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919. Anterior Cingulate Cortex Activity in Implicit and Explicit Emotion Regulation Predicts Cognitive Behavioral Therapy Response in Anxiety and Depression
Biological Psychiatry
Saturday Abstracts
Conclusions: Our results suggest that dysphoric mood and anxiety often accompany psychotic experiences and global cognitive deficits are predictive of psychosis in 22q11DS. Furthermore, negative symptoms and functioning should be taken into account when determining psychosis risk in this population. Supported By: MH087626; MH087636; MH019112, K08 MH079364 Keywords: Schizophrenia Spectrum, Psychosis-Proneness, 22q11 Deletion Syndrome, longitudinal cohort, cognition
917. Genome-Wide Association Study (GWAS) of Toxoplasma Gondii Infection and Evaluation of Schizophrenia Risk by Using a Polygenic Risk Score (PRS) Adriana Lori1, Dimitrios Avramopoulos2, Alex Wang1, Fernando S. Goes2, Jennifer Mulle1, Abigail Powers3, John John McGrath2, Nicholas Massa2, Lei Weng2, Erica Duncan3, Gerald Nestadt2, Karen Conneely3, Paula Wolyniec2, Ruihua Wang2, Myfanwy Hopkins1, Ingo Ruczinski2, Robert Yolken2, Tanja Jovanovic3, Kerry Ressler4, Ann E. Pulver2, and Brad D. Pearce1 Emory University, 2Johns Hopkins University, 3Emory University School of Medicine, 4McLean Hospital Harvard Medical School 1
Background: Toxoplasma gondii (TOXO) infects approximately 1.5 billion people worldwide. TOXO is implicated in a heightened risk for schizophrenia (SCZ). We performed a GWAS with TOXO in an Ashkenazi cohort of SCZ subjects. We then applied the schizophrenia polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately in TOXO-positive and TOXO-negative subjects to explore the hypothesis that SCZ subjects infected by TOXO will have less polygenic risk burden than uninfected subjects. Methods: 790 individuals (519 SCZ-cases; 271 controls) were tested for TOXO positivity. Genotyping was performed using the Affymetrix-SNP-Array-6.0. The SCZ-PRS was calculated using PRSice separately in a) PRS-TOXO positive; b) PRS-toxonegative and c) to establish type2-error by randomly sampling TOXO-negative samples (n5130, repeated 100x). Results: The top SNP was in the gene region of chitinase. Our top hits included a large number of genes involved in neurodevelopment and psychiatric disorders. The SCZ-PGS predicts SCZ as expected In the TOXO-negative group (n5662, p510-4), but not in the TOXO-positive (n5128;, p50.354). In random samplings of the toxo-negative subpopulation to simulate equivalent power between groups, p.0.05 45% of the time, but p.0.354 only 2% of the time. Conclusions: GWAS in this Ashkenazi cohort identified several genes potentially involved in vulnerability to TOXO. We found some evidence that the SCZ-PRS predicts SCZ status in TOXOnegative subjects but not TOXO-infected patients. Although the results are intriguing, we cannot currently rule out a type-2 error. Supported By: NIH R01MH094757, R01MH096764 Keywords: Polygenic Risk Score, Schiizophrenia, Toxoplasma gondii, GWAS
918. Anterior-Posterior Gradient Differences in Lobar and Cingulate Cerebral Blood Flow in Late-Life Depression Margarita Abi Zeid Daou, Brian Boyd, and Warren Taylor Vanderbilt University Medical Center Background: Vascular pathology and dysregulation is common in late-life depression, contributing to altered cerebral blood flow (CBF) and potentially influencing cerebral pathology. Since aging is itself associated with changes in CBF, we sought to examine whether depressed elders exhibit differences in CBF from age- and sex-matched non-depressed subjects. Methods: 22 elderly aged 60 years or older with Major Depressive Disorder and 19 with no psychiatric history completed cranial 3T MRI, including pseudo-continuous Arterial Spin Labeling (pcASL) acquisition. FreeSurfer parcellation of the brain identified frontal, temporal, parietal and cingulate subregions in which CBF was then calculated. White matter hyperintensities (WMH) were measured from FLAIR images. Results: In models controlling for age, sex, and WMH volume, the depressed group exhibited lower normalized frontal lobe CBF (F543.02, p,0.0001), but increased normalized CBF in the parietal (F510.47, p50.0027) and temporal lobes (F520.96, p,0.0001). While no significant group difference was observed for CBF of the cingulate gyrus, CBF differed among cingulate sub-regions. Depressed subjects exhibited lower CBF in anterior regions, including the caudal (F59.99, p50.0032) and rostral (F514.15, p50.0006) anterior cingulate cortex, while they exhibited a higher CBF in the isthmus of the cingulate cortex (F59.96, p50.0033). CBF in the posterior cingulate cortex did not differ between groups. Conclusions: Decreased frontal CBF in depressed elders might either be reflective of or contribute to decreased metabolic activity and parallels differences in anterior cingulate CBF. Parietotemporal increases in CBF may be a compensatory response to either frontal hypoperfusion or early neuro-cognitive pathology in those regions. Supported By: NIH grants R21 MH099218 and K24 MH110598, and CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences. Keywords: Aging, Depression, MRI, ASL MRI
