- Email: [email protected]
COMBINING COGNITIVE AND SOCIAL COGNITIVE TRAINING FOR INDIVIDUALS WITH SCHIZOPHRENIA
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
Methods: We recruited 50 patients with chronic schizophrenia and 58 healthy control subjects. To measure musical ability and cognitive function, we used the Montreal Battery of Evaluation of Amusia (MBEA) and the Brief Assessment of Cognition in Schizophrenia (BACS). We carried out a mediation analysis to investigate a possible pathway to a deficit in musical ability. Results: Compared to controls, the MBEA global score in schizophrenia was significantly lower (p<0.001), and was strongly associated with both the composite cognitive function score (r=0.645, p<0.001) and the negative symptom score (r=−0.504, p<0.001). Our mediation study showed an approximately 43% indirect and 57% direct association between negative symptoms and musical deficit via cognitive impairment, indicating that the effects of negative symptoms on musical disability in patients with schizophrenia are only partially explained by cognitive impairment. Conclusion: In our study, negative symptoms were correlated with the MBEA global score. Patients with schizophrenia also showed a correlation between overall cognitive functions and MBEA global musical score. Examining the relationships between musical deficits, negative symptoms and cognitive dysfunction in schizophrenia may identify shared biological mechanisms. Greater understanding of the connection between musical deficits and cognitive dysfunctions could improve our understanding of the neural substrates of functional impairment in people with this illness, facilitating the development of insight for cognitive remediation through music.
COMBINING COGNITIVE AND SOCIAL COGNITIVE TRAINING FOR INDIVIDUALS WITH SCHIZOPHRENIA Sophia Vinogradov 1,2 , Karuna Subramaniam, Bruno Biagianti, Christine Hooker, Melissa Fisher 1 University of California, San Francisco; 2 Associate Chief of Staff for Mental Health, SFVA MEdical Center In a previous path analysis examining the relationship of neurocognition, self-referential processing, and social cognition to motivation and functional outcome in patients with schizophrena, we demonstrated that: 1) Neurocognition (attention and executive functioning) and self-referential processing are independent, and each uniquely contributes to social cognition, 2) Social cognition and motivation are associated, 3) Motivation, in turn, predicts outcome (social and occupational functioning). The results of these analyses raised several key questions for the design of maximally effective cognitive treatments in schizophrenia: 1) Is social cognition amenable to computerized neuroplasticity-based training? 2) By enhancing both social cognitive and general cognitive abilities through neuroadaptive training, can we optimize motivation and functional outcome? We will present preliminary data on the behavioral and neural system findings from a randomized controlled trial which performs a direct contrast of general cognitive training delivered alone to individuals with schizophrenia, vs. general cognitive training plus social cognitive training. The purpose of this study is to investigate factors that have often been ignored in computerbased cognitive training programs – those related to social cognition– and to delineate their relationship to motivation, functional outcome, and the neural substrates of reward anticipation and emotion processing.
Symposium SCHIZOPHRENIA INTERNEURON PATHOLOGY: LOST IN MIGRATION Chairperson: Cynthia Shannon-Weickert Discussant: Bita Moghaddam Monday, 7 April 2014 2:00 PM – 4:00 PM Overall Abstract: An increased density of neurons below the cortical grey matter represents reproducible cellular evidence for altered neurodevelopment in schizophrenia. In this session we will examine the nature of these cells and consider that white matter neurons (WMNs) may be GABAergic interneurons related to the cortical interneuron deficit in schizophrenia. In this view, excess WMNs could represent improper migration of interneurons to the cortex. In an attempt to illuminate the nature of WMNs in schizophrenia, we will consider data on how laser capture of WMNs combined with RNseq may help us to determine global transcriptional profiles
S27
of these cells and their changes in schizophrenia. We will also provide evidence that interneuron deficits and activation of immune responses within the cortex of people with schizophrenia may be linked to excess WMNs. Next, we will review experimental evidence that birth and migration of new GABAergic interneurons can be seen in the early postnatal rodent brain and that these neurons can migrate to the cortex. This knowledge suggests a further interpretation: that increased WMNs in schizophrenia could represent the harnessing of new neurons in a rebuilding effort. We will then present evidence that in rodent models of schizophrenia elevated oxidative stress, particularly in GABAergic interneurons, precedes symptom onset and may represent a cortical injury-like pathology in disease that could induce recruitment of new interneurons to the cortex. Finally, we will discuss why viewing increased WMNs as part of neurodevelopment, neuropathology or neurorepair, may constrain or inform our efforts to determine the causes of schizophrenia.
INCREASED WHITE MATTER NEURON DENSITY IS RELATED TO HIGH NEUROINFLAMMATION IN PEOPLE WITH SCHIZOPHRENIA Cindy Shannon-Weickert 1,2 , S.J. Fung 3 , D. Joshi 3 , S.G. Fillman 3 , V.S. Catts 3 UNSW; 2 SRI; 3 Schizophrenia Research Institute, Neuroscience Research Australia, and University of New South Wales; Sydney, Australia
1
Background: Increased white matter neuron density is linked to reductions in cortical interneuron mRNA in people with schizophrenia, suggesting aberrant interneuron migration to the cortex may be implicated in the neuropathophysiology. Proinflammatory cytokines are also elevated in the disease and we hypothesize that reduced viability of interneurons relates to increased neuroinflammation and recruitment of interneurons to the cortex in schizophrenia. Methods: Immunohistochemistry (NeuN, GAD65/67) was used to identify white matter neurons, and quantitative RT-PCR of cDNA from 37 people with schizophrenia and 37 matched controls was used to determine expression of cytokines (IL-6, CXCL12), cytokine receptors (CXCR4, CXCR7), interneuron marker (somatostatin), and cell death related mRNAs (FASR, APRIL) in the frontal cortex. Results: A subgroup of individuals with high proinflammatory cytokines (primarily IL-6) was identified (14/37 people with schizophrenia) (Fillman et al, 2012, Mol Psychiatry). Density of white matter neurons was increased in individuals with schizophrenia with high compared to low neuroinflammation (p<6x10-4). Somatostatin was reduced in people with schizophrenia with high compared to low inflammation (p=8.8x10-4), and the cytokine receptor CXCR7 mRNA was increased in the DLPFC of schizophrenics with high neuroinflammation (p=4x10-4). Conclusion: Our findings suggest that inflammation in the brain of people with schizophrenia may be associated with an interneuron deficit, cell death pathways, increased white matter neuron density, and increased expression of cytokine receptor CXCR7. We propose that white matter neurons may represent immature, migrating interneurons increased in people with schizophrenia in response to a cortical neuron deficit.
SUBCORTICAL WHITE MATTER NEURONS IN AUTISM, SCHIZOPHRENIA AND DEPRESSION Schahram Akbarian 1 , Cong L. Lin 2 , Aslihan Dincer 3 , Eustathia Lela Giannaris 4 , Yin Guo 2 , Adriana Akintobe 2 , John Neary 2 , Vahram Haroutunian 5,6 , Andree Lessard 7 , William E. Bunney Jr. 8 , Juerg Straubhaar 9 , Scott E. Hemby 9 , Schahram Akbarian 2,5 1 Icahn School of Medicine at Mount Sinai; 2 Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester MA; 3 Graduate Program in Genetics and Genomic Sciences,Mount Sinai School of Medicine, NY; 4 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester MA; 5 Department of Psychiatry, Mount Sinai School of Medicine, NY; 6 James J. Peters Veterans Affairs Medical Center; 7 Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD; 8 Department of Psychiatry and Human Behavior, University of California at Irvine, CA; 9 Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC Increased numbers and densities of subcortical white matter neurons
Methods: We recruited 50 patients with chronic schizophrenia and 58 healthy control subjects. To measure musical ability and cognitive function, we used the Montreal Battery of Evaluation of Amusia (MBEA) and the Brief Assessment of Cognition in Schizophrenia (BACS). We carried out a mediation analysis to investigate a possible pathway to a deficit in musical ability. Results: Compared to controls, the MBEA global score in schizophrenia was significantly lower (p<0.001), and was strongly associated with both the composite cognitive function score (r=0.645, p<0.001) and the negative symptom score (r=−0.504, p<0.001). Our mediation study showed an approximately 43% indirect and 57% direct association between negative symptoms and musical deficit via cognitive impairment, indicating that the effects of negative symptoms on musical disability in patients with schizophrenia are only partially explained by cognitive impairment. Conclusion: In our study, negative symptoms were correlated with the MBEA global score. Patients with schizophrenia also showed a correlation between overall cognitive functions and MBEA global musical score. Examining the relationships between musical deficits, negative symptoms and cognitive dysfunction in schizophrenia may identify shared biological mechanisms. Greater understanding of the connection between musical deficits and cognitive dysfunctions could improve our understanding of the neural substrates of functional impairment in people with this illness, facilitating the development of insight for cognitive remediation through music.
COMBINING COGNITIVE AND SOCIAL COGNITIVE TRAINING FOR INDIVIDUALS WITH SCHIZOPHRENIA Sophia Vinogradov 1,2 , Karuna Subramaniam, Bruno Biagianti, Christine Hooker, Melissa Fisher 1 University of California, San Francisco; 2 Associate Chief of Staff for Mental Health, SFVA MEdical Center In a previous path analysis examining the relationship of neurocognition, self-referential processing, and social cognition to motivation and functional outcome in patients with schizophrena, we demonstrated that: 1) Neurocognition (attention and executive functioning) and self-referential processing are independent, and each uniquely contributes to social cognition, 2) Social cognition and motivation are associated, 3) Motivation, in turn, predicts outcome (social and occupational functioning). The results of these analyses raised several key questions for the design of maximally effective cognitive treatments in schizophrenia: 1) Is social cognition amenable to computerized neuroplasticity-based training? 2) By enhancing both social cognitive and general cognitive abilities through neuroadaptive training, can we optimize motivation and functional outcome? We will present preliminary data on the behavioral and neural system findings from a randomized controlled trial which performs a direct contrast of general cognitive training delivered alone to individuals with schizophrenia, vs. general cognitive training plus social cognitive training. The purpose of this study is to investigate factors that have often been ignored in computerbased cognitive training programs – those related to social cognition– and to delineate their relationship to motivation, functional outcome, and the neural substrates of reward anticipation and emotion processing.
