Publications by authors named "Chadi G Abdallah"

91 Publications

STRONG STAR and the Consortium to Alleviate PTSD: Shaping the future of combat PTSD and related conditions in military and veteran populations.

Contemp Clin Trials 2021 11 29;110:106583. Epub 2021 Sep 29.

VA VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA; Central Texas Veterans Health Care System, Temple, TX, USA. Electronic address:

The STRONG STAR Consortium (South Texas Research Organizational Network Guiding Studies on Trauma and Resilience) and the Consortium to Alleviate PTSD are interdisciplinary and multi-institutional research consortia focused on the detection, diagnosis, prevention, and treatment of combat-related posttraumatic stress disorder (PTSD) and comorbid conditions in military personnel and veterans. This manuscript outlines the consortia's state-of-the-science collaborative research model and how this can be used as a roadmap for future trauma-related research. STRONG STAR was initially funded for 5 years in 2008 by the U.S. Department of Defense's (DoD) Psychological Health and Traumatic Brain Injury Research Program. Since the initial funding of STRONG STAR, almost 50 additional peer-reviewed STRONG STAR-affiliated projects have been funded through the DoD, the U.S. Department of Veterans Affairs (VA), the National Institutes of Health, and private organizations. In 2013, STRONG STAR investigators partnered with the VA's National Center for PTSD and were selected for joint DoD/VA funding to establish the Consortium to Alleviate PTSD. STRONG STAR and the Consortium to Alleviate PTSD have assembled a critical mass of investigators and institutions with the synergy required to make major scientific and public health advances in the prevention and treatment of combat PTSD and related conditions. This manuscript provides an overview of the establishment of these two research consortia, including their history, vision, mission, goals, and accomplishments. Comprehensive tables provide descriptions of over 70 projects supported by the consortia. Examples are provided of collaborations among over 50 worldwide academic research institutions and over 150 investigators.
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http://dx.doi.org/10.1016/j.cct.2021.106583DOI Listing
November 2021

Transcranial direct current stimulation targeting the medial prefrontal cortex modulates functional connectivity and enhances safety learning in obsessive-compulsive disorder: Results from two pilot studies.

Depress Anxiety 2021 Aug 31. Epub 2021 Aug 31.

Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut, USA.

Background: Exposed-based psychotherapy is a mainstay of treatment for obsessive-compulsive disorder (OCD) and anxious psychopathology. The medial prefrontal cortex (mPFC) and the default mode network (DMN), which is anchored by the mPFC, promote safety learning. Neuromodulation targeting the mPFC might augment therapeutic safety learning and enhance response to exposure-based therapies.

Methods: To characterize the effects of mPFC neuromodulation on functional connectivity, 17 community volunteers completed resting-state functional magnetic resonance imaging scans before and after 20 min of frontopolar anodal multifocal transcranial direct current stimulation (tDCS). To examine the effects of tDCS on therapeutic safety learning, 24 patients with OCD completed a pilot randomized clinical trial; they were randomly assigned (double-blind, 50:50) to receive active or sham frontopolar tDCS before completing an in vivo exposure and response prevention (ERP) challenge. Changes in subjective emotional distress during the ERP challenge were used to index therapeutic safety learning.

Results: In community volunteers, frontal pole functional connectivity with the middle and superior frontal gyri increased, while connectivity with the anterior insula and basal ganglia decreased (ps < .001, corrected) after tDCS; functional connectivity between DMN and salience network also decreased after tDCS (ps < .001, corrected). OCD patients who received active tDCS exhibited more rapid therapeutic safety learning (ps < .05) during the ERP challenge than patients who received sham tDCS.

Conclusions: Frontopolar tDCS may modulate mPFC and DMN functional connectivity and can accelerate therapeutic safety learning. Though limited by small samples, these findings motivate further exploration of the effects of frontopolar tDCS on neural and behavioral targets associated with exposure-based psychotherapies.
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http://dx.doi.org/10.1002/da.23212DOI Listing
August 2021

Novel approaches to estimate prefrontal synaptic strength in vivo in humans: of relevance to depression, schizophrenia, and ketamine.