919. Anterior Cingulate Cortex Activity in Implicit and Explicit Emotion Regulation Predicts Cognitive Behavioral Therapy Response in Anxiety and Depression Heide Klumpp, Kerry Kinney, Julia DiGangi, Amy E Kennedy, Stewart Shankman, Scott Langenecker, and K. Luan Phan University of Illinois at Chicago Background: The anterior cingulate cortex (ACC) predicts treatment response in anxiety and major depressive disorder (MDD). However, findings are largely based on emotion processing studies. Cognitive Behavioral Therapy (CBT) is empirically supported psychotherapy for anxiety disorders
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
S371
Biological Psychiatry
Saturday Abstracts
and MDD. In CBT techniques are aimed at improving emotion regulation. Therefore, baseline variance in ACC activity during regulation is hypothesized to predict CBT outcome as ACC is central to cognitive-emotion interactions. Methods: A week before CBT, 22 with social phobia, 15 with MDD, and 13 with generalized anxiety disorder completed validated explicit and implicit emotion regulation tasks during fMRI. For explicit regulation, patients used cognitive reappraisal to downregulate emotional reactivity to aversive images. For implicit regulation, patients completed a threat interference paradigm comprising negative face 'distractors.' Pre-CBT activity was derived from an anatomy-based (MNI) bilateral ACC mask and responder status was defined as .50% reduction in primary symptom severity after 12 weeks of CBT. Results: Primary symptom severity decreased following CBT (p,0.001) and across patients, 48% were 'responders.' For explicit regulation, less baseline ACC activity classified responder status (AUC50.67, p,0.04) and activation negatively correlated with symptom reduction (r5-0.33, p,0.02). Regarding implicit regulation, greater baseline ACC activity classified responder status (AUC50.67, p,0.038) and activation positively correlated with symptom reduction (r50.40, p,0.01). Conclusions: Findings suggest ACC predicts treatment response in a transdiagnostic sample. The direction of activation (reduced vs. enhanced) appears to depend on the neurocognitive probe of interest – explicit or implicit regulation. ACC as a predictor of CBT outcome has implications for precision medicine. Supported By: K23; NARSAD; R01 Keywords: fMRI, Transdiagnostic, Prediction of Treatment Outcome, Psychotherapy, Anterior Cingulate Cortex
920. Neural Correlates of Mentalizing and Uncertainty in Socially Anxious Adults Khalil Thompson, Erin Tone, Jessica Turner, Kendrick King, and Aral Ahmadi Georgia State University Background: Individuals with social anxiety tend to exhibit atypical cognitive biases. These biases include anticipation of social failure, especially under conditions of uncertainty, as well as beliefs that others will hold them to unreasonably high standards in social interactions. In the present study participants with social anxiety played the Prisoner's Dilemma game in order to model brain activity associated with theory of mind and uncertainty. Methods: 32 non-psychiatric volunteers (Ages 18-28) categorized using Liebowitz Social Anxiety Scale-Self Report (LSAS-SR) scores as having high or low trait anxiety, were scanned in a 3T Siemens scanner while playing the iterated Prisoner's Dilemma task against a computerized confederate whom they were deceived to believe was a human co-player. Results: There was a significant increase in activation within all feedback conditions in the temporoparietal junction (TPJ), the precuneus within all subjects (t(30)52.5, p,.05). Highly anxious individuals exhibited an increased trend of activation in the TPJ but the relationship did not reach significance (t(30)52, p,.05) during trials with diverging responses from the co-player. Highly
S372
anxious individuals also exhibited an increased trend in activation in the midcingulate cortex (MCC) (t(30)52.5, p,.05) during anticipation periods. Conclusions: While the analysis was nonsignificant, activation patterns in the TPJ hint at a tendency among anxious participants to devote more resources to reflection about other people’s thoughts. Anxious participants could also experience elevated feelings of discomfort when the outcome of an interaction is uncertain, as evidenced by the trend in MCC activity. Future research with larger samples would help address these possibilities more conclusively. Supported By: CABI Seed Grant Keywords: social anxiety, Prisoner's Dilemma, Neuroimaging, Cognitive Neuroscience
921. Influence of Age, Type, and Number of Trauma Exposures on the Neural Mechanisms of Conditioned Fear Extinction Iris Lange1, Marie-France Marin2, and Mohammed Milad3 Maastricht University, 2University of Montreal, 3Harvard Medical School, Massachusetts General Hospital 1
Background: Psychopathology following trauma exposure is thought to arise from perturbations in the neural circuits underlying fear conditioning and extinction. The impact of trauma exposure on these mechanisms may depend on trauma-related characteristics. We present novel data on whether 1. age at trauma (childhood-adulthood), 2. number of traumas (single-multiple), and 3. trauma type (sexual-noninterpersonal) differentially affect the neurobiology of fear learning and extinction mechanisms. Methods: Existing data of 71 trauma-exposed individuals were divided based on each research question. Participants underwent a fear conditioning, extinction, extinction recall, and renewal paradigm. Measurements included skin conductance responses (SCR) and fMRI. Region of interest analyses were restricted to the vmPFC, amygdala, hippocampus, insula and dorsal anterior cingulate cortex (pfwe,.05). Results: During fear conditioning, both the childhood and sexual trauma groups showed blunted SCR and lower reactivity in threat-related regions, compared to adulthood and non-interpersonal trauma, respectively (F(1,41)54.058, p5.05; (F(1,37)54.282, p5.046). The SCR-data further demonstrated reduced extinction retention in the childhood group (F(1,36)53.986, p5.047). The sexual trauma group showed aberrant SCR during fear renewal, reflected by lower SCR to the danger stimulus (F(1,31)56.081, p5.02). Both the childhood and sexual trauma group showed reduced vmPFC recruitment across extinction learning and retention phases. The single versus multiple trauma groups showed similar SCR and vmPFC activation across task phases. Conclusions: The results show that sexual trauma and childhood trauma are linked to alterations in fear conditioning and extinction mechanisms. These characteristics may therefore be specifically linked to increased vulnerability for psychopathology, and to non-response to exposure-based therapies in individuals who developed psychopathology.
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
Saturday Abstracts
Conclusions: Our results suggest that dysphoric mood and anxiety often accompany psychotic experiences and global cognitive deficits are predictive of psychosis in 22q11DS. Furthermore, negative symptoms and functioning should be taken into account when determining psychosis risk in this population. Supported By: MH087626; MH087636; MH019112, K08 MH079364 Keywords: Schizophrenia Spectrum, Psychosis-Proneness, 22q11 Deletion Syndrome, longitudinal cohort, cognition
917. Genome-Wide Association Study (GWAS) of Toxoplasma Gondii Infection and Evaluation of Schizophrenia Risk by Using a Polygenic Risk Score (PRS) Adriana Lori1, Dimitrios Avramopoulos2, Alex Wang1, Fernando S. Goes2, Jennifer Mulle1, Abigail Powers3, John John McGrath2, Nicholas Massa2, Lei Weng2, Erica Duncan3, Gerald Nestadt2, Karen Conneely3, Paula Wolyniec2, Ruihua Wang2, Myfanwy Hopkins1, Ingo Ruczinski2, Robert Yolken2, Tanja Jovanovic3, Kerry Ressler4, Ann E. Pulver2, and Brad D. Pearce1 Emory University, 2Johns Hopkins University, 3Emory University School of Medicine, 4McLean Hospital Harvard Medical School 1
Background: Toxoplasma gondii (TOXO) infects approximately 1.5 billion people worldwide. TOXO is implicated in a heightened risk for schizophrenia (SCZ). We performed a GWAS with TOXO in an Ashkenazi cohort of SCZ subjects. We then applied the schizophrenia polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately in TOXO-positive and TOXO-negative subjects to explore the hypothesis that SCZ subjects infected by TOXO will have less polygenic risk burden than uninfected subjects. Methods: 790 individuals (519 SCZ-cases; 271 controls) were tested for TOXO positivity. Genotyping was performed using the Affymetrix-SNP-Array-6.0. The SCZ-PRS was calculated using PRSice separately in a) PRS-TOXO positive; b) PRS-toxonegative and c) to establish type2-error by randomly sampling TOXO-negative samples (n5130, repeated 100x). Results: The top SNP was in the gene region of chitinase. Our top hits included a large number of genes involved in neurodevelopment and psychiatric disorders. The SCZ-PGS predicts SCZ as expected In the TOXO-negative group (n5662, p510-4), but not in the TOXO-positive (n5128;, p50.354). In random samplings of the toxo-negative subpopulation to simulate equivalent power between groups, p.0.05 45% of the time, but p.0.354 only 2% of the time. Conclusions: GWAS in this Ashkenazi cohort identified several genes potentially involved in vulnerability to TOXO. We found some evidence that the SCZ-PRS predicts SCZ status in TOXOnegative subjects but not TOXO-infected patients. Although the results are intriguing, we cannot currently rule out a type-2 error. Supported By: NIH R01MH094757, R01MH096764 Keywords: Polygenic Risk Score, Schiizophrenia, Toxoplasma gondii, GWAS
