Amit Etkin, MD, PhD

All Publications

• Addressing the Causality Gap in Human Psychiatric Neuroscience JAMA PSYCHIATRY Etkin, A. 2018; 75 (1): 3–4

  View details for DOI 10.1001/jamapsychiatry.2017.3610

  View details for Web of Science ID 000419177700001

  View details for PubMedID 29167887

• PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation AMERICAN JOURNAL OF PSYCHIATRY Fonzo, G. A., Goodkind, M. S., Oathes, D. J., Zaiko, Y. V., Harvey, M., Peng, K. K., Weiss, M., Thompson, A. L., Zack, S. E., Lindley, S. E., Arnow, B. A., Jo, B., Gross, J. J., Rothbaum, B. O., Etkin, A. 2017; 174 (12): 1163–74

  View details for DOI 10.1176/appi.ajp.2017.16091072

  View details for Web of Science ID 000417355900010

• Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD AMERICAN JOURNAL OF PSYCHIATRY Fonzo, G. A., Goodkind, M. S., Oathes, D. J., Zaiko, Y. V., Harvey, M., Peng, K. K., Weiss, M., Thompson, A. L., Zack, S. E., Mills-Finnerty, C. E., Rosenberg, B. M., Edelstein, R., Wright, R. N., Kole, C. A., Lindley, S. E., Arnow, B. A., Jo, B., Gross, J. J., Rothbaum, B. O., Etkin, A. 2017; 174 (12): 1175–84

  View details for DOI 10.1176/appi.ajp.2017.16091073

  View details for Web of Science ID 000417355900011

• Identification of Common Neural Circuit Disruptions in Cognitive Control Across Psychiatric Disorders. American journal of psychiatry McTeague, L. M., Huemer, J., Carreon, D. M., Jiang, Y., Eickhoff, S. B., Etkin, A. 2017: appiajp201716040400-?

  Abstract

  Cognitive deficits are a common feature of psychiatric disorders. The authors investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis.A PubMed search was conducted for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with axis I disorders and matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates.The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with various disorders (schizophrenia, bipolar or unipolar depression, anxiety disorders, and substance use disorders). Transdiagnostically abnormal activation was evident in the left prefrontal cortex as well as the anterior insula, the right ventrolateral prefrontal cortex, the right intraparietal sulcus, and the midcingulate/presupplementary motor area. Disruption was also observed in a more anterior cluster in the dorsal cingulate cortex, which overlapped with a network of structural perturbation that the authors previously reported in a transdiagnostic meta-analysis of gray matter volume.These findings demonstrate a common pattern of disruption across major psychiatric disorders that parallels the "multiple-demand network" observed in intact cognition. This network interfaces with the anterior-cingulo-insular or "salience network" demonstrated to be transdiagnostically vulnerable to gray matter reduction. Thus, networks intrinsic to adaptive, flexible cognition are vulnerable to broad-spectrum psychopathology. Dysfunction in these networks may reflect an intermediate transdiagnostic phenotype, which could be leveraged to advance therapeutics.

  View details for DOI 10.1176/appi.ajp.2017.16040400

  View details for PubMedID 28320224

• The neural bases of emotion regulation NATURE REVIEWS NEUROSCIENCE Etkin, A., Buechel, C., Gross, J. J. 2015; 16 (11): 693-?

  View details for DOI 10.1038/nrn4044

  View details for Web of Science ID 000363273000010

• Identification of a Common Neurobiological Substrate for Mental Illness JAMA PSYCHIATRY Goodkind, M., Eickhoff, S. B., Oathes, D. J., Jiang, Y., Chang, A., Jones-Hagata, L. B., Ortega, B. N., Zaiko, Y. V., Roach, E. L., Korgaonkar, M. S., Grieve, S. M., Galatzer-Levy, I., Fox, P. T., Etkin, A. 2015; 72 (4): 305-315

  Abstract

  Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness.To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis.PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data.Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach.We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition.Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning.We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.

  View details for DOI 10.1001/jamapsychiatry.2014.2206

  View details for Web of Science ID 000352487000002

  View details for PubMedID 25651064

• 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

  View details for PubMedCentralID PMC3856839

• 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

• Interhemispheric cortico-cortical paired associative stimulation of the prefrontal cortex jointly modulates frontal asymmetry and emotional reactivity. Brain stimulation Zibman, S., Daniel, E., Alyagon, U., Etkin, A., Zangen, A. 2018

  Abstract

  BACKGROUND: As advances in neuroimaging further our understanding of the brain's functional connectivity, neuropsychology has moved away from a regional approach of attributing behavior to a specific region towards a network approach, attributing behavior to interconnected regions. A prime example of this is the suggested relevance of frontal asymmetry of the lateral prefrontal cortex (LPFC) in emotional processing. Yet, while neuroimaging defines relevant networks, it can only establish correlations and not causality.OBJECTIVE: We address this deficiency by applying cortico-cortical paired associative stimulation (ccPAS) to twenty-seven healthy, human participants (both genders represented equally). ccPAS involves TMS applied to two brain regions contemporaneously, changing the connectivity via Hebbian mechanisms.METHODS: We evaluate modifications in connectivity following ccPAS between the right and left LPFC that are dependent on the direction of ccPAS, i.e., which hemisphere is stimulated first. Participants performed an emotional reactivity task, assessed by measuring attentional bias, and brain activity was recorded with electroencephalogram (EEG) both at rest and in response to TMS pulses.RESULTS: We find that ccPAS modulates attentional bias bidirectionally depending on the order of stimulation. Furthermore, this modulation is accompanied by a change in frontal asymmetry. Measuring the direction of the information flow using TMS evoked potentials provides evidence that ccPAS strengthens inhibition from the hemisphere stimulated first to the hemisphere stimulated second.CONCLUSIONS: Our findings provide causal evidence for the role of frontal asymmetry in emotional processing and establish ccPAS combined with the EEG measures as a tool to causally characterize functionality of neuronal circuits.

  View details for DOI 10.1016/j.brs.2018.10.008

  View details for PubMedID 30392898

• Decoding mood. Nature biotechnology Etkin, A. 2018; 36 (10): 932–33

  View details for DOI 10.1038/nbt.4258

  View details for PubMedID 30307911

• Cognitive Flexibility Predicts PTSD Symptoms: Observational and Interventional Studies FRONTIERS IN PSYCHIATRY Ben-Zion, Z., Fine, N. B., Keynan, N., Admon, R., Green, N., Halevi, M., Fonzo, G. A., Achituv, M., Merin, O., Sharon, H., Halpern, P., Liberzon, I., Etkin, A., Hendler, T., Shalev, A. Y. 2018; 9

  View details for DOI 10.3389/fpsyt.2018.00477

  View details for Web of Science ID 000446343200001

• Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans A Randomized Clinical Trial JAMA PSYCHIATRY Yesavage, J. A., Fairchild, J., Mi, Z., Biswas, K., Davis-Karim, A., Phibbs, C. S., Forman, S. D., Thase, M., Williams, L. M., Etkin, A., O'Hara, R., Georgette, G., Beale, T., Huang, G. D., Noda, A., George, M. S., VA Cooperative Studies Program Stu 2018; 75 (9): 884–93

  Abstract

  Treatment-resistant major depression (TRMD) in veterans is a major clinical challenge given the high risk for suicidality in these patients. Repetitive transcranial magnetic stimulation (rTMS) offers the potential for a novel treatment modality for these veterans.To determine the efficacy of rTMS in the treatment of TRMD in veterans.A double-blind, sham-controlled randomized clinical trial was conducted from September 1, 2012, to December 31, 2016, in 9 Veterans Affairs medical centers. A total of 164 veterans with TRD participated.Participants were randomized to either left prefrontal rTMS treatment (10 Hz, 120% motor threshold, 4000 pulses/session) or to sham (control) rTMS treatment for up to 30 treatment sessions.The primary dependent measure of the intention-to-treat analysis was remission rate (Hamilton Rating Scale for Depression score ≤10, indicating that depression is in remission and not a clinically significant burden), and secondary analyses were conducted on other indices of posttraumatic stress disorder, depression, hopelessness, suicidality, and quality of life.The 164 participants had a mean (SD) age of 55.2 (12.4) years, 132 (80.5%) were men, and 126 (76.8%) were of white race. Of these, 81 were randomized to receive active rTMS and 83 to receive sham. For the primary analysis of remission, there was no significant effect of treatment (odds ratio, 1.16; 95% CI, 0.59-2.26; P = .67). At the end of the acute treatment phase, 33 of 81 (40.7%) of those in the active treatment group achieved remission of depressive symptoms compared with 31 of 83 (37.4%) of those in the sham treatment group. Overall, 64 of 164 (39.0%) of the participants achieved remission.A total of 39.0% of the veterans who participated in this trial experienced clinically significant improvement resulting in remission of depressive symptoms; however, there was no evidence of difference in remission rates between the active and sham treatments. These findings may reflect the importance of close clinical surveillance, rigorous monitoring of concomitant medication, and regular interaction with clinic staff in bringing about significant improvement in this treatment-resistant population.ClinicalTrials.gov Identifier: NCT01191333.

  View details for DOI 10.1001/jamapsychiatry.2018.1483

  View details for Web of Science ID 000443899300006

  View details for PubMedID 29955803

• Increased Attention Regulation from Emotion Regulation Therapy for Generalized Anxiety Disorder COGNITIVE THERAPY AND RESEARCH Renna, M. E., Seeley, S. H., Heimberg, R. G., Etkin, A., Fresco, D. M., Mennin, D. S. 2018; 42 (2): 121–34

  View details for DOI 10.1007/s10608-017-9872-7

  View details for Web of Science ID 000427590800002

• Evaluating web-based cognitive-affective remediation in recent trauma survivors: study rationale and protocol EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY Fine, N. B., Achituv, M., Etkin, A., Merin, O., Shalev, A. Y. 2018; 9 (1): 1442602

  Abstract

  Background: The immediate aftermath of traumatic events is a period of enhanced neural plasticity, following which some survivors remain with post-traumatic stress disorder (PTSD) whereas others recover. Evidence points to impairments in emotional reactivity, emotion regulation, and broader executive functions as critically contributing to PTSD. Emerging evidence further suggests that the neural mechanisms underlying these functions remain plastic in adulthood and that targeted retraining of these systems may enhance their efficiency and could reduce the likelihood of developing PTSD. Administering targeted neurocognitive training shortly after trauma exposure is a daunting challenge. This work describes a study design addressing that challenge. The study evaluated the direct effects of cognitive remediation training on neurocognitive mechanisms that hypothetically underlay PTSD, and the indirect effect of this intervention on emerging PTSD symptoms. Method: We describe a study rationale, design, and methodological choices involving: (a) participants' enrolment; (b) implementation and management of a daily self-administered, web-based intervention; (c) reliable, timely screening and assessment of treatment of eligible survivors; and (d) defining control conditions and outcome measures. We outline the rationale of choices made regarding study sample, timing of intervention, measurements, monitoring participants' adherence, and ways to harmonize and retain interviewers' fidelity and mitigate eventual burnout by repeated contacts with recently traumatized survivors. Conclusion: Early web-based interventions targeting causative mechanisms of PTSD can be informed by the model presented in this paper.

  View details for DOI 10.1080/20008198.2018.1442602

  View details for Web of Science ID 000427790600001

  View details for PubMedID 29535847

  View details for PubMedCentralID PMC5844026

• ARTIST: A fully automated artifact rejection algorithm for single-pulse TMS-EEG data. Human brain mapping Wu, W., Keller, C. J., Rogasch, N. C., Longwell, P., Shpigel, E., Rolle, C. E., Etkin, A. 2018

  Abstract

  Concurrent single-pulse TMS-EEG (spTMS-EEG) is an emerging noninvasive tool for probing causal brain dynamics in humans. However, in addition to the common artifacts in standard EEG data, spTMS-EEG data suffer from enormous stimulation-induced artifacts, posing significant challenges to the extraction of neural information. Typically, neural signals are analyzed after a manual time-intensive and often subjective process of artifact rejection. Here we describe a fully automated algorithm for spTMS-EEG artifact rejection. A key step of this algorithm is to decompose the spTMS-EEG data into statistically independent components (ICs), and then train a pattern classifier to automatically identify artifact components based on knowledge of the spatio-temporal profile of both neural and artefactual activities. The autocleaned and hand-cleaned data yield qualitatively similar group evoked potential waveforms. The algorithm achieves a 95% IC classification accuracy referenced to expert artifact rejection performance, and does so across a large number of spTMS-EEG data sets (n = 90 stimulation sites), retains high accuracy across stimulation sites/subjects/populations/montages, and outperforms current automated algorithms. Moreover, the algorithm was superior to the artifact rejection performance of relatively novice individuals, who would be the likely users of spTMS-EEG as the technique becomes more broadly disseminated. In summary, our algorithm provides an automated, fast, objective, and accurate method for cleaning spTMS-EEG data, which can increase the utility of TMS-EEG in both clinical and basic neuroscience settings.

  View details for DOI 10.1002/hbm.23938

  View details for PubMedID 29331054

• Affective neuroimaging in generalized anxiety disorder: an integrated review DIALOGUES IN CLINICAL NEUROSCIENCE Fonzo, G. A., Etkin, A. 2017; 19 (2): 169–79

  Abstract

  Affective neuroimaging has contributed to our knowledge of generalized anxiety disorder (GAD) through measurement of blood oxygenation level-dependent (BOLD) responses, which facilitate inference on neural responses to emotional stimuli during task-based functional magnetic resonance imaging (fMRI). In this article, the authors provide an integrated review of the task-based affective fMRI literature in GAD. Studies provide evidence for variable presence and directionality of BOLD abnormalities in limbic and prefrontal regions during reactivity to, regulation of, and learning from emotional cues. We conclude that understanding the sources of this variability is key to accelerating progress in this area. We propose that the cardinal symptom of GAD-worry-predominantly reflects stimulus-independent mental processes that impose abnormal, inflexible functional brain configurations, ie, the overall pattern of information transfer among behaviorally relevant neural circuits at a given point in time. These configurations that are inflexible to change from the incoming flux of environmental stimuli may underlie inconsistent task-based findings.

  View details for Web of Science ID 000418014300009

  View details for PubMedID 28867941

  View details for PubMedCentralID PMC5573561

• Erratum: Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nature medicine Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., Schatzberg, A. F., Sudheimer, K., Keller, J., Mayberg, H. S., Gunning, F. M., Alexopoulos, G. S., Fox, M. D., Pascual-Leone, A., Voss, H. U., Casey, B. J., Dubin, M. J., Liston, C. 2017; 23 (2): 264-?