Neuropsychopharmacology 2022 Jan;47(1):399-400

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1038/s41386-021-01122-2DOI Listing
January 2022

Smoking status links habenular volume to glycated hemoglobin: Findings from the Human Connectome Project-Young Adult.

Psychoneuroendocrinology 2021 09 10;131:105321. Epub 2021 Jun 10.

Center for Depression Research and Clinical Care, UT Southwestern Medical Center, Dallas, TX, United States. Electronic address:

Background: The habenula-pancreas axis regulates the stimulatory effects of nicotine on blood glucose levels and may participate in the emergence of type 2 diabetes in human tobacco smokers. This secondary analysis of young adults from the Human Connectome Project (HCP-YA) evaluated whether smoking status links the relationship between habenular volume and glycated hemoglobin (HbA1c), a marker of long-term glycemic control.

Methods: Habenula segmentation was performed using a fully-automated myelin content-based approach in HCP-YA participants and the results were inspected visually (n = 693; aged 22-37 years). A linear regression analysis was used with habenular volume as the dependent variable, the smoking-by-HbA1c interaction as the independent variable of interest, and age, gender, race, ethnicity, education, income, employment status, body mass index, and total gray matter volume as covariates.

Results: Habenula volume and HbA1c were similar in smokers and nonsmokers. There was a significant interaction effect (F= 5.03, p = 0.025) indicating that habenular volume was related to HbA1c in a manner that depended on smoking status. Among participants who were smokers (n = 120), higher HbA1c was associated with apparently larger habenular volume (β = 6.74, standard error=2.36, p = 0.005). No such association between habenular volume and HbA1c was noted among participants who were nonsmokers (n = 573).

Discussion: Blood glucose levels over an extended time period, reflected by HbA1c, were correlated with habenular volume in smokers, consistent with a relationship between the habenula and blood glucose homeostasis in smokers. Future studies are needed to evaluate how habenular function relates to glycemic control in smokers and nonsmokers.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105321DOI Listing
September 2021

Smoking status links habenular volume to glycated hemoglobin: Findings from the Human Connectome Project-Young Adult.

Psychoneuroendocrinology 2021 09 10;131:105321. Epub 2021 Jun 10.

Center for Depression Research and Clinical Care, UT Southwestern Medical Center, Dallas, TX, United States. Electronic address:

Background: The habenula-pancreas axis regulates the stimulatory effects of nicotine on blood glucose levels and may participate in the emergence of type 2 diabetes in human tobacco smokers. This secondary analysis of young adults from the Human Connectome Project (HCP-YA) evaluated whether smoking status links the relationship between habenular volume and glycated hemoglobin (HbA1c), a marker of long-term glycemic control.

Methods: Habenula segmentation was performed using a fully-automated myelin content-based approach in HCP-YA participants and the results were inspected visually (n = 693; aged 22-37 years). A linear regression analysis was used with habenular volume as the dependent variable, the smoking-by-HbA1c interaction as the independent variable of interest, and age, gender, race, ethnicity, education, income, employment status, body mass index, and total gray matter volume as covariates.

Results: Habenula volume and HbA1c were similar in smokers and nonsmokers. There was a significant interaction effect (F= 5.03, p = 0.025) indicating that habenular volume was related to HbA1c in a manner that depended on smoking status. Among participants who were smokers (n = 120), higher HbA1c was associated with apparently larger habenular volume (β = 6.74, standard error=2.36, p = 0.005). No such association between habenular volume and HbA1c was noted among participants who were nonsmokers (n = 573).

Discussion: Blood glucose levels over an extended time period, reflected by HbA1c, were correlated with habenular volume in smokers, consistent with a relationship between the habenula and blood glucose homeostasis in smokers. Future studies are needed to evaluate how habenular function relates to glycemic control in smokers and nonsmokers.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105321DOI Listing
September 2021

Effects of Smoking Status and State on Intrinsic Connectivity.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Feb 19. Epub 2021 Feb 19.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Clinical Neurosciences Division, Veterans Administration National Center for PTSD, West Haven, Connecticut; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.

Background: Smoking behavior during the first 24 hours of a quit attempt is a significant predictor of longer-term abstinence, yet little is known about the neurobiology of early tobacco abstinence. Specifically, the effects of acute tobacco deprivation and reinstatement on brain function-particularly at the level of large-scale network dynamics and assessed across the entire brain-remain incompletely understood. To address this gap, this study used a mixed within- and between-subjects design to assess the effects of smoking status (yes/no smoker) and state (deprived vs. satiated) on whole-brain patterns of intrinsic connectivity.

Methods: Participants included 42 tobacco smokers who underwent resting-state functional magnetic resonance imaging following overnight abstinence (deprived state) and following smoking reinstatement (satiated state, randomized order across participants). Sixty healthy control nonsmokers underwent a single resting-state scan using the same acquisition parameters. Functional connectivity data were analyzed using both a canonical network-of-interest approach and a whole-brain, data-driven approach, i.e., intrinsic connectivity distribution.

Results: Network-of-interest-based analyses indicated decreased functional connectivity within frontoparietal and salience networks among smokers relative to nonsmokers as well as effects of smoking state on default mode connectivity. In addition, intrinsic connectivity distribution analyses identified novel between-group differences in subcortical-cerebellar and corticocerebellar networks that were largely smoking state dependent.

Conclusions: These data demonstrate the importance of considering smoking state and the utility of using both theory- and data-driven analysis approaches. These data provide much-needed insight into the functional neurobiology of early abstinence, which may be used in the development of novel treatments.
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http://dx.doi.org/10.1016/j.bpsc.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373998PMC
February 2021

Neurobiology of the Rapid-Acting Antidepressant Effects of Ketamine: Impact and Opportunities.

Biol Psychiatry 2021 07 15;90(2):85-95. Epub 2020 Dec 15.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; VA National Center for PTSD-Clinical Neuroscience Division, West Haven, Connecticut; Michael E. DeBakey VA Medical Center, Houston, Texas; Menninger Department of Psychiatry, Baylor College of Medicine, Houston, Texas. Electronic address:

The discovery of the rapid-acting antidepressant effects of ketamine has 1) led to a paradigm shift in our perception of what is possible in treating severe depression; 2) spurred a wave of basic, translation, and clinical research; and 3) provided an unprecedented investigational tool to conduct longitudinal mechanistic studies that may capture behavioral changes as complex as clinical remission and relapse within hours and days of treatment. Unfortunately, these advances did not yet translate into clinical biomarkers or novel treatments, beyond ketamine. In contrast to slow-acting antidepressants, in which targeting monoaminergic receptors identified several efficacious drugs with comparable mechanisms, the focus on the receptor targets of ketamine has failed in several clinical trials over the past decade. Thus, it is becoming increasingly crucial that we concentrate our effort on the downstream molecular mechanisms of ketamine and their effects on the brain circuitry and networks. Honoring the legacy of our mentor, friend, and colleague Ron Duman, we provide a historical note on the discovery of ketamine and its putative mechanisms. We then detail the molecular and circuits effect of ketamine based on preclinical findings, followed by a summary of the impact of this work on our understanding of chronic stress pathology across psychiatric disorders, with particular emphasis on the role of synaptic connectivity and its brain network effects in the pathology and treatment of clinical depression.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.006DOI Listing
July 2021

Pretreatment Brain Connectome Fingerprint Predicts Treatment Response in Major Depressive Disorder.

Chronic Stress (Thousand Oaks) 2020 Jan-Dec;4:2470547020984726. Epub 2020 Dec 29.

National Center for PTSD-Clinical Neuroscience Division, US Department of Veterans Affairs, West Haven, Connecticut.

Background: Major depressive disorder (MDD) treatment is characterized by low remission rate and often involves weeks to months of treatment. Identification of pretreatment biomarkers of response may play a critical role in novel drug development, in enhanced prognostic predictions, and perhaps in providing more personalized medicine. Using a network restricted strength predictive modeling (NRS-PM) approach, the goal of the current study was to identify pretreatment functional connectome fingerprints (CFPs) that (1) predict symptom improvement regardless of treatment modality and (2) predict treatment specific improvement.

Methods: Functional magnetic resonance imaging and behavioral data from unmedicated patients with MDD (n = 200) were investigated. Participants were randomized to daily treatment of sertraline or placebo for 8 weeks. NRS-PM with 1000 iterations of 10 cross-validation were implemented to identify brain connectivity signatures that predict percent improvement in depression severity at week-8.

Results: The study identified a pretreatment CFP that significantly predicts symptom improvement independent of treatment modality but failed to identify a treatment specific CFP. Regardless of treatment modality, improved antidepressant response was predicted by high pretreatment connectivity between modules in the default mode network and the rest of the brain, but low external connectivity in the executive network. Moreover, high pretreatment internal nodal connectivity in the bilateral caudate predicted better response.

Conclusions: The identified CFP may contribute to drug development and ultimately to enhanced prognostic predictions. However, the results do not assist with providing personalized medicine, as pretreatment functional connectivity failed to predict treatment specific response.
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http://dx.doi.org/10.1177/2470547020984726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783890PMC
December 2020

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Mol Psychiatry 2021 Aug 7;26(8):4331-4343. Epub 2020 Dec 7.

Department of Psychiatry and Behavioral Health, Penn State College of Medicine, Hershey, PA, USA.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.
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http://dx.doi.org/10.1038/s41380-020-00967-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180531PMC
August 2021

A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.

Neuropsychopharmacology 2021 01 23;46(2):478-485. Epub 2020 Sep 23.

Clinical Neuroscience Division, VA National Center for PTSD, West Haven, CT, USA.

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.
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http://dx.doi.org/10.1038/s41386-020-00864-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852889PMC
January 2021

Chronic stress pathology and ketamine-induced alterations in functional connectivity in major depressive disorder: An abridged review of the clinical evidence.

Adv Pharmacol 2020 14;89:163-194. Epub 2020 May 14.

Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, United States; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.
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http://dx.doi.org/10.1016/bs.apha.2020.04.003DOI Listing
October 2020

Early life stress and glutamate neurotransmission in major depressive disorder.

Eur Neuropsychopharmacol 2020 06 15;35:71-80. Epub 2020 May 15.

Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA.

Early life stress (ELS) and glutamate neurotransmission have been implicated in the pathophysiology of major depressive disorder (MDD). In non-human primates, ELS was positively correlated with cortical Glx (i.e., glutamate + glutamine). However, the relationship between ELS and cortical glutamate in adult patients with MDD is not fully known. Using H Magnetic Resonance Spectroscopy (MRS), we conducted exploratory analyses measuring occipital cortical glutamate and glutamine levels in 36 medication-free patients with MDD. In a subsample (n=11), we measured dynamic glutamate/glutamine cycling (V) using advanced C MRS methods. ELS history was assessed using Early-life Trauma Inventory (ETI). Exploratory analyses suggest a relationship between ETI and glutamine as reflected by a significant positive correlation between ETI scores and occipital glutamine (r=0.39, p=0.017) but not glutamate. Post-hoc analyses showed that the association with glutamine was driven by the ETI emotional abuse (ETI-EA) subscale (r=0.39, p=0.02). V correlation with ETI was at trend level (r=0.55, p=0.087) and significantly correlated with ETI-EA (r=0.67, p=0.03). In this small sample of patients with MDD, those with childhood emotional abuse appear to have increased occipital glutamate neurotransmission as reflected by increased glutamate/glutamine cycling and glutamine level. Future studies would be needed to confirm this pilot evidence and to examine whether ELS effects on glutamate neurotransmission underlie the relationship between ELS and psychopathology.
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http://dx.doi.org/10.1016/j.euroneuro.2020.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913468PMC
June 2020

Ketamine and rapid acting antidepressants: Are we ready to cure, rather than treat depression?

Behav Brain Res 2020 07 11;390:112628. Epub 2020 May 11.

National Center for PTSD - Clinical Neuroscience Division, US Department of Veterans Affairs, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Depression is a leading cause of disability, with often chronic course of illness and high treatment resistance in a large proportion of patients. In the current short perspective paper, we present evidence supporting the presence of synaptic-based chronic stress pathology (CSP) in depression and across a number of psychiatric disorders. We summarize the synaptic connectivity model of CSP, and briefly review related preclinical and clinical evidence, while providing appropriate references for more comprehensive reviews and alternative models. We then underscore some gaps in the literature and provide various tips for future directions.
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http://dx.doi.org/10.1016/j.bbr.2020.112628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316409PMC
July 2020

(2R,6R)-Hydroxynorketamine (HNK) plasma level predicts poor antidepressant response: is this the end of the HNK pipeline?

Authors:
Chadi G Abdallah

Neuropsychopharmacology 2020 07 14;45(8):1245-1246. Epub 2020 Apr 14.

National Center for PTSD-Clinical Neuroscience Division, US Department of Veterans Affairs, West Haven, CT, USA.

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http://dx.doi.org/10.1038/s41386-020-0668-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414015PMC
July 2020

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.

Neuropsychopharmacology 2020 05 24;45(6):990-997. Epub 2020 Feb 24.

National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA.

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
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http://dx.doi.org/10.1038/s41386-020-0644-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162891PMC
May 2020

White matter microstructural alterations in posttraumatic stress disorder: An ROI and whole-brain based meta-analysis.

J Affect Disord 2020 04 16;266:655-670. Epub 2020 Jan 16.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA.

Background: Posttraumatic stress disorder (PTSD) is a debilitating mental illness that is thought to be associated with brain white matter (WM) alterations. Individual diffusion tensor imaging (DTI) studies to date have reported inconsistent alterations in FA across different brain regions in patients with PTSD. Here, we aimed to investigate FA in PTSD using both region-of-interest (ROI)-based and whole-brain-based meta-analytic approaches.

Objectives: Individual ROI-based meta-analysis was carried out in each eligible white matter tract and seed-based D mapping (SDM) meta-analysis was conducted in the whole brain to identify the convergence of FA alterations in PTSD relative to controls.

Results: Seventeen studies were included in ROI-based meta-analysis (≥ 3 studies were included for each ROI, N ≥ 80 and N ≥ 103 per ROI). Fourteen studies with a total of 322 PTSD and 335 controls were included in whole-brain based meta-analysis. Both ROI and whole-brain meta-analyses showed that patients with PTSD have significantly higher FA in the inferior fronto-occipital fasciculus and lower FA in the genu of corpus callosum. Whole-brain meta-analyses also identified higher FA in the left inferior temporal gyrus and lower FA in the anterior cingulum and left corticospinal tract.

Limitations: A small number of studies were included in some ROI tracts. Thus the results should be interpreted with caution.

Conclusions: Our results suggest that PTSD patients have increased FA in areas related to visual processing, but decreased FA in anterior brain regions critical to cognition association and fear regulation.
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http://dx.doi.org/10.1016/j.jad.2020.01.047DOI Listing
April 2020

Of Forests and Trees: Bridging the Gap Between Neurobiology and Behavior in Posttraumatic Stress Disorder.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 02;5(2):135-137

Clinical Neurosciences Division, National Center for Posttraumatic Stress Disorder, Department of Veterans Affairs, West Haven, Connecticut; Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.bpsc.2019.12.010DOI Listing
February 2020

Increased Cortical Thickness in Patients With Major Depressive Disorder Following Antidepressant Treatment.

