- Email: [email protected]
The roles of the dorsolateral prefrontal cortex and hippocampus in working memory and schizophrenia
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BIOLPSYCHIATRY 1994;35:615--747
regions in controls, with very little effect in patients. Cortisol enhanced the performance with respect to primary memory, but impaired secondary (short-term) recall in controls. In schizophrenics cortisol had similar effects on primary memory but secondary recall was unaffected. An integration of cognitive and physiologic challenges may provide a powerful paradigm to investigate the neural bases for defects in information processing in schizophrenia.
THURSDAY, MAY 19
28. LOCAL CEREBRAL BLOOD FLOW DURING MEMORY ACTIVATION IN HEALTHY CONTROLS AND PATIENTS WITH SCHIZOPHRENIA R.C. Gur, R.E. Gut', L.H. Mozley, P.D. Mozley, D. Shtasel, J.D. Ragland, A. Alavi, & M. Reivich University of Pennsylvania, Philadelphia, PA
27. THE ROLES OF THE DORSOLATERAL PREFRONTAL CORTEX AND HIPPOCAMPUS IN WORKING MEMORY AND SCHIZOPHRENIA K.F. Berman, J.L. Ostrem, V.S. Mattay, G. Esposito, J.D. Van Horn, A. Abi-Dargham, E. Fuller Torrey, & D.R. Weinberger NIMH/IRP/Clinicai Brain Disorders Branch/Unit on PET, NIMH Neuroscience Center at St. Elizabeths, Washington, DC 20032 Animal studies suggest that dorsolateral prefrontal cortex (DLPFC) and hippocampus (HIP) play important but different roles in working memory (WM) tasks. For example, delayed response tasks with short delays may be mediated by the DLPFC, while the HIP is more crucial at longer delays and for more complex tasks. Human analogs may be provided by tasks with WM components such as the Wisconsin Card Sorting Test (WCS) and Raven's Progressive Matrices (RPM), the latter being considerably more complex and requiring longer processing for each trial. We explored the roles of DLPFC and HIP in human working memory with the 0-1 5 water PET method for measuring rCBF during WCS and RPM in 10 pairs of normal monozygotic (MZ) twins, 8 normal subjects treated with placebo and amphetamine (AMP), and 9 pairs of MZ twins discordant for schizophrenia (SCZ). In the normal MZ twins, performance of both WCS and RAV reliably provoked DLPFC activation. During WCS HIP activity was relatively suppressed, but RPM activated HIP. AMP produced a double dissociation of behaviorally linked regional activation: during the WCS AMP increased activation in left DLPFC, but produced a decrease in HIP, during RPM the opposite occurred- DLPFC activation decreased while that of the HIP increased (chug x task interaction, P<0.01). in the discordant MZ twins two findings best distinguished SCZ compared with the well twins during the WCS: lower DLPFC ICBF and higher rCBF in the left HIP. The degree to which the HIP was hyperactive in the ill twin relative to the well co-twin tended to predict the degree of relative DLPFC hypoactivity. If, as suggested by preclinical studies, catecholamines increase specific signals in the brain while decreasing nonspeciflc background "noise," the AMP data would suggest that the WCS, a more classic WM paradigm, is most efficiently processed by the DLPFC, while the more complex RPM, which may require a greater memory register than is available in the DLPFC, is also processed with the HIP. The twin data support the concept of DLPFC/HIP connectivity and strengthen the notion that the relative degrees to which these two regions cooperate in WM tasks may influence the outcome. The data moreover suggest aberrant DLPFC/HIP functional connectivity and/or activation of aberrant pathways during WM in SCZ.