  View details for DOI 10.1038/nm0217-264d

  View details for PubMedID 28170383

• Learning in Generalized Anxiety Disorder Benefits From Neither the Carrot Nor the Stick. American journal of psychiatry Etkin, A., Fonzo, G. A. 2017; 174 (2): 87-88

  View details for DOI 10.1176/appi.ajp.2016.16111267

  View details for PubMedID 28142268

• Resting-state connectivity biomarkers define neurophysiological subtypes of depression NATURE MEDICINE Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., Schatzberg, A. F., Sudheimer, K., Keller, J., Mayberg, H. S., Gunning, F. M., Alexopoulos, G. S., Fox, M. D., Pascual-Leone, A., Voss, H. U., Casey, B. J., Dubin, M. J., Liston, C. 2017; 23 (1): 28-38

  Abstract

  Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

  View details for DOI 10.1038/nm.4246

  View details for Web of Science ID 000391646800011

  View details for PubMedID 27918562

• Test-retest reliability of transcranial magnetic stimulation EEG evoked potentials. Brain stimulation Kerwin, L. J., Keller, C. J., Wu, W., Narayan, M., Etkin, A. 2017

  Abstract

  Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (TMS-EEG), offer a powerful tool for measuring causal interactions in the human brain. However, the test-retest reliability of TEPs, critical to their use in clinical biomarker and interventional studies, remains poorly understood.We quantified TEP reliability to: (i) determine the minimal TEP amplitude change which significantly exceeds that associated with simply re-testing, (ii) locate the most reliable scalp regions of interest (ROIs) and TEP peaks, and (iii) determine the minimal number of TEP pulses for achieving reliability.TEPs resulting from stimulation of the left dorsolateral prefrontal cortex were collected on two separate days in sixteen healthy participants. TEP peak amplitudes were compared between alternating trials, split-halves of the same run, two runs five minutes apart and two runs on separate days. Reliability was quantified using concordance correlation coefficient (CCC) and smallest detectable change (SDC).Substantial concordance was achieved in prefrontal electrodes at 40 and 60 ms, centroparietal and left parietal ROIs at 100 ms, and central electrodes at 200 ms. Minimum SDC was found in the same regions and peaks, particularly for the peaks at 100 and 200 ms. CCC, but not SDC, reached optimal values by 60-100 pulses per run with saturation beyond this number, while SDC continued to improve with increased pulse numbers.TEPs were robust and reliable, requiring a relatively small number of trials to achieve stability, and are thus well suited as outcomes in clinical biomarker or interventional studies.

  View details for DOI 10.1016/j.brs.2017.12.010

  View details for PubMedID 29342443

• Test-retest reliability of transcranial magnetic stimulation EEG evoked potentials Brain Stimulation Kerwin, L. J., Keller, C., Wu, W., Narayan, M., Etkin, A. 2017

  Abstract

  Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (TMS-EEG), offer a powerful tool for measuring causal interactions in the human brain. However, the test-retest reliability of TEPs, critical to their use in clinical biomarker and interventional studies, remains poorly understood.We quantified TEP reliability to: (i) determine the minimal TEP amplitude change which significantly exceeds that associated with simply re-testing, (ii) locate the most reliable scalp regions of interest (ROIs) and TEP peaks, and (iii) determine the minimal number of TEP pulses for achieving reliability.TEPs resulting from stimulation of the left dorsolateral prefrontal cortex were collected on two separate days in sixteen healthy participants. TEP peak amplitudes were compared between alternating trials, split-halves of the same run, two runs five minutes apart and two runs on separate days. Reliability was quantified using concordance correlation coefficient (CCC) and smallest detectable change (SDC).Substantial concordance was achieved in prefrontal electrodes at 40 and 60 ms, centroparietal and left parietal ROIs at 100 ms, and central electrodes at 200 ms. Minimum SDC was found in the same regions and peaks, particularly for the peaks at 100 and 200 ms. CCC, but not SDC, reached optimal values by 60-100 pulses per run with saturation beyond this number, while SDC continued to improve with increased pulse numbers.TEPs were robust and reliable, requiring a relatively small number of trials to achieve stability, and are thus well suited as outcomes in clinical biomarker or interventional studies.

  View details for DOI 10.1016/j.brs.2017.12.010

• Major depressive disorder NATURE REVIEWS DISEASE PRIMERS Otte, C., Gold, S. M., Penninx, B. W., Pariante, C. M., Etkin, A., Fava, M., Mohr, D. C., Schatzberg, A. F. 2016; 2

  Abstract

  Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

  View details for DOI 10.1038/nrdp.2016.65

  View details for Web of Science ID 000384877200001

  View details for PubMedID 27629598

• Limbic Activity Modulation Guided by Functional Magnetic Resonance Imaging-Inspired Electroencephalography Improves Implicit Emotion Regulation BIOLOGICAL PSYCHIATRY Keynan, J. N., Meir-Hasson, Y., Gilam, G., Cohen, A., Jackont, G., Kinreich, S., Ikar, L., Or-Borichev, A., Etkin, A., Gyurak, A., Klovatch, I., Intrator, N., Hendler, T. 2016; 80 (6): 490-496

  Abstract

  The amygdala has a pivotal role in processing traumatic stress; hence, gaining control over its activity could facilitate adaptive mechanism and recovery. To date, amygdala volitional regulation could be obtained only via real-time functional magnetic resonance imaging (fMRI), a highly inaccessible procedure. The current article presents high-impact neurobehavioral implications of a novel imaging approach that enables bedside monitoring of amygdala activity using fMRI-inspired electroencephalography (EEG), hereafter termed amygdala-electrical fingerprint (amyg-EFP). Simultaneous EEG/fMRI indicated that the amyg-EFP reliably predicts amygdala-blood oxygen level-dependent activity. Implementing the amyg-EFP in neurofeedback demonstrated that learned downregulation of the amyg-EFP facilitated volitional downregulation of amygdala-blood oxygen level-dependent activity via real-time fMRI and manifested as reduced amygdala reactivity to visual stimuli. Behavioral evidence further emphasized the therapeutic potential of this approach by showing improved implicit emotion regulation following amyg-EFP neurofeedback. Additional EFP models denoting different brain regions could provide a library of localized activity for low-cost and highly accessible brain-based diagnosis and treatment.

  View details for DOI 10.1016/j.biopsych.2015.12.024

  View details for Web of Science ID 000382260500015

  View details for PubMedID 26996601

• Perturbed connectivity of the amygdala and its subregions with the central executive and default mode networks in chronic pain. Pain Jiang, Y., Oathes, D., Hush, J., Darnall, B., Charvat, M., Mackey, S., Etkin, A. 2016; 157 (9): 1970-1978

  Abstract

  Maladaptive responses to pain-related distress, such as pain catastrophizing, amplify the impairments associated with chronic pain. Many of these aspects of chronic pain are similar to affective distress in clinical anxiety disorders. In light of the role of the amygdala in pain and affective distress, disruption of amygdalar functional connectivity in anxiety states, and its implication in the response to noxious stimuli, we investigated amygdala functional connectivity in 17 patients with chronic low back pain and 17 healthy comparison subjects, with respect to normal targets of amygdala subregions (basolateral vs centromedial nuclei), and connectivity to large-scale cognitive-emotional networks, including the default mode network, central executive network, and salience network. We found that patients with chronic pain had exaggerated and abnormal amygdala connectivity with central executive network, which was most exaggerated in patients with the greatest pain catastrophizing. We also found that the normally basolateral-predominant amygdala connectivity to the default mode network was blunted in patients with chronic pain. Our results therefore highlight the importance of the amygdala and its network-level interaction with large-scale cognitive/affective cortical networks in chronic pain, and help link the neurobiological mechanisms of cognitive theories for pain with other clinical states of affective distress.

