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422. Fronto-Parietal Effective Connectivity in Schizophrenia Patients and Participants with Subclinical Delusional Ideation
Biological Psychiatry
Friday Abstracts
Supported By: NIH 5KL2TR000434 Keywords: Schizophrenia, Social Cognition, BOLD fMRI, effective connectivity
421. Discovering the “Functional Dysconnectome” in Schizophrenia: Dynamic Modulation of Brain Network Dysfunction during Learning and Visuo-Motor Processing Vaibhav Diwadkar Wayne State University School of Medicine Background: Structural brain networks are subject to dynamic functional demands (Park & Friston, 2013). As fMRI signals are sensitive to task-induced modulation (Logothetis, 2008), inducing functional dynamics can clarify aspects of the functional dysconnectome in schizophrenia (SCZ). We assessed the dysconnectome in two domains: a) Associative learning targeting frontal-striatal-hippocampal sub-networks and b) Basic visuo-motor integration targeting uni- and hetero-modal networks. Undirected functional connectivity (uFC) analysis of signals in the time domain (Silverstein et al., 2016) was employed. Methods: fMRI (3T) was collected in right-handed SCZ and controls (n565 total) and typically modeled (SPM8). a) During learning, subjects encoded associations between object-location pairs for subsequent cued retrieval. b) During visuo-motor integration, subjects detected briefly presented probes (11 in size appearing at a retinal eccentricity of 71 along the horizontal meridian). Intra-subject correlation coefficients (Spearman’s Rho or Pearson’s R) between sub-network pairs were computed, normalized (Fischer’s Z), and submitted for inter-group analyses (p,.05, Bonferroni). Results: The functional dysconnectome was diffuse: a) For learning, the dPFC and the basal ganglia emerged as dysconnection hubs during encoding and retrieval, with reduced uFC with the hippocampus, and dorsal anterior cingulate (dACC). b) For visuo-motor integration the supplementary motor area, the dACC and the primary visual cortex emerged as dysconnection hubs, showing reduced uFC with multiple sensori-motor regions. Conclusions: The functional dysconnectome in SCZ is dynamic, and by implication, structural dysconnection exercises soft constraints on the functional dysconnectome. Understanding the functional dysconnectome in schizophrenia is a challenging instance of the complex dialectic between brain structure and function. Supported By: MH111177; NARSAD Keywords: fMRI, Schizophrenia, Brain networks, Dysconnectivity, associative learning
422. Fronto-Parietal Effective Connectivity in Schizophrenia Patients and Participants with Subclinical Delusional Ideation Florian Schlagenhauf1, Yu Fukuda2, Teresa Katthagen2, Jakob Kaminski2, Lorenz Deserno1, and Andreas Heinz2 Max Planck Institute, 2Department of Psychiatry, Chrité Universitätsmedizin Berlin
1
Background: Impairment in working memory (WM) is one of the core cognitive dysfunctions in schizophrenia patients and
S172
subjects with high-risk for psychosis. Recent imaging studies have identified abnormalities in prefrontal activation and in connectivity between frontal and parietal regions in different stages of psychosis. However, it still remains unexplored whether comparable functional changes are found in participants with subclinical levels of psychosis. Methods: We investigated schizophrenia patients and healthy controls with and without subclinical delusional ideations with functional MRI during numeric WM. Participants with high subclinical delusional ideations were identified using the Peters Delusion Inventory. Dynamical causal modeling (DCM) was used to assess effective connectivity between frontal and parietal brain regions during WM performance. Unsupervised classification was used to identify patient subgroups based on DCM parameters. Results: We previously found in schizophrenia patients reduced WM-dependent effective connectivity from dorsolateral-prefrontal to parietal cortex compared to healthy controls. High PDI subjects were no impaired behaviorally but displayed increased local activation in dlPFC. DCM analysis revealed reduced modulatory WM-dependent fronto-parietal connectivity and increased intrinsic parieto-frontal connectivity in subjects with high delusional ideation. In patients unsupervised classification revealed subgroups differing on negative symptoms. Conclusions: Subjects with high delusional ideation showed an inefficient dlPFC recruitment resulting from altered effective connectivity within the fronto-parietal network in accordance with a dimensional view of psychosis. Furthermore, our results suggest that parameters derived from generative models of neural activation during working memory can be feasible to identify mechanistically informed subgroups in schizophrenia patients. Supported By: Geram Research Foundation SCHL1969/1-1 Keywords: delusions, Working memory, effective connectivity, BOLD fMRI
423. NMDAR Antagonism via Ketamine Differentially Modulates Thalamic versus Hippocampal Functional Connectivity Alan Anticevic1, Charlie Schleifer1, Vinod Srihari1, John Krystal2, John Murray1, Grega Repovs3, Gordon Xu4, Lisa Ji1, Youngsun Cho1, Nicole Santamauro1, Jennifer Foss-Feig4, Genevieve Yang1, Peter Morgan1, and Aleksandar Savic5 1 3
Yale University, 2Yale University School of Medicine, University of Ljubljana, 4MSSM, 5University of Zagreb
Background: Disruption in brain-wide resting-state functional connectivity (rs-fcMRI) has been implicated in schizophrenia. This type of system-level disturbance has not yet been adequately mapped onto synaptic-level mechanisms, where pharmacological intervention occurs. Antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor is a prevailing pharmacological model for schizophrenia symptoms. Methods: Using the NMDAR antagonism model, we examined effect of sub-anesthetic doses of ketamine on thalamic and hippocampal rs-fcMRI in healthy control subjects (HCS, n527) relative to a placebo infusion. Neuroimaging data were acquired and processed in line with Human Connectome Project (HCP) methods. Across analyses, rs-fcMRI was computed between