The t33Xenon method for measuring cortical CBF suggested mid-temporal activation in healthy volunteers during word and face recognition tasks. Patients with schizophrenia failed to activate this region and instead activated other regions. This study examined subeortical regions using PET with tS0xygen labeled water infusion. Samples were 21 patients and 21 socio-demographically balanced healthy controls screened for medical condition affecting brain metabolism. Controls were also screened for psychopathology in tint-degree relatives. Scans were obtained in experimental (Face and Word recognition) and one control (Face-Word discrimination) conditions. ROls for anatomically co-registered PET images included caudate, insula, globus pallidus, lenticular nucleus, thalamus, parahippocampal gyms, uncus, hippocampus, amygdala, mammillary bodies, anterior and posterior cingulum (subeortical regions), mid-frontal, dorsolateral prefrontal, inferior frontal, orbitofrontal, rectal gyms, superior temporal, midtemporal, inferotemporal, parietal, sensorimotor, occipitotemporal, and occipital (cortical regions), anterior and posterior corpus callosum, cerebellum and midbrain. Cortical effects replicated our earlier findings, with controls showing hemispherically-appropriate activation (R> L for face and L R for word recognition) restricted to midtemporal cortex, while patients not showing this effect. Activation effects for subcortical regions were considerably more pronounced than for cortex, and a striking effect emerged for the mammillaries, in view of the small size of this region we performed a crossvalidation study by dividing the sample randomly in two. Both subsamples showed the effects. We also placed same sized ROls around the mammillaries as well as on the slices above and below. The effect was seen only in the mammillaries. The ability to replicate with PET findings obtained with 133Xenon clearance is encouraging. The finding on mammillary body activation by these memory tasks is surprising in its magnitude, although studies using 2-DG autoradiography in rats have shown circumscribed effects in the same region for recognition tasks.
29. ECHO PLANAR MRI OF SCHIZOPHRENICS AND NORMAL CONTROLS DURING WORD PRODUCTION D.A. Yurgelun-Todd, P.F. Renshaw, & B.M. Cohen Brain Imaging Center, McLean Hospital, Belmont, MA 02178 Recent studies (Kwong et al. 1992) have demonstrated that echo planar MRi techniques (EPMRI) can be used with challenge paradigms to create images of visual and motor cortex which are sensitive to changes in local brain perfusion and oxygenation. Abnormal language functions, including difficulties with word association tasks, verbal fluency, and semantic priming, possibly reflecting regional abnormalities in brain function, have been repeatedly observed in schizophrenic patients. Therefore, in an effort to further characterize the neurophysiological abnormalities in schizophrenia, we have applied EPMRI to both schizophrenic patients and normal controls during verbal cognitive challenge paradigms. We studied eight subjects, five non-psychiatric controls and three subjects with DSM3-R schizophrenia. Scanning was performed on a i.5T GE Signa, retrofitted with a high speed imaging coil. 7 mm images were acquired in succession using a modified echo planar imaging technique for each activation
BIOLPSYCHIATRY 1994;35:615--747
regions in controls, with very little effect in patients. Cortisol enhanced the performance with respect to primary memory, but impaired secondary (short-term) recall in controls. In schizophrenics cortisol had similar effects on primary memory but secondary recall was unaffected. An integration of cognitive and physiologic challenges may provide a powerful paradigm to investigate the neural bases for defects in information processing in schizophrenia.
THURSDAY, MAY 19
28. LOCAL CEREBRAL BLOOD FLOW DURING MEMORY ACTIVATION IN HEALTHY CONTROLS AND PATIENTS WITH SCHIZOPHRENIA R.C. Gur, R.E. Gut', L.H. Mozley, P.D. Mozley, D. Shtasel, J.D. Ragland, A. Alavi, & M. Reivich University of Pennsylvania, Philadelphia, PA
27. THE ROLES OF THE DORSOLATERAL PREFRONTAL CORTEX AND HIPPOCAMPUS IN WORKING MEMORY AND SCHIZOPHRENIA K.F. Berman, J.L. Ostrem, V.S. Mattay, G. Esposito, J.D. Van Horn, A. Abi-Dargham, E. Fuller Torrey, & D.R. Weinberger NIMH/IRP/Clinicai Brain Disorders Branch/Unit on PET, NIMH Neuroscience Center at St. Elizabeths, Washington, DC 20032 Animal studies suggest that dorsolateral prefrontal cortex (DLPFC) and hippocampus (HIP) play important but different roles in working memory (WM) tasks. For example, delayed response tasks with short delays may be mediated by the DLPFC, while the HIP is more crucial at longer delays and for more complex tasks. Human analogs may be provided by tasks with WM components such as the Wisconsin Card Sorting Test (WCS) and Raven's Progressive Matrices (RPM), the latter being considerably more complex and requiring longer processing for each trial. We explored the roles of DLPFC and HIP in human working memory