  View details for DOI 10.1097/j.pain.0000000000000606

  View details for PubMedID 27168362

• Transdiagnostic impairment of cognitive control in mental illness. Journal of psychiatric research McTeague, L. M., Goodkind, M. S., Etkin, A. 2016; 83: 37-46

  Abstract

  Intact cognitive control or executive function has characteristic patterns in both behavior and functional neurocircuitry. Functional neuroimaging studies have shown that a frontal-cingulate-parietal-insular (i.e., "multiple demand") network forms a common functional substrate undergirding successful adaptation to diverse cognitive processing demands. Separate work on intact neurocognitive performance implicates a higher order factor that largely explains performance across domains and may reflect trait cognitive control capacity. In the current review we highlight findings from respective psychiatric disorders (i.e., psychotic, bipolar and unipolar depressive, anxiety, and substance use disorders) suggesting that cognitive control perturbations amidst psychopathology are most pronounced within these common brain and behavioral indices of adaptive cognitive functioning and moreover, are evident across disorders (i.e., transdiagnostically). Specifically, within each of the disorder classes impairments are consistent in the multiple demand network across a wide range of cognitive tasks. While severity varies between disorders, broad as opposed to domain-specific impairments consistently emerge in neurocognitive performance. Accumulating findings have revealed that phenotypically diverse psychiatric disorders share a common factor or vulnerability to dysfunction that is in turn related to broad neurocognitive deficits. Furthermore, we have observed that regions of the multiple demand network, which overlap with the salience network (dorsal anterior cingulate and bilateral anterior insula) are characterized by reduced gray matter transdiagnostically and predict weaker neurocognitive performance. In summary, transdiagnostic (as opposed to disorder-specific) patterns of symptomatic distress and neurocognitive performance deficits, concurrent with parallel anomalies of brain structure and function may largely contribute to the real-world socio-occupational impairment common across disorders.

  View details for DOI 10.1016/j.jpsychires.2016.08.001

  View details for PubMedID 27552532

• Emotion regulation involves both model-based and model-free processes. Nature reviews. Neuroscience Etkin, A., Büchel, C., Gross, J. J. 2016; 17 (8): 532-?

  View details for DOI 10.1038/nrn.2016.79

  View details for PubMedID 27277866

• Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study LANCET PSYCHIATRY Shilyansky, C., Williams, L. M., Gyurak, A., Harris, A., Usherwood, T., Etkin, A. 2016; 3 (5): 425-435

  Abstract

  Antidepressant treatment failure is a common problem worldwide. In this study, we assess whether or not an important aspect of depression, cognitive impairment, is untreated by antidepressants by studying the effect of acute antidepressant treatment on a range of cognitive domains.In this randomised longitudinal study, which is part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D) trial, we assessed the effects of acute antidepressant treatment in a large patient population, across clinical remission outcomes, on a range of cognitive domains: attention, response inhibition, executive function during visuospatial navigation, cognitive flexibility, verbal memory, working memory, decision speed, information processing speed, and psychomotor response speed. We enrolled patients from primary or specialty care clinics in a multicentre, international, open-label, randomised, prospective trial. Eligible patients (aged 18-65 years) were previously untreated or were willing to undergo a 1-week medication washout before the study start, and could not have had inadequate response to study medications in the past. We enrolled a large population of medication-free (ie, untreated) outpatients in a depressive episode and assessed them for cognitive function at enrolment (pre-treatment), and again after 8 weeks of treatment with one of three antidepressant drugs (escitalopram, sertraline, or venlafaxine extended-release). Patients were randomly assigned (1:1:1) to one of the three antidepressants using a blocked randomisation procedure (block size of 12). As a comparison group, we also simultaneously enrolled matched healthy participants. Healthy participants received no medication or intervention, but were assessed for change in cognitive and clinical measures during the same interval and testing protocol. Therefore, this group acts as a test-retest control for the primary outcome measure examined in this study, change in cognitive measures over 8 weeks of treatment in depressed patients. This study is registered with ClinicalTrials.gov, number NCT00693849.Between Dec 8, 2008, and Sept 30, 2011, we enrolled 1008 eligible people into the study. Impairment in five domains-attention, response inhibition, verbal memory, decision speed, and information processing-showed no relative improvement with acute treatment (controlling for time or repeated testing), irrespective of antidepressant treatment group, even in patients whose depression remitted acutely according to clinical measures. Broader cognitive impairment was associated with greater illness chronicity (earlier illness onset) but not with symptom severity or previous antidepressant failures.Depression is associated with impairments in higher-order cognitive functions and information processing, which persist independently of clinical symptom change with treatment. We recorded no difference between the three antidepressants tested, with none showing efficacy for these impairments. Although the 8-week treatment period limits interpretation to acute treatment effects, it does highlight cognitive impairment as an untargeted contributor to incomplete treatment success.Brain Resource Company Operations Pty Ltd and NIH.

  View details for DOI 10.1016/S2215-0366(16)00012-2

  View details for Web of Science ID 000376262300024

  View details for PubMedID 26995298

• Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project BMC PSYCHIATRY Williams, L. M., Goldstein-Piekarski, A. N., Chowdhry, N., Grisanzio, K. A., Haug, N. A., Samara, Z., Etkin, A., O'Hara, R., Schatzberg, A. F., Suppes, T., Yesavage, J. 2016; 16

  Abstract

  Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time.Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing.This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward.ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.

  View details for DOI 10.1186/s12888-016-0771-3

  View details for Web of Science ID 000372738400001

  View details for PubMedCentralID PMC4793523

• Going Beyond Finding the "Lesion": A Path for Maturation of Neuroimaging. American journal of psychiatry Eickhoff, S. B., Etkin, A. 2016; 173 (3): 302-303

  View details for DOI 10.1176/appi.ajp.2015.15101350

  View details for PubMedID 26926133

• History of childhood maltreatment augments dorsolateral prefrontal processing of emotional valence in PTSD. Journal of psychiatric research Fonzo, G. A., Huemer, J., Etkin, A. 2016; 74: 45-54

  Abstract

  Posttraumatic stress disorder (PTSD) is characterized by conflicting findings of both increased and decreased amygdala and prefrontal reactivity to threat or trauma stimuli. Childhood maltreatment (CM), a potent risk factor for PTSD, exerts long-lasting influences on threat processing and prefrontal-amygdala function. This suggests that CM history may influence PTSD neural phenotypes related to threat processing. Here, we adapt a well-characterized emotional conflict paradigm to investigate CM effects on both emotional conflict and emotional valence processing within PTSD stratified by task relevance. Forty-two individuals with PTSD (22 reporting extensive CM history (PTSD-CM)) and 20 trauma-exposed healthy controls (TEHCs) underwent functional magnetic resonance imaging while identifying affect of emotional faces (fear and happy) overlaid with a goal-irrelevant emotional distractor word ("FEAR" or "HAPPY"). We examined effects of CM on conflict, conflict adaptation, valence-related activation (fear vs. happy) for goal-relevant (face) and goal-irrelevant stimuli (word), and valence effects in interaction with goal-relevancy (face vs. word). Though no activation differences between groups were observed for conflict contrasts nor for valence effects in the amygdala, CM status interacted with valence processing differences as a function of goal relevance in the left dorsolateral prefrontal cortex (dlPFC). Here, PTSD-CM displayed greater activation relative to PTSD to negative valence when stimuli were goal-irrelevant. CM history also moderated relationships between activation abnormalities and PTSD re-experiencing symptoms. These findings provide initial evidence that CM history augments dorsolateral prefrontal bias to implicitly processed stimulus valence in PTSD.

