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Abnormalities of cerebral vascular distribution in schizophrenia
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in two extrastriate areas. Contrasting congruent and neutral conditions (Facilitation) rCBF increased in right anterior cingulate and decreased in right inferior frontal and extrastriate areas. Directly contrasting incongruent and congruent conditions revealed differences in prefrontal and inferior parietal cortex and a third extrastriate region. Preliminary analysis of time on task effects showed initially anterior cingulate and extrastriate changes predominating, but with time on task prefrontal and, for Interference, parietal changes predominating. These results conform to predictions from a connectionist model that modular systems representing multiple aspects of word reading and color naming interact to determine Stroop performance. Schizophrenia patient data will be presented. This study was supported in part by a NARSAD Young Investigator Award to Dr. Carter.
ABNORMALITIES OF CEREBRAL VASCULAR DISTRIBUTION IN SCHIZOPHRENIA B.M. Cohen*, D. Yurgelun-Todd, P.F. Renshaw
Brain Imaging Center, McLean Hospital 115 Mill Street, Belmont, MA 02178, USA Using functional magnetic resonance imaging (fMRI), we have reported that patients with schizophrenia have an exaggerated activation of visual cortex in response to photic stimulation. Possible explanations for this phenomenon include structural or functional anomalies of cortical circuitry in schizophrenia. However, as fMRI depends on changes in regional blood flow and volume to estimate local cerebral activation, an alternative explanation of the difference observed is that cerebral vascular distribution is abnormal in schizophrenia. To address this possibility, we determined activation of visual cortex in response to photic stimulation, estimated by Blood Oxygenation Level Detection (BOLD) fMRI, and cerebral blood volume (CBV) in visual cortex, estimated by Dynamic Susceptibility Contrast Imaging (DSCI) following gadolinium injection, in 5 subjects with schizophrenia and 5 control subjects. Subjects with schizophrenia had a greater increase in MR signal intensity bilaterally (repeated measure ANOVA, F(1.8) = 2.67, p = 0.02) in visual cortex in response to photic stimulation (Left: 5.90+1.45; Right: 4.82+1.06) than control subjects (Left: 3.58+1.72; Right: 2.70+1.14). However, these same schizophrenic subjects also had greater CBV in visual cortex bilaterally at baseline (Left: 2.09+0.21; Right: 2.02+0.25) than control subjects (Left: 1.78+0.40; Right: 1.51+0.31) (repeated measure ANOVA, F(1.8)=6.19, p=0.04). The results suggest an abnormality of cerebral vasculature in schizophrenia which may be related to the etiology, pathophysiology, or treatment of this illness. The findings may also be important in interpreting the results of fMRI and other techniques which rely on the assumption that vascular distribution is similar in ill and well subjects.
11C N M S P R E C E P T O R O C C U P A N C Y B Y CLOZAPINE AND HALOPERIDOL IN SCHIZOPHRENIC SUBJECTS Robert Conley*, Deborah Medoff, Dean Wong, Carol Tamminga
Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228, USA Preclinical and clinical studies have demonstrated several interesting properties of clozapine, potentially connected with its unique properties: (1) it appears "limbic selective" in neurochemical and behavioral measures; (2) it preferentially causes depolarization blockade in A10 but not in m 9 neurons; (3) it has a broad profile of receptor blockade; (4) it causes fewer animal oral dyskinesias than any other antipsychotic drug; (5) it causes almost no motor side effects in humans. The receptor binding profile of clozapine is remarkable. The drug has a relatively low but measurable affinity at the D2 postsynaptic receptor, lower by more than an order of magnitude than any other marketed antipsychotic. It also has almost equivalent affinity to 52, D t, AI, A2, and muscarinic receptors. Moreover, recent work demonstrates a high affinity for the D4 receptor as well. In prior work our group has shown that mean percent of tC NMSP receptor occupancy in the stratum with haloperidol treatment was 80.2%_+9.2 in comparison with clozapine 19.1%+6.0. In this presentation we will report differential, higher occupancy of NMSP receptors by clozapine in extrastriatal areas. Occupancy is also determined by the specific analyte technique used. We will compare different techniques used by Farde and by Wong in this data set. Eight patients who met DSM-III-R and RDC criteria for schizophrenia were entered into the study. After subjects were screened and had signed informed consent, they began a fixed-duration six-week treatment with clorpromazine, at 600 mg/d. At the end of a two week drug-free period, a PET/NMSP scan was done. The patients then were treated for six weeks with haloperidol 30 mg/d followed by 11C-NMSP/PET. Finally, six weeks of treatment with clozapine, 450 mg/d, was given followed by 11CNMSP/PET. The differential activity of clozapine is likely to be highly related to its unique receptor binding pattern in the human brain.
