- Email: [email protected]
235. Deep Brain Stimulation Modulates Frontostriatal Inhibitory Control in Obsessive-Compulsive Disorder
Biological Psychiatry
Thursday Abstracts
Results: No genome-wide associations were significant at 5310-8. Our top hit variant, in a schizophrenia susceptibility gene, showed an association with MADRS score change. This gene has been implicated in post-ketamine treatment down regulation of GABA and glutamate levels in the rat prefrontal cortex and hippocampus, resulting in an antidepressant effect. We also observed a suggestive association between remission status and a genetic variant upstream of neuro-specific gene expressed in the hypothalamus and amygdala, suggesting a role in synaptic neurotransmitter signalling. Our top hit pathways included processes in the metabolic pathway of amyloid precursor protein. Conclusions: Our findings suggest novel gene variant associations with measures of venlafaxine remission in older adults, as well as, interesting neuro-relevant genetic pathways. A new, larger study of geriatric depression treatment will confirm these novel findings. Keywords: GWAS, Depression, Venlafaxine, Antidepressant, Genetics
233. BDNF Methylation and Stress Response in a Clinical Population with Major Depressive Disorder Maria Claudia Latigg2, Victor Andres Villamizar2, Alejandra Gaviria2, José David Angel2, Catalina Cañizares2, Eugenio Ferro1, Alvaro Arenas3, and Yvonne Gomez2 1 Clínica Montserrat, Inmaculada
2
Los Andes University,
3
Clínica La
Background: Major Depressive Disorder (MDD) is a multifactorial disease with a heritability of 35-40%. BDNF Gene Val66Met (rs6265) variant has a well-established role in neuronal plasticity and decreased levels have been observed in MDD. Previous studies support that vulnerability to environmental stress is mediated by the rs6265 variant. Changes in methylation patterns in exon VI of BDNF are emerging as a possible explanation for how Early Life Stress (ELS) can disrupt BDNF expression. However, there is still controversy because most of these studies are in non-clinical populations. Methods: We present a case-control study in clinical population, with matched controls. Informed consent was provided by all individuals. ELS was assessed by clinical questionnaire and stressful live events questionnaire. The rs6265 variant was genotyped using real time PCR. Methylation patterns in exon IV of BDNF were assessed by bisulfite treatment (EZ-96 DNA Methylation kit-Zymo research), Sanger sequencing and quantification of methylation percentage at each CpG region. Results: No significant differences were observed in overall methylation patterns between cases and controls. However, methylation in CpG islands 2, 6, 9, 14, 15 and 16 was higher in cases with MDD compared to controls (P50,001). There was association in methylation patterns among controls that experienced ELS (P50,005), however this association was not observed in cases. Conclusions: Exon IV methylation in specific CpG islands is higher in MDD. Increased methylation in controls with ELS may
S96
suggest a predisposition to MDD. Higher methylation in cases may not necessarily be related to ELS. Further sample should be completed to support conclusions. Supported By: Colciencias, Los Andes University, ICSNClinica Montserrat Keywords: Major Depression, brain-derived neurotrophic factor, Epigenetics, Early Life Stress
234. Search for Risk Variants in TrkB and BDNF that Predispose to Lithium Responsiveness in Bipolar Disorder Nathaniel Miller1, Seth A. Ament2, Tatyana Shekhtman3, Jared C. Roach2, The Bipolar Genome Study4, and John R. Kelsoe3 1
Department of Psychiatry, UCSD School of Medicine, Institute for Systems Biology, 3Department of Psychiatry, UCSD, 4The Bipolar Genome Study 2
Background: BDNF and its receptor TrkB have been implicated in bipolar disorder and lithium response. Lithium induces release of BDNF which is essential for its function. We have previously shown that variants in the TrkB gene are associated with lithium response and bipolar disorder. The goal of this study was to identify sequence variants in these two genes that affect the action of lithium in bipolar disorder. Methods: 73 lithium responsive (LiR) and 47 non-responsive (NR) retrospective samples were used for targeted sequencing of exons and regulatory regions. Samples were combined into pools of 23 to 37 individuals. Paired-end sequencing was done using Custom Amplicons (Illumina). Variants were called with Genome Analysis Toolkit. PLINK was used to calculate a chi-square statistic. Annotation was done using SIFT and PolyPhen-2. Results: For BDNF, 35 variants were called. Using a conservative Bonferroni correction for 174 comparisons, a statistically significant p-value would be ,2.8x10-4. Two suggestive variants were found for BDNF. For TrkB, 159 variants were called. A minor allele variant was found more frequently than expected in the LiR samples in the promoter region of TrkB, having a p-value of 2.93 x 10-6. RegulomeDB predicts this variant is important for transcription factor binding. Conclusions: Targeted sequencing revealed the over abundance of a minor allele in the promoter of TrkB for LiR but not in NR. Lithium efficacy for the treatment of bipolar disorder is likely to involve the BDNF/TrkB pathway. This study provides a likely candidate region to further investigate the function of lithium in bipolar individuals. Supported By: R25 MH101072 Keywords: Bipolar Disorder, lithium response, BDNF, NTRK2, Next Generation Sequencing
235. Deep Brain Stimulation Modulates Frontostriatal Inhibitory Control in Obsessive-Compulsive Disorder Martijn Figee1, Matthijs Vink2, Judy Luigjes1, Guido van Wingen1, and Damiaan Denys1
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Biological Psychiatry
Thursday Abstracts
1
Academical Medical Center, Amsterdam, 2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht Background: Patients with obsessive-compulsive disorder (OCD) are unable to stop unwanted compulsive behaviors, which has been linked to dysfunctional brain networks of inhibitory control. Deep brain stimulation (DBS) targeted at the ventral limb of the anterior capsule (vALIC) is efficacious for therapy-refractory OCD. Here, we explored if DBS restores sensorimotor frontostriatal pathways that are involved in inhibitory control.: Methods8 DBS implanted OCD patients performed a stop-signal with DBS ON and then one week later with DBS OFF. The task included reactive inhibition, i.e. outright stopping in response to a stop-signal, and proactive inhibition, i.e. anticipation of a potential stop signal. We assessed BOLD fMRI activation differences over the two scans between patients (DBS ON and OFF) and 13 matched healthy controls in the right striatum and right inferior frontal cortex. Results: DBS OFF increased obsessive-compulsive symptoms with 37% (t7524.36, p50.003). Reactive inhibition and frontostriatal activiation did not differ between patients (DBS ON or OFF) and controls. Behaviorally, DBS did not significantly change proactive inhibition compared to controls. However, DBS induced significant changes in proactive inhibitory activation in the right striatum (group x scan interaction F1,1955.74, p50.027) and right inferior frontal cortex (group x scan interaction F1,1957.63, p50.012). Patients with DBS OFF had lower activity in these regions than healthy controls, whereas activity during DBS ON did no longer differ significantly from controls. Conclusions: DBS normalized frontostriatal activity during proactive inhibition. These results suggest that DBS for OCD interrupts a pathological frontostriatal loop, allowing successful inhibition of unwanted behaviors and restoration of goaldirected actions. Keywords: Deep Brain Stimulation, Response inhibition, Obsessive Compulsive Disorder (OCD), BOLD fMRI
activated, TSPO levels are increased. The primary aim of the present study is to apply [18F]FEPPA PET to determine whether TSPO VT is greater in OCD within the dorsal caudate, orbitofrontal cortex (OFC), thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex (ACC). Methods: [18F]FEPPA PET was applied to measure TSPO VT in the hypothesized regions in OCD participants (n520) and health (n520) (matched for age). All participants were antidepressant-free, and had no additional current psychiatric or medical illnesses. Results: TSPO VT was elevated in OCD within the hypothesized regions by 26.0% - 34.7%. Calculation of analysis of variance resulted in the effects of diagnosis by region: dorsal caudate F1,32514.4, P5.001; OFC F1,32511.3, P5.002; thalamus F1,32513.7, P5.001; ventral striatum F1,32514.7, P,.001; dorsal putamen F1,32513.4, P5.001; and ACC F1,32510.7, P5.002. The Yale-Brown obsessive compulsive scale distress associated with compulsive behaviours subscale score was positively correlated with TSPO VT in the OFC (r 0.62, P5.005). Conclusions: This is the first study to demonstrate neuroinflammation in OCD. The most likely interpretation of elevated TSPO levels is microglia activation and an important clinical implication is that this abnormality may be targeted by neuromodulatory therapeutics. Supported By: CIHR Keywords: Obsessive Compulsive Disorder (OCD), Positron Emission Tomography, Translocator Protein (TSPO), Neuroinflammation, [18F]FEPPA