with the 0-1 5 water PET method for measuring rCBF during WCS and RPM in 10 pairs of normal monozygotic (MZ) twins, 8 normal subjects treated with placebo and amphetamine (AMP), and 9 pairs of MZ twins discordant for schizophrenia (SCZ). In the normal MZ twins, performance of both WCS and RAV reliably provoked DLPFC activation. During WCS HIP activity was relatively suppressed, but RPM activated HIP. AMP produced a double dissociation of behaviorally linked regional activation: during the WCS AMP increased activation in left DLPFC, but produced a decrease in HIP, during RPM the opposite occurred- DLPFC activation decreased while that of the HIP increased (chug x task interaction, P<0.01). in the discordant MZ twins two findings best distinguished SCZ compared with the well twins during the WCS: lower DLPFC ICBF and higher rCBF in the left HIP. The degree to which the HIP was hyperactive in the ill twin relative to the well co-twin tended to predict the degree of relative DLPFC hypoactivity. If, as suggested by preclinical studies, catecholamines increase specific signals in the brain while decreasing nonspeciflc background "noise," the AMP data would suggest that the WCS, a more classic WM paradigm, is most efficiently processed by the DLPFC, while the more complex RPM, which may require a greater memory register than is available in the DLPFC, is also processed with the HIP. The twin data support the concept of DLPFC/HIP connectivity and strengthen the notion that the relative degrees to which these two regions cooperate in WM tasks may influence the outcome. The data moreover suggest aberrant DLPFC/HIP functional connectivity and/or activation of aberrant pathways during WM in SCZ.
The t33Xenon method for measuring cortical CBF suggested mid-temporal activation in healthy volunteers during word and face recognition tasks. Patients with schizophrenia failed to activate this region and instead activated other regions. This study examined subeortical regions using PET with tS0xygen labeled water infusion. Samples were 21 patients and 21 socio-demographically balanced healthy controls screened for medical condition affecting brain metabolism. Controls were also screened for psychopathology in tint-degree relatives. Scans were obtained in experimental (Face and Word recognition) and one control (Face-Word discrimination) conditions. ROls for anatomically co-registered PET images included caudate, insula, globus pallidus, lenticular nucleus, thalamus, parahippocampal gyms, uncus, hippocampus, amygdala, mammillary bodies, anterior and posterior cingulum (subeortical regions), mid-frontal, dorsolateral prefrontal, inferior frontal, orbitofrontal, rectal gyms, superior temporal, midtemporal, inferotemporal, parietal, sensorimotor, occipitotemporal, and occipital (cortical regions), anterior and posterior corpus callosum, cerebellum and midbrain. Cortical effects replicated our earlier findings, with controls showing hemispherically-appropriate activation (R> L for face and L R for word recognition) restricted to midtemporal cortex, while patients not showing this effect. Activation effects for subcortical regions were considerably more pronounced than for cortex, and a striking effect emerged for the mammillaries, in view of the small size of this region we performed a crossvalidation study by dividing the sample randomly in two. Both subsamples showed the effects. We also placed same sized ROls around the mammillaries as well as on the slices above and below. The effect was seen only in the mammillaries. The ability to replicate with PET findings obtained with 133Xenon clearance is encouraging. The finding on mammillary body activation by these memory tasks is surprising in its magnitude, although studies using 2-DG autoradiography in rats have shown circumscribed effects in the same region for recognition tasks.
29. ECHO PLANAR MRI OF SCHIZOPHRENICS AND NORMAL CONTROLS DURING WORD PRODUCTION D.A. Yurgelun-Todd, P.F. Renshaw, & B.M. Cohen Brain Imaging Center, McLean Hospital, Belmont, MA 02178 Recent studies (Kwong et al. 1992) have demonstrated that echo planar MRi techniques (EPMRI) can be used with challenge paradigms to create images of visual and motor cortex which are sensitive to changes in local brain perfusion and oxygenation. Abnormal language functions, including difficulties with word association tasks, verbal fluency, and semantic priming, possibly reflecting regional abnormalities in brain function, have been repeatedly observed in schizophrenic patients. Therefore, in an effort to further characterize the neurophysiological abnormalities in schizophrenia, we have applied EPMRI to both schizophrenic patients and normal controls during verbal cognitive challenge paradigms. We studied eight subjects, five non-psychiatric controls and three subjects with DSM3-R schizophrenia. Scanning was performed on a i.5T GE Signa, retrofitted with a high speed imaging coil. 7 mm images were acquired in succession using a modified echo planar imaging technique for each activation