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Poster #S183 CHRONIC SOCIAL DEFEAT STRESS INDUCES INCREASED EXPRESSION OF D2-DIMMER IN THE PREFRONTAL CORTEX OF MICE
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
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higher gamma band activity change between standard and target conditions in the left frontal area (p<0.001). The standard to target activity change was positive in patients and negative in controls. For the proposed P300 response pathway, the F-model was a better fit than the other two in patients, while the B-model was better in healthy controls. Attending the DMN pathway, the FB-model was the best fit in patients while the F-model was the corresponding best option in healthy controls. Discussion: Abnormal bi-directional (forward-backward) frontal connectivity in the DMN, mediating between task conditions, may underlay the standard to target gamma band activity decrease found in the left frontal region in patients with schizophrenia. A lack of backward control (frontal to parietal) in the P300 response pathway may be also related to the high-frequency alteration in patients.
leftward frontal α-activation during criticism and schizotypy and anxiety suggests increasing withdrawal from and emotional reactivity to criticism. However, more criticism from predominantly low-EE relatives was associated with greater leftward frontal high α-activation during positive comments. This finding indicates greater ’approach motivation’, i.e. both heightened attention to, and more evaluation of positive comments.
Poster #S181 GREATER LEFTWARD FRONTAL ALPHA ACTIVATION DURING CRITICISM IS ASSOCIATED WITH SCHIZOTYPAL TRAITS AND ANXIETY
Background: Disruptions in filtering of sensory information have frequently been observed in patients with schizophrenia. Successful sensory gating is believed to prevent sensory overload of higher brain functions by filtering out irrelevant stimuli before they can reach the higher brain areas. Deficits in sensory gating may therefore result in an overload of irrelevant information reaching the higher brain areas, which in turn might contribute to the formation of psychotic symptoms. One well-established paradigm to assess sensory gating is P50 suppression in humans, or the very similar double click paradigm in rats. In this paradigm, patients with schizophrenia score significantly lower than healthy controls. In schizophrenia both a reduction in prefrontal dopaminergic activity and an increased noradrenergic activity have been suggested to be involved in the disease. In the current study we aimed to further investigate the involvement of these neurotransmitters by using the norepinephrine reuptake inhibitor (NRI) reboxetine and the dopamine antagonist haloperidol, respectively. Furthermore our aim was to investigate if any potential drug effect found in humans could be translated to rats. Methods: The design of the human experiment was a double-blind, placebocontrolled, cross-over study. In the humans a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo was administered to 21 healthy male subjects at four separate visits with a minimum of two weeks apart. The subjects were subsequently tested in The Copenhagen Psychophysiological Test Battery (CPTB) which, amongst others, measures P50 suppression using electroencephalography (EEG). Very similar to our human setting the animal experiment consisted of 22 rats (n=22) that received a dose of either, reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo with one week apart to allow washout of compounds. The rats were hereafter tested in an EEG setting. Results: In humans we found a significant reduction in P50 suppression following separate administration of either reboxetine or haloperidol as well as following their combined administration compared to placebo. In the rats we found a similar significant reduction of sensory gating (N40) in the hippocampus (CA3-region), but not in cortical placed electrodes after the haloperidol and combination treatments and a trend in reducing sensory gating following the reboxetine treatment compared to placebo. Discussion: The obtained results suggest that increased noradrenergic and decreased dopaminergic activities are involved in P50 suppression. However we did not observe a synergistic effect of the combination of the compounds, which may indicate either a ceiling effect or a drug/drug interaction. The animal studies confirmed the human data to some degree, suggesting a predictive validity of the P50 suppression to hippocampal sites but not cortical areas. Since sensory gating in schizophrenia patients is usually found to be reduced compared to controls our results may indicate similar underlying neurotransmitter activities.
Preethi Premkumar 1 , Miguel Espirito-Santo 2 , Juliana Onwumere 3 , Veena Kumari 4 , Maddie Groom 5 , Elizabeth Kuipers 3 1 Nottingham Trent University; 2 School of Psychology, University of Nottingham, Nottingham, UK; 3 King’s College London Institute of Psychiatry, London, UK; 4 Institute of Psychiatry, London; 5 Division of Psychiatry, Institute of Mental Health, University of Nottingham, Nottingham, UK Background: Criticism from a caregiver predicts relapse, longer hospitalization and greater symptom severity in schizophrenia. Characterised by its tone and content, criticism may be seen as a standardised construct that elicits a specific neural response in those perceiving it. fMRI research indicates that listening to criticism activates the superior frontal gyrus in patients with schizophrenia a d individuals with high schizotypy. Greater anxiety is associated with greater superior-to-middle frontal gyral connectivity during standardized criticism. The electrocortical response to insult is increased leftward frontal alpha (α) activation. The study aimed to determine the relation between leftward frontal α activation during standardised criticism and schizotypy, anxiety and criticism from a close relative. Methods: Twenty-two healthy individuals (mean age=23 years; range 18-40 years; 15 women) underwent electroencephalography (EEG) while listening to a standard set of comments (criticism, positive and neutral comments) spoken in a male or female voice and imagining them to be spoken by a close relative. Ten of these participants (7 women; 3 men) were also assessed on schizotypy and anxiety. Their close relative (6 partners, 3 siblings, 1 parent) was assessed on Expressed Emotion (a standard measure of criticism) using the Camberwell Family Interview. The absolute spectral power during the comment and event-related synchronization/desynchronization (ERS/ERD) within 500ms epochs of the comment in the low (8-10Hz) and high (10-12 Hz) α frequency bands were extracted in the middle-lateral (F3, F4, FC3, FC4) and lateral frontal sites (F5, FC5, F6, FC6). Asymmetry was calculated by subtracting spectral power in the left from right hemisphere electrodes. Analysis of variance was performed followed by post hoc paired-sample t-tests. Planned Spearman correlations were performed between spectral power, schizotypy, anxiety and carer criticism. Results: Three out of ten participants had a high EE relative. Participants, on average, had low positive schizotypy (mean number of unusual experiences=3.7, range 0-7). At the F3/F4, an emotion-by by-hemisphere-gender interaction in low α-activation was explained by greater activation during female criticism than neutral comments. At F5/F6, a main effect of emotion in high α-activation revealed more activation during male criticism than neutral comments. At FC3/FC4, an emotion-by-hemisphere-by-gender interaction in low α ERS/ERD showed greater ERS during female criticism and positive comments than neutral comments at the 0-500ms epoch. Greater impulsive non-conformity and anxiety correlated with lower leftward low α-activation at F3/F4 sites during female criticism. More relative criticism correlated with greater leftward high α-activation at F5/F6 sites during male positive comments. Greater introvertive anhedonia correlated with lower leftward FC5/FC6 ERS/ERD asymmetry at 0-500ms during female positive comments. Discussion: Greater frontal α-activation during criticism than neutral comments suggests greater cognitive appraisal of criticism, with low α-activation indicating greater general attention and high α-activation indicating greater semantic processing. The inverse association between
Poster #S182 THE EFFECT OF REBOXETINE AND HALOPERIDOL ON SENSORY GATING IN HEALTHY HUMANS AND RATS Louise M. Witten 1 , Birte Glenthøj 1 , Jesper Bastlund 2 , Arne Mørk 2 , Björn Steiniger-Brach 2 , Bob Oranje 1 1 CNSR and CINS; 2 H. Lundbeck.com
Poster #S183 CHRONIC SOCIAL DEFEAT STRESS INDUCES INCREASED EXPRESSION OF D2-DIMMER IN THE PREFRONTAL CORTEX OF MICE Tarique R. Bagalkot, Hong-Mei Jin, Yin Cui Chonbuk National University Background: Chronic social defeat stress is a potent stressor that promotes the development of various psychiatric disorders such as depression, anxiety and schizophrenia. Dopaminergic dysfunctioning is a key mechanism
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Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
in pathogenesis of schizophrenia. Few studies with rodents have shown that social defeat leads to dopaminergic hyperactivity and to behavioral sensitization. The purposes of present study were to explore the effects of social defeat stress on the expression of D1DR, D2-dimmer, D2-long form, D2-short form, DAT and NCS-1 in mouse brain. Methods: Male C57BL/6J mice were exposed to social defeat stress for 10 days. On 11th day social avoidance test were carried out to divide into two groups (susceptible and unsusceptible groups). D1DR, D2-dimmer, D2-long form, D2-short form, DAT and NCS-1 expression was measured in the mouse prefrontal cortex (PFC), striatum, amygdala and hippocampus using Western blotting technique and real time (RT)-PCR. The results were compared between susceptible and unsusceptible groups and control group. Results: There was no significant difference in D1DR, DAT, and NCS-1 protein level between control, susceptible and unsusceptible groups. However, there were significant increased expression of D2 dimmer in the prefrontal cortex (PFC), decreased expressions of D2-long form and D2-short form in hippocampus of susceptible group compared with control and unsusceptible group, and increased expression of D2-short form in the PFC of susceptible group compared to control group. For mRNA expression, there were no significant differences in D1DR and DAT mRNA level between control, susceptible and unsusceptible groups. However, there were significantly decreased D2-Long form mRNA levels in striatum, amygdala and hippocampus of susceptible group compared with control and unsusceptible group. Also, significantly decrease mRNA level of D2-short form was observed in the striatum of susceptible group compared to control group. Discussion: Our finding, increased expression of D2 dimer in the PFC is in same line with a recent report that significantly enhanced expression of D2Rs dimers in post-mortem striatal tissue of schizophrenia patients was observed. This may suggest that social defeat stress causes a dopaminergic dysregulation and social defeat stress model could be used as an animal model for schizophrenia.
Poster #S184 META-ANALYSIS OF “LEARNING POTENTIAL” ON THE DYNAMIC WISCONSIN CARD SORTING TEST (D-WCST): DISTINCT COGNITIVE SUBGROUPS WITH DIVERGENT FUNCTIONAL OUTCOMES Joseph Bisoglio 1 , Josh Mervis 2 , Jimmy Choi 1 1 Mental Health Services & Policy Research, Columbia University Medical Center; 2 Columbia University Medical Center Background: Behavioral interventions have been shown to ameliorate some of the cognitive and functional deficits prevalent in schizophrenia. However, effect sizes of these interventions are typically modest and outcomes are highly heterogeneous. A better understanding of individual differences and their relationship to treatment response could facilitate better clinical decision making and improve treatment outcomes. The dynamic administration of the Wisconsin Card Sorting Test (D-WCST) is a test-train-retest method for identifying individual differences in “learning potential”. While there are several methodological variations, a categorical approach based on an index of reliable change is the most frequent (e.g., Wiedl, 1999). Individuals are categorized according to one of three groups based on performance. High Performers (HPs) score in the upper range on both tests; Learners (Ls) perform poorly at first but make significant gains after training; and Non-Retainers (NRs) perform poorly and do not improve after training. We conducted a systematic review and meta-analysis of the D-WCST learner groups to examine the relative frequency of each group, neurocognitive differences, and relationship between group membership and response to psychosocial intervention. Methods: Studies were identified using PsychINFO, PubMed, and Google Scholar. We identified 11 studies reporting data on relative frequency (N=628), 6 studies on neurocognitive performance (N=442), and 3 studies on response to intervention (N=87). For relative frequency of each group we calculated mean relative frequencies with confidence intervals. For neurocognitive performance, effect sizes were calculated for the relative differences between the three groups using a fixed-effect model and corrections for small sample size. For response to intervention, categorical outcomes were first dichotomized as “improvement” vs. “no improvement”, and participants categorized as “Responders” vs. “Non-Responders”. We then ran Chi-squared tests and calculated odds ratios (OR). Results: Across 9 different sites from 3 different counties, the mean relative
frequencies for each group were HPs: 45.7% [39.05%, 52.43%], Ls: 36.1% [31.87%, 40.33%], and NRs: 18.2% [13.63%, 22.77%]. Differences in the neurocognitive profiles were robust, and despite excluding data from D-WCST performance there was a complete separation of the three groups based on more than 20 neurocognitive data points, with HPs > Ls (d=0.377*), HPs > NRs (d=0.994***), and Ls > NRs (d=0.623***). For response to psychosocial intervention, 70% of HPs were classified as “Responders” (23 of 33), and 53% of Ls (19 of 36), but only 6% of NRs (1 of 17). The effect of group on outcome was highly significant (χ2 =19.46, p<0.0001). We then chose to examine the predictive value of NR status versus the other two groups (HPs and Ls). NR status was highly predictive of poor response to psychosocial intervention (OR=26.44, p=0.002). Discussion: The three D-WCST groups showed a surprising degree of stability across multiple sites. The three groups also showed marked differences in neurocognition. Interestingly, while the Ls and NRs were indistinguishable on initial administration of the WCST, the overall neurocognitive performance of Ls was much closer to HPs. Moreover, Ls and HPs had similar outcomes, with >50% improving, while NRs were extremely unlikely to show improvement (6%). This may indicate a need for an alternate training approach for NRs such as errorless learning. While this finding is preliminary given the small number of studies, the strength of the effect (OR=26.44), suggests that the D-WCST may have strong predictive value for neurocognitive function and response to psychosocial intervention.
Poster #S185 ATTRIBUTION OF MENTAL STATES DURING CONVERSATION IN SCHIZOPHRENIA: PROFILE OF POOR MENTALISERS Maud Champagne-Lavau 1 , Hélène Wilquin 1 , Catherine Faget 2 , Florence Vaillant 2 , Stéphane Rauzy 1 , Laurent Boyer 3 , Christophe Lançon 2 1 Aix-Marseille Université, CNRS, LPL, UMR 7309, 13100 Aix-en-Provence, France; 2 Department of Psychiatry, Sainte-Marguerite University Hospital, 13009 Marseille, France; 3 Aix-Marseille Univ, EA 3279 – Public Health, Chronic Diseases and Quality of Life - Research Unit, 13005 Marseille, France Background: A deficit in social cognition including theory of mind (ToM) is one of the most disabling clinical characteristics of schizophrenia. Very few studies have investigated these impairments in schizophrenia during natural communication situations (McCabe et al. 2004, Champagne-Lavau et al. 2009). Recent findings have shown that people with schizophrenia (SZ) may be more or less impaired in their ToM skills (Pickup and Frith, 2001; Champagne-Lavau et al., 2009; Brüne and Schaub, 2012). Indeed, 50% to 80% of SZ patients may show difficulties to attribute mental states (Brüne & Schaub, 2012). Using a classical ToM task (i.e. MSAT), Brüne & Schaub (2012) showed that, by comparison to SZ patients with fair ToM abilities, SZ patients with poor ToM abilities were characterized by social behavioral abnormalities, disorganization and excitement symptoms, with absence of executive dysfunction. However, observing a social interaction is not equivalent to participating in a social interaction in terms of the cognitive processes involved in the attribution of mental states to other. Thus, the aim of the present study was to examine characteristics of relatively impaired SZ patients (SZ-I) and relatively unimpaired SZ patients (SZ-U) on a ToM task assessing attribution of knowledge during a situation of conversation Methods: Thirty individuals with a DSM-IV diagnosis of schizophrenia (SZ) were recruited. They were all native French speakers. Severity of symptoms was measured using the Positive and Negative Symptom Scale (PANSS; Kay et al., 1987). Patients were assessed on their ToM ability during a situation of conversation with the referential communication task (Champagne-Lavau et al., 2009). They were also submitted to a neuropsychological evaluation (flexibility, fluency, episodic and working memory, planning) and were assessed on their social functioning. Results: A K-means cluster analysis was used to classify the SZ data into relatively unimpaired (SZ-U, N=15) versus relatively impaired (SZ-I, N=15) on the ToM task. A ToM index reflecting ToM performances of the SZ patients during the conversation was calculated and used for this K-means cluster analysis. A series of t-tests showed that the two SZ subgroups were comparable in age (t(28) = 1.511, p>0.05), education level (t(28) = −0.564, p>0.05), duration of illness (t(28) = 1.895, p>0.05), IQ (NART (t(28) = 2.036, p>0.05), flexibility measured by the WCST (WCST-categories: t(28) = −0.696, p>0.05, WCST-perseveration: t(28) = 0.258, p>0.05), mem-
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higher gamma band activity change between standard and target conditions in the left frontal area (p<0.001). The standard to target activity change was positive in patients and negative in controls. For the proposed P300 response pathway, the F-model was a better fit than the other two in patients, while the B-model was better in healthy controls. Attending the DMN pathway, the FB-model was the best fit in patients while the F-model was the corresponding best option in healthy controls. Discussion: Abnormal bi-directional (forward-backward) frontal connectivity in the DMN, mediating between task conditions, may underlay the standard to target gamma band activity decrease found in the left frontal region in patients with schizophrenia. A lack of backward control (frontal to parietal) in the P300 response pathway may be also related to the high-frequency alteration in patients.