918. Anterior-Posterior Gradient Differences in Lobar and Cingulate Cerebral Blood Flow in Late-Life Depression Margarita Abi Zeid Daou, Brian Boyd, and Warren Taylor Vanderbilt University Medical Center Background: Vascular pathology and dysregulation is common in late-life depression, contributing to altered cerebral blood flow (CBF) and potentially influencing cerebral pathology. Since aging is itself associated with changes in CBF, we sought to examine whether depressed elders exhibit differences in CBF from age- and sex-matched non-depressed subjects. Methods: 22 elderly aged 60 years or older with Major Depressive Disorder and 19 with no psychiatric history completed cranial 3T MRI, including pseudo-continuous Arterial Spin Labeling (pcASL) acquisition. FreeSurfer parcellation of the brain identified frontal, temporal, parietal and cingulate subregions in which CBF was then calculated. White matter hyperintensities (WMH) were measured from FLAIR images. Results: In models controlling for age, sex, and WMH volume, the depressed group exhibited lower normalized frontal lobe CBF (F543.02, p,0.0001), but increased normalized CBF in the parietal (F510.47, p50.0027) and temporal lobes (F520.96, p,0.0001). While no significant group difference was observed for CBF of the cingulate gyrus, CBF differed among cingulate sub-regions. Depressed subjects exhibited lower CBF in anterior regions, including the caudal (F59.99, p50.0032) and rostral (F514.15, p50.0006) anterior cingulate cortex, while they exhibited a higher CBF in the isthmus of the cingulate cortex (F59.96, p50.0033). CBF in the posterior cingulate cortex did not differ between groups. Conclusions: Decreased frontal CBF in depressed elders might either be reflective of or contribute to decreased metabolic activity and parallels differences in anterior cingulate CBF. Parietotemporal increases in CBF may be a compensatory response to either frontal hypoperfusion or early neuro-cognitive pathology in those regions. Supported By: NIH grants R21 MH099218 and K24 MH110598, and CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences. Keywords: Aging, Depression, MRI, ASL MRI
919. Anterior Cingulate Cortex Activity in Implicit and Explicit Emotion Regulation Predicts Cognitive Behavioral Therapy Response in Anxiety and Depression Heide Klumpp, Kerry Kinney, Julia DiGangi, Amy E Kennedy, Stewart Shankman, Scott Langenecker, and K. Luan Phan University of Illinois at Chicago Background: The anterior cingulate cortex (ACC) predicts treatment response in anxiety and major depressive disorder (MDD). However, findings are largely based on emotion processing studies. Cognitive Behavioral Therapy (CBT) is empirically supported psychotherapy for anxiety disorders
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
S371
Biological Psychiatry
Saturday Abstracts
and MDD. In CBT techniques are aimed at improving emotion regulation. Therefore, baseline variance in ACC activity during regulation is hypothesized to predict CBT outcome as ACC is central to cognitive-emotion interactions. Methods: A week before CBT, 22 with social phobia, 15 with MDD, and 13 with generalized anxiety disorder completed validated explicit and implicit emotion regulation tasks during fMRI. For explicit regulation, patients used cognitive reappraisal to downregulate emotional reactivity to aversive images. For implicit regulation, patients completed a threat interference paradigm comprising negative face 'distractors.' Pre-CBT activity was derived from an anatomy-based (MNI) bilateral ACC mask and responder status was defined as .50% reduction in primary symptom severity after 12 weeks of CBT. Results: Primary symptom severity decreased following CBT (p,0.001) and across patients, 48% were 'responders.' For explicit regulation, less baseline ACC activity classified responder status (AUC50.67, p,0.04) and activation negatively correlated with symptom reduction (r5-0.33, p,0.02). Regarding implicit regulation, greater baseline ACC activity classified responder status (AUC50.67, p,0.038) and activation positively correlated with symptom reduction (r50.40, p,0.01). Conclusions: Findings suggest ACC predicts treatment response in a transdiagnostic sample. The direction of activation (reduced vs. enhanced) appears to depend on the neurocognitive probe of interest – explicit or implicit regulation. ACC as a predictor of CBT outcome has implications for precision medicine. Supported By: K23; NARSAD; R01 Keywords: fMRI, Transdiagnostic, Prediction of Treatment Outcome, Psychotherapy, Anterior Cingulate Cortex