  View details for DOI 10.1016/j.jpsychires.2015.12.015

  View details for PubMedID 26741277

• Frontoparietal Activation During Response Inhibition Predicts Remission to Antidepressants in Patients With Major Depression BIOLOGICAL PSYCHIATRY Gyurak, A., Patenaude, B., Korgaonkar, M. S., Grieve, S. M., Williams, L. M., Etkin, A. 2016; 79 (4): 274-281

  View details for DOI 10.1016/j.biopsych.2015.02.037

  View details for Web of Science ID 000368102300006

• NEURAL CIRCUITS Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior SCIENCE Ferenczi, E. A., Zalocusky, K. A., Liston, C., Grosenick, L., Warden, M. R., Amatya, D., Katovich, K., Mehta, H., Patenaude, B., Ramakrishnan, C., Kalanithi, P., Etkin, A., Knutson, B., Glover, G. H., Deisseroth, K. 2016; 351 (6268): 41-U59

  View details for DOI 10.1126/science.aac9698

  View details for Web of Science ID 000367364200035

• EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study CLINICAL NEUROPHYSIOLOGY Arns, M., Bruder, G., Hegerl, U., Spooner, C., Palmer, D. M., Etkin, A., Fallahpour, K., Gatt, J. M., Hirshberg, L., Gordon, E. 2016; 127 (1): 509-519

  View details for DOI 10.1016/j.clinph.2015.05.032

  View details for Web of Science ID 000367540800061

• Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science Ferenczi, E. A., Zalocusky, K. A., Liston, C., Grosenick, L., Warden, M. R., Amatya, D., Katovich, K., Mehta, H., Patenaude, B., Ramakrishnan, C., Kalanithi, P., Etkin, A., Knutson, B., Glover, G. H., Deisseroth, K. 2016; 351 (6268)

  Abstract

  Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

  View details for DOI 10.1126/science.aac9698

  View details for PubMedID 26722001

  View details for PubMedCentralID PMC4772156

• Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project. BMC psychiatry Williams, L. M., Goldstein-Piekarski, A. N., Chowdhry, N., Grisanzio, K. A., Haug, N. A., Samara, Z., Etkin, A., O'Hara, R., Schatzberg, A. F., Suppes, T., Yesavage, J. 2016; 16 (1): 68-?

  Abstract

  Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time.Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing.This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward.ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.

  View details for DOI 10.1186/s12888-016-0771-3

  View details for PubMedID 26980207

• Amygdala responses to salient social cues vary with oxytocin receptor genotype in youth NEUROPSYCHOLOGIA Marusak, H. A., Furman, D. J., Kuruvadi, N., Shattuck, D. W., Joshi, S. H., Joshi, A. A., Etkin, A., Thomason, M. E. 2015; 79: 1-9

  View details for DOI 10.1016/j.neuropsychologia.2015.10.015

  View details for Web of Science ID 000366879300001

  View details for PubMedID 26477647

• The neural bases of emotion regulation. Nature reviews. Neuroscience Etkin, A., Büchel, C., Gross, J. J. 2015; 16 (11): 693-700

  Abstract

  Emotions are powerful determinants of behaviour, thought and experience, and they may be regulated in various ways. Neuroimaging studies have implicated several brain regions in emotion regulation, including the ventral anterior cingulate and ventromedial prefrontal cortices, as well as the lateral prefrontal and parietal cortices. Drawing on computational approaches to value-based decision-making and reinforcement learning, we propose a unifying conceptual framework for understanding the neural bases of diverse forms of emotion regulation.

  View details for DOI 10.1038/nrn4044

  View details for PubMedID 26481098

• The effects of age, sex, and hormones on emotional conflict-related brain response during adolescence. Brain and cognition Cservenka, A., Stroup, M. L., Etkin, A., Nagel, B. J. 2015; 99: 135-150

  Abstract

  While cognitive and emotional systems both undergo development during adolescence, few studies have explored top-down inhibitory control brain activity in the context of affective processing, critical to informing adolescent psychopathology. In this study, we used functional magnetic resonance imaging to examine brain response during an Emotional Conflict (EmC) Task across 10-15-year-old youth. During the EmC Task, participants indicated the emotion of facial expressions, while disregarding emotion-congruent and incongruent words printed across the faces. We examined the relationships of age, sex, and gonadal hormones with brain activity on Incongruent vs. Congruent trials. Age was negatively associated with middle frontal gyrus activity, controlling for performance and movement confounds. Sex differences were present in occipital and parietal cortices, and were driven by activation in females, and deactivation in males to Congruent trials. Testosterone was negatively related with frontal and striatal brain response in males, and cerebellar and precuneus response in females. Estradiol was negatively related with fronto-cerebellar, cingulate, and precuneus brain activity in males, and positively related with occipital response in females. To our knowledge, this is the first study reporting the effects of age, sex, and sex steroids during an emotion-cognition task in adolescents. Further research is needed to examine longitudinal development of emotion-cognition interactions and deviations in psychiatric disorders in adolescence.

  View details for DOI 10.1016/j.bandc.2015.06.002

  View details for PubMedID 26175008

• Associations Between Childhood Abuse, Posttraumatic Stress Disorder, and Implicit Emotion Regulation Deficits: Evidence From a Low-Income, Inner-City Population PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES Powers, A., Etkin, A., Gyurak, A., Bradley, B., Jovanovic, T. 2015; 78 (3): 251-264

  View details for DOI 10.1080/00332747.2015.1069656

  View details for Web of Science ID 000363596900010

  View details for PubMedID 26391833

• Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial NEUROPSYCHOPHARMACOLOGY Williams, L. M., Korgaonkar, M. S., Song, Y. C., Paton, R., Eagles, S., Goldstein-Piekarski, A., Grieve, S. M., Harris, A. W., Usherwood, T., Etkin, A. 2015; 40 (10): 2398-2408

  Abstract

  Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.Neuropsychopharmacology advance online publication, 29 April 2015; doi:10.1038/npp.2015.89.