leftward frontal α-activation during criticism and schizotypy and anxiety suggests increasing withdrawal from and emotional reactivity to criticism. However, more criticism from predominantly low-EE relatives was associated with greater leftward frontal high α-activation during positive comments. This finding indicates greater ’approach motivation’, i.e. both heightened attention to, and more evaluation of positive comments.
Poster #S181 GREATER LEFTWARD FRONTAL ALPHA ACTIVATION DURING CRITICISM IS ASSOCIATED WITH SCHIZOTYPAL TRAITS AND ANXIETY
Background: Disruptions in filtering of sensory information have frequently been observed in patients with schizophrenia. Successful sensory gating is believed to prevent sensory overload of higher brain functions by filtering out irrelevant stimuli before they can reach the higher brain areas. Deficits in sensory gating may therefore result in an overload of irrelevant information reaching the higher brain areas, which in turn might contribute to the formation of psychotic symptoms. One well-established paradigm to assess sensory gating is P50 suppression in humans, or the very similar double click paradigm in rats. In this paradigm, patients with schizophrenia score significantly lower than healthy controls. In schizophrenia both a reduction in prefrontal dopaminergic activity and an increased noradrenergic activity have been suggested to be involved in the disease. In the current study we aimed to further investigate the involvement of these neurotransmitters by using the norepinephrine reuptake inhibitor (NRI) reboxetine and the dopamine antagonist haloperidol, respectively. Furthermore our aim was to investigate if any potential drug effect found in humans could be translated to rats. Methods: The design of the human experiment was a double-blind, placebocontrolled, cross-over study. In the humans a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo was administered to 21 healthy male subjects at four separate visits with a minimum of two weeks apart. The subjects were subsequently tested in The Copenhagen Psychophysiological Test Battery (CPTB) which, amongst others, measures P50 suppression using electroencephalography (EEG). Very similar to our human setting the animal experiment consisted of 22 rats (n=22) that received a dose of either, reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo with one week apart to allow washout of compounds. The rats were hereafter tested in an EEG setting. Results: In humans we found a significant reduction in P50 suppression following separate administration of either reboxetine or haloperidol as well as following their combined administration compared to placebo. In the rats we found a similar significant reduction of sensory gating (N40) in the hippocampus (CA3-region), but not in cortical placed electrodes after the haloperidol and combination treatments and a trend in reducing sensory gating following the reboxetine treatment compared to placebo. Discussion: The obtained results suggest that increased noradrenergic and decreased dopaminergic activities are involved in P50 suppression. However we did not observe a synergistic effect of the combination of the compounds, which may indicate either a ceiling effect or a drug/drug interaction. The animal studies confirmed the human data to some degree, suggesting a predictive validity of the P50 suppression to hippocampal sites but not cortical areas. Since sensory gating in schizophrenia patients is usually found to be reduced compared to controls our results may indicate similar underlying neurotransmitter activities.
