function, and Functional Speculations.
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
1,923 citations
TL;DR: Using positron emission tomography, cerebral glucose metabolism in drug-free, age- and sex-matched, right-handed patients with unipolar depression, bipolar depression, obsessive-compulsive disorder (OCD) with secondary depression, OCD without major depression, and normal controls is studied.
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.
1,288 citations
TL;DR: Research in animals and of cognitive function in normal, brain-injured, and schizophrenic subjects support the theory that a defect in working memory--the ability to guide behavior by representations--may be the fundamental impairment leading to schizophrenic thought disorder.
Abstract: Recent advances in anatomical, behavioral, and physiological techniques have produced new information about the nature of prefrontal function, its cellular basis, and its anatomical underpinnings in nonhuman primates. These findings are changing our views of prefrontal function and providing insight into possible bases for human mental disorder. A major advance is the recognition that various prefrontal areas are engaged in holding information "on line" and updating past and current information on a moment-to-moment basis. Studies of animals and of cognitive function in normal, brain-injured, and schizophrenic subjects support the theory that a defect in working memory--the ability to guide behavior by representations--may be the fundamental impairment leading to schizophrenic thought disorder.
1,050 citations
TL;DR: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss, bringing about an activity-dependent down-regulation associated with the functional hypoactivity of the DLPFC and implying that overall cortical neuronal migration had not been compromised in development.
Abstract: Background: Up-regulation of γ-aminobutyric acid A (GABA A ) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development. Methods: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA-expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 µm in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calciumcalmodulin-dependent protein kinase (CamIIK) were quantified. Results: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics. The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activitydependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression. Conclusions: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotrans mitter-related gene expression.
983 citations
References
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01 Jan 1970
TL;DR: The STAI as mentioned in this paper is an indicator of two types of anxiety, the state and trait anxiety, and measure the severity of the overall anxiety level, which is appropriate for those who have at least a sixth grade reading level.
Abstract: The STAI serves as an indicator of two types of anxiety, the state and trait anxiety, and measure the severity of the overall anxiety level.The STAI, which is appropriate for those who have at least a sixth grade reading level, contains four-point Likert items. The instrument is divided into two sections, each having twenty questions. Approximately 15 minutes are required for adults to complete the both STAI. The number on the scale is positively correlated to the anxiety related to in the question.
24,997 citations
TL;DR: The method can be applied to most laboratory animals in the conscious state and is based on the use of 2‐deoxy‐D‐[14C]glucose as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues.
Abstract: — A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.
The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.
5,988 citations
TL;DR: Initial scale development and reliability studies of the items and the scale scores are reported on.
Abstract: • The Schedule for Affective Disorders and Schizophrenia (SADS) was developed to reduce information variance in both the descriptive and diagnostic evaluation of a subject. The SADS is unique among rating scales in that it provides for (1) a detailed description of the features of the current episode of illness when they were at their most severe; (2) a description of the level of severity of manifestations of major dimensions of psychopathology during the week preceding the evaluation, which can then be used as a measure of change; (3) a progression of questions and criteria, which provides information for making diagnoses; and (4) a detailed description of past psychopathology and functioning relevant to an evaluation of diagnosis, prognosis, and overall severity of disturbance. This article reports on initial scale development and reliability studies of the items and the scale scores.
5,623 citations
TL;DR: The data indicate that cerebral FDG‐6‐PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases, and that cerebral blood FDG activity levels were found to be a minor fraction of tissue activity.
Abstract: Tracer techniques and quantitative autoradiographic and tissue counting models for measurement of metabolic rates were combined with positron computed tomography (PCT) and (F-18)2-fluoro-2-deoxy-D-glucose (FDG) for the measurement of local cerebral metabolic rate for glucose (LCMRGlc) in humans. A three-compartment model, which incorporates hydrolysis of FDG-6-PO4 to FDG, was developed for the measure of kinetic constants and calculation of LCMRGlc. Our model is an extension of that developed by Sokoloff et al. Although small, hydrolysis of FDG-6-PO4 was found to be significant. A PCT system, the ECAT, was used to determine the rate constants, lumped constant, and stability of the model in human beings. The data indicate that cerebral FDG-6-PO4 in humans increases for about 90 minutes, plateaus, and then slowly decreases. After 10 minutes, cerebral blood FDG activity levels were found to be a minor fraction of tissue activity. Precursor pool turnover rate, distribution volumes, and red blood cell-plasma concentration ratios were determined. Reproducibility (precision) of LCMRGlc measurements (approximate 2 cm2 regions) was +/- 5.5% over a 5-hour period. The replacement of arterial blood sampling with venous sampling was validated.
2,252 citations