  View details for DOI 10.1038/npp.2015.89

  View details for Web of Science ID 000359493700012

  View details for PubMedID 25824424

• Does implicit emotion regulation in binge eating disorder matter? Eating behaviors Robinson, A., Safer, D. L., Austin, J. L., Etkin, A. 2015; 18: 186-191

  Abstract

  To examine if implicit emotion regulation (occurring outside of awareness) is related to binge eating disorder (BED) symptomatology and explicit emotion regulation (occurring within awareness), and can be altered via intervention.Implicit emotion regulation was assessed via the Emotion Conflict Task (ECT) among a group of adults with BED. Study 1 correlated BED symptomatology and explicit emotion regulation with ECT performance at baseline (BL) and after receiving BED treatment (PT). Study 2 generated effect sizes comparing ECT performance at BL and PT with healthy (non-eating disordered) controls (HC).Study 1 yielded significant correlations (p<.05) between both BED symptomatology and explicit emotion regulation with ECT performance. Study 2 found that compared to BL ECT performance, PT shifted (d=-.27), closer to HC. Preliminary results suggest a) BED symptomatology and explicit emotion regulation are associated with ECT performance, and b) PT ECT performance normalized after BED treatment.Implicit emotion regulation may be a BED treatment mechanism because psychotherapy, directly or indirectly, decreased sensitivity to implicit emotional conflict. Further understanding implicit emotion regulation may refine conceptualizations and effective BED treatments.

  View details for DOI 10.1016/j.eatbeh.2015.05.011

  View details for PubMedID 26117164

• Predicting treatment response in posttraumatic stress disorder. journal of clinical psychiatry Etkin, A. 2015; 76 (8): e1035-6

  View details for DOI 10.4088/JCP.14com09752

  View details for PubMedID 26335090

• Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Arnow, B. A., Blasey, C., Williams, L. M., Palmer, D. M., Rekshan, W., Schatzberg, A. F., Etkin, A., Kulkarni, J., Luther, J. F., Rush, A. J. 2015; 172 (8): 743-750

  Abstract

  The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications.Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report).Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect.There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.

  View details for DOI 10.1176/appi.ajp.2015.14020181

  View details for Web of Science ID 000359274700014

  View details for PubMedID 25815419

• COGNITION-CHILDHOOD MALTREATMENT INTERACTIONS IN THE PREDICTION OF ANTIDEPRESSANT OUTCOMES IN MAJOR DEPRESSIVE DISORDER PATIENTS: RESULTS FROM THE iSPOT-D TRIAL DEPRESSION AND ANXIETY Miller, S., McTeague, L. M., Gyurak, A., Patenaude, B., Williams, L. M., Grieve, S. M., Korgaonkar, M. S., Etkin, A. 2015; 32 (8): 594-604

  Abstract

  Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients.Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes.Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment.The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes.

  View details for DOI 10.1002/da.22368

  View details for Web of Science ID 000358621900006

• Frontal and rostral anterior cingulate (rACC) theta EEG in depression: Implications for treatment outcome? EUROPEAN NEUROPSYCHOPHARMACOLOGY Arns, M., Etkin, A., Hegerl, U., Williams, L. M., DeBattista, C., Palmer, D. M., Fitzgerald, P. B., Harris, A., deBeuss, R., Gordon, E. 2015; 25 (8): 1190-1200

  Abstract

  In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.

  View details for DOI 10.1016/j.euroneuro.2015.03.007

  View details for Web of Science ID 000359875500014

  View details for PubMedID 25936227

• ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Schatzberg, A. F., DeBattista, C., Lazzeroni, L. C., Etkin, A., Murphy, G. M., Williams, L. M. 2015; 172 (8): 751-759

  Abstract

  The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

  View details for DOI 10.1176/appi.ajp.2015.14050680

  View details for Web of Science ID 000359274700015

  View details for PubMedID 25815420

• Optogenetics and the circuit dynamics of psychiatric disease. JAMA Deisseroth, K., Etkin, A., Malenka, R. C. 2015; 313 (20): 2019-2020

  View details for DOI 10.1001/jama.2015.2544

  View details for PubMedID 25974025

• Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report JOURNAL OF AFFECTIVE DISORDERS Day, C. V., Gatt, J. M., Etkin, A., DeBattista, C., Schatzberg, A. F., Williams, L. M. 2015; 176: 141-150

  Abstract

  Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception.MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history.Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity.Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task.Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior.

  View details for DOI 10.1016/j.jad.2015.01.061

  View details for Web of Science ID 000350975500019

  View details for PubMedID 25710095

• A Cognitive-Emotional Biomarker for Predicting Remission with Antidepressant Medications: A Report from the iSPOT-D Trial NEUROPSYCHOPHARMACOLOGY Etkin, A., Patenaude, B., Song, Y. J., Usherwood, T., Rekshan, W., Schatzberg, A. F., Rush, A. J., Williams, L. M. 2015; 40 (6): 1332-1342

  Abstract

  Depression involves impairments in a range of cognitive and emotional capacities. It is unknown whether these functions can inform medication choice when considered as a composite predictive biomarker. We tested whether behavioral tests, grounded in the neurobiology of cognitive and emotional functions, predict outcome with common antidepressants. Medication-free outpatients with nonpsychotic major depressive disorder (N=1008; 665 completers) were assessed before treatment using 13 computerized tests of psychomotor, executive, memory-attention, processing speed, inhibitory, and emotional functions. Matched healthy controls (N=336) provided a normative reference sample for test performance. Depressed participants were then randomized to escitalopram, sertraline, or venlafaxine-extended release, and were assessed using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) and the 17-item Hamilton Rating Scale for Depression. Given the heterogeneity of depression, analyses were furthermore stratified by pretreatment performance. We then used pattern classification with cross-validation to determine individual patient-level composite predictive biomarkers of antidepressant outcome based on test performance. A subgroup of depressed participants (approximately one-quarter of patients) were found to be impaired across most cognitive tests relative to the healthy norm, from which they could be discriminated with 91% accuracy. These patients with generally impaired cognitive task performance had poorer treatment outcomes. For this impaired subgroup, task performance furthermore predicted remission on the QIDS-SR16 at 72% accuracy specifically following treatment with escitalopram but not the other medications. Therefore, tests of cognitive and emotional functions can form a clinically meaningful composite biomarker that may help drive general treatment outcome prediction for optimal treatment selection in depression, particularly for escitalopram.

  View details for DOI 10.1038/npp.2014.333

  View details for Web of Science ID 000352968100004

  View details for PubMedID 25547711

  View details for PubMedCentralID PMC4397406

• Attitudes Toward Neuroscience Education in Psychiatry: a National Multi-stakeholder Survey ACADEMIC PSYCHIATRY Fung, L. K., Akil, M., Widge, A., Roberts, L. W., Etkin, A. 2015; 39 (2): 139-146

  Abstract

  The objective of this study is to assess the attitudes of chairs of psychiatry departments, psychiatrists, and psychiatry trainees toward neuroscience education in residency programs and beyond in order to inform future neuroscience education approaches.This multi-stakeholder survey captured data on demographics, self-assessments of neuroscience knowledge, attitudes toward neuroscience education, preferences in learning modalities, and interests in specific neuroscience topics. In 2012, the authors distributed the surveys: by paper to 133 US psychiatry department chairs and electronically through the American Psychiatric Association to 3,563 of its members (1,000 psychiatrists and 2,563 trainees).The response rates for the chair, psychiatrist, and trainee surveys were 53, 9, and 18 %, respectively. A large majority of respondents agreed with the need for more neuroscience education in general and with respect to their own training. Most respondents believed that neuroscience will help destigmatize mental illness and begin producing new treatments or personalized medicines in 5-10 years. Only a small proportion of trainees and psychiatrists, however, reported a strong knowledge base in neuroscience. Respondents also reported broad enthusiasm for transdiagnostic topics in neuroscience (such as emotion regulation and attention/cognition) and description at the level of neural circuits.This study demonstrates the opportunity and enthusiasm for teaching more neuroscience in psychiatry among a broad range of stakeholder groups. A high level of interest was also found for transdiagnostic topics and approaches. We suggest that a transdiagnostic framework may be an effective way to deliver neuroscience education to the psychiatric community and illustrate this through a case example, drawing the similarity between this neuroscience approach and problem-based formulations familiar to clinicians.

