Publications by authors named "Douglas E Williamson"

64 Publications

Transcriptomic organization of the human brain in post-traumatic stress disorder.

Nat Neurosci 2021 01 21;24(1):24-33. Epub 2020 Dec 21.

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

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
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http://dx.doi.org/10.1038/s41593-020-00748-7DOI Listing
January 2021

Transcriptomic organization of the human brain in post-traumatic stress disorder.

Nat Neurosci 2021 01 21;24(1):24-33. Epub 2020 Dec 21.

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

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
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http://dx.doi.org/10.1038/s41593-020-00748-7DOI Listing
January 2021

Corrigendum to "Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD" [Psychoneuroendocrinology (2020) Article 104749].

Psychoneuroendocrinology 2020 10 10;120:104802. Epub 2020 Jul 10.

University of Texas Health Science Center at San Antonio, Department of Psychiatry and Behavioral Sciences, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA; South Texas Veterans Health Care System, Research and Development Service, 7400 Merton Minter, San Antonio, TX 78229, USA; University of Texas at San Antonio, Department of Psychology, One UTSA Circle, San Antonio, TX 78249, USA.

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http://dx.doi.org/10.1016/j.psyneuen.2020.104802DOI Listing
October 2020

Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome.

Alzheimers Dement 2020 09 26;16(9):1280-1292. Epub 2020 Jun 26.

Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA.

Introduction: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies.

Methods: We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses.

Results: We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations.

Discussion: We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.
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http://dx.doi.org/10.1002/alz.12128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769164PMC
September 2020

Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD.

Psychoneuroendocrinology 2020 09 8;119:104749. Epub 2020 Jun 8.

University of Texas Health Science Center at San Antonio, Department of Psychiatry and Behavioral Sciences, 7703 Floyd Curl Dr., San Antonio, TX, 78229, USA; South Texas Veterans Health Care System, Research and Development Service, 7400 Merton Minter, San Antonio, TX, 78229, USA; University of Texas at San Antonio, Department of Psychology, One UTSA Circle, San Antonio, TX, 78249, USA. Electronic address:

Posttraumatic stress disorder (PTSD) is associated with dysregulation of the neuroendocrine system, including cortisol, allopregnanolone, and pregnanolone. Preliminary evidence from animal models suggests that baseline levels of these biomarkers may predict response to PTSD treatment. We report the change in biomarkers over the course of PTSD treatment. Biomarkers were sampled from individuals participating in (1) a randomized controlled trial comparing a web-version of Prolonged Exposure (Web-PE) therapy to in-person Present-Centered Therapy (PCT) and (2) from individuals participating in a nonrandomized effectiveness study testing PE delivered in-person as part of an intensive outpatient PTSD program. We found that higher cortisol reactivity during script-driven imagery was associated with higher baseline PTSD severity and that baseline allopregnanolone, pregnanolone, and cortisol reactivity were associated with PTSD treatment responder status over the course of intensive outpatient treatment. These findings demonstrate that peripherally assessed biomarkers are associated with PTSD severity and likelihood of successful treatment outcome of PE delivered daily over two weeks. These assessments could be used to determine which patients are likely to respond to treatment and which patients require augmentation to increase the likelihood of optimal response to PTSD treatment.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104749DOI Listing
September 2020

Convergent Evidence for Predispositional Effects of Brain Gray Matter Volume on Alcohol Consumption.

Biol Psychiatry 2020 04 13;87(7):645-655. Epub 2019 Sep 13.

Department of Psychological and Brain Sciences, Washington University, St. Louis, Missouri. Electronic address:

Background: Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors or causal consequences of alcohol use remains poorly understood.

Methods: Data came from 3 neuroimaging samples (N = 2423), spanning childhood or adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use or a causal consequence of alcohol use. Finally, we used heritability, gene-set enrichment, and transcriptome-wide association study approaches to evaluate whether genome-wide association study-defined genomic risk for alcohol consumption is enriched for genes that are preferentially expressed in regions that were identified in our neuroimaging analyses.

Results: Smaller right dorsolateral prefrontal cortex (DLPFC) (i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest that these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene sets that were preferentially expressed in the DLPFC and was associated with replicable differential gene expression in the DLPFC.