237. PTSD Exposure-Based Treatment Changes Amygdala and Hippocampus Resting State Functional Connectivity in PTSD Xi Zhu1, Benjamin Suarez-Jimenez2, Liat Helpman2, John Markowitz2, Santiago Papini3, Ariel Durosky2, Anne Hilburn2, Franklin Schneier2, Martin Lindquist4, Tor Wager5, and Yuval Neria2 1
236. Inflammation in the Neurocircuitry of Obsessive Compulsive Disorder Sophia Attwells1, Elaine Setiawan1, Alan A. Wilson1, Pablo M. Rusjan1, Romina Mizrahi1, Laura Miler1, Margaret Anne Richter2, and Jeffrey Meyer1 1 Centre for Addiction and Mental Health, University of Toronto, 2Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre
Background: An autoimmune model was proposed for a small minority of obsessive compulsive disorder (OCD) cases associated with Streptococcal infections, however, elevated neuroinflammation could be broadly important in OCD. Identification of a neuroinflammatory phenotype in the brain is possible with positron emission tomography (PET) for measuring translocator protein total distribution volume (TSPO VT), an index of TSPO density. When microglia are
College of Physicians and Surgeons, Columbia University/ New York State Psychiatry, 2Columbia University, 3The University of Texas at Austin, 4Johns Hopkins University, 5 University of Colorado Boulder
Background: Recent research suggests that posttraumatic stress disorder (PTSD) is associated with decreased amygdala and hippocampal resting-state functional connectivity (rsFC) with the prefrontal cortex (PFC). It remains unknown whether Prolonged Exposure (PE), a first-line, exposure based treatment, can change these connections. We assessed rsFC in patients with PTSD and trauma-exposed healthy controls (TEHCs), investigating the association of a 10-week PE treatment with enhanced rsFC between amygdala and PFC, and between hippocampus and PFC. Methods: Fifty participants (PTSD524; TEHC526) underwent resting functional magnetic resonance imaging (fMRI) scan at baseline and 10 weeks later, during which time patients with PTSD completed PE treatment. RsFC patterns of the amygdala and hippocampus were investigated before and after treatment.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S97
Thursday Abstracts
Results: No genome-wide associations were significant at 5310-8. Our top hit variant, in a schizophrenia susceptibility gene, showed an association with MADRS score change. This gene has been implicated in post-ketamine treatment down regulation of GABA and glutamate levels in the rat prefrontal cortex and hippocampus, resulting in an antidepressant effect. We also observed a suggestive association between remission status and a genetic variant upstream of neuro-specific gene expressed in the hypothalamus and amygdala, suggesting a role in synaptic neurotransmitter signalling. Our top hit pathways included processes in the metabolic pathway of amyloid precursor protein. Conclusions: Our findings suggest novel gene variant associations with measures of venlafaxine remission in older adults, as well as, interesting neuro-relevant genetic pathways. A new, larger study of geriatric depression treatment will confirm these novel findings. Keywords: GWAS, Depression, Venlafaxine, Antidepressant, Genetics
233. BDNF Methylation and Stress Response in a Clinical Population with Major Depressive Disorder Maria Claudia Latigg2, Victor Andres Villamizar2, Alejandra Gaviria2, José David Angel2, Catalina Cañizares2, Eugenio Ferro1, Alvaro Arenas3, and Yvonne Gomez2 1 Clínica Montserrat, Inmaculada
2
Los Andes University,
3
Clínica La
Background: Major Depressive Disorder (MDD) is a multifactorial disease with a heritability of 35-40%. BDNF Gene Val66Met (rs6265) variant has a well-established role in neuronal plasticity and decreased levels have been observed in MDD. Previous studies support that vulnerability to environmental stress is mediated by the rs6265 variant. Changes in methylation patterns in exon VI of BDNF are emerging as a possible explanation for how Early Life Stress (ELS) can disrupt BDNF expression. However, there is still controversy because most of these studies are in non-clinical populations. Methods: We present a case-control study in clinical population, with matched controls. Informed consent was provided by all individuals. ELS was assessed by clinical questionnaire and stressful live events questionnaire. The rs6265 variant was genotyped using real time PCR. Methylation patterns in exon IV of BDNF were assessed by bisulfite treatment (EZ-96 DNA Methylation kit-Zymo research), Sanger sequencing and quantification of methylation percentage at each CpG region. Results: No significant differences were observed in overall methylation patterns between cases and controls. However, methylation in CpG islands 2, 6, 9, 14, 15 and 16 was higher in cases with MDD compared to controls (P50,001). There was association in methylation patterns among controls that experienced ELS (P50,005), however this association was not observed in cases. Conclusions: Exon IV methylation in specific CpG islands is higher in MDD. Increased methylation in controls with ELS may