  View details for DOI 10.1007/s40596-014-0183-y

  View details for Web of Science ID 000351433800003

  View details for PubMedID 25001432

• Childhood Trauma Exposure Disrupts the Automatic Regulation of Emotional Processing NEUROPSYCHOPHARMACOLOGY Marusak, H. A., Martin, K. R., Etkin, A., Thomason, M. E. 2015; 40 (5): 1250-1258

  Abstract

  Early-life trauma is one of the strongest risk factors for later emotional psychopathology. Although research in adults highlights that childhood trauma predicts deficits in emotion regulation that persist decades later, it is unknown whether neural and behavioral changes that may precipitate illness are evident during formative, developmental years. This study examined whether automatic regulation of emotional conflict is perturbed in a high-risk urban sample of trauma-exposed children and adolescents. A total of 14 trauma-exposed and 16 age-, sex-, and IQ-matched comparison youth underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring an overlying emotion word. Engagement of the conflict regulation system was evaluated at neural and behavioral levels. Results showed that trauma-exposed youth failed to dampen dorsolateral prefrontal cortex activity and engage amygdala-pregenual cingulate inhibitory circuitry during the regulation of emotional conflict, and were less able to regulate emotional conflict. In addition, trauma-exposed youth showed greater conflict-related amygdala reactivity that was associated with diminished levels of trait reward sensitivity. These data point to a trauma-related deficit in automatic regulation of emotional processing, and increase in sensitivity to emotional conflict in neural systems implicated in threat detection. Aberrant amygdala response to emotional conflict was related to diminished reward sensitivity that is emerging as a critical stress-susceptibility trait that may contribute to the emergence of mental illness during adolescence. These results suggest that deficits in conflict regulation for emotional material may underlie heightened risk for psychopathology in individuals that endure early-life trauma.

  View details for DOI 10.1038/npp.2014.311

  View details for Web of Science ID 000351022900021

  View details for PubMedID 25413183

• Neurobiological signatures of anxiety and depression in resting-state functional magnetic resonance imaging. Biological psychiatry Oathes, D. J., Patenaude, B., Schatzberg, A. F., Etkin, A. 2015; 77 (4): 385-393

  Abstract

  There is increasing interest in using neurobiological measures to inform psychiatric nosology. It is unclear at the present time whether anxiety and depression are neurobiologically distinct or similar processes. It is also unknown if the best way to examine these disorders neurobiologically is by contrasting categorical definitions or by examining symptom dimensions.A cross-sectional neuroimaging study was conducted of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), comorbid GAD and MDD (GAD/MDD), or neither GAD nor MDD (control subjects). There were 90 participants, all medication-free (17 GAD, 12 MDD, 23 GAD/MDD, and 38 control subjects). Diagnosis/category and dimensions/symptoms were assessed to determine the best fit for neurobiological data. Symptoms included general distress, common to anxiety and depression, and anxiety-specific (anxious arousal) or depression-specific (anhedonia) symptoms. Low-frequency (.008-.1 Hz) signal amplitude and functional connectivity analyses of resting-state functional magnetic resonance imaging data focused on a priori cortical and subcortical regions of interest.Support was found for effects of diagnosis above and beyond effects related to symptom levels as well as for effects of symptom levels above and beyond effects of diagnostic categories. The specific dimensional factors of general distress and anxious arousal as well as a diagnosis of MDD explained unique proportions of variance in signal amplitude or functional connectivity.Using resting-state functional magnetic resonance imaging, our data show that a single conceptual model alone (i.e., categorical diagnoses or symptom dimensions) provides an incomplete mapping of psychopathology to neurobiology. Instead, the data support an additive model that best captures abnormal neural patterns in patients with anxiety and depression.

  View details for DOI 10.1016/j.biopsych.2014.08.006

  View details for PubMedID 25444162

  View details for PubMedCentralID PMC4297561

• The International Study to Predict Optimized Treatment in Depression (iSPOT-D): Outcomes from the acute phase of antidepressant treatment. Journal of psychiatric research Saveanu, R., Etkin, A., Duchemin, A., Goldstein-Piekarski, A., Gyurak, A., DeBattista, C., Schatzberg, A. F., Sood, S., Day, C. V., Palmer, D. M., Rekshan, W. R., Gordon, E., Rush, A. J., Williams, L. M. 2015; 61: 1-12

  Abstract

  We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.

  View details for DOI 10.1016/j.jpsychires.2014.12.018

  View details for PubMedID 25586212

• Identifying predictors, moderators, and mediators of antidepressant response in major depressive disorder: neuroimaging approaches. American journal of psychiatry Phillips, M. L., Chase, H. W., Sheline, Y. I., Etkin, A., Almeida, J. R., Deckersbach, T., Trivedi, M. H. 2015; 172 (2): 124-138

  Abstract

  Despite significant advances in neuroscience and treatment development, no widely accepted biomarkers are available to inform diagnostics or identify preferred treatments for individuals with major depressive disorder.In this critical review, the authors examine the extent to which multimodal neuroimaging techniques can identify biomarkers reflecting key pathophysiologic processes in depression and whether such biomarkers may act as predictors, moderators, and mediators of treatment response that might facilitate development of personalized treatments based on a better understanding of these processes.The authors first highlight the most consistent findings from neuroimaging studies using different techniques in depression, including structural and functional abnormalities in two parallel neural circuits: serotonergically modulated implicit emotion regulation circuitry, centered on the amygdala and different regions in the medial prefrontal cortex; and dopaminergically modulated reward neural circuitry, centered on the ventral striatum and medial prefrontal cortex. They then describe key findings from the relatively small number of studies indicating that specific measures of regional function and, to a lesser extent, structure in these neural circuits predict treatment response in depression.Limitations of existing studies include small sample sizes, use of only one neuroimaging modality, and a focus on identifying predictors rather than moderators and mediators of differential treatment response. By addressing these limitations and, most importantly, capitalizing on the benefits of multimodal neuroimaging, future studies can yield moderators and mediators of treatment response in depression to facilitate significant improvements in shorter- and longer-term clinical and functional outcomes.

  View details for DOI 10.1176/appi.ajp.2014.14010076

  View details for PubMedID 25640931

• Impairment and distress patterns distinguishing the melancholic depression subtype: An iSPOT-D report. Journal of affective disorders Day, C. V., John Rush, A., Harris, A. W., Boyce, P. M., Rekshan, W., Etkin, A., DeBattista, C., Schatzberg, A. F., Arnow, B. A., Williams, L. M. 2015; 174: 493-502

  Abstract

  This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress.Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress.Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants.Due to the cross-sectional nature of this study, causal pathways cannot be concluded.Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.

