Saturday Abstracts SATURDAY, MAY 16 PLENARY

Saturday Abstracts

Biological Psychiatry

SATURDAY, MAY 16

802. Sensitive Periods in Affective Nonlinear Maturation of Fear Learning

PLENARY SESSION Plenary Session – Neurodevelopment Saturday, May 16, 2015, 8:05 AM – 11:30 AM Canadian – Convention Floor Chair: Amit Etkin

Development:

Francis S. Lee Department of Psychiatry, Pharmacology, Weill Medical College of Cornell University, New York, NY

800. Modeling Psychiatric Disease with Genetically Programmed Human Neurons Fred H. Gage Laboratory of Genetics, Salk Institute, LaJolla, CA Cellular reprogramming of somatic cells provides an important advance for the study of human Neurodegenerative and Psychiatic diseases in live human neurons. Great progress is being made in the study of developing neurons from patients. For example, reprogramming cells from patients with neurological diseases allows the study of molecular pathways particular to specific subtypes of neurons (ex: Hippocampal neurons in Schizophrenia or Bipolar disease); such an experiment can only be done using neurons differentiated from programed or reprogrammed somatic cells, as it is too invasive to isolate these neurons from patients’ brains. In addition, reprogramming technology allows for the study of human neurons during development, where disease-specific pathways can be investigated prior to and during disease onset. Detecting disease-specific molecular signatures in live human neurons, as opposed to late stage post-mortem tissues, opens possibilities for early intervention therapies and new diagnostic tools. Importantly, it is now feasible to obtain neurons that capture the genetic material from the patient, which includes not only the mutated gene(s) – if the gene is known – but also the genetic modifiers that play an important but yet largely unknown role in the pathology of Neurological and Psychiatric diseases. Examples of recent findings obtained from this approach will be presented.

References 1. Yu, D. X., F. P. Di Giorgio, J. Yao, M. C. Marchetto, K. Brennand, R. Wright, A. Mei, L. McHenry, D. Lisuk, J. M. Grasmick, P. Silberman, G. Silberman, R. Jappelli and F. H. Gage. “Modeling Hippocampal Neurogenesis Using Human Pluripotent Stem Cells.” Stem Cell Reports 2, no. 3 (2014): 295-310. 2. Gage, F. H. and S. Temple. “Neural Stem Cells: Generating and Regenerating the Brain” Neuron 80, no. 3 (2013): 588-601 3. Brennand, K. J., A. Simone, J. Jou, C. Gelboin-Burkhart, N. Tran, S. Sangar, Y. Li, Y. Mu, G. Chen, D. Yu, S. McCarthy, J. Sebat, and F. H. Gage. “Modeling Schizophrenia Using Human Induced Pluripotent Stem Cells.” Nature 473, no. 7346 (2011): 221-5.

801. The Depressed Brain: Sobering and Hopeful Lessons Huda Akil University of Michigan, Ann Arbor, MI This talk will discuss the challenges of understanding the pathophysiology of Major Depressive Disorder at the molecular and cellular level and the surprising insights derived from genomics and human postmortem studies. It then describes how animal models and neuroscience studies at multiple levels (from gene to behavior) can be used to test and validate new targets for treatment and/or as biomarkers of the illness. It focuses in particular on the notion of “molecular organizers” that play a broad role in neuroplasticity, in development, adaptation to the environment, and responsiveness to treatment.

Adolescence is associated with an increased incidence of anxiety disorders, and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. Exposure-based cognitive behavioral therapy is the most common treatment for anxiety disorders, based on basic principles of fear extinction learning, whereby a person is desensitized to fearful triggers through repeated exposures in a safe context. At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. Conserved neural circuitry of rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory that lie at the heart of many anxiety disorders (Casey et al, 2013). Here, I will review the nonlinear developmental aspects of fear learning and memory during a sensitive period in peri-adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. In particular, recent mouse and human studies indicate that adolescents have diminished fear extinction relative to younger or older age groups (Pattwell et al., 2012). This suggests that exposure therapies in clinical practice that build on principles of fear extinction may be less effective during adolescence than during childhood or adulthood (Drysdale et al., 2014). This illustrates the importance of age as a potential predictor of treatment response and even a target for novel treatments. I will provide a neurodevelopmental model that may help to inform novel treatment strategies for children and adolescents with fear-related disorders (Lee et al., 2014).