Conclusions: These data suggest that smaller DLPFC and insula GMV plausibly represent genetically conferred predispositional risk factors for, as opposed to consequences of, alcohol use. DLPFC and insula GMV represent promising biomarkers for alcohol-consumption liability and related psychiatric and behavioral phenotypes.
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http://dx.doi.org/10.1016/j.biopsych.2019.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412715PMC
April 2020

Childhood Trauma and Stressful Life Events Are Independently Associated with Sleep Disturbances in Adolescents.

Behav Sci (Basel) 2019 Oct 10;9(10). Epub 2019 Oct 10.

Duke Psychiatry & Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.

Adolescence is a critical developmental period associated with an increase in stress, the appearance of anxiety and depressive symptoms, and changes in sleep patterns. Even though the disruption of sleep patterns in stress and anxiety and depressive disorders is well known, the independent effects of childhood trauma and stressful life events on sleep patterns are less understood. We tested the independent effects of stress (childhood trauma and stressful life events) while controlling for anxiety and depression on adolescent sleep patterns. Seven hundred fifty-two adolescents (age 12-15 years) completed self-report questionnaires about childhood trauma, stressful life events, anxiety, and depression. Four sleep factors identifying movement during sleep, sleep regularity, sleep disturbances, and sleep pressure were extracted in the principal component analysis of sleep questions. Both childhood trauma and recent stressful life events were significantly associated with sleep disturbances before and after controlling for anxiety and depression.
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http://dx.doi.org/10.3390/bs9100108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826433PMC
October 2019

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Authors:
Caroline M Nievergelt Adam X Maihofer Torsten Klengel Elizabeth G Atkinson Chia-Yen Chen Karmel W Choi Jonathan R I Coleman Shareefa Dalvie Laramie E Duncan Joel Gelernter Daniel F Levey Mark W Logue Renato Polimanti Allison C Provost Andrew Ratanatharathorn Murray B Stein Katy Torres Allison E Aiello Lynn M Almli Ananda B Amstadter Søren B Andersen Ole A Andreassen Paul A Arbisi Allison E Ashley-Koch S Bryn Austin Esmina Avdibegovic Dragan Babić Marie Bækvad-Hansen Dewleen G Baker Jean C Beckham Laura J Bierut Jonathan I Bisson Marco P Boks Elizabeth A Bolger Anders D Børglum Bekh Bradley Megan Brashear Gerome Breen Richard A Bryant Angela C Bustamante Jonas Bybjerg-Grauholm Joseph R Calabrese José M Caldas-de-Almeida Anders M Dale Mark J Daly Nikolaos P Daskalakis Jürgen Deckert Douglas L Delahanty Michelle F Dennis Seth G Disner Katharina Domschke Alma Dzubur-Kulenovic Christopher R Erbes Alexandra Evans Lindsay A Farrer Norah C Feeny Janine D Flory David Forbes Carol E Franz Sandro Galea Melanie E Garrett Bizu Gelaye Elbert Geuze Charles Gillespie Aferdita Goci Uka Scott D Gordon Guia Guffanti Rasha Hammamieh Supriya Harnal Michael A Hauser Andrew C Heath Sian M J Hemmings David Michael Hougaard Miro Jakovljevic Marti Jett Eric Otto Johnson Ian Jones Tanja Jovanovic Xue-Jun Qin Angela G Junglen Karen-Inge Karstoft Milissa L Kaufman Ronald C Kessler Alaptagin Khan Nathan A Kimbrel Anthony P King Nastassja Koen Henry R Kranzler William S Kremen Bruce R Lawford Lauren A M Lebois Catrin E Lewis Sarah D Linnstaedt Adriana Lori Bozo Lugonja Jurjen J Luykx Michael J Lyons Jessica Maples-Keller Charles Marmar Alicia R Martin Nicholas G Martin Douglas Maurer Matig R Mavissakalian Alexander McFarlane Regina E McGlinchey Katie A McLaughlin Samuel A McLean Sarah McLeay Divya Mehta William P Milberg Mark W Miller Rajendra A Morey Charles Phillip Morris Ole Mors Preben B Mortensen Benjamin M Neale Elliot C Nelson Merete Nordentoft Sonya B Norman Meaghan O'Donnell Holly K Orcutt Matthew S Panizzon Edward S Peters Alan L Peterson Matthew Peverill Robert H Pietrzak Melissa A Polusny John P Rice Stephan Ripke Victoria B Risbrough Andrea L Roberts Alex O Rothbaum Barbara O Rothbaum Peter Roy-Byrne Ken Ruggiero Ariane Rung Bart P F Rutten Nancy L Saccone Sixto E Sanchez Dick Schijven Soraya Seedat Antonia V Seligowski Julia S Seng Christina M Sheerin Derrick Silove Alicia K Smith Jordan W Smoller Scott R Sponheim Dan J Stein Jennifer S Stevens Jennifer A Sumner Martin H Teicher Wesley K Thompson Edward Trapido Monica Uddin Robert J Ursano Leigh Luella van den Heuvel Miranda Van Hooff Eric Vermetten Christiaan H Vinkers Joanne Voisey Yunpeng Wang Zhewu Wang Thomas Werge Michelle A Williams Douglas E Williamson Sherry Winternitz Christiane Wolf Erika J Wolf Jonathan D Wolff Rachel Yehuda Ross McD Young Keith A Young Hongyu Zhao Lori A Zoellner Israel Liberzon Kerry J Ressler Magali Haas Karestan C Koenen