S96
suggest a predisposition to MDD. Higher methylation in cases may not necessarily be related to ELS. Further sample should be completed to support conclusions. Supported By: Colciencias, Los Andes University, ICSNClinica Montserrat Keywords: Major Depression, brain-derived neurotrophic factor, Epigenetics, Early Life Stress
234. Search for Risk Variants in TrkB and BDNF that Predispose to Lithium Responsiveness in Bipolar Disorder Nathaniel Miller1, Seth A. Ament2, Tatyana Shekhtman3, Jared C. Roach2, The Bipolar Genome Study4, and John R. Kelsoe3 1
Department of Psychiatry, UCSD School of Medicine, Institute for Systems Biology, 3Department of Psychiatry, UCSD, 4The Bipolar Genome Study 2
Background: BDNF and its receptor TrkB have been implicated in bipolar disorder and lithium response. Lithium induces release of BDNF which is essential for its function. We have previously shown that variants in the TrkB gene are associated with lithium response and bipolar disorder. The goal of this study was to identify sequence variants in these two genes that affect the action of lithium in bipolar disorder. Methods: 73 lithium responsive (LiR) and 47 non-responsive (NR) retrospective samples were used for targeted sequencing of exons and regulatory regions. Samples were combined into pools of 23 to 37 individuals. Paired-end sequencing was done using Custom Amplicons (Illumina). Variants were called with Genome Analysis Toolkit. PLINK was used to calculate a chi-square statistic. Annotation was done using SIFT and PolyPhen-2. Results: For BDNF, 35 variants were called. Using a conservative Bonferroni correction for 174 comparisons, a statistically significant p-value would be ,2.8x10-4. Two suggestive variants were found for BDNF. For TrkB, 159 variants were called. A minor allele variant was found more frequently than expected in the LiR samples in the promoter region of TrkB, having a p-value of 2.93 x 10-6. RegulomeDB predicts this variant is important for transcription factor binding. Conclusions: Targeted sequencing revealed the over abundance of a minor allele in the promoter of TrkB for LiR but not in NR. Lithium efficacy for the treatment of bipolar disorder is likely to involve the BDNF/TrkB pathway. This study provides a likely candidate region to further investigate the function of lithium in bipolar individuals. Supported By: R25 MH101072 Keywords: Bipolar Disorder, lithium response, BDNF, NTRK2, Next Generation Sequencing
235. Deep Brain Stimulation Modulates Frontostriatal Inhibitory Control in Obsessive-Compulsive Disorder Martijn Figee1, Matthijs Vink2, Judy Luigjes1, Guido van Wingen1, and Damiaan Denys1
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Biological Psychiatry
Thursday Abstracts
1
Academical Medical Center, Amsterdam, 2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht Background: Patients with obsessive-compulsive disorder (OCD) are unable to stop unwanted compulsive behaviors, which has been linked to dysfunctional brain networks of inhibitory control. Deep brain stimulation (DBS) targeted at the ventral limb of the anterior capsule (vALIC) is efficacious for therapy-refractory OCD. Here, we explored if DBS restores sensorimotor frontostriatal pathways that are involved in inhibitory control.: Methods8 DBS implanted OCD patients performed a stop-signal with DBS ON and then one week later with DBS OFF. The task included reactive inhibition, i.e. outright stopping in response to a stop-signal, and proactive inhibition, i.e. anticipation of a potential stop signal. We assessed BOLD fMRI activation differences over the two scans between patients (DBS ON and OFF) and 13 matched healthy controls in the right striatum and right inferior frontal cortex. Results: DBS OFF increased obsessive-compulsive symptoms with 37% (t7524.36, p50.003). Reactive inhibition and frontostriatal activiation did not differ between patients (DBS