  View details for DOI 10.1016/j.jad.2014.10.046

  View details for PubMedID 25554994

• Disrupted insula-based neural circuit organization and conflict interference in trauma-exposed youth NEUROIMAGE-CLINICAL Marusak, H. A., Etkin, A., Thomason, M. E. 2015; 8: 516-525

  Abstract

  Childhood trauma exposure is a potent risk factor for psychopathology. Emerging research suggests that aberrant saliency processing underlies the link between early trauma exposure and later cognitive and socioemotional deficits that are hallmark of several psychiatric disorders. Here, we examine brain and behavioral responses during a face categorization conflict task, and relate these to intrinsic connectivity of the salience network (SN). The results demonstrate a unique pattern of SN dysfunction in youth exposed to trauma (n = 14) relative to comparison youth (n = 19) matched on age, sex, IQ, and sociodemographic risk. We find that trauma-exposed youth are more susceptible to conflict interference and this correlates with higher fronto-insular responses during conflict. Resting-state functional connectivity data collected in the same participants reveal increased connectivity of the insula to SN seed regions that is associated with diminished reward sensitivity, a critical risk/resilience trait following stress. In addition to altered intrinsic connectivity of the SN, we observed altered connectivity between the SN and default mode network (DMN) in trauma-exposed youth. These data uncover network-level disruptions in brain organization following one of the strongest predictors of illness, early life trauma, and demonstrate the relevance of observed neural effects for behavior and specific symptom dimensions. SN dysfunction may serve as a diathesis that contributes to illness and negative outcomes following childhood trauma.

  View details for DOI 10.1016/j.nicl.2015.04.007

  View details for Web of Science ID 000373187100055

• Neuroimaging and the future of personalized treatment in psychiatry. Depression and anxiety Etkin, A. 2014; 31 (11): 899-901

  View details for DOI 10.1002/da.22325

  View details for PubMedID 25407576

• Default Mode Network Mechanisms of Transcranial Magnetic Stimulation in Depression BIOLOGICAL PSYCHIATRY Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. T., Gordon, R., Leuchter, B., Voss, H. U., Casey, B. J., Etkin, A., Dubin, M. J. 2014; 76 (7): 517-526

  Abstract

  Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response.We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects.Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement.Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

  View details for DOI 10.1016/j.biopsych.2014.01.023

  View details for Web of Science ID 000343094000005

  View details for PubMedCentralID PMC4209727

• Default mode network mechanisms of transcranial magnetic stimulation in depression. Biological psychiatry Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. T., Gordon, R., Leuchter, B., Voss, H. U., Casey, B. J., Etkin, A., Dubin, M. J. 2014; 76 (7): 517-526

  Abstract

  Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response.We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects.Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement.Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

  View details for DOI 10.1016/j.biopsych.2014.01.023

  View details for PubMedID 24629537

• Connectivity Underlying Emotion Conflict Regulation in Older Adults with 5-HTTLPR Short Allele: A Preliminary Investigation. American journal of geriatric psychiatry Waring, J. D., Etkin, A., Hallmayer, J. F., O'Hara, R. 2014; 22 (9): 946-950

  Abstract

  The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes.Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation).There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation.This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders.

  View details for DOI 10.1016/j.jagp.2013.08.004

  View details for PubMedID 24119861

• Beyond the DSM: Development of a Transdiagnostic Psychiatric Neuroscience Course. Academic psychiatry Etkin, A., Cuthbert, B. 2014; 38 (2): 145-150

  Abstract

  Clinical and neurobiological data suggest that psychiatric disorders, as traditionally defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), are (1) more comorbid than expected by chance, (2) often share neurobiological signatures, and (3) reflect alterations across multiple brain systems that mediate particular mental processes. As such, emerging conceptualizations such at the National Institute of Mental Health's Research Domain Criteria Project (RDoC) have suggested that a different way to understand psychopathology may be with respect to the degree of dysfunction in each of these brain systems, seen dimensionally, which both cross traditional diagnostic boundaries and extend to a healthy range of functioning. At present, however, this scientific perspective has not been incorporated into neuroscience education in psychiatry, nor has its relationship to clinical care been made clear.We describe the rationale and implementation of a reformulated neuroscience course given to psychiatric residents at Stanford University centered on the conceptual framework of RDoC. Data are presented on resident feedback before and after revision of the course.A clear motivation and rationale exists for teaching neuroscience in a transdiagnostic framework. This course was taken up well by the residents, with overall feedback significantly more positive than that prior to the course revision.This "proof of concept" neuroscience course illustrates a potential route for bridging between rapid advances in psychiatric neuroscience and the clinical education for trainees not otherwise versed in neuroscience but who are needed for scientific advances to translate to the clinic. The promise of this approach may be in part related to the similarity between this framework and problem-based approaches common in routine clinical care. In such approaches, clinicians focus on the expressed complaints of their individual patient and identify specific symptoms as the target of treatment-symptoms which are presumably the expression of dysfunction in specific brain systems.

  View details for DOI 10.1007/s40596-013-0032-4

  View details for PubMedID 24493358

• Transforming Neuroscience Education in Psychiatry ACADEMIC PSYCHIATRY Akil, M., Etkin, A. 2014; 38 (2): 116-120

  View details for DOI 10.1007/s40596-014-0065-3

  View details for Web of Science ID 000334414300002

  View details for PubMedID 24567033

• Attitudes toward neuroscience education among psychiatry residents and fellows. Academic psychiatry Fung, L. K., Akil, M., Widge, A., Roberts, L. W., Etkin, A. 2014; 38 (2): 127-134

  Abstract

  The purpose of this study is to assess the attitudes of psychiatry trainees toward neuroscience education in psychiatry residency and subsequent training in order to inform neuroscience education approaches in the future.This online survey was designed to capture demographic information, self-assessed neuroscience knowledge, attitudes toward neuroscience education, preferences in learning modalities, and interest in specific neuroscience topics. Volunteers were identified through the American Psychiatric Association, which invited 2,563 psychiatry trainees among their members.Four hundred thirty-six trainees completed the survey. Nearly all agreed that there is a need for more neuroscience education in psychiatry residency training (94 %) and that neuroscience education could help destigmatize mental illness (91 %). Nearly all (94 %) expressed interest in attending a 3-day course on neuroscience. Many neuroscience topics and modes of learning were viewed favorably by participants. Residents in their first 2 years of training expressed attitudes similar to those of more advanced residents and fellows. Some differences were found based on the level of interest in a future academic role.This web-based study demonstrates that psychiatry residents see neuroscience education as important in their training and worthy of greater attention. Our results suggest potential opportunities for advancing neuroscience education.

  View details for DOI 10.1007/s40596-014-0034-x

  View details for PubMedID 24493359

• 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

  Abstract

  Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD.The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n = 102), test the findings in the second half, and then extend the analyses to the total sample.International Study to Predict Optimized Treatment - in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.

  View details for DOI 10.1186/1745-6215-14-224

  View details for Web of Science ID 000322542800001

  View details for PubMedCentralID PMC3729660

• 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

  View details for DOI 10.1186/1744-8069-9-33

  View details for Web of Science ID 000323054600001

• 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

• 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 (1): 224-?

  Abstract

  Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD.The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n = 102), test the findings in the second half, and then extend the analyses to the total sample.International Study to Predict Optimized Treatment - in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.

  View details for DOI 10.1186/1745-6215-14-224

  View details for PubMedID 23866851

• 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

• 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 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