Preethi Premkumar 1 , Miguel Espirito-Santo 2 , Juliana Onwumere 3 , Veena Kumari 4 , Maddie Groom 5 , Elizabeth Kuipers 3 1 Nottingham Trent University; 2 School of Psychology, University of Nottingham, Nottingham, UK; 3 King’s College London Institute of Psychiatry, London, UK; 4 Institute of Psychiatry, London; 5 Division of Psychiatry, Institute of Mental Health, University of Nottingham, Nottingham, UK Background: Criticism from a caregiver predicts relapse, longer hospitalization and greater symptom severity in schizophrenia. Characterised by its tone and content, criticism may be seen as a standardised construct that elicits a specific neural response in those perceiving it. fMRI research indicates that listening to criticism activates the superior frontal gyrus in patients with schizophrenia a d individuals with high schizotypy. Greater anxiety is associated with greater superior-to-middle frontal gyral connectivity during standardized criticism. The electrocortical response to insult is increased leftward frontal alpha (α) activation. The study aimed to determine the relation between leftward frontal α activation during standardised criticism and schizotypy, anxiety and criticism from a close relative. Methods: Twenty-two healthy individuals (mean age=23 years; range 18-40 years; 15 women) underwent electroencephalography (EEG) while listening to a standard set of comments (criticism, positive and neutral comments) spoken in a male or female voice and imagining them to be spoken by a close relative. Ten of these participants (7 women; 3 men) were also assessed on schizotypy and anxiety. Their close relative (6 partners, 3 siblings, 1 parent) was assessed on Expressed Emotion (a standard measure of criticism) using the Camberwell Family Interview. The absolute spectral power during the comment and event-related synchronization/desynchronization (ERS/ERD) within 500ms epochs of the comment in the low (8-10Hz) and high (10-12 Hz) α frequency bands were extracted in the middle-lateral (F3, F4, FC3, FC4) and lateral frontal sites (F5, FC5, F6, FC6). Asymmetry was calculated by subtracting spectral power in the left from right hemisphere electrodes. Analysis of variance was performed followed by post hoc paired-sample t-tests. Planned Spearman correlations were performed between spectral power, schizotypy, anxiety and carer criticism. Results: Three out of ten participants had a high EE relative. Participants, on average, had low positive schizotypy (mean number of unusual experiences=3.7, range 0-7). At the F3/F4, an emotion-by by-hemisphere-gender interaction in low α-activation was explained by greater activation during female criticism than neutral comments. At F5/F6, a main effect of emotion in high α-activation revealed more activation during male criticism than neutral comments. At FC3/FC4, an emotion-by-hemisphere-by-gender interaction in low α ERS/ERD showed greater ERS during female criticism and positive comments than neutral comments at the 0-500ms epoch. Greater impulsive non-conformity and anxiety correlated with lower leftward low α-activation at F3/F4 sites during female criticism. More relative criticism correlated with greater leftward high α-activation at F5/F6 sites during male positive comments. Greater introvertive anhedonia correlated with lower leftward FC5/FC6 ERS/ERD asymmetry at 0-500ms during female positive comments. Discussion: Greater frontal α-activation during criticism than neutral comments suggests greater cognitive appraisal of criticism, with low α-activation indicating greater general attention and high α-activation indicating greater semantic processing. The inverse association between
Poster #S182 THE EFFECT OF REBOXETINE AND HALOPERIDOL ON SENSORY GATING IN HEALTHY HUMANS AND RATS Louise M. Witten 1 , Birte Glenthøj 1 , Jesper Bastlund 2 , Arne Mørk 2 , Björn Steiniger-Brach 2 , Bob Oranje 1 1 CNSR and CINS; 2 H. Lundbeck.com
Poster #S183 CHRONIC SOCIAL DEFEAT STRESS INDUCES INCREASED EXPRESSION OF D2-DIMMER IN THE PREFRONTAL CORTEX OF MICE Tarique R. Bagalkot, Hong-Mei Jin, Yin Cui Chonbuk National University Background: Chronic social defeat stress is a potent stressor that promotes the development of various psychiatric disorders such as depression, anxiety and schizophrenia. Dopaminergic dysfunctioning is a key mechanism
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Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
in pathogenesis of schizophrenia. Few studies with rodents have shown that social defeat leads to dopaminergic hyperactivity and to behavioral sensitization. The purposes of present study were to explore the effects of social defeat stress on the expression of D1DR, D2-dimmer, D2-long form, D2-short form, DAT and NCS-1 in mouse brain. Methods: Male C57BL/6J mice were exposed to social defeat stress for 10 days. On 11th day social avoidance test were carried out to divide into two groups (susceptible and unsusceptible groups). D1DR, D2-dimmer, D2-long form, D2-short form, DAT and NCS-1 expression was measured in the mouse prefrontal cortex (PFC), striatum, amygdala and hippocampus using Western blotting technique and real time (RT)-PCR. The results were compared between susceptible and unsusceptible groups and control group. Results: There was no significant difference in D1DR, DAT, and