VBR AND PREMORBID SCHIZOPHRENIA
STATUS IN
John R. DeQuardo*, Shawna Red Cloud, Rajiv Tandon, Robert Goldman, Marlene Giroux, James A. Brunberg, Lorraine Kim
Schizophrenia Program, Universityof Michigan, Ann Arbor, M148109-0116, USA Ventricular enlargement is a consistently documented abnormality in schizophrenia, seen in 1/3-1/2 of patients; ventriclebrain ratio (VBR) is the most frequently used index of ventricle
in two extrastriate areas. Contrasting congruent and neutral conditions (Facilitation) rCBF increased in right anterior cingulate and decreased in right inferior frontal and extrastriate areas. Directly contrasting incongruent and congruent conditions revealed differences in prefrontal and inferior parietal cortex and a third extrastriate region. Preliminary analysis of time on task effects showed initially anterior cingulate and extrastriate changes predominating, but with time on task prefrontal and, for Interference, parietal changes predominating. These results conform to predictions from a connectionist model that modular systems representing multiple aspects of word reading and color naming interact to determine Stroop performance. Schizophrenia patient data will be presented. This study was supported in part by a NARSAD Young Investigator Award to Dr. Carter.
ABNORMALITIES OF CEREBRAL VASCULAR DISTRIBUTION IN SCHIZOPHRENIA B.M. Cohen*, D. Yurgelun-Todd, P.F. Renshaw
Brain Imaging Center, McLean Hospital 115 Mill Street, Belmont, MA 02178, USA Using functional magnetic resonance imaging (fMRI), we have reported that patients with schizophrenia have an exaggerated activation of visual cortex in response to photic stimulation. Possible explanations for this phenomenon include structural or functional anomalies of cortical circuitry in schizophrenia. However, as fMRI depends on changes in regional blood flow and volume to estimate local cerebral activation, an alternative explanation of the difference observed is that cerebral vascular distribution is abnormal in schizophrenia. To address this possibility, we determined activation of visual cortex in response to photic stimulation, estimated by Blood Oxygenation Level Detection (BOLD) fMRI, and cerebral blood volume (CBV) in visual cortex, estimated by Dynamic Susceptibility Contrast Imaging (DSCI) following gadolinium injection, in 5 subjects with schizophrenia and 5 control subjects. Subjects with schizophrenia had a greater increase in MR signal intensity bilaterally (repeated measure ANOVA, F(1.8) = 2.67, p = 0.02) in visual cortex in response to photic stimulation (Left: 5.90+1.45; Right: 4.82+1.06) than control subjects (Left: 3.58+1.72; Right: 2.70+1.14). However, these same schizophrenic subjects also had greater CBV in visual cortex bilaterally at baseline (Left: 2.09+0.21; Right: 2.02+0.25) than control subjects (Left: 1.78+0.40; Right: 1.51+0.31) (repeated measure ANOVA, F(1.8)=6.19, p=0.04). The results suggest an abnormality of cerebral vasculature in schizophrenia which may be related to the etiology, pathophysiology, or treatment of this illness. The findings may also be important in interpreting the results of fMRI and other techniques which rely on the assumption that vascular distribution is similar in ill and well subjects.
11C N M S P R E C E P T O R O C C U P A N C Y B Y CLOZAPINE AND HALOPERIDOL IN SCHIZOPHRENIC SUBJECTS Robert Conley*, Deborah Medoff, Dean Wong, Carol Tamminga
Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228, USA Preclinical and clinical studies have demonstrated several interesting properties of clozapine, potentially connected with its unique properties: (1) it appears "limbic selective" in neurochemical and behavioral measures; (2) it preferentially causes depolarization blockade in A10 but not in m 9 neurons; (3) it has a broad profile of receptor blockade; (4) it causes fewer animal oral dyskinesias than any other antipsychotic drug; (5) it causes almost no motor side effects in humans. The receptor binding profile of clozapine is remarkable. The drug has a relatively low but measurable affinity at the D2 postsynaptic receptor, lower by more than an order of magnitude than any other marketed antipsychotic. It also has almost equivalent affinity to 52, D t, AI, A2, and muscarinic receptors. Moreover, recent work demonstrates a high affinity for the D4 receptor as well. In prior work our group has shown that mean percent of tC NMSP receptor occupancy in the stratum with haloperidol treatment was 80.2%_+9.2 in comparison with clozapine 19.1%+6.0. In this presentation we will report differential, higher occupancy of NMSP receptors by clozapine in extrastriatal areas. Occupancy is also determined by the specific analyte technique used. We will compare different techniques used by Farde and by Wong in this data set. Eight patients who met DSM-III-R and RDC criteria for schizophrenia were entered into the study. After subjects were screened and had signed informed consent, they began a fixed-duration six-week treatment with clorpromazine, at 600 mg/d. At the end of a two week drug-free period, a PET/NMSP scan was done. The patients then were treated for six weeks with haloperidol 30 mg/d followed by 11C-NMSP/PET. Finally, six weeks of treatment with clozapine, 450 mg/d, was given followed by 11CNMSP/PET. The differential activity of clozapine is likely to be highly related to its unique receptor binding pattern in the human brain.
VBR AND PREMORBID SCHIZOPHRENIA
STATUS IN
John R. DeQuardo*, Shawna Red Cloud, Rajiv Tandon, Robert Goldman, Marlene Giroux, James A. Brunberg, Lorraine Kim
Schizophrenia Program, Universityof Michigan, Ann Arbor, M148109-0116, USA Ventricular enlargement is a consistently documented abnormality in schizophrenia, seen in 1/3-1/2 of patients; ventriclebrain ratio (VBR) is the most frequently used index of ventricle