References 1. Casey BJ, Pattwell SS, Glatt CE, Lee FS (2013). Treating the developing brain: implications from human imaging and mouse genetics. Annual Review of Medicine 64:427-439. 2. Drysdale AT, Hartley CA, Pattwell SS, Ruberry EJ, Somerville LH. Compton SN, Lee FS, Casey BJ, Walkup JT (2014). Fear and anxiety from principle to practice: Implications for when to treat youth with anxiety disorders. Biological Psychiatry 75:19-20. 3. Lee FS, Heimer H, Giedd JN, Lein ES, Sestan N, Weinberger DR, Casey BJ (2014). Adolescent mental health – opportunity and an obligation. Science 346:547-549. 4. Pattwell SS, Duhoux S, Hartley CA, Johnson D, Jing DQ, Elliot MD, Ruberry EJ, Powers A, Mehta N, Yang RR, Soliman F, Glatt CE, Casey BJ*, Ninan I*, Lee FS* (2012). Altered fear learning across development in both mouse and human. Proc. Natl. Acad. Sci. 109:16318-23.

803. Brain Transcriptional Dynamics of Neurodevelopmental Disorders Daniel Weinberger Psychiatry, Neurology, Neuroscience and The Institute of Genetic Medicine, Leiber Institute for Brain Development, Baltimore, MD Genetic association for most CNS disorders involves primarily variation that influences gene processing rather than protein sequence (e.g.transcript abundance, splicing) and thus the molecular identification of genetic regulation of the transcriptome is a critical step in understanding genetic mechanisms and discover-

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Saturday Abstracts


ing novel isoforms that underlie disease mechanisms and that may be targetable for the development of new therapies. PCR based studies of transcript characterization of genes associated with schizophrenia have suggested that specific transcript isoforms are often associated with genetic risk and tend to be developmentally regulated (e.g. GRM3, DISC1, NRG1, NRG3, GAD1, ZNF804a). The availability of transcriptome-wide analyses, using oligonucleotide arrays and RNA sequencing, enable a more unstructured analysis of genetic association with transcription. Using the BrainCloud array database profiling during normal human development,, we showed that gene sets associated with developmental neuropsychiatric disorders (e.g. ASD, Schizophrenia, syndromal ND) are enriched for genes showing relatively fetally abundant expression (Birnbaum et al 2014). Using RNA seq in a normal developmental brain series and an analytic tool for differential expression analysis at single base resolution independent of prior annotation (“derfinder”), we have identified 50,000 differentially expressed transcriptome regions, 40% are in previously unannotated transcripts (Jaffe et al 2014). GWAS signals related to risk for schizophrenia and other neurodevelopmental disorders significantly map to DERs which are related to changing neuronal phenotypes. RNA sequencing in human brain is an essential tool for translating clinical association into molecular mechanisms of risk and construction of cell and animal models based on the molecular association.

