- Email: [email protected]
THE REVISED DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: EVIDENCE FROM PHARMACOLOGICAL MRI STUDIES WITH ATYPICAL ANTIPSYCHOTIC MEDICATION
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Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
Results: We found comparable activation patterns between the groups for both gesture types vs. baseline (fixation cross), in predominantly bilateral occipital, temporal and frontal regions. However, in contrast to patients only healthy subjects show more activation in left temporal and frontal regions for the processing of metaphoric gestures in comparison to iconic co-verbal gestures. Conclusions: Our preliminary results are consistent with the evidence of impaired gesture (e.g. Berndl et al. 1986) and metaphor comprehension in patients with schizophrenia (e.g. Kircher et al., 2007). Patients with schizophrenia possibly fail to activate left hemispheric temporal and frontal areas which seem to be important for the comprehension of metaphoric co-verbal utterances. Acknowledgements: This research project is supported by a grant from the Interdisciplinary Center for Clinical Research “BIOMAT” (IZKF VV N68) and the Deutsche Forschungsgemeinschaft (DFG, IRTG 1328). References [1] Berndl, K., v.Cranach, M., Grusser, O.J., 1986. Impairment of perception and recognition of faces, mimic expression and gestures in schizophrenic patients. Eur Arch Psychiatry Neurol.Sci. 235, 282-291. [2] Kircher, T.T., Leube, D.T., Erb, M., Grodd, W., Ra pp, A.M., 2007. Neural correlates of metaphor processing in schizophrenia. NeuroImage 34, 281-289.
114 – THE RELATIONSHIP BETWEEN DOPAMINE D2 RECEPTOR OCCUPANCY BY ATYPICAL ANTIPSYCHOTIC DRUGS AND COGNITIVE FUNCTION IN PATIENTS WITH SCHIZOPHRENIA Mevhibe N. Tumuklu 1 , Robert M. Kessler 2 , Karu Jayathilake 3 , Herbert Y. Meltzer 3 1 Gaziosmanpasha Univ., Dept of Psychiatry, Tokat, Turkey; 2 Vanderbilt University Dept. of Radiology, Nashville TN; 3 Vanderbilt University Dept of Psychopharmacology, Nashville TN, USA [email protected] Introduction: The relationship between D2 receptor occupancy of antipsychotic drugs (APD) and clinical response is still unsettled despite poorly substantiated claims that minimum occupancy of 60% in the dorsal striatum is required for therapeutic response (Kapur, 1996). It is also unlikely that atypical APDs such as clozapine and olanzapine, which are distinguished from typical APDs by higher affinity for 5-HT2A receptors (Meltzer, 1989), require the same degree of occupancy as typical antipsychotic drugs (Kessler, 2005). Methods: Twenty-four patients with schizophrenia were scanned with PET [18F] fallypride, using a GE Advance PET scanner in the 3D mode after at least 6 weeks of treatment with atypical APDs (clozapine, quetiapine, risperidone, olanzapine). Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and a comprehensive cognitive battery (Hagger, 1999). Results: D2 receptor occupancy were not correlated with BPRS Total or Positive symptom. WAIS-R Digit symbol substitution test scores were significantly negatively correlated with D2 occupancy in putamen (r = -0.54, p=0.02) and ventral pallidum (r = -0.55, p= 0.02). Spatial working memory test delay scores were significantly negatively correlated with occupancy in substantia nigra (r= -0.85, p=0.02). Continuous Performance Test scores were found to be significantly negatively correlated with occupancy in substantia nigra (r = -0.56, p=0.03) and ventral pallidum (r=-0.59, p=0.03). Conclusions: These findings are consistent with the hypothesis that lower occupancy of D2 receptors by atypical APDs may contribute to better cognitive performance with these agents than with typical APDs. References [1] Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S et al (1996). High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiat 153:948–950.