NCS-1 protein level between control, susceptible and unsusceptible groups. However, there were significant increased expression of D2 dimmer in the prefrontal cortex (PFC), decreased expressions of D2-long form and D2-short form in hippocampus of susceptible group compared with control and unsusceptible group, and increased expression of D2-short form in the PFC of susceptible group compared to control group. For mRNA expression, there were no significant differences in D1DR and DAT mRNA level between control, susceptible and unsusceptible groups. However, there were significantly decreased D2-Long form mRNA levels in striatum, amygdala and hippocampus of susceptible group compared with control and unsusceptible group. Also, significantly decrease mRNA level of D2-short form was observed in the striatum of susceptible group compared to control group. Discussion: Our finding, increased expression of D2 dimer in the PFC is in same line with a recent report that significantly enhanced expression of D2Rs dimers in post-mortem striatal tissue of schizophrenia patients was observed. This may suggest that social defeat stress causes a dopaminergic dysregulation and social defeat stress model could be used as an animal model for schizophrenia.
Poster #S184 META-ANALYSIS OF “LEARNING POTENTIAL” ON THE DYNAMIC WISCONSIN CARD SORTING TEST (D-WCST): DISTINCT COGNITIVE SUBGROUPS WITH DIVERGENT FUNCTIONAL OUTCOMES Joseph Bisoglio 1 , Josh Mervis 2 , Jimmy Choi 1 1 Mental Health Services & Policy Research, Columbia University Medical Center; 2 Columbia University Medical Center Background: Behavioral interventions have been shown to ameliorate some of the cognitive and functional deficits prevalent in schizophrenia. However, effect sizes of these interventions are typically modest and outcomes are highly heterogeneous. A better understanding of individual differences and their relationship to treatment response could facilitate better clinical decision making and improve treatment outcomes. The dynamic administration of the Wisconsin Card Sorting Test (D-WCST) is a test-train-retest method for identifying individual differences in “learning potential”. While there are several methodological variations, a categorical approach based on an index of reliable change is the most frequent (e.g., Wiedl, 1999). Individuals are categorized according to one of three groups based on performance. High Performers (HPs) score in the upper range on both tests; Learners (Ls) perform poorly at first but make significant gains after training; and Non-Retainers (NRs) perform poorly and do not improve after training. We conducted a systematic review and meta-analysis of the D-WCST learner groups to examine the relative frequency of each group, neurocognitive differences, and relationship between group membership and response to psychosocial intervention. Methods: Studies were identified using PsychINFO, PubMed, and Google Scholar. We identified 11 studies reporting data on relative frequency (N=628), 6 studies on neurocognitive performance (N=442), and 3 studies on response to intervention (N=87). For relative frequency of each group we calculated mean relative frequencies with confidence intervals. For neurocognitive performance, effect sizes were calculated for the relative differences between the three groups using a fixed-effect model and corrections for small sample size. For response to intervention, categorical outcomes were first dichotomized as “improvement” vs. “no improvement”, and participants categorized as “Responders” vs. “Non-Responders”. We then ran Chi-squared tests and calculated odds ratios (OR). Results: Across 9 different sites from 3 different counties, the mean relative
frequencies for each group were HPs: 45.7% [39.05%, 52.43%], Ls: 36.1% [31.87%, 40.33%], and NRs: 18.2% [13.63%, 22.77%]. Differences in the neurocognitive profiles were robust, and despite excluding data from D-WCST performance there was a complete separation of the three groups based on more than 20 neurocognitive data points, with HPs > Ls (d=0.377*), HPs > NRs (d=0.994***), and Ls > NRs (d=0.623***). For response to psychosocial intervention, 70% of HPs were classified as “Responders” (23 of 33), and 53% of Ls (19 of 36), but only 6% of NRs (1 of 17). The effect of group on outcome was highly significant (χ2 =19.46, p<0.0001). We then chose to examine the predictive value of NR status versus the other two groups (HPs and Ls). NR status was highly predictive of poor response to psychosocial intervention (OR=26.44, p=0.002). Discussion: The three D-WCST groups showed a surprising degree of stability across multiple sites. The three groups also showed marked differences in neurocognition. Interestingly, while the Ls and NRs were indistinguishable on initial administration of the WCST, the overall neurocognitive performance of Ls was much closer to HPs. Moreover, Ls and HPs had similar outcomes, with >50% improving, while NRs were extremely unlikely to show improvement (6%). This may indicate a need for an alternate training approach for NRs such as errorless learning. While this finding is preliminary given the small number of studies, the strength of the effect (OR=26.44), suggests that the D-WCST may have strong predictive value for neurocognitive function and response to psychosocial intervention.