Chronic Stress (Thousand Oaks) 2020 Jan-Dec;4. Epub 2020 Jan 14.

VA National Center for PTSD-Clinical Neuroscience Division, US Department of Veterans Affairs, West Haven, CT, USA.

Background: Considering the slow-acting properties of traditional antidepressants, an important challenge in the field is the identification of early treatment response biomarkers. Reduced cortical thickness has been reported in neuroimaging studies of depression. However, little is known whether antidepressants reverse this abnormality. In this brief report, we investigated early cortical thickness changes following treatment with sertraline compared to placebo.

Methods: Participants (n=215) with major depressive disorder were randomized to a selective serotonin reuptake inhibitor, sertraline, or to placebo. Structural magnetic resonance imaging scans were acquired at baseline and one week following treatment. Response was defined as at least 50% improvement in Hamilton rating scale for depression score at week 8. In a vertex-wise approach, we examined the effects of treatment, response, and treatment×response.

Results: Following correction for multiple comparisons, we found a significant effect of treatment, with widespread increase in cortical thickness following sertraline compared to placebo. Clusters with increased thickness were found in the left medial prefrontal cortex, right medial and lateral prefrontal cortex, and within the right parieto-temporal lobes. There were no sertraline-induced cortical thinning, and no significant response effects or treatment×response interactions.

Conclusion: Our findings suggest that cortical thickness abnormalities may be responsive to antidepressant treatment. However, a relationship between these early cortical changes and later treatment response was not demonstrated. Future studies would be needed to investigate whether those early effects are maintained at eight weeks and are associated with enhanced response.
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http://dx.doi.org/10.1177/2470547019899962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959134PMC
January 2020

A Unique Brain Connectome Fingerprint Predates and Predicts Response to Antidepressants.

iScience 2020 Jan 23;23(1):100800. Epub 2019 Dec 23.

National Center for PTSD - Clinical Neuroscience Division, US Department of Veterans Affairs, 950 Campbell Avenue 151 E, West Haven, CT 06516, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

More than six decades have passed since the discovery of monoaminergic antidepressants. Yet, it remains a mystery why these drugs take weeks to months to achieve therapeutic effects, although their monoaminergic actions are present rapidly after treatment. In an attempt to solve this mystery, rather than studying the acute neurochemical effects of antidepressants, here we propose focusing on the early changes in the brain functional connectome using traditional statistics and machine learning approaches. Capitalizing on three independent datasets (n = 1,261) and recent developments in data and network science, we identified a specific connectome fingerprint that predates and predicts response to monoaminergic antidepressants. The discovered fingerprint appears to generalize to antidepressants with differing mechanism of action. We also established a consensus whole-brain hierarchical connectivity architecture and provided a set of model-based features engineering approaches suitable for identifying connectomic signatures of brain function in health and disease.
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http://dx.doi.org/10.1016/j.isci.2019.100800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992944PMC
January 2020

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

Mol Psychiatry 2021 Aug 19;26(8):4315-4330. Epub 2019 Dec 19.

Department of Psychiatry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.
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http://dx.doi.org/10.1038/s41380-019-0631-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302988PMC
August 2021

Determining the Hierarchical Architecture of the Human Brain Using Subject-Level Clustering of Functional Networks.

Sci Rep 2019 12 17;9(1):19290. Epub 2019 Dec 17.

Clinical Neurosciences Division-National Center for PTSD, United States Department of Veterans Affairs, West Haven, CT, 06516, USA.

Optimal integration and segregation of neuronal connections are necessary for efficient large-scale network communication between distributed cortical regions while allowing for modular specialization. This dynamic in the cortex is enabled at the network mesoscale by the organization of nodes into communities. Previous in vivo efforts to map the mesoscale architecture in humans had several limitations. Here we characterize a consensus multiscale community organization of the functional cortical network. We derive this consensus from the clustering of subject-level networks. We applied this analysis to magnetic resonance imaging data from 1003 healthy individuals part of the Human Connectome Project. The hierarchical atlas and code will be made publicly available for future investigators.
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http://dx.doi.org/10.1038/s41598-019-55738-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917755PMC
December 2019

When the "Golden Chain" Breaks: Sleep Disturbance and the Vicious Cycle of Chronic Stress.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 12;4(12):1018-1020

National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, Department of Veterans Affairs, West Haven, Connecticut; Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.bpsc.2019.10.004DOI Listing
December 2019

Apolipoprotein E gene polymorphism, posttraumatic stress disorder, and cognitive function in older U.S. veterans: Results from the National Health and Resilience in Veterans Study.

Depress Anxiety 2019 09 6;36(9):834-845. Epub 2019 Aug 6.

U.S. Department of Veterans Affairs National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut.

Background: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction.

Methods: We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status.

Results: APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59).

Conclusions: APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.
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http://dx.doi.org/10.1002/da.22912DOI Listing
September 2019

Salience Network Disruption in U.S. Army Soldiers With Posttraumatic Stress Disorder.

Chronic Stress (Thousand Oaks) 2019 Jan-Dec;3. Epub 2019 May 15.

Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Background: Better understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of active duty US Army soldiers with PTSD compared to controls.

Methods: 102 participants with (n=50) or without PTSD (n=52) completed functional magnetic resonance imaging (MRI) at rest and during symptom provocation using subject-specific script imagery. Vertex/voxel global brain connectivity with global signal regression (GBCr), a measure of nodal strength, was calculated as the average of its functional connectivity with all other vertices/voxels in the brain gray matter.

Results: In contrast to during resting-state, where there were no group differences, we found a significantly higher GBCr during symptom provocation, in PTSD participants compared to controls, in areas within the right hemisphere, including anterior insula, caudal-ventrolateral prefrontal, and rostral-ventrolateral parietal cortices. Overall, these clusters overlapped with the ventral and dorsal salience networks. analysis showed increased GBCr in these salience clusters during symptom provocation compared to resting-state. In addition, resting-state GBCr in the salience clusters predicted GBCr during symptom provocation in PTSD participants but not in controls.

Conclusion: In PTSD, increased connectivity within the salience network has been previously hypothesized, based primarily on seed-based connectivity findings. The current results strongly support this hypothesis using whole-brain network measure in a fully data-driven approach. It remains to be seen in future studies whether these identified salience disturbances would normalize following treatment.
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http://dx.doi.org/10.1177/2470547019850467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529942PMC
May 2019

Reduced Salience and Enhanced Central Executive Connectivity Following PTSD Treatment.

Chronic Stress (Thousand Oaks) 2019 Jan-Feb;3. Epub 2019 Apr 15.

Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Background: In soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (MRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would normalize following effective PTSD treatment.

Methods: 69 US Army soldiers with (n = 42) and without PTSD (n = 27) completed MRI at rest and during symptom provocation using subject-specific script imagery. Then, participants with PTSD received 6 weeks (12 sessions) of group cognitive processing therapy (CPT) or present-centered therapy (PCT). At week 8, all participants repeated the MRI scans. The primary analysis used a region-of-interest approach to determine the effect of treatment on salience GBCr. A secondary analysis was conducted to explore the pattern of GBCr alterations posttreatment in PTSD participants compared to controls.

Results: Over the treatment period, PCT significantly reduced salience GBCr ( = .02). Compared to controls, salience GBCr was high pretreatment (PCT, = .01; CPT, = .03) and normalized post-PCT ( = .53), but not post-CPT ( = .006). Whole-brain secondary analysis found high GBCr within the central executive network in PTSD participants compared to controls. exploratory analyses showed significant increases in executive GBCr following CPT treatment ( = .01).

Conclusion: The results support previous models relating CPT to central executive network and enhanced cognitive control while unraveling a previously unknown neurobiological mechanism of PCT treatment, demonstrating treatment-specific reduction in salience connectivity during trauma recollection.
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http://dx.doi.org/10.1177/2470547019838971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469713PMC
April 2019

Repeated ketamine infusions for antidepressant-resistant PTSD: Methods of a multicenter, randomized, placebo-controlled clinical trial.

Contemp Clin Trials 2019 06 15;81:11-18. Epub 2019 Apr 15.

National Center for PTSD, Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepressants. Therefore, there is a tremendous need to identify more effective and more rapidly acting pharmacotherapies for PTSD that work through novel neural mechanisms. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug for PTSD has not yet been tested in active duty military or veteran populations. Here, we report the design and methods of a study funded under the Consortium to Alleviate PTSD. The study is a multisite, placebo-controlled, double-blind, randomized clinical trial to examine the dose-related efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD symptomatology in veterans and active duty military populations with antidepressant-resistant PTSD. Approximately 198 eligible participants who meet criteria for PTSD will be randomized to the study drug (i.e., ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. This ongoing study is the only trial of therapeutic effects of ketamine for PTSD and the first placebo-controlled trial to determine the dose-related effects of repeated ketamine on PTSD.
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http://dx.doi.org/10.1016/j.cct.2019.04.009DOI Listing
June 2019

Ketamine: A Paradigm Shift for Depression Research and Treatment.

Neuron 2019 03;101(5):774-778

Departments of Psychiatry, Neuroscience, and Psychology, Yale University, New Haven, CT, USA; National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA.

Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.
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http://dx.doi.org/10.1016/j.neuron.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560624PMC
March 2019

A Review of fMRI Affective Processing Paradigms Used in the Neurobiological Study of Posttraumatic Stress Disorder.

Chronic Stress (Thousand Oaks) 2019 Jan-Dec;3. Epub 2019 Feb 25.

Clinical Neurosciences Division, United States Department of Veterans Affairs, National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA.

Posttraumatic stress disorder (PTSD) is a chronic and debilitating psychiatric disorder with a complex clinical presentation. The last two decades have seen a proliferation of literature on the neurobiological mechanisms subserving affective processing in PTSD. The current review will summarize the neuroimaging results of the most common experimental designs used to elucidate the affective signature of PTSD. From this summary, we will provide a heuristic to organize the various paradigms discussed and report neural patterns of activations using this heuristic as a framework. Next, we will compare these results to the traditional functional neurocircuitry model of PTSD and discuss biological and analytic variables which may account for the heterogeneity within this literature. We hope that this approach may elucidate the role of experimental parameters in influencing neuroimaging findings.
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http://dx.doi.org/10.1177/2470547019829035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391723PMC
February 2019

Are There Effective Psychopharmacologic Treatments for PTSD?

J Clin Psychiatry 2018 12 18;80(3). Epub 2018 Dec 18.

National Center for PTSD-Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, Connecticut, USA.

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http://dx.doi.org/10.4088/JCP.18ac12473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436624PMC
December 2018

Neurobiological studies of trauma-related psychopathology: a public health perspective.

Eur J Psychotraumatol 2018 20;9(1):1556554. Epub 2018 Dec 20.

Clinical Neurosciences Division National Center for PTSD, United States Department of Veterans Affairs, West Haven, CT, USA.

The societal burden of psychiatric disorders that result after exposure to psychological trauma is enormous. The study of trauma-related disorders using neurobiological and public health approaches is often disjointed. It is critical to emphasize the translational potential of neurobiological work and its relevance to the public health burden of psychological trauma. Applying a public health model to traumatology that includes primary, secondary, and tertiary levels, we highlight ways in which advancing the field of neurobiology can pave the way for scalable interventions that can improve outcomes and help to address the public health problem.
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http://dx.doi.org/10.1080/20008198.2018.1556554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319465PMC
December 2018
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