[2] Meltzer HY, Matsubara S, Lee J-C (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Therapeut 251: 238–246. [3] Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B et al (2005). Occupancy of striatal and extrastriatal DA D2/3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30: 2283–2289. [4] Hagger, C; Buckley, P.; Kenny, J.T.; Freidman, L.; Ubogy, D.; and Meltzer, H.Y. Improvement in cognitive function and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biological Psychiatry, 34:702-712, 1993.
115 – HALLUCINATIONS ARE ASSOCIATED WITH ABERRENT ACTIVATION IN INNER SPEECH REGIONS DURING SOURCE MONITORING Todd S. Woodward, Sara Weinstein, Tara A. Cairo, Paul Metzak, Elton T.C. Ngan, Devvarta Kumar University of British Columbia, Vancouver, BC, Canada [email protected] Introduction: Previous research suggests that the dysfunctional cognitive operations underpinning hallucinations in schizophrenia overlap with those leading to inner/outer (i.e., self/other) confusions in source memory. Specifically, associations are observed between internal-toexternal source misattributions (i.e., externalizations) and hallucinations. In the current study we investigated the neural underpinnings of this association using functional magnetic resonance imaging (fMRI). Methods: 10 hallucinating and 15 nonhallucinating patients with schizophrenia alternated between saying and hearing words prior to scanning. During scanning, each of these words was displayed visually, and subjects were required to indicate, by keypress, whether they had previously sai d or heard the words. Results: Both groups of patients showed activation in left Brodmann area (BA) 40 and 44 during this task of inner/outer source monitoring in memory, but hallucinating patients showed more widespread activation in these regions, with significantly increased activation in regions immediately adjacent to left BA 40 and 44. Conclusions: The more widespread activation adjacent to BA 40 and 44 for hallucinating compared to nonhallucinating patients has implications for specification of the cognitive operations underpinning hallucinations. Working memory studies show that BA 40 and 44 are involved in phonological storage/inner speech, suggesting that heightened neural intensity when producing inner speech may explain the overlap between inner/outer source monitoring and hallucinations. For example, an intensely experienced inner voice might add perceptual qualities to memories of internally generated events, leading to source externalizations for hallucinating patients. References [1] Woodward, T.S., Menon, M., & Whitman, J.C. (2007). Source monitoring biases and auditory hallucinations. Cognitive Neuropsychiatry, 12(6), 477-494. [2] Larøi, F. & Woodward, T.S. (2007). Hallucinations from a cognitive perspective. Harvard Review of Psychiatry, 15(3), 109-117.
116 – THE REVISED DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: EVIDENCE FROM PHARMACOLOGICAL MRI STUDIES WITH ATYPICAL ANTIPSYCHOTIC MEDICATION Fabiana da Silva Alves, Martijn Figee, Therese van Amelsvoort, Dick Veltman, Lieuwe de Haan Academic Medical Centre (AMC), Amsterdam, The Netherlands [email protected] Introduction: The revised dopamine hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the dopaminergic (DA) system.
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 Methods: In this study we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies (fMRI) in schizophrenia. Because atypical drugs are thought to have a normalizing effect on dopaminergic neurotransmission, we have focused on pharmacological MRI (PhMRI) studies that explore the effect of these drugs on prefrontal and striatal brain activity in schizophrenia patients. Results: We encountered a total of 13 studies, most of which reported enhanced prefrontal activity associated with alleviation of negative symptoms and improvement of cognitive functions, following treatment with atypical antipsychotics. Besides increasing prefrontal cortex activity, atypical antipsychotics have also shown to be effective in the regulation of striatal functioning. Conclusions: The current PhMRI findings support the revised dopamine hypothesis of schizophrenia by confirming hypo-activity of the prefrontal cortex in schizophrenia and, following atypical antipsychotics, improvement of prefrontal and subcortical functions reflecting enhanced dopaminergic activity.
117 – DISRUPTED SMALL-WORLD FUNCTIONAL INTERCONNECTIVITY IN SCHIZOPHRENIA Martijn van den Heuvel, René Mandl, Judy Luigjes, Thomas Scheewe, Wiepke Cahn, René Kahn, Hilleke Hulshoff Pol University Medical Center Utrecht, Department of Psychiatry, Utrecht, The Netherlands [email protected] Introduction: Schizophrenia has been associated with disrupted functional brain connectivity. Functional connectivity expresses the coherency of neuronal activity between separate brain regions, and has been examined with resting-state fMRI. Small-world networks are known for their high level of connectivity between the voxels that belong to the same functional group - reflected by a high clusteringcoefficient, but still with an average short distance between all voxels. Small-world networks are known to have a high level of communication efficiency. Small world properties of the functionally connected brain in schizophrenia were examined. Methods: 3 Tesla resting-state fMRI was acquired in 20 patients with schizophrenia and 17 healthy comparisons. Acquisition parameters: 3DPRESTO-SENSE, 1000 timeframes, 8 minutes, 4mm voxelsize. For each dataset, the correlation between each possible voxel pair was calculated and thresholded (0.35), resulting in an undirected network of 8000x8000 voxels. Small-world properties of these individual networks were calculated and analyzed between the two groups. Results: A significant lower cluster-coefficient was found for the patients as compared to the healthy comparisons, reflecting reduced communication efficiency. Conclusions: A lower degree of interconnectivity of resting-state functional networks was found in the brains of patients with schizophrenia. The findings suggest that a disrupted functional integration of brain networks is present in schizophrenia. References [1] Friston, K.J. (1998) Schizophr Res 30, 115-125. [2] Sporns, O. (2006) Bio Systems 85, 55-64.
118 – FUNCTIONAL INTEGRATION BETWEEN THE ANTERIOR HIPPOCAMPUS AND INFERIOR FRONTAL CORTEX IS IMPAIRED IN BOTH SCHIZOPHRENIA AND THE “AT RISK MENTAL STATE” Stefania Benetti 1 , Andrea Mechelli 2 , Marco Picchioni 1 , Pall Matthiasson 1 , Matthew R Broome 2 , Sara Weinstein 3 , Steven C.R. Williams 1 , Philip K. McGuire 1 1 King’s College London - Institute of Psychiatry, London; 2 King’s College London- Institute of Psychiatry, London; 3 King’s College London - Institute of Psychiatry, London, UK [email protected] Introduction: Recent studies have reported deficits in functional inte-
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gration between prefrontal cortex and hippocampal formation (HF) in schizophrenia. It is unclear whether these alterations are specific to patients with a psychotic disorder or are also evident in those at increased risk of developing psychosis. We investigated prefrontal-hippocampal interactions and whether such interactions varied for anterior and posterior hippocampus in the “at risk mental state” (ARMS) and in first episode schizophrenia using functional MRI (fMRI) in conjunction with a visual object working memory task. Methods: Using fMRI we measured brain responses from 16 individuals with the ARMS, 10 patients with first episode schizophrenia, and 14 healthy controls during a visual delayed matching to sample (DMTS) task. Dynamic causal modeling (DCM) was used to estimate the functional influence of the inferior frontal region on both the anterior and posterior hippocampal regions and vice versa (“effective connectivity”). Results: Effective connectivity from the posterior hippocampus to the inferior frontal gyrus (IFG) was significantly decreased in patients with schizophrenia and individuals with ARMS relative to controls in the right but not the left hemisphere (ANOVA; F = 8.16, p = 0.007). Neuronal interactions between the IFG and the anterior hippocampus did not differ across the three groups. Conclusions: Our results are consistent with previous evidence of perturbed hippocampal-prefrontal interactions in schizophrenia, but suggest that this may also be (i) observed in individuals at high risk of developing psychosis and (ii) most evident in the posterior HF during a visual working memory task.