Methods: Two such instruments from the Philadelphia Neurodevelopmental Cohort, Penn Computerized Neurocognitive Battery (CNB) and GOASSESS clinical interview, measure latent traits that exemplify RDoC-consistent dimensions. The CNB comprises fourteen tests, validated with functional neuroimaging, measuring performance accuracy and speed on specific neurobehavioral domains. The GOASSESS is a structured comprehensive interview. Both the CNB and GOASSESS are optimal for exploratory and confirmatory factor analysis (EFA and CFA, respectively) for the purposes of, a) discovering the latent dimensions underlying them, and b) calculating the corresponding dimensional scores based on models with the best structural validity possible. Results: The psychometric analyses of the GOASSESS and CNB were conducted on the entire PNC community sample (N ≈ 9500; ages 8 – 21). We demonstrated how a particular type of measurement model, the bifactor, allows for substantive analysis using the sub-dimensions composing the CNB and GOASSESS, despite moderate correlations among those dimensions. Statistical “fit” of all models was acceptable. Conclusions: Bifactor modeling, used either to calculate scores or as a measurement model within a structural equation model, promises to allow testing of very specific hypotheses that are difficult to approach in the presence of multiple correlated dimensions.

References

Keywords: Psychometrics, Assessment, Factor Analysis, Bifactor, Neurocognition Supported by: T32MH019112

1. Birnbaum R , Jaffe AR, Hyde TM, Kleinman JE, Weinberger DR: Prenatal expression patterns of genes associated with neuropsychiatric disorders. American Journal of Psychiatry 171:758-767, 2014. 2. Jaffe, AE, Shin J, Collado-Torres L, Leek JT, Tao R, Li C Gao Y, Jia, Y Maher BJ, Hyde TE, Kleinman, JE. Weinberger, DR; Developmental regulation of human cortex transcription and its clinical relevance at base resolution. Nature Neuroscience 2014. 3. Birnbaum R, Jaffe AR, Chen, Q, Hyde TM, Kleinman JE, Weinberger DR: Investigation of the prenatal expression patterns of 108 schizophrenia-associated genetic loci. Biological Psychiatry 2015.

SYMPOSIUM The Philadelphia Neurodevelopmental Cohort: A Resource for Elucidating Developmental Psychopathology Saturday, May 16, 2015, 12:30 PM – 2:30 PM Ontario – Convention Floor Chair: Ruben C. Gur* Co-Chair: Raquel E. Gur *Supported by: P50MH096891, T32MH019112, RC2MH089983

804. Latent Dimensions Underlying Psychopathology and Neurocognition: Discovery, Modeling, and Use in Research Tyler M. Moore Psychiatry, University of Pennsylvania, Philadelphia, PA Background: The NIMH RDoC initiative posits that psychopathology is best conceptualized along continuous dimensions rather than discrete categories. Such dimensions are more biologically feasible than diagnostic categories, and most effectively measured using psychometric approaches such as latent trait theory. Because such endophenotypic traits are not observed directly, they are inferred using behavioral instruments that require careful construction. 288S

805. Clinical Phenotypic Characterization of the Philadelphia Neurodevelopmental Cohort: Foundations for Integrative Investigations of Psychiatric Disorders Monica E. Calkins1, Kathleen R. Merikangas2, Marcy Burstein3, Theodore Satterthwaite4, Daniel Wolf4, Tyler M. Moore4, Kosha Ruparel4, Hakon Hakonarson5, Ruben C. Gur4, Raquel E. Gur4 1 University of Pennsylvania School of Medicine, 2Chief, Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, 3 NIMH, National Institute of Mental Health, Bethesda, MD, 4 Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, 5Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA Background: An integrative multidisciplinary approach is required to elucidate the multiple factors that shape neurodevelopmental trajectories of mental disorders. We present here recruitment and clinical assessment results from the Philadelphia Neurodevelopmental Cohort (PNC), which was designed to characterize clinical and neurobehavioral phenotypes of young people in the community. Methods: Participants (age 8-21) were recruited from a large pool of previously identified and genotyped youths. A structured computerized tool (GOASSESS) administered at Time 1 to probands and collateral informants assessed psychopathology domains including anxiety, mood, eating, behavior disorders and a broad “spectrum” of psychosis-relevant experiences. A sub-sample of participants, selected based on the presence or absence of psychosis spectrum symptoms, participated in a Time 2 follow-up (mean=18 months) including the Structured Interview for Prodromal Syndromes, the K-SADS, and other clinical measures of symptoms and function.

Biological Psychiatry May 1, 2015;77:1S-444S www.sobp.org/journal

Saturday Abstracts


Results: A total of 9,498 youths (mean age=14.2; European-American=55.8%; African-American=32.9%; Other=11.4%) were enrolled at Time 1, and 503 at Time 2. Rates and sex ratios of psychopathology at Time 1 were generally consistent with prior population studies. Threshold psychosis was endorsed by 3.7% of youths, and sub-psychosis by 12.3%. At Time 2, psychosis spectrum features persisted or worsened in 51% of youths, and were associated with comorbid psychopathology, substance use, and social/occupational dysfunction. Conclusions: The PNC public domain resource can accelerate collaborative research and advance our understanding of the complex inter-relationships among genes, cognition, brain and behavior involved in the neurodevelopment of common mental disorders. Keywords: psychopathology, neurodevelopment, prospective Supported by: RC2MH089983; RC2MH089924; K08MH079364

806. Exploring Dimensions of Psychopathology in Development Using Multimodal Neuroimaging Theodore Satterthwaite Psychiatry, University of Pennsylvania, Philadlephia, PA Background: Adolescence and early adulthood is a critical period for neurodevelopment and many neuropsychiatric disorders manifest during this period. Here we present an overview of neuroimaging results from the Philadelphia Neurodevelopmental Cohort, and summarize recent insights from this data regarding normal brain development and sex differences in brain maturation. We additionally present new results on the relationship between abnormal patterns of brain development and dimensions of psychopathology. Methods: Cross-sectional imaging data was acquired on 1,601 adolescents aged 8-21, longitudinal imaging data at a 2-year follow-up has been collected on 404 subjects. Imaging sequences acquired include task-related fMRI (n-back working memory task, facial emotion identification task), resting-state fMRI, diffusion tensor imaging, perfusion imaging using arterial spin labeling, and T1-weighted imaging of brain structure. Multimodal imaging data was related to subject age, subject gender, cognitive task performance, categorical psychiatric diagnosis, and dimensions of psychopathology derived from factor-analysis of clinical data. Analysis methods include standard mass-univariate linear regression, nonlinear developmental analyses using penalized splines, and application of multivariate pattern analysis techniques. Results: Multimodal imaging delineated clear age-related effects informative of neurodevelopment, with prominent sex differences in multiple imaging measures including hippocampal structure, brain perfusion, inter-hemispheric structural connectivity, and functional network segregation. Analysis of categorical diagnosis revealed common loci of dysfunction across multiple disorders, which could be dissociated using a dimensional framework. Conclusions: These data provide convergent evidence regarding the parameters indicating brain maturation, and provide evidence of specific brain abnormalities that may be linked to distinct dimensions of evolving psychopathology.

807. Integrating Clinical, Neurocognitive and Neuroimaging Parameters to Elucidate Normative Brain Development and Vulnerability to Psychosis Ruben C. Gur Psychiatry, University of Pennsylvania, Philadelphia, PA Background: Contemporary medicine aims toward early vulnerability detection so that intervention can avert pathological processes that, if allowed to continue unabated, could lead to illness. In this context the PNC affords an unprecedented wealth of data on a community sample that is sensitive to age effects and sex differences and may distinguish individuals at risk for psychosis. The followup data permit testing whether individuals identified as at risk at intake maintain that status and probe the intake data for predictors of symptom progression. Methods: The Psychosis factor scores from intake were correlated with the neurocognitive factors and the multimodal neuroimaging parameters to establish the brain-behavior signature of psychosis proneness. In the followup, we identified individuals with persistent symptoms and those who remitted. We examined the differences between these groups at intake brain-behavior measures. Results: Individuals with persistent symptoms were distinguishable by multiple parameters of brain functional integrity. They had worse neurocognitive performance at intake specifically for face memory and social cognition. For the sample with neuroimaging data at intake, the best predictors of continued psychotic symptoms were brain volumes, which were lower for caudate, hippocampus, anterior cingulate, anterior and posterior insula, supplementary motor cortex, inferior and superior temporal gyri, precuneus, superior occipital and occipital fusiform gyri and calcarine cortex. Conclusions: The combination of clinical and brain-behavior data can provide a powerful set of predictors of persistence of psychotic symptoms. These measures can also suggest avenues for intervention by delineating vulnerable brain systems linked to circumscribed neurocognitive domains. Keywords: Multimodal neuroimaging, clinical high riusk predictors, endophenotypes, brain maturation, devlopmental psychopathology Supported by: NIMH

Keywords: Neuroimaging, Development, Adolescence, fMRI, Dimensions Supported by: K23MH098130, MH089983, MH089924


Saturday Abstracts


SYMPOSIUM iPSC Models of Neural Development and Plasticity in Psychiatric Disorders Saturday, May 16, 2015, 12:30 PM – 2:30 PM Canadian – Convention Floor Chair: Sue O’Shea* Co-Chair: Melvin McInnis *Supported by: Prechter Bipolar Research Fund (UM), Steven Schwartzberg Memorial Fund, Richard Tam Foundation

808. Using Patient-Specific iPSC Models for Characterizing Disease Pathophysiology & Therapeutic Screening in Bipolar Disorder Stephen J. Haggarty1, Roy H. Perlis2 1 Departments of Neurology & Psychiatry, Massachusetts General Hospital & Harvard Medical School, Boston, MA, 2 Department of Psychiatry, Massachusetts General Hospital & Harvard Medical School, Boston, MA Background: Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we are using reprogramming technology to create a continually expanding cohort of iPSC lines from which expandable neural progenitor cells (NPCs) and differentiated neurons have been generated. Methods: Global transcriptome analysis and functional assays of key pathways implicated in neurodevelopment were applied to characterize BD iPSC models. Using iPSC-derived NPCs, a high-throughput screen of over 300,000 compounds for modulators of lithium-sensitive signaling and other neuroplasticity pathways was conducted. We also began to systematically profile NPCs and neurons after perturbation with a collection of pharmacological agents using a high-throughput, multiplexed gene expression assay. Results: Our studies provide new cellular and molecular tools for dissecting the pathophysiology of BD and provide evidence for dysregulation of both coding and non-coding RNA transcripts at early stages of NPC formation that impacts subsequent neuron differentiation. This first-generation “Neuro-Connectivity Map” was found an effective tool for exploring human neuropharmacology. Conclusions: Further characterization of phenotypes of BD iPSCs and the integration of these results with data generated as part of the NIMH Research Domain Research Domain Criteria project (RDoC) holds promise for developing new treatments for BD. Keywords: bipolar disorder, stem cells, neuroplasticity, lithium, WNT signaling Supported by: NIMH 4R33MH087896; NIMH 1P50MH106933

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809. The Ups and Downs of Bipolar Disorder: Patterning in iPSC-derived neurons Aislinn J. Williams1, Monica Bame1, Cynthia J. DeLong2, Omar Mabrouk3, Robert Kennedy3, Melvin G. McInnis1, K. Sue O’Shea2 1 Psychiatry, University of Michigan, Ann Arbor, MI, 2Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 3Chemistry, University of Michigan, Ann Arbor, MI Background: Neuropsychiatric disorders, including bipolar disorder (BP), are increasingly considered to have a developmental basis, although the factors underlying this are unknown. Methods: To study neuronal cell fate, we derived iPSC from three individuals with BP and three controls (C), and differentiated them into telencephalic neurons. These neurons were analyzed by microarray, mass spectrometry, and exposed to patterning factors to investigate the role of cell fate patterning in BP. Results: Microarray analysis of RNAs from iPSC-derived neurons identified increased expression of transcripts that confer dorsal telencephalic fate in the C group, including: EMX2, HHIP, KIF7, LEFTY1,2, PAX6, SOX6, TBR2, TCF3,4, VGLUT1, ZNF536. Neurons derived from BP iPSC expressed transcripts involved in the differentiation of ventral (MGE) brain regions, including: FOXP2, NKX2-1, and LHX8, which controls neuronal expression of SHH. Mass spectrometry of neuronal culture supernatants indicated that GABA release from BP neurons was elevated compared to C neurons throughout the 7-week culture period, and GABA release from BP neurons was significantly higher following KCl-mediated depolarization (p < 0.018, ANOVA). iPSC were responsive to patterning factors: both BP and C iPSC increased expression of the dorsal marker EMX2 following lithium exposure, but only C iPSC responded to ventral cues by downregulating EMX2. Conclusions: Neurons from individuals with BP express different patterning factors, different neurotransmitter release profiles, and respond differently to patterning factors than C neurons. Alterations in neuronal fate allocation during early CNS development, tangential cell migration, or the function of cortical neurons could alter cortical lamination and circuitry in BP. Keywords: biolar disorder, induced pluripotent stem cells, induced neurons, cell fate patterning, neurodevelopment Supported by: Prechter Bipolar Research Fund

810. Regulation of Neural Development by Risk Genes for Mental Disorders Guo-li Ming Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD Background: Psychotic mental illnesses, such as schizophrenia and affective disorders, are chronic and disabling brain disorders affecting more than 1% of the general population. The causes of these neural developmental disorders are multifactorial, but with a prominent genetic basis. Methods: DISC1 is by far the best-characterized risk genes for schizophrenia and other major mental disorders. How mutation of DISC1 gene in patients impact the development of human neurons is completely unknown and we are using induced pluripotent stem cells (iPSCs) as a model system to address this question.

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Saturday Abstracts


Results: We have derived iPSCs from multiple patients from one family with a DISC1 mutation and with major mental disorders. I will discuss our recent findings on the roles of DISC1 in morphological developmental and synaptic development of human neurons derived from patient specific iPSCs. Conclusions: Our study demonstrate a causal role of DISC1 mutation in dysregulated synaptic function.

SYMPOSIUM Strategies to Enhance Emotion Regulation Skills: Models Derived from Neuroscience Saturday, May 16, 2015, 12:30 PM – 2:30 PM Confederation 3 – Mezzanine Chair: Harold W. Koenigsberg* *Supported by: NIMH R01MH077813

Keywords: DISC1, schizophrenia, synapse, iPSC Supported by: MSCRF

811. Studying the Neurodevelopmental Factors Contributing to Schizophrenia Using hiPSC Kristen Brennand Department of Psychiatry, Mt Sinai School of Medicine, New York, NY Background: Schizophrenia (SZ) is a common and debilitating psychiatric disease for which the mechanisms responsible remain unclear. Methods: To identify the cellular and molecular factors contributing to SZ, fibroblasts from SZ patients were reprogrammed into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated into neural progenitor cells (NPCs) and neurons. Gene expression comparisons of our hiPSC-derived neural progenitor cells (NPCs) and 6-week-old neurons to the Allen BrainSpan Atlas indicate that our hiPSC neural cells, from controls and patients with SZ, most resemble fetal rather than adult brain tissue, indicating that hiPSC-based models may not yet be suited for the study of the late features of this disorder. Results: We observed aberrant migration and increased oxidative stress in SZ hiPSC NPCs, and diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression in SZ hiPSC neurons. Key cellular and molecular elements of the SZ phenotype were ameliorated following treatment of SZ hiPSC neurons with the antipsychotic loxapine. Conclusions: To confirm these findings across a larger cohort of patients, we have now generated hiPSCs from thirteen patients with childhood-onset SZ (COS) and twelve additional controls. COS is a rare and particularly severe form of the disorder, with an onset of psychosis prior to age twelve. We anticipate that neural cells derived from patients with COS will have accelerated and/or more severe cellular phenotypes relative to those we have already reported for adult-onset SZ, and so might be better suited for stem-cell based models of SZ predisposition. Keywords: schizophrenia, induced pluripotent stem cell, neural progenitor cell Supported by: NIMH R01MH101464 ; NYSCF

812. Does Training Help? Behavioral and Neural Impacts of Longitudinal Emotion Regulation Training to Enhance Cognitive Reappraisal in Healthy Adults Bryan T. Denny1,2, Marika C. Inhoff3, Noam Zerubavel2, Lila Davachi3, Kevin N. Ochsner2 1 Psychiatry, Ichan School of Medicine at Mount Sinai, New York, NY, 2Psychology, Columbia University, New York, NY, 3 Psychology, New York University, New York, NY Background: Cognitive reappraisal involves reframing an emotional stimulus in a way that changes its emotional impact. Reappraisal has been shown to be effective in single sessions, eliciting prefrontal cortex (PFC) to down-regulate amygdala activity. Little is known, however, about whether one can improve over time in implementing reappraisal, and how reappraisal responses endure. Two studies addressing these questions will be presented. Methods: The first study examined whether healthy adults could improve in their ability to use reappraisal to down-regulate negative emotion over the course of four experimental sessions over two weeks using an image-based reappraisal task. Three groups were recruited: reappraisal-by-distancing (N=33), reappraisal-by-reinterpretation (N=33), and a no-regulation control group (N=33). In the second study, healthy adults (N=17) completed massed reappraisal-by-distancing training on day one, followed one day later by an fMRI scan during reappraisal task performance. One week later, participants were scanned again while passively viewing previously presented and novel images. Results: In the first study, reappraisal-by-distancing participants showed significant longitudinal reductions in self-reported negative affect that were not attributable to habituation and further uniquely showed reductions in perceived stress in daily life. In the second study, amygdala activity was attenuated and ventrolateral PFC activity increased as a function of both reappraisal-by-distancing and prior training. One week later, viewing former reappraisal training images uniquely showed sustained attenuation of amygdala, without a corresponding increase in PFC activity. Conclusions: These studies show that reappraisal, particularly reappraisal-by-distancing, is trainable and suggest that neural reactivity in amygdala drives the sustained effects of reappraisal training. Keywords: emotion regulation, longitudinal, training, fMRI, amygdala Supported by: R01MH076137; R01MH074692


Saturday Abstracts


813. Cognitive Reappraisal Training Enhances Emotion Regulation in Borderline Personality Disorder Harold W. Koenigsberg1, Bryan Denny1, Jin Fan1, Kevin N. Ochsner2, Marianne Goodman1, Antonia S. New1, Antonia McMaster1, Heather Alexander1, Larry J. Siever1 1 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 2Department of Psychology, Columbia University, New York, NY Background: Borderline personality disorder (BPD) is the prototypical disorder of emotion dysregulation. We have shown previously that BPD patients do not activate brain regions known to participate in cognitive reappraisal as healthy subjects (HCs) do. This may contribute to their impaired emotion regulation. This study tests the hypothesis that BPD patients can be trained to enhance cognitive reappraisal-by-distancing, which instructs participants to view stimuli as impartial, objective observers. Methods: On each of 5 study days, BPD (n=10) and HC (n=13) subjects were shown 60 negative social emotional pictures and instructed to employ reappraisal-by-distancing to half and to look, without reappraising, at the other half. Negative emotion self-reports were obtained after each picture presentation. Day 1 was baseline and days 2 through 5 (spaced 2 days apart) afforded training through practice on novel pictures. 3T fMRI images were obtained on days 1 and 5. Results: BPD patients showed significantly reduced negative emotion self-reports (p