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Pet-directed postmortem tissue analysis in schizophrenia
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Oral Session XVII Can NMDA Receptor Disturbances be Detected with Electrodes on the Scalp or with PET?: Studies of the Hippocampus and Anterior Cingulate MISMATCH NEGATIVITY POTENTIALS IN RELATION TO COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA S.R. Hirsch, T. Baldeweg, A. K l u g m a n , T. Kondel, J. Gruzelier
Division of Neuroscience & Psychological Medicine, Imperial College School of Medicine, London, U.K. Objective: We previously found that loss of NMDA receptor subunit NR1 mRNA in the superior temporal gyrus (STG) to be highly correlated with the degree of ante-mortem intellectual impairment in schizophrenic subjects (Humphries et al. 1996). Here we investigated whether an evoked potential marker of auditory sensory memory termed mismatch negativity (MMN), which has been shown to be NMDA-dependent (Javitt et al. 1996), is related to the degree of memory impairment in schizophrenic subjects, Method: 30 schizophrenic subjects were tested using a battery of neuropsychological tests. Based on performance on a test of everyday memory performance patients were divided into three groups: normal memory, mild and marked memory deficit. MMN potentials were recorded in response to duration deviants embedded in a sequence of brief auditory stimuli. Results: Two separate components of MMN were differentially affected by diagnostic group and memory status: MMN recorded from frontal electrodes reflecting activity in bilateral STG was markedly reduced in all three patient groups (p<0.0001). Among patients this STG-MMN was also significantly affected by memory status: patients with normal memory differed from controls (p < 0.006) and patients with mild and severe memory deficits differed significantly from patients with normal memory (p <0.049 and p < 0.009 respectively). In contrast, mismatch responses recorded from mastoid electrodes showed no significant difference between patients and controls and no difference according to memory status. Conclusion: These MMN data support the role of NMDA dysfunction in schizophrenia and in the memory impairment associated with the disorder.
PET-DIRECTED POSTMORTEM ANALYSIS IN SCHIZOPHRENIA
TISSUE
C.A. T a m m i n g a , X.-M. G a o , R.A. Lahti, M.W. Vogel
University of Maryland School of Medicine. Maryland Psychtatrie Research Center. PO Box 21247, Baltimore, Maryland 21228, USA
Although human postmortem tissue analysis can provide specific high resolution data about human brain diseases of a histologic and neurochemical variety, the problem in diseases like schizophrenia is to know not only what to measure, but where to meaure it. Localizing information from human PET studies in schizophrenia and neurochemical hypotheses developed from an animal of psychosis, provided guidance to a human postmortem experiment in psychosis. Based on several of our own PET studies in schizophrenia which generated data consistent with considerable published literature, we selected the hippocampus and anterior cingulate cortex for study. Based on our animal studies with PCP, we selected markers of the hippocampal NMDA sensitive glutamate receptor function in schizophrenia and normal tissue. In this study, we report that the schizophrenic hippocampus evidences an abnormal composition of the NMDA-sensitive glutamate receptors, with diminished NR 1 mRNA and elevated NRzB mRNA. We further hypothesize that this alteration will diminish the hippocampal efferent glutamatergic signal to its limbic projection targets. Therefore, the anterior cingulate cortex will show evidence of reduced afferent glutamatergic activation from hippocampal afferents. Several observations from the literature already support this; and we continue to generate data to address the hypothesis further.