119 – TEMPORAL PROCESSING IN SCHIZOPHRENIA: EFFECTS OF TASK-DIFFICULTY ON BEHAVIORAL DISCRIMINATION AND NEURONAL RESPONSES Deana Davalos 1 , Donald Rojas 2 , Jason Tregellas 2 State University, Fort Collins, CO; 2 University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA [email protected] 1 Colorado
Introduction: Timing deficits in schizophrenia have been observed in behavioral and electrophysiological studies for many years. The functional neuroanatomy of timing in schizophrenia is, however, poorly understood. Recent neurophysiological research suggests that timing deficits in this population may not be widespread across all timing tasks, but specifically associated with high levels of difficulty. Methods: The current study evaluated differences between individuals with schizophrenia (N= 15) and healthy subjects (N=20) during a temporal discrimination task at two levels of difficulty. Subjects were scanned at 3T while judging tone duration. A control task using tones identical in duration was included. Results: Behavioral data show that the schizophrenia group performed worse than controls only during the difficult condition. However, group differences in patterns of brain activation were detected on both levels of difficulty. In both conditions, individuals with schizophrenia showed less activation in the supplementary motor area and insula/opercula, regions known to be involved in timing processing, with greater differences observed in the difficult condition. In addition, the striatum was less active in individuals with schizophrenia. Conclusions: Comparing the difficult to easy conditions revealed robust differences in the bilateral striatum and lesser differences in the insula/opercula, suggesting that the striatum plays a key role in timing deficits in schizophrenia, especially under difficult conditions. Finally, the observation of group differences during the “easy” task using fMRI contrasted with the absence of behavioral differences suggests that fMRI may be more sensitive to subtle timing deficits in schizophrenia that may not be detected with purely behavioral measures. References [1] Davalos, D.B., Kisley, M.A., & Freedman, R. (2005). Mismatch negativity and behavioral discrimination of auditory temporal stimuli in schizophrenia. Journal of Neuropsychiatry and Clinical Neurosciences, 17(4), 517-525. [2] Volz, H., Nenadic, I., Gaser, C., et al. (2001). Time estimation
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
Results: We found comparable activation patterns between the groups for both gesture types vs. baseline (fixation cross), in predominantly bilateral occipital, temporal and frontal regions. However, in contrast to patients only healthy subjects show more activation in left temporal and frontal regions for the processing of metaphoric gestures in comparison to iconic co-verbal gestures. Conclusions: Our preliminary results are consistent with the evidence of impaired gesture (e.g. Berndl et al. 1986) and metaphor comprehension in patients with schizophrenia (e.g. Kircher et al., 2007). Patients with schizophrenia possibly fail to activate left hemispheric temporal and frontal areas which seem to be important for the comprehension of metaphoric co-verbal utterances. Acknowledgements: This research project is supported by a grant from the Interdisciplinary Center for Clinical Research “BIOMAT” (IZKF VV N68) and the Deutsche Forschungsgemeinschaft (DFG, IRTG 1328). References [1] Berndl, K., v.Cranach, M., Grusser, O.J., 1986. Impairment of perception and recognition of faces, mimic expression and gestures in schizophrenic patients. Eur Arch Psychiatry Neurol.Sci. 235, 282-291. [2] Kircher, T.T., Leube, D.T., Erb, M., Grodd, W., Ra pp, A.M., 2007. Neural correlates of metaphor processing in schizophrenia. NeuroImage 34, 281-289.