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

Frontal Lobe Circuitry in Posttraumatic Stress Disorder.

Chronic Stress (Thousand Oaks) 2019 Jan-Dec/;3. Epub 2019 May 23.

Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.

Symptoms of posttraumatic stress disorder include hyperarousal, avoidance of trauma-related stimuli, re-experiencing of trauma, and mood changes. This review focuses on the frontal cortical areas that form crucial links in circuitry pertinent to posttraumatic stress disorder symptomatology: (1) the conditioned fear extinction circuit, (2) the salience circuit, and (3) the mood circuit. These frontal areas include the ventromedial prefrontal cortex (conditioned fear extinction), the dorsal anterior cingulate and insular cortices (salience), and the lateral orbitofrontal and subgenual cingulate cortices (mood). Frontal lobe structural abnormalities in posttraumatic stress disorder, including volumetric reductions in the cingulate cortices, impact all three circuits. Functional analyses of frontal cortices in posttraumatic stress disorder show abnormal activation in all three according to task demand and emotional valence. Network analyses reveal altered amygdalo-frontal connectivity and failure to suppress the default mode network during cognitive engagement. Spine shape alterations also have been detected in the medial orbito-frontal cortex in posttraumatic stress disorder postmortem brains, suggesting reduced synaptic plasticity. Importantly, frontal lobe abnormalities in posttraumatic stress disorder extend beyond emotion-related circuits to include the lateral prefrontal cortices that mediate executive functions. In conclusion, widespread frontal lobe dysfunction in posttraumatic stress disorder provides a neurobiologic basis for the core symptomatology of the disorder, as well as for executive function impairment.
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http://dx.doi.org/10.1177/2470547019850166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703563PMC
May 2019

Neurosteroid Levels in the Orbital Frontal Cortex of Subjects with PTSD and Controls: A Preliminary Report.

Chronic Stress (Thousand Oaks) 2019 Jan-Dec/;3. Epub 2019 Apr 18.

Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.

Background: Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD (n = 18) and controls (n = 35).

Methods: Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography - tandem mass spectrometry (GC/MS/MS).

Results: Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( = 0.03) compared to control males and females with PTSD had significantly increased levels of pregnenolone ( = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( = 2.37, = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( = -2.25, = 0.03) relative to control females.

Conclusions: To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and in a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC.
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http://dx.doi.org/10.1177/2470547019838570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604657PMC
April 2019

An epidemiological evaluation of trauma types in a cohort of deployed service members.

Psychol Trauma 2019 Nov 9;11(8):877-885. Epub 2019 May 9.

Department of Psychiatry and Behavioral Sciences, Duke University.

Objective: Using Stein et al.'s (2012) categorization scheme for typing Criterion A events (i.e., Life Threat to Self, Life Threat to Other, Aftermath of Violence, Traumatic Loss, Moral Injury by Self, and Moral Injury by Other) and extending Litz et al.'s (2018) prior work, we investigated the prevalence of trauma types, prevalence of posttraumatic stress disorder within each trauma type, and associations between trauma types and behavioral and mental health outcomes for an epidemiological sample of service members.

Method: Criterion A events coded by independent raters (kappas = .85-1.00) were used to determine prevalence rates and to conduct two path models examining all trauma types in relation to mental health outcomes.