Poster #S185 ATTRIBUTION OF MENTAL STATES DURING CONVERSATION IN SCHIZOPHRENIA: PROFILE OF POOR MENTALISERS Maud Champagne-Lavau 1 , Hélène Wilquin 1 , Catherine Faget 2 , Florence Vaillant 2 , Stéphane Rauzy 1 , Laurent Boyer 3 , Christophe Lançon 2 1 Aix-Marseille Université, CNRS, LPL, UMR 7309, 13100 Aix-en-Provence, France; 2 Department of Psychiatry, Sainte-Marguerite University Hospital, 13009 Marseille, France; 3 Aix-Marseille Univ, EA 3279 – Public Health, Chronic Diseases and Quality of Life - Research Unit, 13005 Marseille, France Background: A deficit in social cognition including theory of mind (ToM) is one of the most disabling clinical characteristics of schizophrenia. Very few studies have investigated these impairments in schizophrenia during natural communication situations (McCabe et al. 2004, Champagne-Lavau et al. 2009). Recent findings have shown that people with schizophrenia (SZ) may be more or less impaired in their ToM skills (Pickup and Frith, 2001; Champagne-Lavau et al., 2009; Brüne and Schaub, 2012). Indeed, 50% to 80% of SZ patients may show difficulties to attribute mental states (Brüne & Schaub, 2012). Using a classical ToM task (i.e. MSAT), Brüne & Schaub (2012) showed that, by comparison to SZ patients with fair ToM abilities, SZ patients with poor ToM abilities were characterized by social behavioral abnormalities, disorganization and excitement symptoms, with absence of executive dysfunction. However, observing a social interaction is not equivalent to participating in a social interaction in terms of the cognitive processes involved in the attribution of mental states to other. Thus, the aim of the present study was to examine characteristics of relatively impaired SZ patients (SZ-I) and relatively unimpaired SZ patients (SZ-U) on a ToM task assessing attribution of knowledge during a situation of conversation Methods: Thirty individuals with a DSM-IV diagnosis of schizophrenia (SZ) were recruited. They were all native French speakers. Severity of symptoms was measured using the Positive and Negative Symptom Scale (PANSS; Kay et al., 1987). Patients were assessed on their ToM ability during a situation of conversation with the referential communication task (Champagne-Lavau et al., 2009). They were also submitted to a neuropsychological evaluation (flexibility, fluency, episodic and working memory, planning) and were assessed on their social functioning. Results: A K-means cluster analysis was used to classify the SZ data into relatively unimpaired (SZ-U, N=15) versus relatively impaired (SZ-I, N=15) on the ToM task. A ToM index reflecting ToM performances of the SZ patients during the conversation was calculated and used for this K-means cluster analysis. A series of t-tests showed that the two SZ subgroups were comparable in age (t(28) = 1.511, p>0.05), education level (t(28) = −0.564, p>0.05), duration of illness (t(28) = 1.895, p>0.05), IQ (NART (t(28) = 2.036, p>0.05), flexibility measured by the WCST (WCST-categories: t(28) = −0.696, p>0.05, WCST-perseveration: t(28) = 0.258, p>0.05), mem-