114 – THE RELATIONSHIP BETWEEN DOPAMINE D2 RECEPTOR OCCUPANCY BY ATYPICAL ANTIPSYCHOTIC DRUGS AND COGNITIVE FUNCTION IN PATIENTS WITH SCHIZOPHRENIA Mevhibe N. Tumuklu 1 , Robert M. Kessler 2 , Karu Jayathilake 3 , Herbert Y. Meltzer 3 1 Gaziosmanpasha Univ., Dept of Psychiatry, Tokat, Turkey; 2 Vanderbilt University Dept. of Radiology, Nashville TN; 3 Vanderbilt University Dept of Psychopharmacology, Nashville TN, USA [email protected] Introduction: The relationship between D2 receptor occupancy of antipsychotic drugs (APD) and clinical response is still unsettled despite poorly substantiated claims that minimum occupancy of 60% in the dorsal striatum is required for therapeutic response (Kapur, 1996). It is also unlikely that atypical APDs such as clozapine and olanzapine, which are distinguished from typical APDs by higher affinity for 5-HT2A receptors (Meltzer, 1989), require the same degree of occupancy as typical antipsychotic drugs (Kessler, 2005). Methods: Twenty-four patients with schizophrenia were scanned with PET [18F] fallypride, using a GE Advance PET scanner in the 3D mode after at least 6 weeks of treatment with atypical APDs (clozapine, quetiapine, risperidone, olanzapine). Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and a comprehensive cognitive battery (Hagger, 1999). Results: D2 receptor occupancy were not correlated with BPRS Total or Positive symptom. WAIS-R Digit symbol substitution test scores were significantly negatively correlated with D2 occupancy in putamen (r = -0.54, p=0.02) and ventral pallidum (r = -0.55, p= 0.02). Spatial working memory test delay scores were significantly negatively correlated with occupancy in substantia nigra (r= -0.85, p=0.02). Continuous Performance Test scores were found to be significantly negatively correlated with occupancy in substantia nigra (r = -0.56, p=0.03) and ventral pallidum (r=-0.59, p=0.03). Conclusions: These findings are consistent with the hypothesis that lower occupancy of D2 receptors by atypical APDs may contribute to better cognitive performance with these agents than with typical APDs. References [1] Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S et al (1996). High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiat 153:948–950.
[2] Meltzer HY, Matsubara S, Lee J-C (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Therapeut 251: 238–246. [3] Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B et al (2005). Occupancy of striatal and extrastriatal DA D2/3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30: 2283–2289. [4] Hagger, C; Buckley, P.; Kenny, J.T.; Freidman, L.; Ubogy, D.; and Meltzer, H.Y. Improvement in cognitive function and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biological Psychiatry, 34:702-712, 1993.
115 – HALLUCINATIONS ARE ASSOCIATED WITH ABERRENT ACTIVATION IN INNER SPEECH REGIONS DURING SOURCE MONITORING Todd S. Woodward, Sara Weinstein, Tara A. Cairo, Paul Metzak, Elton T.C. Ngan, Devvarta Kumar University of British Columbia, Vancouver, BC, Canada [email protected] Introduction: Previous research suggests that the dysfunctional cognitive operations underpinning hallucinations in schizophrenia overlap with those leading to inner/outer (i.e., self/other) confusions in source memory. Specifically, associations are observed between internal-toexternal source misattributions (i.e., externalizations) and hallucinations. In the current study we investigated the neural underpinnings of this association using functional magnetic resonance imaging (fMRI). Methods: 10 hallucinating and 15 nonhallucinating patients with schizophrenia alternated between saying and hearing words prior to scanning. During scanning, each of these words was displayed visually, and subjects were required to indicate, by keypress, whether they had previously sai d or heard the words. Results: Both groups of patients showed activation in left Brodmann area (BA) 40 and 44 during this task of inner/outer source monitoring in memory, but hallucinating patients showed more widespread activation in these regions, with significantly increased activation in regions immediately adjacent to left BA 40 and 44. Conclusions: The more widespread activation adjacent to BA 40 and 44 for hallucinating compared to nonhallucinating patients has implications for specification of the cognitive operations underpinning hallucinations. Working memory studies show that BA 40 and 44 are involved in phonological storage/inner speech, suggesting that heightened neural intensity when producing inner speech may explain the overlap between inner/outer source monitoring and hallucinations. For example, an intensely experienced inner voice might add perceptual qualities to memories of internally generated events, leading to source externalizations for hallucinating patients. References [1] Woodward, T.S., Menon, M., & Whitman, J.C. (2007). Source monitoring biases and auditory hallucinations. Cognitive Neuropsychiatry, 12(6), 477-494. [2] Larøi, F. & Woodward, T.S. (2007). Hallucinations from a cognitive perspective. Harvard Review of Psychiatry, 15(3), 109-117.