Results: Consistent with prior research, we found events containing Life Threat to Self (51.1%) and Life Threat to Other (30.8%) to be most prevalent, and a majority of events (62.9%) were coded with one trauma type. Although least prevalent, Aftermath of Violence (12.0%) and Moral Injury by Self (4.8%) were most frequently and strongly associated with worse mental health outcomes. Path models predicted a very small amount of variance in continuous outcomes, thus limiting the interpretation of findings.

Conclusion: More epidemiological research is needed to understand the role of trauma type in relation to mental health among nontreatment-seeking service members. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/tra0000465DOI Listing
November 2019

The role of familial risk, parental psychopathology, and stress for first-onset depression during adolescence.

J Affect Disord 2019 06 22;253:232-239. Epub 2019 Apr 22.

Translational Center for Stress-Related Disorders, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States; Research Division, Durham Veterans Affairs Medical Center, Durham, NC, United States.

Background: Adolescence represents a critical developmental period during which the initial onset of depression emerges. Family risk for depression is a salient risk factor for the initial onset of Major Depressive Disorder (MDD). We examined the effects of familial risk, stress, and behavior on the risk of developing first-onset depression.

Methods: Adolescents aged 12 to 15 with high (n = 166) or low (n = 159) familial risk for depression were assessed annually for up to five years. Stress was assessed using the Stressful Life Events Schedule and Childhood Trauma Questionnaire. The Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version was administered to the adolescents and their parents to assess lifetime psychiatric conditions and diagnose MDD onset. Survival and path analyses were used in tandem to determine the risk for first-onset depression as well as the contributions of additional direct and indirect pathways to onset.

Results: High-risk adolescents were eight times more likely to develop first-onset depression compared with low-risk adolescents. The path analyses revealed that the presence of maternal behavioral disorders and increased recent life stress directly predicted an initial onset of MDD in high-risk adolescents.

Limitations: The small samples used in this study limit the generalizability of these findings.

Conclusions: Adolescents at high familial risk for depression had an increased risk for the emergence of first-onset depression during adolescence. Stress and maternal behavioral psychopathology directly contributed to depression onset independently of familial risk, while childhood trauma exerted an indirect effect on first-onset MDD through recent stress.
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http://dx.doi.org/10.1016/j.jad.2019.04.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620141PMC
June 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

Relative abundance of Akkermansia spp. and other bacterial phylotypes correlates with anxiety- and depressive-like behavior following social defeat in mice.

Sci Rep 2019 03 1;9(1):3281. Epub 2019 Mar 1.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 27710, USA.

As discussion of stress and stress-related disorders rapidly extends beyond the brain, gut microbiota have emerged as a promising contributor to individual differences in the risk of illness, disease course, and treatment response. Here, we employed chronic mild social defeat stress and 16S rRNA gene metagenomic sequencing to investigate the role of microbial composition in mediating anxiety- and depressive-like behavior. In socially defeated animals, we found significant reductions in the overall diversity and relative abundances of numerous bacterial genera, including Akkermansia spp., that positively correlated with behavioral metrics of both anxiety and depression. Functional analyses predicted a reduced frequency of signaling molecule pathways, including G-protein-coupled receptors, in defeated animals. Collectively, our data suggest that shifts in microbial composition may play a role in the pathogenesis of anxiety and depression.
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http://dx.doi.org/10.1038/s41598-019-40140-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397238PMC
March 2019

Comparative evaluation of a new magnetic bead-based DNA extraction method from fecal samples for downstream next-generation 16S rRNA gene sequencing.

PLoS One 2018 23;13(8):e0202858. Epub 2018 Aug 23.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.

We are colonized by a vast population of genetically diverse microbes, the majority of which are unculturable bacteria that reside within the gastrointestinal tract. As affordable, advanced next-generation sequencing technologies become more widely available, important discoveries about the composition and function of these microbes become increasingly possible. In addition to rapid advancement in sequencing technologies, automated systems have been developed for nucleic acid extraction; however, these methods have yet to be widely used for the isolation of bacterial DNA from fecal samples. Here, we adapted Promega's Maxwell® RSC PureFood GMO and Authentication kit for use with fecal samples and compared it to the commonly used Qiagen QIAamp® PowerFecal® kit. Results showed that the two approaches yielded similar measures of DNA purity and successful next-generation sequencing amplification and produced comparable composition of microbial communities. However, DNA extraction with the Maxwell® RSC kit produced higher concentrations with a lower fecal sample input weight and took a fraction of the time compared to the QIAamp® PowerFecal® protocol. The results of this study demonstrate that the Promega Maxwell® RSC system can be used for medium-throughput DNA extraction in a time-efficient manner without compromising the quality of the downstream sequencing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202858PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107275PMC
February 2019

Trajectories of Alcohol Initiation and Use During Adolescence: The Role of Stress and Amygdala Reactivity.

J Am Acad Child Adolesc Psychiatry 2018 08 18;57(8):550-560. Epub 2018 Jun 18.

Duke University, the Durham Veterans Affairs Medical Center, Durham, NC, and the University of Texas Health at San Antonio.

Objective: Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, little is known about developmental trajectories of alcohol use initiation and their putative biological and environmental correlates.

Method: Adolescents (N = 330) with high or low familial loading for depression were assessed annually for up to 6 years. Data were collected assessing affective symptoms, alcohol use, and stress at each assessment. Adolescents also participated in a functional magnetic resonance imaging protocol that included measurement of threat-related amygdala and reward-related ventral striatum activity.

Results: Latent class analyses identified 2 trajectories of alcohol use initiation. Early initiators (n = 32) reported greater baseline alcohol use and rate of change of use compared with late initiators and/or current abstainers (n = 298). Early initiators reported higher baseline levels of stressful life events (p = .001) and exhibited higher amygdala (p = .001) but not ventral striatum activity compared with late initiators. Early initiators were 15.3 times more likely to have a full drink (p < .0001), 9.1 times more likely to experience intoxication (p < .0001), and 6.7 times more likely to develop an alcohol use disorder by 19 years of age compared with late initiators (p = .003).

Conclusion: Adolescents on a trajectory of early alcohol use initiation have higher levels of stress, have increased threat-related amygdala activity, are more likely to consume a full standard alcoholic drink, are more likely to experience early intoxication, and are at a heightened risk for the onset of an alcohol use disorder.
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http://dx.doi.org/10.1016/j.jaac.2018.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396321PMC
August 2018

Intensive prolonged exposure therapy for combat-related posttraumatic stress disorder: Design and methodology of a randomized clinical trial.

Contemp Clin Trials 2018 09 25;72:126-136. Epub 2018 Jul 25.

VA Boston Healthcare System, Boston, MA, USA; Boston University, Boston, MA, USA. Electronic address:

Combat-related posttraumatic stress disorder (PTSD) is the most common psychological health condition in military service members and veterans who have deployed to the combat theater since September 11, 2001. One of the highest research priorities for the Department of Defense and the Department of Veterans Affairs is to develop and evaluate the most efficient and efficacious treatments possible for combat-related PTSD. However, the treatment of combat-related PTSD in military service members and veterans has been significantly more challenging than the treatment of PTSD in civilians. Randomized clinical trials have demonstrated large posttreatment effect sizes for PTSD in civilian populations. However, recent randomized clinical trials of service members and veterans have achieved lesser reductions in PTSD symptoms. These results suggest that combat-related PTSD is unique. Innovative approaches are needed to augment established evidence-based treatments with targeted interventions that address the distinctive elements of combat-related traumas. This paper describes the design, methodology, and protocol of a randomized clinical trial to compare two intensive prolonged exposure therapy treatments for combat-related PTSD in active duty military service members and veterans and that can be administered in an acceptable, efficient manner in this population. Both interventions include intensive daily treatment over a 3-week period and a number of treatment enhancements hypothesized to result in greater reductions in combat-related PTSD symptoms. The study is designed to advance the delivery of care for combat-related PTSD by developing and evaluating the most potent treatments possible to reduce PTSD symptomatology and improve psychological, social, and occupational functioning.
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http://dx.doi.org/10.1016/j.cct.2018.07.016DOI Listing
September 2018

Paradoxical associations between familial affective responsiveness, stress, and amygdala reactivity.

Emotion 2019 Jun 12;19(4):645-654. Epub 2018 Jul 12.

Laboratory of Neurogenetics.

Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving maps onto individual differences in threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/emo0000467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330163PMC
June 2019

Inflammatory markers as predictors of depression and anxiety in adolescents: Statistical model building with component-wise gradient boosting.

J Affect Disord 2018 07 12;234:276-281. Epub 2018 Mar 12.

Division of Translational Neuroscience, Department of Psychiatry and Behavioral Sciences, Duke University and the Durham VA Medical Center Durham, NC, USA.

Background: Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression and anxiety. However, whether specific immune mediators play an early role in the etiopathogenesis of these disorders remains unknown.

Methods: In a longitudinal design, component-wise gradient boosting was used to build models of depression, assessed by the Mood-Feelings Questionnaire-Child (MFQC), and anxiety, assessed by the Screen for Child Anxiety Related Emotional Disorders (SCARED) in 254 adolescents from a large set of candidate predictors, including sex, race, 39 inflammatory proteins, and the interactions between those proteins and time. Each model was reduced via backward elimination to maximize parsimony and generalizability.

Results: Component-wise gradient boosting and model reduction found that female sex, growth- regulated oncogene (GRO), and transforming growth factor alpha (TGF-alpha) predicted depression, while female sex predicted anxiety.

Limitations: Differential onset of puberty as well as a lack of control for menstrual cycle may also have been responsible for differences between males and females in the present study. In addition, investigation of all possible nonlinear relationships between the predictors and the outcomes was beyond the computational capacity and scope of the present research.

Conclusions: This study highlights the need for novel statistical modeling to identify reliable biological predictors of aberrant psychological behavior.
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http://dx.doi.org/10.1016/j.jad.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895481PMC
July 2018

Mothers' childhood hardship forecasts adverse pregnancy outcomes: Role of inflammatory, lifestyle, and psychosocial pathways.

Brain Behav Immun 2017 Oct 25;65:11-19. Epub 2017 Apr 25.

Center for Healthcare Studies, Northwestern University Feinberg School of Medicine, United States; Department of Obstetrics and Gynecology, NorthShore University Health System, University of Chicago, Pritzker School of Medicine, United States; Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, United States.

Research suggests the health consequences of economic hardship can be transmitted across generations. Some of these disparities are thought to be passed to offspring during gestation. But this hypothesis has not been tested in contemporary American samples, and the mechanisms of transmission have not been characterized. Accordingly, this study had two goals: first, to determine if women exposed to economic hardship during childhood showed higher rates of adverse birth outcomes; and second, to evaluate the contribution of inflammation, psychosocial, lifestyle, and obstetric characteristics to this phenomenon. This prospective study enrolled 744 women with singleton pregnancies (59.1% White; 16.3% Black; 18.7% Latina; 5.9% Other). Childhood economic hardship was measured by self-report. Birth outcomes included length of gestation and incidence of preterm birth; birth weight percentile and small for gestational age; length of hospital stay and admission to Special Care Nursery. Analyses revealed that mothers' childhood economic hardship was independently associated with multiple adverse birth outcomes, even following adjustment for demographics, maternal education, and obstetrical confounders. Women raised in economically disadvantaged conditions had shorter gestation length and higher preterm delivery rates. Their babies had lower birth weights, were more likely to be small for gestational age, stayed in the hospital longer, and had more Special Care Nursery admissions. Mediation analyses suggested these associations arose through multiple pathways, and highlighted roles for inflammation, education, adiposity, and obstetric complications. Collectively, these findings suggest that childhood economic hardship predisposes women to adverse birth outcomes, and highlights likely behavioral and biological mechanisms.
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http://dx.doi.org/10.1016/j.bbi.2017.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537016PMC
October 2017

Amygdala reactivity predicts adolescent antisocial behavior but not callous-unemotional traits.

Dev Cogn Neurosci 2017 04 27;24:84-92. Epub 2017 Feb 27.

Department of Psychiatry & Behavioral Sciences, Duke University, 417 Chapel Drive, Durham, NC 27708, USA; Durham VA Medical Center, 508 Fulton St, Durham, NC 27705, USA.

Recent neuroimaging studies have suggested divergent relationships between antisocial behavior (AB) and callous-unemotional (CU) traits and amygdala reactivity to fearful and angry facial expressions in adolescents. However, little work has examined if these findings extend to dimensional measures of behavior in ethnically diverse, non-clinical samples, or if participant sex, ethnicity, pubertal stage, and age moderate associations. We examined links between amygdala reactivity and dimensions of AB and CU traits in 220 Hispanic and non-Hispanic Caucasian adolescents (age 11-15; 49.5% female; 38.2% Hispanic), half of whom had a family history for depression and thus were at relatively elevated risk for late starting, emotionally dysregulated AB. We found that AB was significantly related to increased right amygdala reactivity to angry facial expressions independent of sex, ethnicity, pubertal stage, age, and familial risk status for depression. CU traits were not related to fear- or anger-related amygdala reactivity. The present study further demonstrates that AB is related to increased amygdala reactivity to interpersonal threat cues in adolescents, and that this relationship generalizes across sex, ethnicity, pubertal stage, age, and familial risk status for depression.
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http://dx.doi.org/10.1016/j.dcn.2017.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429212PMC
April 2017

Prevalence, Correlates, and Predictors of Insomnia in the US Army prior to Deployment.

Sleep 2016 Oct 1;39(10):1795-1806. Epub 2016 Oct 1.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC.

Study Objectives: To determine the prevalence, correlates, and predictors of insomnia in US Army personnel prior to deployment.

Methods: Cross-sectional cohort design assessing insomnia and other psychosocial variables in active duty service members (n = 4,101), at Fort Hood, Texas, prior to military deployment. Insomnia was defined as an Insomnia Severity Index ≥ 15.

Results: The prevalence of insomnia was 19.9%. Enlisted personnel were five times more likely to report insomnia than officers (odds ratio [OR] = 5.17). Insomnia was higher among American Indian/Alaskan Natives than other groups (ORs = 1.86-2.85). Those in the Insomnia Group were older, had longer military careers, and reported more marriages, children, and military deployments (s = 0.13-0.34) than the No Insomnia group. The Insomnia Group reported more severe mental health symptoms, more recent stressful life events, greater childhood abuse, and lower levels of trait resilience, social support, and unit cohesion (Cohen s = 0.27-1.29). After controlling for covariates, the Insomnia Group was more likely to have a history of head injuries and clinically significant posttraumatic stress disorder (PTSD), anxiety, depression, alcohol use problems, back pain, extremity pain, headaches, and fatigue (ORs = 1.40-3.30). A simultaneous logistic regression found that greater PTSD, depression, fatigue, stressful life events, headaches, anxiety, alcohol use problems, extremity pain, history of head injury, childhood physical neglect, back pain, number of times married, and lower leader support/unit cohesion and tangible social support were statistically significant predictors of insomnia status.

Conclusions: Insomnia occurs in about one of five service members prior to a military deployment and is associated with a wide array of psychosocial stressors and mental and physical health problems.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020361PMC
http://dx.doi.org/10.5665/sleep.6156DOI Listing
October 2016

An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents.

Mol Psychiatry 2017 02 24;22(2):209-214. Epub 2016 May 24.

Division of Translational Neuroscience, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27708 USA.

Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.
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http://dx.doi.org/10.1038/mp.2016.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122474PMC
February 2017

BA11 FKBP5 expression levels correlate with dendritic spine density in postmortem PTSD and controls.

Neurobiol Stress 2015 3;2:67-72. Epub 2015 Sep 3.

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

Genetic variants of the immunophilin FKBP5 have been implicated in susceptibility to post-traumatic stress disorder (PTSD) and other stress-related disorders. We examined the relationship between mushroom, stubby, thin and filopodial spine densities measured with Golgi staining and FKBP5 gene expression in the medial orbitofrontal cortex (BA11) in individuals diagnosed with PTSD and normal controls (n = 8/8). ANCOVA revealed PTSD cases had a significantly elevated density of stubby spines (29%, P < 0.037) and a trend for a reduction in mushroom spine density (25%, p < 0.082). Levels of FKBP5 mRNA were marginally elevated in the PTSD cases (z = 1.94, p = 0.053) and levels correlated inversely with mushroom (Spearman's rho = -0.83, p < 0.001) and overall spine density (rho = -0.75, p < 0.002) and directly with stubby spine density (rho = 0.55, p < 0.027). These data suggest that FKBP5 may participate in a cellular pathway modulating neuronal spine density changes in the brain, and that this pathway may be dysregulated in PTSD.
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http://dx.doi.org/10.1016/j.ynstr.2015.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721476PMC
February 2016

Depression, obesity, and metabolic syndrome: prevalence and risks of comorbidity in a population-based representative sample of Mexican Americans.

J Clin Psychiatry 2015 Oct;76(10):e1300-5

Department of Psychiatry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229

Introduction: We examined the prevalence of depression, obesity, and metabolic syndrome and associations between them in a population-based representative cohort of Mexican Americans living on the United States-Mexico border.

Method: The sample in this cross-sectional analysis consisted of 1,768 Mexican American adults (≥ 18 years of age) assessed between the years 2004 and 2010, with whom we tested our central hypothesis of a significant relationship between obesity and depression. Depression was measured using the Center for Epidemiologic Studies-Depression scale (CES-D) with a cutoff score of ≥ 16 for depression and a cutoff score of ≥ 27 for severe depression. We categorized body mass index (BMI) values as obese (≥ 30kg/m(2)) and later subdivided the obese subjects into obese (30-39 kg/m(2)[inclusive]) and morbidly obese (≥ 40 kg/m(2)). Metabolic syndrome was defined using the American Heart Association definition requiring at least 3 of the following: increased waist circumference, elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure, and elevated fasting glucose. Weighted data were analyzed to establish prevalence of depression, obesity, and metabolic syndrome. Univariate and multivariable weighted regression models were used to test potential associations between these disorders.

Results: Using weighted prevalence, we observed high rates of depression (30%), obesity (52%), and metabolic syndrome (45%). Univariate models revealed female gender (P = .0004), low education (P = .003), low HDL level (P = .009), and increased waist circumference (P = .03) were associated with depression. Female gender (P = .01), low education (P = .003), and morbid obesity (P = .002) were risk factors for severe depression and remained significant in multivariable models.

Conclusions: In this large cohort of Mexican Americans, obesity, female gender, and low education were identified risk factors for depression. These indicators may serve as targets for early detection, prevention, and intervention in this population.
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http://dx.doi.org/10.4088/JCP.14m09118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836315PMC
October 2015

Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms.

Biol Psychiatry 2015 Nov 27;78(9):598-605. Epub 2015 May 27.

Department of Psychiatry, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas.

Background: Emotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect.

Methods: We examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later.

Results: We found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology.

Conclusions: Our results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes.
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http://dx.doi.org/10.1016/j.biopsych.2015.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593720PMC
November 2015

Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data.

Neuroimage 2015 May 4;111:300-11. Epub 2015 Mar 4.

Anatomy & Neurobiology Department, Washington University in St. Louis, St. Louis, USA.

The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h(2)=0.53-0.90, p<10(-5)), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application.
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http://dx.doi.org/10.1016/j.neuroimage.2015.02.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387079PMC
May 2015

Resting-state regional cerebral blood flow during adolescence: associations with initiation of substance use and prediction of future use disorders.

Drug Alcohol Depend 2015 Apr 20;149:40-8. Epub 2015 Jan 20.

Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Departments of Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.

Background: Adolescence is a period of developmental flux when brain systems are vulnerable to influences of early substance use, which in turn relays increased risk for substance use disorders. Our study intent was to assess adolescent regional cerebral blood flow (rCBF) as it relates to current and future alcohol use. The aim was to identify brain-based predictors for initiation of alcohol use and onset of future substance use disorders.

Methods: Quantitative rCBF was assessed in 100 adolescents (age 12-15). Prospective behavioral assessments were conducted annually over a three-year follow-up period to characterize onset of alcohol initiation, future drinking patterns and use disorders. Comparisons amongst use groups (i.e., current-, future-, and non-alcohol using adolescents) identified rCBF associated with initiation of alcohol use. Regression by future drinking patterns identified rCBF predictive of heavier drinking. Survival analysis determined whether or not baseline rCBF predicted later development of use disorders.

Results: Baseline rCBF was decreased to the parietal cortex and increased to mesolimbic regions in adolescents currently using alcohol as well as those who would use alcohol in the future. Higher baseline rCBF to the left fusiform gyrus and lower rCBF to the right inferior parietal cortex and left cerebellum was associated with future drinking patterns as well as predicted the onset of alcohol and substance use disorders in this cohort.

Conclusions: Variations in resting rCBF to regions within reward and default mode or control networks appear to represent trait markers of alcohol use initiation and are predictive of future development of use disorders.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361292PMC
April 2015