HOW SPECIFIC ARE DEFICITS IN GENERATION OF MISMATCH NEGATIVITY TO SCHIZOPHRENIA? D. U m b r i c h t , F.X. Vollenweider, L. Schmid, R. Koller
Psychiatric University Hospital Zurich, Department of Research, PO Box 68, 8029 Zurich, Switzerland Mismatch negativity ( M M N ) is a preattentive event-related potential that elicited by infrequent deviant stimuli presented among frequently presented standard stimuli. It manifests the automatic detection of stimulus deviance and indexes the functioning of echoic memory a simple 'working' memory system at the level of the auditory sensory cortex. Animal and human data indicate an involvement of NMDA-receptors in MMN generation. In schizophrenia deficits in MMN generation and echoic memory have repeatedly been demonstrated. The specificity of this deficit to schizophrenia has not been established. We are conducting a study comparing MMN generation in healthy controls and in age-matched patients with a diagnosis of schizophrenia or schizo-affective disorder, biporal disorder and major depression. Patients are matched on duration of illness. MMN is recorded both in a duration deviance and pitch deviance condition. Preliminary analyses of 53 subjects (Healthy controls N = 14; schizophrenic/schizoaffective patients N = 21; bipolar patients N = 9; depressed patients N = 8) demonstrate the greatest deficit in MMN generation in both conditions in patients with schizophrenia or schizoaffective disorder. Only schizophreniz/schizoaffective patients showed significantly smaller MMN than normal controls. The difference was more
Oral Session XVII Can NMDA Receptor Disturbances be Detected with Electrodes on the Scalp or with PET?: Studies of the Hippocampus and Anterior Cingulate MISMATCH NEGATIVITY POTENTIALS IN RELATION TO COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA S.R. Hirsch, T. Baldeweg, A. K l u g m a n , T. Kondel, J. Gruzelier
Division of Neuroscience & Psychological Medicine, Imperial College School of Medicine, London, U.K. Objective: We previously found that loss of NMDA receptor subunit NR1 mRNA in the superior temporal gyrus (STG) to be highly correlated with the degree of ante-mortem intellectual impairment in schizophrenic subjects (Humphries et al. 1996). Here we investigated whether an evoked potential marker of auditory sensory memory termed mismatch negativity (MMN), which has been shown to be NMDA-dependent (Javitt et al. 1996), is related to the degree of memory impairment in schizophrenic subjects, Method: 30 schizophrenic subjects were tested using a battery of neuropsychological tests. Based on performance on a test of everyday memory performance patients were divided into three groups: normal memory, mild and marked memory deficit. MMN potentials were recorded in response to duration deviants embedded in a sequence of brief auditory stimuli. Results: Two separate components of MMN were differentially affected by diagnostic group and memory status: MMN recorded from frontal electrodes reflecting activity in bilateral STG was markedly reduced in all three patient groups (p<0.0001). Among patients this STG-MMN was also significantly affected by memory status: patients with normal memory differed from controls (p < 0.006) and patients with mild and severe memory deficits differed significantly from patients with normal memory (p <0.049 and p < 0.009 respectively). In contrast, mismatch responses recorded from mastoid electrodes showed no significant difference between patients and controls and no difference according to memory status. Conclusion: These MMN data support the role of NMDA dysfunction in schizophrenia and in the memory impairment associated with the disorder.
PET-DIRECTED POSTMORTEM ANALYSIS IN SCHIZOPHRENIA
TISSUE
C.A. T a m m i n g a , X.-M. G a o , R.A. Lahti, M.W. Vogel
University of Maryland School of Medicine. Maryland Psychtatrie Research Center. PO Box 21247, Baltimore, Maryland 21228, USA
Although human postmortem tissue analysis can provide specific high resolution data about human brain diseases of a histologic and neurochemical variety, the problem in diseases like schizophrenia is to know not only what to measure, but where to meaure it. Localizing information from human PET studies in schizophrenia and neurochemical hypotheses developed from an animal of psychosis, provided guidance to a human postmortem experiment in psychosis. Based on several of our own PET studies in schizophrenia which generated data consistent with considerable published literature, we selected the hippocampus and anterior cingulate cortex for study. Based on our animal studies with PCP, we selected markers of the hippocampal NMDA sensitive glutamate receptor function in schizophrenia and normal tissue. In this study, we report that the schizophrenic hippocampus evidences an abnormal composition of the NMDA-sensitive glutamate receptors, with diminished NR 1 mRNA and elevated NRzB mRNA. We further hypothesize that this alteration will diminish the hippocampal efferent glutamatergic signal to its limbic projection targets. Therefore, the anterior cingulate cortex will show evidence of reduced afferent glutamatergic activation from hippocampal afferents. Several observations from the literature already support this; and we continue to generate data to address the hypothesis further.
HOW SPECIFIC ARE DEFICITS IN GENERATION OF MISMATCH NEGATIVITY TO SCHIZOPHRENIA? D. U m b r i c h t , F.X. Vollenweider, L. Schmid, R. Koller
Psychiatric University Hospital Zurich, Department of Research, PO Box 68, 8029 Zurich, Switzerland Mismatch negativity ( M M N ) is a preattentive event-related potential that elicited by infrequent deviant stimuli presented among frequently presented standard stimuli. It manifests the automatic detection of stimulus deviance and indexes the functioning of echoic memory a simple 'working' memory system at the level of the auditory sensory cortex. Animal and human data indicate an involvement of NMDA-receptors in MMN generation. In schizophrenia deficits in MMN generation and echoic memory have repeatedly been demonstrated. The specificity of this deficit to schizophrenia has not been established. We are conducting a study comparing MMN generation in healthy controls and in age-matched patients with a diagnosis of schizophrenia or schizo-affective disorder, biporal disorder and major depression. Patients are matched on duration of illness. MMN is recorded both in a duration deviance and pitch deviance condition. Preliminary analyses of 53 subjects (Healthy controls N = 14; schizophrenic/schizoaffective patients N = 21; bipolar patients N = 9; depressed patients N = 8) demonstrate the greatest deficit in MMN generation in both conditions in patients with schizophrenia or schizoaffective disorder. Only schizophreniz/schizoaffective patients showed significantly smaller MMN than normal controls. The difference was more