116 – THE REVISED DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: EVIDENCE FROM PHARMACOLOGICAL MRI STUDIES WITH ATYPICAL ANTIPSYCHOTIC MEDICATION Fabiana da Silva Alves, Martijn Figee, Therese van Amelsvoort, Dick Veltman, Lieuwe de Haan Academic Medical Centre (AMC), Amsterdam, The Netherlands [email protected] Introduction: The revised dopamine hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the dopaminergic (DA) system.
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 Methods: In this study we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies (fMRI) in schizophrenia. Because atypical drugs are thought to have a normalizing effect on dopaminergic neurotransmission, we have focused on pharmacological MRI (PhMRI) studies that explore the effect of these drugs on prefrontal and striatal brain activity in schizophrenia patients. Results: We encountered a total of 13 studies, most of which reported enhanced prefrontal activity associated with alleviation of negative symptoms and improvement of cognitive functions, following treatment with atypical antipsychotics. Besides increasing prefrontal cortex activity, atypical antipsychotics have also shown to be effective in the regulation of striatal functioning. Conclusions: The current PhMRI findings support the revised dopamine hypothesis of schizophrenia by confirming hypo-activity of the prefrontal cortex in schizophrenia and, following atypical antipsychotics, improvement of prefrontal and subcortical functions reflecting enhanced dopaminergic activity.
117 – DISRUPTED SMALL-WORLD FUNCTIONAL INTERCONNECTIVITY IN SCHIZOPHRENIA Martijn van den Heuvel, René Mandl, Judy Luigjes, Thomas Scheewe, Wiepke Cahn, René Kahn, Hilleke Hulshoff Pol University Medical Center Utrecht, Department of Psychiatry, Utrecht, The Netherlands [email protected] Introduction: Schizophrenia has been associated with disrupted functional brain connectivity. Functional connectivity expresses the coherency of neuronal activity between separate brain regions, and has been examined with resting-state fMRI. Small-world networks are known for their high level of connectivity between the voxels that belong to the same functional group - reflected by a high clusteringcoefficient, but still with an average short distance between all voxels. Small-world networks are known to have a high level of communication efficiency. Small world properties of the functionally connected brain in schizophrenia were examined. Methods: 3 Tesla resting-state fMRI was acquired in 20 patients with schizophrenia and 17 healthy comparisons. Acquisition parameters: 3DPRESTO-SENSE, 1000 timeframes, 8 minutes, 4mm voxelsize. For each dataset, the correlation between each possible voxel pair was calculated and thresholded (0.35), resulting in an undirected network of 8000x8000 voxels. Small-world properties of these individual networks were calculated and analyzed between the two groups. Results: A significant lower cluster-coefficient was found for the patients as compared to the healthy comparisons, reflecting reduced communication efficiency. Conclusions: A lower degree of interconnectivity of resting-state functional networks was found in the brains of patients with schizophrenia. The findings suggest that a disrupted functional integration of brain networks is present in schizophrenia. References [1] Friston, K.J. (1998) Schizophr Res 30, 115-125. [2] Sporns, O. (2006) Bio Systems 85, 55-64.