920. Neural Correlates of Mentalizing and Uncertainty in Socially Anxious Adults Khalil Thompson, Erin Tone, Jessica Turner, Kendrick King, and Aral Ahmadi Georgia State University Background: Individuals with social anxiety tend to exhibit atypical cognitive biases. These biases include anticipation of social failure, especially under conditions of uncertainty, as well as beliefs that others will hold them to unreasonably high standards in social interactions. In the present study participants with social anxiety played the Prisoner's Dilemma game in order to model brain activity associated with theory of mind and uncertainty. Methods: 32 non-psychiatric volunteers (Ages 18-28) categorized using Liebowitz Social Anxiety Scale-Self Report (LSAS-SR) scores as having high or low trait anxiety, were scanned in a 3T Siemens scanner while playing the iterated Prisoner's Dilemma task against a computerized confederate whom they were deceived to believe was a human co-player. Results: There was a significant increase in activation within all feedback conditions in the temporoparietal junction (TPJ), the precuneus within all subjects (t(30)52.5, p,.05). Highly anxious individuals exhibited an increased trend of activation in the TPJ but the relationship did not reach significance (t(30)52, p,.05) during trials with diverging responses from the co-player. Highly
S372
anxious individuals also exhibited an increased trend in activation in the midcingulate cortex (MCC) (t(30)52.5, p,.05) during anticipation periods. Conclusions: While the analysis was nonsignificant, activation patterns in the TPJ hint at a tendency among anxious participants to devote more resources to reflection about other people’s thoughts. Anxious participants could also experience elevated feelings of discomfort when the outcome of an interaction is uncertain, as evidenced by the trend in MCC activity. Future research with larger samples would help address these possibilities more conclusively. Supported By: CABI Seed Grant Keywords: social anxiety, Prisoner's Dilemma, Neuroimaging, Cognitive Neuroscience
921. Influence of Age, Type, and Number of Trauma Exposures on the Neural Mechanisms of Conditioned Fear Extinction Iris Lange1, Marie-France Marin2, and Mohammed Milad3 Maastricht University, 2University of Montreal, 3Harvard Medical School, Massachusetts General Hospital 1
Background: Psychopathology following trauma exposure is thought to arise from perturbations in the neural circuits underlying fear conditioning and extinction. The impact of trauma exposure on these mechanisms may depend on trauma-related characteristics. We present novel data on whether 1. age at trauma (childhood-adulthood), 2. number of traumas (single-multiple), and 3. trauma type (sexual-noninterpersonal) differentially affect the neurobiology of fear learning and extinction mechanisms. Methods: Existing data of 71 trauma-exposed individuals were divided based on each research question. Participants underwent a fear conditioning, extinction, extinction recall, and renewal paradigm. Measurements included skin conductance responses (SCR) and fMRI. Region of interest analyses were restricted to the vmPFC, amygdala, hippocampus, insula and dorsal anterior cingulate cortex (pfwe,.05). Results: During fear conditioning, both the childhood and sexual trauma groups showed blunted SCR and lower reactivity in threat-related regions, compared to adulthood and non-interpersonal trauma, respectively (F(1,41)54.058, p5.05; (F(1,37)54.282, p5.046). The SCR-data further demonstrated reduced extinction retention in the childhood group (F(1,36)53.986, p5.047). The sexual trauma group showed aberrant SCR during fear renewal, reflected by lower SCR to the danger stimulus (F(1,31)56.081, p5.02). Both the childhood and sexual trauma group showed reduced vmPFC recruitment across extinction learning and retention phases. The single versus multiple trauma groups showed similar SCR and vmPFC activation across task phases. Conclusions: The results show that sexual trauma and childhood trauma are linked to alterations in fear conditioning and extinction mechanisms. These characteristics may therefore be specifically linked to increased vulnerability for psychopathology, and to non-response to exposure-based therapies in individuals who developed psychopathology.
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal