Bio

Clinical Focus


  • Psychiatry

Honors & Awards


  • Dana Neuroscience Scholar award, Dana Foundation (2012)
  • Biobehavioral Research Awards for Innovative New Scientists (BRAINS) R01 Award, NIMH (2010)
  • Travel Award, ACNP (2010)
  • Resident Research Award, APA/Lilly (2010)
  • Outstanding Resident Award, NIMH (2008)
  • Resident Psychiatric Research Scholar Award, APIRE/Janssen (2008)
  • Travel Award, Society of Biological Psychiatry (2008)
  • Career Development Travel Award, Anxiety Disorders Association of America (2006)
  • Clifford Yorke Young Investigator Award, International Neurospsychoanalysis Society (2006)
  • PhD awarded with distinction, Columbia University (2005)
  • Phi Beta Kappa, MIT (1997)

Professional Education


  • Medical Education:Columbia University College of Physicians and Surgeons (05/2006) NY
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (2011)
  • Board Certification, American Board of Psychiatry and Neurology, Psychiatry (2011)
  • Residency:Stanford University Medical Center (06/30/2010) CA
  • MD, Columbia University (2006)
  • PhD, Columbia University, Neurobiology (2005)
  • MPhil, Columbia University (2003)
  • BS, Mass. Institute of Technology (1997)

Research & Scholarship

Current Research and Scholarly Interests


The overarching aim of the Etkin lab is to understand the neural basis of emotional disorders and their treatment, and to leverage this knowledge to develop novel treatment interventions. Our work is organized around the study of affective neuroscience of emotion regulation in healthy subjects and individuals with psychiatric disorders.

Emotion regulation: A successful affective neuroscience approach to psychopathology and treatment requires understanding the basic mechanisms involved in emotion regulation. Although our initial work thus far has yielded important insights, we are far from a thorough understanding of how emotion is regulated. Ongoing work in the lab is focused on understanding the factors which govern emotion regulation, the relationship between implicit (i.e. nonconscious) and explicit (i.e. conscious) regulation, and whether there are ways to improve implicit emotion regulation through training.

Neural basis of psychopathology: Our recent work suggests that a deficit in implicit emotion regulation may be a core feature of anxiety, which is evident in patients with generalized anxiety disorder (GAD), including in the context of major depressive disorder (MDD). We are also currently examining how patients with different, but related, conditions, such as post-traumatic stress disorder (PTSD) implicitly regulate emotion and how this reflects common versus disorder-specific neural signatures. In taking a life-span perspective on emotion regulation, we are also currently studying older healthy subjects and those with geriatric anxiety or depression.

Neural circuits subserving emotion: An element integral to the studies above is a delineation of the neural circuits that underlie emotion processing. We have, for example, demonstrated that the major amygdalar subregions in humans have distinct patterns of resting-state functional connectivity, which are perturbed in GAD. Ongoing work in the lab is focused on extending this mapping of circuitry important for emotion, using functional connectivity, in both healthy subjects and patients with mood or anxiety disorders.

Neural mechanisms of existing treatments: Very little is known about the mechanisms of action of existing treatments in psychiatry, across both pharmacological and non-pharmacological approaches. Current studies, for example, include work investigating the neural mechanisms of psychotherapy (e.g. exposure therapy for PTSD), treatment of depression with antidepressant medication, and non-invasive brain stimulation with transcranial magnetic stimulation (TMS) for medication-resistant depression.

Neuroplasticity-based brain training: We develop and test a variety of novel approaches for training emotion regulatory circuits through neuroplasticity-based computer/web-delivered brain training methods. These methods have broad applicability in psychiatry and are also readily disseminable as interventions since they are delivered over the web. Work in this area includes interventions in healthy subjects, individuals at risk for psychiatric disorders and patients with anxiety, depression or PTSD.

Probing and manipulating neural circuits in humans: A key technique in the lab for probing and, ultimately manipulating, neural circuits in humans is simulataneous TMS while imaging brain activity with functional magnetic resonance imaging (fMRI). Simultaneous TMS/fMRI allows us to understand how activity in one brain region translates into activation in its interconnected network of partners, and how communication within and between defined neural circuits can be manipulated by repetitive TMS protocols, which induce plasticity in the target cortex. This work opens up the potential for the development of rationale, circuit-based interventions informed by neuroimaging studies such as those described above.

Clinical Trials


  • International Study to Predict Optimised Treatment - in Depression Recruiting

    The aim of this study is to identify genetic, physical (brain) and psychological (cognitive) markers (or combinations of them) that predict specific response to a range of antidepressants treatment (Escitalopram, Venlafaxine, Sertraline) in patients diagnosed with major depressive disorder. This study is focused on outcomes which may impact on how "personalised medicine" is implemented in depression.

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  • Brain Imaging of Psychotherapy for Posttraumatic Stress Disorder (PTSD) Recruiting

    The investigators are seeking people who have been exposed to a traumatic event in the past and have symptoms of posttraumatic stress disorder (PTSD) currently. A person with PTSD may feel significant distress when reminded of a traumatic event or feel depressed, anxious or jumpy. As a part of this study, participants will receive brain MRIs and office assessments before and after psychotherapy. The investigators provide the gold-standard psychotherapy for PTSD, "Prolonged Exposure", free of charge; additionally participants are compensated for their time during assessment procedures. This study is exploring the brain circuitry involved in improvement in response to psychotherapy.

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  • Neurobehavioral Intervention as a Novel Treatment Approach for Emotion-Regulatory Deficits Recruiting

    The present study will explore the effectiveness of a computer based neurobehavioral intervention in alleviating symptoms and improving emotion regulation in psychiatric populations. It will increase understanding of psychopathology at a neural-circuit level and aid development of new non-pharmacological treatment for emotion regulatory deficits.

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Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Causal interactions between fronto-parietal central executive and default-mode networks in humans PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chen, A. C., Oathes, D. J., Chang, C., Bradley, T., Zhou, Z., Williams, L. M., Glover, G. H., Deisseroth, K., Etkin, A. 2013; 110 (49): 19944-19949

    Abstract

    Information processing during human cognitive and emotional operations is thought to involve the dynamic interplay of several large-scale neural networks, including the fronto-parietal central executive network (CEN), cingulo-opercular salience network (SN), and the medial prefrontal-medial parietal default mode networks (DMN). It has been theorized that there is a causal neural mechanism by which the CEN/SN negatively regulate the DMN. Support for this idea has come from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. Here we undertook a direct test of this mechanism by combining transcranial magnetic stimulation (TMS) with functional MRI to causally excite or inhibit TMS-accessible prefrontal nodes within the CEN or SN and determine consequent effects on the DMN. Single-pulse excitatory stimulations delivered to only the CEN node induced negative DMN connectivity with the CEN and SN, consistent with the CEN/SN's hypothesized negative regulation of the DMN. Conversely, low-frequency inhibitory repetitive TMS to the CEN node resulted in a shift of DMN signal from its normally low-frequency range to a higher frequency, suggesting disinhibition of DMN activity. Moreover, the CEN node exhibited this causal regulatory relationship primarily with the medial prefrontal portion of the DMN. These findings significantly advance our understanding of the causal mechanisms by which major brain networks normally coordinate information processing. Given that poorly regulated information processing is a hallmark of most neuropsychiatric disorders, these findings provide a foundation for ways to study network dysregulation and develop brain stimulation treatments for these disorders.

    View details for DOI 10.1073/pnas.1311772110

    View details for Web of Science ID 000327744900066

    View details for PubMedID 24248372

  • Common Abnormalities and Disorder-Specific Compensation During Implicit Regulation of Emotional Processing in Generalized Anxiety and Major Depressive Disorders AMERICAN JOURNAL OF PSYCHIATRY Etkin, A., Schatzberg, A. F. 2011; 168 (9): 968-978

    Abstract

    Anxiety and depressive disorders are both associated with abnormalities in the processing and regulation of emotion. However, little is known about the similarities and differences between anxiety and depression at the neural level. The authors examined emotional conflict processing using a salient stimulus associated with observable and interpretable behavioral outcomes and with activation in limbic and prefrontal regions implicated in anxiety and depression.Thirty-two healthy comparison subjects, 18 patients with generalized anxiety disorder only, 14 patients with major depression only, and 25 patients with comorbid generalized anxiety disorder and major depression were studied using functional MRI while they performed an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. The authors used behavioral and neural measures to compare trial-by-trial changes in conflict regulation, a test of implicit regulation of emotional processing.Behavioral data indicated that only patients with generalized anxiety (i.e., the anxiety-only and comorbid groups) failed to implicitly regulate emotional conflict. By contrast, deficits in activation and connectivity of the ventral anterior cingulate and amygdala, areas previously implicated in regulating emotional conflict, were found in all patient groups. Depression-only patients, however, compensated for this deficit by also activating the left and right anterior lateral prefrontal cortices, in which activity was correlated with behavioral evidence of successful implicit regulation, thus mediating the disorder-specificity of the behavioral phenotype.These data support the existence of a common abnormality in anxiety and depression in the ventral cingulate and the amygdala, which may be related to a shared genetic etiology. Compensatory engagement of cognitive control circuitry in depression illustrates how the complex nature of psychopathology arises from the interaction of deficits and compensation, all of which can occur at an implicit level.

    View details for DOI 10.1176/appi.ajp.2011.10091290

    View details for Web of Science ID 000294484100016

    View details for PubMedID 21632648

  • Failure of Anterior Cingulate Activation and Connectivity With the Amygdala During Implicit Regulation of Emotional Processing in Generalized Anxiety Disorder AMERICAN JOURNAL OF PSYCHIATRY Etkin, A., Prater, K. E., Hoeft, F., Menon, V., Schatzberg, A. F. 2010; 167 (5): 545-554

    Abstract

    Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder.Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation.Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups.These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.

    View details for DOI 10.1176/appi.ajp.2009.09070931

    View details for Web of Science ID 000277237100012

    View details for PubMedID 20123913

  • Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder ARCHIVES OF GENERAL PSYCHIATRY Etkin, A., Prater, K. E., Schatzberg, A. F., Menon, V., Greicius, M. D. 2009; 66 (12): 1361-1372

    Abstract

    Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD.To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD.Cross-sectional study.Academic medical center.Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry.Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network.Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

    View details for Web of Science ID 000272494700011

    View details for PubMedID 19996041

  • Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia AMERICAN JOURNAL OF PSYCHIATRY Etkin, A., Wager, T. D. 2007; 164 (10): 1476-1488

    Abstract

    The study of human anxiety disorders has benefited greatly from functional neuroimaging approaches. Individual studies, however, vary greatly in their findings. The authors searched for common and disorder-specific functional neurobiological deficits in several anxiety disorders. The authors also compared these deficits to the neural systems engaged during anticipatory anxiety in healthy subjects.Functional magnetic resonance imaging and positron emission tomography studies of posttraumatic stress disorder (PTSD), social anxiety disorder, specific phobia, and fear conditioning in healthy individuals were compared by quantitative meta-analysis. Included studies compared negative emotional processing to baseline, neutral, or positive emotion conditions.Patients with any of the three disorders consistently showed greater activity than matched comparison subjects in the amygdala and insula, structures linked to negative emotional responses. A similar pattern was observed during fear conditioning in healthy subjects. Hyperactivation in the amygdala and insula were, of interest, more frequently observed in social anxiety disorder and specific phobia than in PTSD. By contrast, only patients with PTSD showed hypoactivation in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex-structures linked to the experience and regulation of emotion.This meta-analysis allowed us to synthesize often disparate findings from individual studies and thereby provide neuroimaging evidence for common brain mechanisms in anxiety disorders and normal fear. Effects unique to PTSD furthermore suggested a mechanism for the emotional dysregulation symptoms in PTSD that extend beyond an exaggerated fear response. Therefore, these findings help refine our understanding of anxiety disorders and their interrelationships.

    View details for DOI 10.1176/appi.ajp.2007.07030504

    View details for Web of Science ID 000250049600008

    View details for PubMedID 17898336

  • Resolving emotional conflict: A role for the rostral anterior cingulate cortex in modulating activity in the amygdala NEURON Etkin, A., Egner, T., Peraza, D. M., Kandel, E. R., Hirsch, J. 2006; 51 (6): 871-882

    Abstract

    Effective mental functioning requires that cognition be protected from emotional conflict due to interference by task-irrelevant emotionally salient stimuli. The neural mechanisms by which the brain detects and resolves emotional conflict are still largely unknown, however. Drawing on the classic Stroop conflict task, we developed a protocol that allowed us to dissociate the generation and monitoring of emotional conflict from its resolution. Using functional magnetic resonance imaging (fMRI), we find that activity in the amygdala and dorsomedial and dorsolateral prefrontal cortices reflects the amount of emotional conflict. By contrast, the resolution of emotional conflict is associated with activation of the rostral anterior cingulate cortex. Activation of the rostral cingulate is predicted by the amount of previous-trial conflict-related neural activity and is accompanied by a simultaneous and correlated reduction of amygdalar activity. These data suggest that emotional conflict is resolved through top-down inhibition of amygdalar activity by the rostral cingulate cortex.

    View details for DOI 10.1016/j.neuron.2006.07.029

    View details for Web of Science ID 000240997900023

    View details for PubMedID 16982430

  • Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces NEURON Etkin, A., Klemenhagen, K. C., Dudman, J. T., Rogan, M. T., Hen, R., Kandel, E. R., Hirsch, J. 2004; 44 (6): 1043-1055

    Abstract

    Responses to threat-related stimuli are influenced by conscious and unconscious processes, but the neural systems underlying these processes and their relationship to anxiety have not been clearly delineated. Using fMRI, we investigated the neural responses associated with the conscious and unconscious (backwardly masked) perception of fearful faces in healthy volunteers who varied in threat sensitivity (Spielberger trait anxiety scale). Unconscious processing modulated activity only in the basolateral subregion of the amygdala, while conscious processing modulated activity only in the dorsal amygdala (containing the central nucleus). Whereas activation of the dorsal amygdala by conscious stimuli was consistent across subjects and independent of trait anxiety, activity in the basolateral amygdala to unconscious stimuli, and subjects' reaction times, were predicted by individual differences in trait anxiety. These findings provide a biological basis for the unconscious emotional vigilance characteristic of anxiety and a means for investigating the mechanisms and efficacy of treatments for anxiety.

    View details for Web of Science ID 000225842300017

    View details for PubMedID 15603746

  • A neurobiological approach to the cognitive deficits of psychiatric disorders. Dialogues in clinical neuroscience Etkin, A., Gyurak, A., O'Hara, R. 2013; 15 (4): 419-429

    Abstract

    Deficits in brain networks that support cognitive regulatory functions are prevalent in many psychiatric disorders. Findings across neuropsychology and neuroimaging point to broad-based impairments that cross traditional diagnostic boundaries. These dysfunctions are largely separate from the classical symptoms of the disorders, and manifest in regulatory problems in both traditional cognitive and emotional domains. As such, they relate to the capacity of patients to engage effectively in their daily lives and activity, often persist even in the face of symptomatically effective treatment, and are poorly targeted by current treatments. Advances in cognitive neuroscience now allow us to ground an understanding of these cognitive regulatory deficits in the function and interaction of key brain networks. This emerging neurobiological understanding furthermore points to several promising routes for novel neuroscience-informed treatments targeted more specifically at improving cognitive function in a range of psychiatric disorders.

    View details for PubMedID 24459409

  • Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder NEUROPSYCHOPHARMACOLOGY Chen, A. C., Etkin, A. 2013; 38 (10): 1889-1898

    Abstract

    Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), for example, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences amongst anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal default-mode network, while the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional MRI-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar versus different features of two major anxiety disorders, through a translational framework built on animal work and carefully-selected clinical disorders.Neuropsychopharmacology accepted article preview online, 15 May 2013; doi:10.1038/npp.2013.122.

    View details for DOI 10.1038/npp.2013.122

    View details for Web of Science ID 000323165500007

    View details for PubMedID 23673864

  • Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial TRIALS Grieve, S. M., Korgaonkar, M. S., Etkin, A., Harris, A., Koslow, S. H., Wisniewski, S., Schatzberg, A. F., Nemeroff, C. B., Gordon, E., Williams, L. M. 2013; 14
  • Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients MOLECULAR PAIN Tzabazis, A., Aparici, C. M., Rowbotham, M. C., Schneider, M. B., Etkin, A., Yeomans, D. C. 2013; 9
  • Using Standardized fMRI Protocols to Identify Patterns of Prefrontal Circuit Dysregulation that are Common and Specific to Cognitive and Emotional Tasks in Major Depressive Disorder: First Wave Results from the iSPOT-D Study NEUROPSYCHOPHARMACOLOGY Korgaonkar, M. S., Grieve, S. M., Etkin, A., Koslow, S. H., Williams, L. M. 2013; 38 (5): 863-871

    Abstract

    Functional neuroimaging studies have implicated dysregulation of prefrontal circuits in major depressive disorder (MDD), and these circuits are a viable target for predicting treatment outcomes. However, because of the heterogeneity of tasks and samples used in studies to date, it is unclear whether the central dysfunction is one of prefrontal hyperreactivity or hyporeactivity. We used a standardized battery of tasks and protocols for functional magnetic resonance imaging, to identify the common vs the specific prefrontal circuits engaged by these tasks in the same 30 outpatients with MDD compared with 30 matched, healthy control participants, recruited as part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Reflecting cognitive neuroscience theory and established evidence, the battery included cognitive tasks designed to assess functions of selective attention, sustained attention-working memory and response inhibition, and emotion tasks to assess explicit conscious and implicit nonconscious viewing of facial emotion. MDD participants were distinguished by a distinctive biosignature of: hypoactivation of the dorsolateral prefrontal cortex during working memory updating and during conscious negative emotion processing; hyperactivation of the dorsomedial prefrontal cortex during working memory and response inhibition cognitive tasks and hypoactivation of the dorsomedial prefrontal during conscious processing of positive emotion. These results show that the use of standardized tasks in the same participants provides a way to tease out prefrontal circuitry dysfunction related to cognitive and emotional functions, and not to methodological or sample variations. These findings provide the frame of reference for identifying prefrontal biomarker predictors of treatment outcomes in MDD.

    View details for DOI 10.1038/npp.2012.252

    View details for Web of Science ID 000316161300015

    View details for PubMedID 23303059

  • The neural correlates of emotion-based cognitive control in adults with early childhood behavioral inhibition BIOLOGICAL PSYCHOLOGY Jarcho, J. M., Fox, N. A., Pine, D. S., Etkin, A., Leibenluft, E., Shechner, T., Ernst, M. 2013; 92 (2): 306-314

    Abstract

    The present study is the first to assess whether the neural correlates of cognitive control processes differ in adults with and without a behaviorally inhibited temperament during early childhood. Adults with and without childhood behavioral inhibition completed an emotional conflict task while undergoing functional magnetic resonance imaging scanning. While no group differences in behavior were observed, adults with childhood behavioral inhibition, relative to adults without childhood behavioral inhibition, exhibited greater dorsomedial prefrontal cortex activity during conflict detection and greater putamen activity during conflict adaptation. Lifetime psychopathology predicted behavioral, but not brain-related, differences in conflict adaptation. These data suggest that the brain regions underlying cognitive control processes are differentially influenced by childhood behavioral inhibition, and may be differently related to psychopathology.

    View details for DOI 10.1016/j.biopsycho.2012.09.008

    View details for Web of Science ID 000315315700029

    View details for PubMedID 23046903

  • Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data AMERICAN JOURNAL OF PSYCHIATRY Hamilton, J. P., Etkin, A., Furman, D. J., Lemus, M. G., Johnson, R. F., Gotlib, I. H. 2012; 169 (7): 693-703

    Abstract

    Functional neuroimaging investigations of major depressive disorder can advance both the neural theory and treatment of this debilitating illness. Inconsistency of neuroimaging findings and the use of region-of-interest approaches have hindered the development of a comprehensive, empirically informed neural model of major depression. In this context, the authors sought to identify reliable anomalies in baseline neural activity and neural response to affective stimuli in major depressive disorder.The authors applied voxel-wise, whole-brain meta-analysis to neuroimaging investigations comparing depressed to healthy comparison groups with respect to baseline neural activity or neural response to positively and/or negatively valenced stimuli.Relative to healthy subjects, those with major depression had reliably higher baseline activity, bilaterally, in the pulvinar nucleus. The analysis of neural response studies using negative stimuli showed greater response in the amygdala, insula, and dorsal anterior cingulate cortex and lower response in the dorsal striatum and dorsolateral prefrontal cortex in individuals with major depressive disorder than in healthy subjects.The meta-analytic results support an elegant and neuroanatomically viable model of the salience of negative information in major depressive disorder. In this proposed model, high baseline pulvinar activity in depression first potentiates responding of the brain's salience network to negative information; next, and owing potentially to low striatal dopamine levels in depression, this viscerally charged information fails to propagate up the cortical-striatal-pallidalthalamic circuit to the dorsolateral prefrontal cortex for contextual processing and reappraisal.

    View details for DOI 10.1176/appi.ajp.2012.11071105

    View details for Web of Science ID 000305853400007

    View details for PubMedID 22535198

  • NEUROBIOLOGY OF ANXIETY: FROM NEURAL CIRCUITS TO NOVEL SOLUTIONS? DEPRESSION AND ANXIETY Etkin, A. 2012; 29 (5): 355-358

    View details for DOI 10.1002/da.21957

    View details for Web of Science ID 000303440700001

    View details for PubMedID 22553005

  • Emotional processing in anterior cingulate and medial prefrontal cortex TRENDS IN COGNITIVE SCIENCES Etkin, A., Egner, T., Kalisch, R. 2011; 15 (2): 85-93

    Abstract

    Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.

    View details for Web of Science ID 000287295500005

    View details for PubMedID 21167765

  • Explicit and implicit emotion regulation: A dual-process framework COGNITION & EMOTION Gyurak, A., Gross, J. J., Etkin, A. 2011; 25 (3): 400-412

    Abstract

    It is widely acknowledged that emotions can be regulated in an astonishing variety of ways. Most research to date has focused on explicit (effortful) forms of emotion regulation. However, there is growing research interest in implicit (automatic) forms of emotion regulation. To organise emerging findings, we present a dual-process framework that integrates explicit and implicit forms of emotion regulation, and argue that both forms of regulation are necessary for well-being. In the first section of this review, we provide a broad overview of the construct of emotion regulation, with an emphasis on explicit and implicit processes. In the second section, we focus on explicit emotion regulation, considering both neural mechanisms that are associated with these processes and their experiential and physiological consequences. In the third section, we turn to several forms of implicit emotion regulation, and integrate the burgeoning literature in this area. We conclude by outlining open questions and areas for future research.

    View details for DOI 10.1080/02699931.2010.544160

    View details for Web of Science ID 000288672700002

    View details for PubMedID 21432682

  • A meta-analysis of instructed fear studies: Implications for conscious appraisal of threat NEUROIMAGE Mechias, M., Etkin, A., Kalisch, R. 2010; 49 (2): 1760-1768

    Abstract

    In classical Pavlovian fear conditioning, a neutral stimulus (conditioned stimulus, CS) comes to be evaluated as threatening due to its association with an aversive stimulus (unconditioned stimulus, UCS), and elicits fear. In a subtype of fear conditioning paradigms, called instructed fear or anticipatory anxiety, subjects are made aware of the CS-UCS association prior to actually experiencing it. Initial fear elicitation during this type of conditioning results from the negative evaluation of the CS as a consequence of CS-UCS contingency awareness. Prior reports have suggested that this conscious appraisal process is mediated by a variety of brain regions, including rostral dorsomedial prefrontal/dorsal anterior cingulate cortex (dmPFC/dACC), lateral prefrontal cortex (lPFC), posterior cingulate, hippocampus/parahippocampus, and nucleus accumbens, but there is little overlap between results. We reasoned that a formal meta-analysis of existing instructed fear studies should help narrow down the search for conscious appraisal areas in fear conditioning to those consistently activated across studies. We found consistent activation in rostral dmPFC but not in the other candidate areas. These results allow for maintaining the theory that the rostral dmPFC is involved in conscious threat appraisal. We also report a meta-analysis of uninstructed (classical) fear conditioning studies in which we found notable activation in more posterior parts of the dmPFC/dACC that overlapped with some of the instructed fear activations. These data suggest that mid regions of the dmPFC/dACC are part of a "core" fear network that is activated irrespective of how fear was learnt.

    View details for DOI 10.1016/j.neuroimage.2009.09.040

    View details for Web of Science ID 000272808400059

    View details for PubMedID 19786103

  • Functional neuroanatomy of anxiety: a neural circuit perspective. Current topics in behavioral neurosciences Etkin, A. 2010; 2: 251-277

    Abstract

    Anxiety is a commonly experienced subjective state that can have both adaptive and maladaptive properties. Clinical disorders of anxiety are likewise also common, and range widely in their symptomatology and consequences for the individual. Cognitive neuroscience has provided an increasingly sophisticated understanding of the processes underlying normal human emotion, and its disruption or dysregulation in clinical anxiety disorders. In this chapter, I review functional neuroimaging studies of emotion in healthy and anxiety-disordered populations. A limbic-medial prefrontal circuit is emphasized and an information processing model is proposed for the processing of negative emotion. Data on negative emotion processing in a variety of anxiety disorders are presented and integrated within an understanding of the functions of elements within the limbic-medial prefrontal circuit. These data suggest that anxiety disorders may be usefully conceptualized as differentially affecting emotional reactivity and regulatory processes--functions that involve different neurobiological mechanisms. While the neural bases of several anxiety disorders are increasingly better understood, advances have lagged significantly behind in others. Nonetheless, the conceptual framework provided by convergent findings in studies of emotional processing in normative and anxiety-disordered populations promises to yield continued insights and nuances, and will likely provide useful information in the search for etiology and novel treatments.

    View details for PubMedID 21309113

  • Dissociable neural systems resolve conflict from emotional versus nonemotional distracters CEREBRAL CORTEX Egner, T., Etkin, A., Gale, S., Hirsch, J. 2008; 18 (6): 1475-1484

    Abstract

    The human brain protects the processing of task-relevant stimuli from interference ("conflict") by task-irrelevant stimuli via attentional biasing mechanisms. The lateral prefrontal cortex has been implicated in resolving conflict between competing stimuli by selectively enhancing task-relevant stimulus representations in sensory cortices. Conversely, recent data suggest that conflict from emotional distracters may be resolved by an alternative route, wherein the rostral anterior cingulate cortex inhibits amygdalar responsiveness to task-irrelevant emotional stimuli. Here we tested the proposal of 2 dissociable, distracter-specific conflict resolution mechanisms, by acquiring functional magnetic resonance imaging data during resolution of conflict from either nonemotional or emotional distracters. The results revealed 2 distinct circuits: a lateral prefrontal "cognitive control" system that resolved nonemotional conflict and was associated with enhanced processing of task-relevant stimuli in sensory cortices, and a rostral anterior cingulate "emotional control" system that resolved emotional conflict and was associated with decreased amygdalar responses to emotional distracters. By contrast, activations related to both emotional and nonemotional conflict monitoring were observed in a common region of the dorsal anterior cingulate. These data suggest that the neuroanatomical networks recruited to overcome conflict vary systematically with the nature of the conflict, but that they may share a common conflict-detection mechanism.

    View details for DOI 10.1093/cercor/bhm179

    View details for Web of Science ID 000255988200024

    View details for PubMedID 17940084

  • A role in learning for SRF: Deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context NEURON Etkin, A., ALARCON, J. M., Weisberg, S. P., Touzani, K., Huang, Y. Y., Nordheim, A., Kandel, E. R. 2006; 50 (1): 127-143

    Abstract

    Whereas significant insight exists as to how LTP-related changes can contribute to the formation of long-term memory, little is known about the role of hippocampal LTD-like changes in learning and memory storage. We describe a mouse lacking the transcription factor SRF in the adult forebrain. This mouse could not acquire a hippocampus-based immediate memory for a novel context even across a few minute timespan, which led to a profound but selective deficit in explicit spatial memory. These animals were also impaired in the induction of LTD, including LTD triggered by a cholinergic agonist. Moreover, genes regulating two processes essential for LTD-calcium release from intracellular stores and phosphatase activation-were abnormally expressed in knockouts. These findings suggest that for the hippocampus to form associative spatial memories through LTP-like processes, it must first undergo learning of the context per se through exploration and the learning of familiarity, which requires LTD-like processes.

    View details for DOI 10.1016/j.neuron.2006.03.013

    View details for Web of Science ID 000236811300016

    View details for PubMedID 16600861

  • Toward a neurobiology of psychotherapy: Basic science and clinical applications JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES Etkin, A., Phil, M., Pittenger, C., Polan, H. J., Kandel, E. R. 2005; 17 (2): 145-158

    Abstract

    Psychotherapy is used commonly to treat a variety of mental illnesses, yet surprisingly little is known about its biological mechanisms especially in comparison with pharmacotherapy. In this review we survey the current knowledge about changes in brain function following psychotherapeutic intervention that are detectable with current neuroimaging techniques. We also consider the possible role for neuroimaging in refining clinical diagnoses and predicting treatment outcome, which would benefit both clinical decision-making and the cognitive neuroscience of psychotherapy.

    View details for Web of Science ID 000229541000003

    View details for PubMedID 15939967

  • A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia CELL Si, K., Giustetto, M., Etkin, A., Hsu, R., Janisiewicz, A. M., Miniaci, M. C., Kim, J. H., Zhu, H. X., Kandel, E. R. 2003; 115 (7): 893-904

    Abstract

    Synapse-specific facilitation requires rapamycin-dependent local protein synthesis at the activated synapse. In Aplysia, rapamycin-dependent local protein synthesis serves two functions: (1) it provides a component of the mark at the activated synapse and thereby confers synapse specificity and (2) it stabilizes the synaptic growth associated with long-term facilitation. Here we report that a neuron-specific isoform of cytoplasmic polyadenylation element binding protein (CPEB) regulates this synaptic protein synthesis in an activity-dependent manner. Aplysia CPEB protein is upregulated locally at activated synapses, and it is needed not for the initiation but for the stable maintenance of long-term facilitation. We suggest that Aplysia CPEB is one of the stabilizing components of the synaptic mark.

    View details for Web of Science ID 000187664700012

    View details for PubMedID 14697206

  • Drugs and therapeutics in the age of the genome JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Etkin, A. 2000; 284 (21): 2786-2787

    View details for Web of Science ID 000165509500037

    View details for PubMedID 11105190

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