Symposium SCHIZOPHRENIA INTERNEURON PATHOLOGY: LOST IN MIGRATION Chairperson: Cynthia Shannon-Weickert Discussant: Bita Moghaddam Monday, 7 April 2014 2:00 PM – 4:00 PM Overall Abstract: An increased density of neurons below the cortical grey matter represents reproducible cellular evidence for altered neurodevelopment in schizophrenia. In this session we will examine the nature of these cells and consider that white matter neurons (WMNs) may be GABAergic interneurons related to the cortical interneuron deficit in schizophrenia. In this view, excess WMNs could represent improper migration of interneurons to the cortex. In an attempt to illuminate the nature of WMNs in schizophrenia, we will consider data on how laser capture of WMNs combined with RNseq may help us to determine global transcriptional profiles
S27
of these cells and their changes in schizophrenia. We will also provide evidence that interneuron deficits and activation of immune responses within the cortex of people with schizophrenia may be linked to excess WMNs. Next, we will review experimental evidence that birth and migration of new GABAergic interneurons can be seen in the early postnatal rodent brain and that these neurons can migrate to the cortex. This knowledge suggests a further interpretation: that increased WMNs in schizophrenia could represent the harnessing of new neurons in a rebuilding effort. We will then present evidence that in rodent models of schizophrenia elevated oxidative stress, particularly in GABAergic interneurons, precedes symptom onset and may represent a cortical injury-like pathology in disease that could induce recruitment of new interneurons to the cortex. Finally, we will discuss why viewing increased WMNs as part of neurodevelopment, neuropathology or neurorepair, may constrain or inform our efforts to determine the causes of schizophrenia.
INCREASED WHITE MATTER NEURON DENSITY IS RELATED TO HIGH NEUROINFLAMMATION IN PEOPLE WITH SCHIZOPHRENIA Cindy Shannon-Weickert 1,2 , S.J. Fung 3 , D. Joshi 3 , S.G. Fillman 3 , V.S. Catts 3 UNSW; 2 SRI; 3 Schizophrenia Research Institute, Neuroscience Research Australia, and University of New South Wales; Sydney, Australia
1
Background: Increased white matter neuron density is linked to reductions in cortical interneuron mRNA in people with schizophrenia, suggesting aberrant interneuron migration to the cortex may be implicated in the neuropathophysiology. Proinflammatory cytokines are also elevated in the disease and we hypothesize that reduced viability of interneurons relates to increased neuroinflammation and recruitment of interneurons to the cortex in schizophrenia. Methods: Immunohistochemistry (NeuN, GAD65/67) was used to identify white matter neurons, and quantitative RT-PCR of cDNA from 37 people with schizophrenia and 37 matched controls was used to determine expression of cytokines (IL-6, CXCL12), cytokine receptors (CXCR4, CXCR7), interneuron marker (somatostatin), and cell death related mRNAs (FASR, APRIL) in the frontal cortex. Results: A subgroup of individuals with high proinflammatory cytokines (primarily IL-6) was identified (14/37 people with schizophrenia) (Fillman et al, 2012, Mol Psychiatry). Density of white matter neurons was increased in individuals with schizophrenia with high compared to low neuroinflammation (p<6x10-4). Somatostatin was reduced in people with schizophrenia with high compared to low inflammation (p=8.8x10-4), and the cytokine receptor CXCR7 mRNA was increased in the DLPFC of schizophrenics with high neuroinflammation (p=4x10-4). Conclusion: Our findings suggest that inflammation in the brain of people with schizophrenia may be associated with an interneuron deficit, cell death pathways, increased white matter neuron density, and increased expression of cytokine receptor CXCR7. We propose that white matter neurons may represent immature, migrating interneurons increased in people with schizophrenia in response to a cortical neuron deficit.
SUBCORTICAL WHITE MATTER NEURONS IN AUTISM, SCHIZOPHRENIA AND DEPRESSION Schahram Akbarian 1 , Cong L. Lin 2 , Aslihan Dincer 3 , Eustathia Lela Giannaris 4 , Yin Guo 2 , Adriana Akintobe 2 , John Neary 2 , Vahram Haroutunian 5,6 , Andree Lessard 7 , William E. Bunney Jr. 8 , Juerg Straubhaar 9 , Scott E. Hemby 9 , Schahram Akbarian 2,5 1 Icahn School of Medicine at Mount Sinai; 2 Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester MA; 3 Graduate Program in Genetics and Genomic Sciences,Mount Sinai School of Medicine, NY; 4 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester MA; 5 Department of Psychiatry, Mount Sinai School of Medicine, NY; 6 James J. Peters Veterans Affairs Medical Center; 7 Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD; 8 Department of Psychiatry and Human Behavior, University of California at Irvine, CA; 9 Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC Increased numbers and densities of subcortical white matter neurons