118 – FUNCTIONAL INTEGRATION BETWEEN THE ANTERIOR HIPPOCAMPUS AND INFERIOR FRONTAL CORTEX IS IMPAIRED IN BOTH SCHIZOPHRENIA AND THE “AT RISK MENTAL STATE” Stefania Benetti 1 , Andrea Mechelli 2 , Marco Picchioni 1 , Pall Matthiasson 1 , Matthew R Broome 2 , Sara Weinstein 3 , Steven C.R. Williams 1 , Philip K. McGuire 1 1 King’s College London - Institute of Psychiatry, London; 2 King’s College London- Institute of Psychiatry, London; 3 King’s College London - Institute of Psychiatry, London, UK [email protected] Introduction: Recent studies have reported deficits in functional inte-
97
gration between prefrontal cortex and hippocampal formation (HF) in schizophrenia. It is unclear whether these alterations are specific to patients with a psychotic disorder or are also evident in those at increased risk of developing psychosis. We investigated prefrontal-hippocampal interactions and whether such interactions varied for anterior and posterior hippocampus in the “at risk mental state” (ARMS) and in first episode schizophrenia using functional MRI (fMRI) in conjunction with a visual object working memory task. Methods: Using fMRI we measured brain responses from 16 individuals with the ARMS, 10 patients with first episode schizophrenia, and 14 healthy controls during a visual delayed matching to sample (DMTS) task. Dynamic causal modeling (DCM) was used to estimate the functional influence of the inferior frontal region on both the anterior and posterior hippocampal regions and vice versa (“effective connectivity”). Results: Effective connectivity from the posterior hippocampus to the inferior frontal gyrus (IFG) was significantly decreased in patients with schizophrenia and individuals with ARMS relative to controls in the right but not the left hemisphere (ANOVA; F = 8.16, p = 0.007). Neuronal interactions between the IFG and the anterior hippocampus did not differ across the three groups. Conclusions: Our results are consistent with previous evidence of perturbed hippocampal-prefrontal interactions in schizophrenia, but suggest that this may also be (i) observed in individuals at high risk of developing psychosis and (ii) most evident in the posterior HF during a visual working memory task.
119 – TEMPORAL PROCESSING IN SCHIZOPHRENIA: EFFECTS OF TASK-DIFFICULTY ON BEHAVIORAL DISCRIMINATION AND NEURONAL RESPONSES Deana Davalos 1 , Donald Rojas 2 , Jason Tregellas 2 State University, Fort Collins, CO; 2 University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA [email protected] 1 Colorado
Introduction: Timing deficits in schizophrenia have been observed in behavioral and electrophysiological studies for many years. The functional neuroanatomy of timing in schizophrenia is, however, poorly understood. Recent neurophysiological research suggests that timing deficits in this population may not be widespread across all timing tasks, but specifically associated with high levels of difficulty. Methods: The current study evaluated differences between individuals with schizophrenia (N= 15) and healthy subjects (N=20) during a temporal discrimination task at two levels of difficulty. Subjects were scanned at 3T while judging tone duration. A control task using tones identical in duration was included. Results: Behavioral data show that the schizophrenia group performed worse than controls only during the difficult condition. However, group differences in patterns of brain activation were detected on both levels of difficulty. In both conditions, individuals with schizophrenia showed less activation in the supplementary motor area and insula/opercula, regions known to be involved in timing processing, with greater differences observed in the difficult condition. In addition, the striatum was less active in individuals with schizophrenia. Conclusions: Comparing the difficult to easy conditions revealed robust differences in the bilateral striatum and lesser differences in the insula/opercula, suggesting that the striatum plays a key role in timing deficits in schizophrenia, especially under difficult conditions. Finally, the observation of group differences during the “easy” task using fMRI contrasted with the absence of behavioral differences suggests that fMRI may be more sensitive to subtle timing deficits in schizophrenia that may not be detected with purely behavioral measures. References [1] Davalos, D.B., Kisley, M.A., & Freedman, R. (2005). Mismatch negativity and behavioral discrimination of auditory temporal stimuli in schizophrenia. Journal of Neuropsychiatry and Clinical Neurosciences, 17(4), 517-525. [2] Volz, H., Nenadic, I., Gaser, C., et al. (2001). Time estimation