ON or OFF) and controls. Behaviorally, DBS did not significantly change proactive inhibition compared to controls. However, DBS induced significant changes in proactive inhibitory activation in the right striatum (group x scan interaction F1,1955.74, p50.027) and right inferior frontal cortex (group x scan interaction F1,1957.63, p50.012). Patients with DBS OFF had lower activity in these regions than healthy controls, whereas activity during DBS ON did no longer differ significantly from controls. Conclusions: DBS normalized frontostriatal activity during proactive inhibition. These results suggest that DBS for OCD interrupts a pathological frontostriatal loop, allowing successful inhibition of unwanted behaviors and restoration of goaldirected actions. Keywords: Deep Brain Stimulation, Response inhibition, Obsessive Compulsive Disorder (OCD), BOLD fMRI
activated, TSPO levels are increased. The primary aim of the present study is to apply [18F]FEPPA PET to determine whether TSPO VT is greater in OCD within the dorsal caudate, orbitofrontal cortex (OFC), thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex (ACC). Methods: [18F]FEPPA PET was applied to measure TSPO VT in the hypothesized regions in OCD participants (n520) and health (n520) (matched for age). All participants were antidepressant-free, and had no additional current psychiatric or medical illnesses. Results: TSPO VT was elevated in OCD within the hypothesized regions by 26.0% - 34.7%. Calculation of analysis of variance resulted in the effects of diagnosis by region: dorsal caudate F1,32514.4, P5.001; OFC F1,32511.3, P5.002; thalamus F1,32513.7, P5.001; ventral striatum F1,32514.7, P,.001; dorsal putamen F1,32513.4, P5.001; and ACC F1,32510.7, P5.002. The Yale-Brown obsessive compulsive scale distress associated with compulsive behaviours subscale score was positively correlated with TSPO VT in the OFC (r 0.62, P5.005). Conclusions: This is the first study to demonstrate neuroinflammation in OCD. The most likely interpretation of elevated TSPO levels is microglia activation and an important clinical implication is that this abnormality may be targeted by neuromodulatory therapeutics. Supported By: CIHR Keywords: Obsessive Compulsive Disorder (OCD), Positron Emission Tomography, Translocator Protein (TSPO), Neuroinflammation, [18F]FEPPA
237. PTSD Exposure-Based Treatment Changes Amygdala and Hippocampus Resting State Functional Connectivity in PTSD Xi Zhu1, Benjamin Suarez-Jimenez2, Liat Helpman2, John Markowitz2, Santiago Papini3, Ariel Durosky2, Anne Hilburn2, Franklin Schneier2, Martin Lindquist4, Tor Wager5, and Yuval Neria2 1
236. Inflammation in the Neurocircuitry of Obsessive Compulsive Disorder Sophia Attwells1, Elaine Setiawan1, Alan A. Wilson1, Pablo M. Rusjan1, Romina Mizrahi1, Laura Miler1, Margaret Anne Richter2, and Jeffrey Meyer1 1 Centre for Addiction and Mental Health, University of Toronto, 2Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre
Background: An autoimmune model was proposed for a small minority of obsessive compulsive disorder (OCD) cases associated with Streptococcal infections, however, elevated neuroinflammation could be broadly important in OCD. Identification of a neuroinflammatory phenotype in the brain is possible with positron emission tomography (PET) for measuring translocator protein total distribution volume (TSPO VT), an index of TSPO density. When microglia are
College of Physicians and Surgeons, Columbia University/ New York State Psychiatry, 2Columbia University, 3The University of Texas at Austin, 4Johns Hopkins University, 5 University of Colorado Boulder
Background: Recent research suggests that posttraumatic stress disorder (PTSD) is associated with decreased amygdala and hippocampal resting-state functional connectivity (rsFC) with the prefrontal cortex (PFC). It remains unknown whether Prolonged Exposure (PE), a first-line, exposure based treatment, can change these connections. We assessed rsFC in patients with PTSD and trauma-exposed healthy controls (TEHCs), investigating the association of a 10-week PE treatment with enhanced rsFC between amygdala and PFC, and between hippocampus and PFC. Methods: Fifty participants (PTSD524; TEHC526) underwent resting functional magnetic resonance imaging (fMRI) scan at baseline and 10 weeks later, during which time patients with PTSD completed PE treatment. RsFC patterns of the amygdala and hippocampus were investigated before and after treatment.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
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