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
Friday Abstracts
Supported By: NIH 5KL2TR000434 Keywords: Schizophrenia, Social Cognition, BOLD fMRI, effective connectivity
421. Discovering the “Functional Dysconnectome” in Schizophrenia: Dynamic Modulation of Brain Network Dysfunction during Learning and Visuo-Motor Processing Vaibhav Diwadkar Wayne State University School of Medicine Background: Structural brain networks are subject to dynamic functional demands (Park & Friston, 2013). As fMRI signals are sensitive to task-induced modulation (Logothetis, 2008), inducing functional dynamics can clarify aspects of the functional dysconnectome in schizophrenia (SCZ). We assessed the dysconnectome in two domains: a) Associative learning targeting frontal-striatal-hippocampal sub-networks and b) Basic visuo-motor integration targeting uni- and hetero-modal networks. Undirected functional connectivity (uFC) analysis of signals in the time domain (Silverstein et al., 2016) was employed. Methods: fMRI (3T) was collected in right-handed SCZ and controls (n565 total) and typically modeled (SPM8). a) During learning, subjects encoded associations between object-location pairs for subsequent cued retrieval. b) During visuo-motor integration, subjects detected briefly presented probes (11 in size appearing at a retinal eccentricity of 71 along the horizontal meridian). Intra-subject correlation coefficients (Spearman’s Rho or Pearson’s R) between sub-network pairs were computed, normalized (Fischer’s Z), and submitted for inter-group analyses (p,.05, Bonferroni). Results: The functional dysconnectome was diffuse: a) For learning, the dPFC and the basal ganglia emerged as dysconnection hubs during encoding and retrieval, with reduced uFC with the hippocampus, and dorsal anterior cingulate (dACC). b) For visuo-motor integration the supplementary motor area, the dACC and the primary visual cortex emerged as dysconnection hubs, showing reduced uFC with multiple sensori-motor regions. Conclusions: The functional dysconnectome in SCZ is dynamic, and by implication, structural dysconnection exercises soft constraints on the functional dysconnectome. Understanding the functional dysconnectome in schizophrenia is a challenging instance of the complex dialectic between brain structure and function. Supported By: MH111177; NARSAD Keywords: fMRI, Schizophrenia, Brain networks, Dysconnectivity, associative learning
422. Fronto-Parietal Effective Connectivity in Schizophrenia Patients and Participants with Subclinical Delusional Ideation Florian Schlagenhauf1, Yu Fukuda2, Teresa Katthagen2, Jakob Kaminski2, Lorenz Deserno1, and Andreas Heinz2 Max Planck Institute, 2Department of Psychiatry, Chrité Universitätsmedizin Berlin
1
Background: Impairment in working memory (WM) is one of the core cognitive dysfunctions in schizophrenia patients and
S172
subjects with high-risk for psychosis. Recent imaging studies have identified abnormalities in prefrontal activation and in connectivity between frontal and parietal regions in different stages of psychosis. However, it still remains unexplored whether comparable functional changes are found in participants with subclinical levels of psychosis. Methods: We investigated schizophrenia patients and healthy controls with and without subclinical delusional ideations with functional MRI during numeric WM. Participants with high subclinical delusional ideations were identified using the Peters Delusion Inventory. Dynamical causal modeling (DCM) was used to assess effective connectivity between frontal and parietal brain regions during WM performance. Unsupervised classification was used to identify patient subgroups based on DCM parameters. Results: We previously found in schizophrenia patients reduced WM-dependent effective connectivity from dorsolateral-prefrontal to parietal cortex compared to healthy controls. High PDI subjects were no impaired behaviorally but displayed increased local activation in dlPFC. DCM analysis revealed reduced modulatory WM-dependent fronto-parietal connectivity and increased intrinsic parieto-frontal connectivity in subjects with high delusional ideation. In patients unsupervised classification revealed subgroups differing on negative symptoms. Conclusions: Subjects with high delusional ideation showed an inefficient dlPFC recruitment resulting from altered effective connectivity within the fronto-parietal network in accordance with a dimensional view of psychosis. Furthermore, our results suggest that parameters derived from generative models of neural activation during working memory can be feasible to identify mechanistically informed subgroups in schizophrenia patients. Supported By: Geram Research Foundation SCHL1969/1-1 Keywords: delusions, Working memory, effective connectivity, BOLD fMRI
423. NMDAR Antagonism via Ketamine Differentially Modulates Thalamic versus Hippocampal Functional Connectivity Alan Anticevic1, Charlie Schleifer1, Vinod Srihari1, John Krystal2, John Murray1, Grega Repovs3, Gordon Xu4, Lisa Ji1, Youngsun Cho1, Nicole Santamauro1, Jennifer Foss-Feig4, Genevieve Yang1, Peter Morgan1, and Aleksandar Savic5 1 3
Yale University, 2Yale University School of Medicine, University of Ljubljana, 4MSSM, 5University of Zagreb
Background: Disruption in brain-wide resting-state functional connectivity (rs-fcMRI) has been implicated in schizophrenia. This type of system-level disturbance has not yet been adequately mapped onto synaptic-level mechanisms, where pharmacological intervention occurs. Antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor is a prevailing pharmacological model for schizophrenia symptoms. Methods: Using the NMDAR antagonism model, we examined effect of sub-anesthetic doses of ketamine on thalamic and hippocampal rs-fcMRI in healthy control subjects (HCS, n527) relative to a placebo infusion. Neuroimaging data were acquired and processed in line with Human Connectome Project (HCP) methods. Across analyses, rs-fcMRI was computed between
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal