publications

2022

1. Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results from the ENIGMA-PGC PTSD Consortium

   Sun, Delin, Rakesh, Gopalkumar, Clarke-Rubright, Emily K, Haswell, Courtney C, Logue, Mark, O’Leary, Erin N, Cotton, Andrew S, Xie, Hong, Dennis, Emily L, Jahanshad, Neda, Salminen, Lauren E, Thomopoulos, Sophia I, Rashid, Faisal, Ching, Christopher R K, Koch, Saskia B J, Frijling, Jessie L, Nawijn, Laura, Zuiden, Mirjam, Zhu, Xi, Suarez-Jimenez, Benjamin, Sierk, Anika, Walter, Henrik, Manthey, Antje, Stevens, Jennifer S, Fani, Negar, Rooij, Sanne J H, Stein, Murray, Bomyea, Jessica, Koerte, Inga, Choi, Kyle, Werff, Steven J A, Vermeiren, Robert R J M, Herzog, Julia, Lebois, Lauren A M, Baker, Justin T, Ressler, Kerry J, Olson, Elizabeth A, Straube, Thomas, Korgaonkar, Mayuresh S, Andrew, Elpiniki, Zhu, Ye, Li, Gen, Ipser, Jonathan, Hudson, Anna,  Peverill, Matthew, Sambrook, Kelly, Gordon, Evan, Baugh, Lee, Forster, Gina, Simons, Raluca, Simons, Jeffrey, Magnotta, Vincent, Maron-Katz, Adi, Plessis, Stefan, Disner, Seth, Davenport, Nicholas, Grupe, Dan, Nitschke, Jack, deRoon-Cassini, Terri A, Fitzgerald, Jacklynn, Krystal, John H, Levy, Ifat, Olff, Miranda, Veltman, Dick J, Wang, Li, Neria, Yuval, De Bellis, Michael D, Jovanovic, Tanja, Daniels, Judith K, Shenton, Martha, Wee, Nic J A, Schmahl, Christian, Kaufman, Milissa L, Rosso, Isabelle M, Sponheim, Scott R, Hofmann, David Bernd, Bryant, Richard A, Fercho, Kelene A, Stein, Dan J, Mueller, Sven C, Phan, Luan, McLaughlin, Katie A, Davidson, Richard J, Larson, Christine, May, Geoffrey, Nelson, Steven M, Abdallah, Chadi G, Gomaa, Hassaan, Etkin, Amit, Seedat, Soraya, Harpaz-Rotem, Ilan, Liberzon, Israel, Wang, Xin, Thompson, Paul M, and Morey, Rajendra A

   Biological psychiatry. Cognitive neuroscience and neuroimaging Mar 2022

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   BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA).METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in \textgreater1,300 PTSD cases and \textgreater2,000 trauma-exposed controls (age 6.2-85.2 years) by the ENIGMA-PGC PTSD working group. Cortical regions in the network were rank-ordered by effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2 to 148) regions with the largest effect size for PTSD \textgreater non-PTSD formed hypertrophic networks, the largest effect size for PTSD \textless non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared to the mean SC of 5,000 randomly generated n-region networks.RESULTS: Patients with PTSD, relative to non-PTSD controls, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex and age modulated covariance differences of PTSD-related structural networks.CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The structural covariance networks that are perturbed in PTSD comport with converging evidence from resting state functional connectivity networks and networks impacted by inflammatory processes, and stress hormones in PTSD.

2. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

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

   Biological Psychiatry Apr 2022

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   Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

3. A comparison of methods to harmonize cortical thickness measurements across scanners and sites

   Sun, Delin, Rakesh, Gopalkumar, Haswell, Courtney C., Logue, Mark, Baird, C. Lexi, O’Leary, Erin N., Cotton, Andrew S., Xie, Hong, Tamburrino, Marijo, Chen, Tian, Dennis, Emily L., Jahanshad, Neda, Salminen, Lauren E., Thomopoulos, Sophia I., Rashid, Faisal, Ching, Christopher R. K., Koch, Saskia B. J., Frijling, Jessie L., Nawijn, Laura, Zuiden, Mirjam, Zhu, Xi, Suarez-Jimenez, Benjamin, Sierk, Anika, Walter, Henrik, Manthey, Antje, Stevens, Jennifer S., Fani, Negar, Rooij, Sanne J. H., Stein, Murray, Bomyea, Jessica, Koerte, Inga K., Choi, Kyle, Werff, Steven J. A., Vermeiren, Robert R. J. M., Herzog, Julia, Lebois, Lauren A. M., Baker, Justin T., Olson, Elizabeth A., Straube, Thomas, Korgaonkar, Mayuresh S., Andrew, Elpiniki, Zhu, Ye, Li, Gen, Ipser, Jonathan, Hudson, Anna R.,  Peverill, Matthew, Sambrook, Kelly, Gordon, Evan, Baugh, Lee, Forster, Gina, Simons, Raluca M., Simons, Jeffrey S., Magnotta, Vincent, Maron-Katz, Adi, Plessis, Stefan, Disner, Seth G., Davenport, Nicholas, Grupe, Daniel W., Nitschke, Jack B., deRoon-Cassini, Terri A., Fitzgerald, Jacklynn M., Krystal, John H., Levy, Ifat, Olff, Miranda, Veltman, Dick J., Wang, Li, Neria, Yuval, De Bellis, Michael D., Jovanovic, Tanja, Daniels, Judith K., Shenton, Martha, Wee, Nic J. A., Schmahl, Christian, Kaufman, Milissa L., Rosso, Isabelle M., Sponheim, Scott R., Hofmann, David Bernd, Bryant, Richard A., Fercho, Kelene A., Stein, Dan J., Mueller, Sven C., Hosseini, Bobak, Phan, K. Luan, McLaughlin, Katie A., Davidson, Richard J., Larson, Christine L., May, Geoffrey, Nelson, Steven M., Abdallah, Chadi G., Gomaa, Hassaan, Etkin, Amit, Seedat, Soraya, Harpaz-Rotem, Ilan, Liberzon, Israel, Erp, Theo G. M., Quidé, Yann, Wang, Xin, Thompson, Paul M., and Morey, Rajendra A.

   NeuroImage Nov 2022

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   Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p \textless 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values \textless 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values \textless 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values \textless 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values \textless 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values \textless 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

4. Rare copy number variation in posttraumatic stress disorder

   Maihofer, Adam X., Engchuan, Worrawat, Huguet, Guillaume, Klein, Marieke, MacDonald, Jeffrey R., Shanta, Omar, Thiruvahindrapuram, Bhooma, Jean-louis, Martineau, Saci, Zohra, Jacquemont, Sebastien, Scherer, Stephen W., Ketema, Elizabeth, Aiello, Allison E., Amstadter, Ananda B., Avdibegović, Esmina, Babic, Dragan, Baker, Dewleen G., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Bryant, Richard A., Bustamante, Angela C., Caldas-de-Almeida, Jose Miguel, Cardoso, Graça, Deckert, Jurgen, Delahanty, Douglas L., Domschke, Katharina, Dunlop, Boadie W., Dzubur-Kulenovic, Alma, Evans, Alexandra, Feeny, Norah C., Franz, Carol E., Gautam, Aarti, Geuze, Elbert, Goci, Aferdita, Hammamieh, Rasha, Jakovljevic, Miro, Jett, Marti, Jones, Ian, Kaufman, Milissa L., Kessler, Ronald C., King, Anthony P., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A. M., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Mavissakalian, Matig R., McLaughlin, Katie A., McLean, Samuel A., Mehta, Divya, Mellor, Rebecca, Morris, Charles Phillip, Muhie, Seid, Orcutt, Holly K.,  Peverill, Matthew, Ratanatharathorn, Andrew, Risbrough, Victoria B., Rizzo, Albert, Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rutten, Bart P. F., Schijven, Dick, Seng, Julia S., Sheerin, Christina M., Sorenson, Michael A., Teicher, Martin H., Uddin, Monica, Ursano, Robert J., Vinkers, Christiaan H., Voisey, Joanne, Weber, Heike, Winternitz, Sherry, Xavier, Miguel, Yang, Ruoting, McD Young, Ross, Zoellner, Lori A., Salem, Rany M., Shaffer, Richard A., Wu, Tianying, Ressler, Kerry J., Stein, Murray B., Koenen, Karestan C., Sebat, Jonathan, and Nievergelt, Caroline M.

   Molecular Psychiatry Sep 2022

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   Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q \textless 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

2021

1. Alterations in neural circuits underlying emotion regulation following child maltreatment: a mechanism underlying trauma-related psychopathology

   Jenness, Jessica L.,  Peverill, Matthew, Miller, Adam Bryant, Heleniak, Charlotte, Robertson, Madeline M., Sambrook, Kelly A., Sheridan, Margaret A., and McLaughlin, Katie A.

   Psychological Medicine Sep 2021

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   BackgroundDisruptions in neural circuits underlying emotion regulation (ER) may be a mechanism linking child maltreatment with psychopathology. We examined the associations of maltreatment with neural responses during passive viewing of negative emotional stimuli and attempts to modulate emotional responses. We investigated whether the influence of maltreatment on neural activation during ER differed across development and whether alterations in brain function mediated the association between maltreatment and a latent general psychopathology (‘p’) factor.MethodsYouth aged 8–16 years with (n = 79) and without (n = 72) exposure to maltreatment completed an ER task assessing neural responses during passive viewing of negative and neutral images and effortful attempts to regulate emotional responses to negative stimuli. P-factor scores were defined by a bi-factor model encompassing internalizing and externalizing psychopathology.ResultsMaltreated youth had greater activation in left amygdala and salience processing regions and reduced activation in multiple regions involved in cognitive control (bilateral superior frontal gyrus, middle frontal gyrus, and dorsal anterior cingulate cortex) when viewing negative v. neutral images than youth without maltreatment exposure. Reduced neural recruitment in cognitive control regions mediated the association of maltreatment with p-factor in whole-brain analysis. Maltreated youth exhibited increasing recruitment with age in ventrolateral prefrontal cortex during reappraisal while control participants exhibited decreasing recruitment with age. Findings were similar after adjusting for co-occurring neglect.ConclusionsChild maltreatment influences the development of regions associated with salience processing and cognitive control during ER in ways that contribute to psychopathology.

2. Socioeconomic status and child psychopathology in the United States: A meta-analysis of population-based studies

   Peverill, Matthew, Dirks, Melanie A., Narvaja, Tomás, Herts, Kate L., Comer, Jonathan S., and McLaughlin, Katie A.

   Clinical Psychology Review Sep 2021

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   Children raised in families with low socioeconomic status (SES) are more likely to exhibit symptoms of psychopathology. However, the strength of this association, the specific indices of SES most strongly associated with childhood psychopathology, and factors moderating the association are strikingly inconsistent across studies. We conducted a meta-analysis of 120 estimates of the association between family SES and child psychopathology in 13 population-representative cohorts of children studied in the US since 1980. Among 26,715 participants aged 3–19 years, we observed small to moderate associations of low family income (g = 0.19), low Hollingshead index (g = 0.21), low subjective SES (g = 0.24), low parental education (g = 0.25), poverty status (g = 0.25), and receipt of public assistance (g = 0.32) with higher levels of childhood psychopathology. Moderator testing revealed that receipt of public assistance showed an especially strong association with psychopathology and that SES was more strongly related to externalizing than internalizing psychopathology. Dispersion in our final, random effects, model suggested that the relation between SES and child psychopathology is likely to vary in different populations of children and in different communities. These findings highlight the need for additional research on the mechanisms of SES-related psychopathology risk in children in order to identify targets for potential intervention.

3. Structural Covariance Networks in Post-Traumatic Stress Disorder: A Multisite ENIGMA-PGC Study

   Rakesh, Gopalkumar, Sun, Delin, Logue, Mark, Clarke-Rubright, Emily, O’Leary, Brian M, Haswell, Courtney, Xie, Hong, Thompson, Paul, Dennis, Emily, Jahanshad, Neda, and others,

   bioRxiv Sep 2021
4. Executive function as a mechanism linking socioeconomic status to internalizing and externalizing psychopathology in children and adolescents

   McNeilly, Elizabeth A,  Peverill, Matthew, Jung, Jiwon, and McLaughlin, Katie A

   Journal of Adolescence Sep 2021
5. Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume

   Zheng, Yuanchao, Garrett, Melanie E., Sun, Delin, Clarke-Rubright, Emily K., Haswell, Courtney C., Maihofer, Adam X., Elman, Jeremy A., Franz, Carol E., Lyons, Michael J., Kremen, William S.,  Peverill, Matthew, Sambrook, Kelly, McLaughlin, Katie A., Davenport, Nicholas D., Disner, Seth, Sponheim, Scott R., Andrew, Elpiniki, Korgaonkar, Mayuresh, Bryant, Richard, Varkevisser, Tim, Geuze, Elbert, Coleman, Jonathan, Beckham, Jean C., Kimbrel, Nathan A., Sullivan, Danielle, Miller, Mark, Hayes, Jasmeet, Verfaellie, Mieke, Wolf, Erika, Salat, David, Spielberg, Jeffrey M., Milberg, William, McGlinchey, Regina, Dennis, Emily L., Thompson, Paul M., Medland, Sarah, Jahanshad, Neda, Nievergelt, Caroline M., Ashley-Koch, Allison E., Logue, Mark W., and Morey, Rajendra A.

   Translational Psychiatry Dec 2021

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   The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10−20), thalamus (p = 7.46 × 10−10), caudate (p = 1.97 × 10−18), putamen (p = 1.7 × 10−12), and nucleus accumbens (p = 1.99 × 10−7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = −0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p \textless 1 × 10−19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10−7) or PTSD (rs10861272; p = 1.78 × 10−6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

2020

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

   Wang, Xin, Xie, Hong, Chen, Tian, Cotton, Andrew S., Salminen, Lauren E., Logue, Mark W., Clarke-Rubright, Emily K., Wall, John, Dennis, Emily L., O’Leary, Brian M., Abdallah, Chadi G., Andrew, Elpiniki, Baugh, Lee A., Bomyea, Jessica, Bruce, Steven E., Bryant, Richard, Choi, Kyle, Daniels, Judith K., Davenport, Nicholas D., Davidson, Richard J., DeBellis, Michael, deRoon-Cassini, Terri, Disner, Seth G., Fani, Negar, Fercho, Kelene A., Fitzgerald, Jacklynn, Forster, Gina L., Frijling, Jessie L., Geuze, Elbert, Gomaa, Hassaan, Gordon, Evan M., Grupe, Dan, Harpaz-Rotem, Ilan, Haswell, Courtney C., Herzog, Julia I., Hofmann, David, Hollifield, Michael, Hosseini, Bobak, Hudson, Anna R., Ipser, Jonathan, Jahanshad, Neda, Jovanovic, Tanja, Kaufman, Milissa L., King, Anthony P., Koch, Saskia B. J., Koerte, Inga K., Korgaonkar, Mayuresh S., Krystal, John H., Larson, Christine, Lebois, Lauren A. M., Levy, Ifat, Li, Gen, Magnotta, Vincent A., Manthey, Antje, May, Geoffrey, McLaughlin, Katie A., Mueller, Sven C., Nawijn, Laura, Nelson, Steven M., Neria, Yuval, Nitschke, Jack B., Olff, Miranda, Olson, Elizabeth A.,  Peverill, Matthew, Luan Phan, K., Rashid, Faisal M., Ressler, Kerry, Rosso, Isabelle M., Sambrook, Kelly, Schmahl, Christian, Shenton, Martha E., Sierk, Anika, Simons, Jeffrey S., Simons, Raluca M., Sponheim, Scott R., Stein, Murray B., Stein, Dan J., Stevens, Jennifer S., Straube, Thomas, Suarez-Jimenez, Benjamin, Tamburrino, Marijo, Thomopoulos, Sophia I., Wee, Nic J. A., Werff, Steven J. A., Erp, Theo G. M., Rooij, Sanne J. H., Zuiden, Mirjam, Varkevisser, Tim, Veltman, Dick J., Vermeiren, Robert R. J. M., Walter, Henrik, Wang, Li, Zhu, Ye, Zhu, Xi, Thompson, Paul M., Morey, Rajendra A., and Liberzon, Israel

   Molecular Psychiatry Dec 2020

   Abs

   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 \textless 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.

2. Reduced hippocampal and amygdala volume as a mechanism underlying stress sensitization to depression following childhood trauma

   Weissman, David G., Lambert, Hilary K., Rodman, Alexandra M.,  Peverill, Matthew, Sheridan, Margaret A., and McLaughlin, Katie A.

   Depression and Anxiety Dec 2020

   Abs

   Background Stressful life events are more likely to trigger depression among individuals exposed to childhood adversity. However, the mechanisms underlying this stress sensitization remain largely unknown. Any such mechanism must be altered by childhood adversity and interact with recent stressful life events, magnifying their association with depression. Aim This study investigated whether reduced hippocampal and amygdala volume are potential mechanisms underlying stress sensitization following childhood violence exposure. Method A sample of 149 youth (aged 8–17 years), with (N = 75) and without (N = 74) exposure to physical abuse, sexual abuse, or domestic violence participated. Participants completed a structural MRI scan and assessments of depression. Approximately 2 years later, stressful life events were assessed along with depression symptoms in 120 participants (57 violence exposed). Results Childhood violence exposure was associated with smaller hippocampal and amygdala volume. Stressful life events occurring during the follow-up period predicted worsening depression over time, and this association was magnified among those with smaller hippocampal and amygdala volumes. Significant moderated mediation models revealed the indirect effects of violence exposure on increasing depression over time through hippocampal and amygdala volumes, particularly among youths who experienced more stressful life events. Conclusions These results provide evidence for reduced hippocampal and amygdala volume as potential mechanisms of stress sensitization to depression following exposure to violence. More broadly, these patterns suggest that hippocampal and amygdala-mediated emotional and cognitive processes may confer vulnerability to stressful life events among children who have experienced violence.

3. Molecular genetic overlap between posttraumatic stress disorder and sleep phenotypes

   Lind, Mackenzie J, Brick, Leslie A, Gehrman, Philip R, Duncan, Laramie E, Gelaye, Bizu, Maihofer, Adam X, Nievergelt, Caroline M, Nugent, Nicole R, Stein, Murray B, and Amstadter, Ananda B

   Sleep Apr 2020

   Abs

   Study Objectives Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes). Methods Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations. Results Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36–0.49), oversleeping (rg range 0.32–0.44), undersleeping (rg range 0.48–0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD. Conclusion Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.

2019

1. Dynamic associations between stressful life events and adolescent internalizing psychopathology in a multiwave longitudinal study

   Jenness, Jessica L.,  Peverill, Matthew, King, Kevin M., Hankin, Benjamin L., and McLaughlin, Katie A.

   Journal of Abnormal Psychology Aug 2019

   Abs

   Associations between stressful life events (SLEs) and internalizing psychopathology are complex and bidirectional, involving interactions among stressors across development to predict psychopathology (i.e., stress sensitization) and psychopathology predicting greater exposure to SLEs (i.e., stress generation). Although stress sensitization and generation theoretical models inherently focus on within-person effects, most previous research has compared average levels of stress and psychopathology across individuals in a sample (i.e., between-person effects). The present study addressed this gap by investigating stress sensitization and stress generation effects in a multiwave, prospective study of SLEs and adolescent depression and anxiety symptoms. Depression, anxiety, and SLE exposure were assessed every 3 months for 2 years (8 waves of data) in a sample of adolescents (n = 382, aged 11 to 15 at baseline). Multilevel modeling revealed within-person stress sensitization effects such that the association between within-person increases in SLEs and depression, but not anxiety, symptoms were stronger among adolescents who experienced higher average levels of SLEs across 2 years. We also observed within-person stress generation effects, such that adolescents reported a greater number of dependent-interpersonal SLEs during time periods after experiencing higher levels of depression at the previous wave than was typical for them. Although no within-person stress generation effects emerged for anxiety, higher overall levels of anxiety predicted greater exposure to dependent-interpersonal SLEs. Our findings extend prior work by demonstrating stress sensitization in predicting depression following normative forms of SLEs and stress generation effects for both depression and anxiety using a multilevel modeling approach. Clinical implications include an individualized approach to interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

2. Atypical Prefrontal–Amygdala Circuitry Following Childhood Exposure to Abuse: Links With Adolescent Psychopathology

   Peverill, Matthew, Sheridan, Margaret A., Busso, Daniel S., and McLaughlin, Katie A.

   Child Maltreatment May 2019

   Abs

   Adverse childhood experiences have been associated with more negative coupling between the ventromedial prefrontal cortex (vmPFC) and amygdala, a brain network involved in emotion regulation in both children and adults. This pattern may be particularly likely to emerge in individuals exposed to threatening experiences during childhood (e.g., exposure to child abuse), although this has not been examined in prior research. We collected functional magnetic resonance imaging data on 57 adolescents during an emotion regulation task. Greater negative functional connectivity between vmPFC and amygdala occurred during viewing of negative compared to neutral images. This vmPFC-amygdala task-related functional connectivity was more negative in adolescents exposed to physical, sexual, or emotional abuse than those without a history of maltreatment and was associated with abuse severity. This pattern of more negative functional connectivity was associated with higher levels of externalizing psychopathology concurrently and 2 years later. Greater negative connectivity in the vmPFC-amygdala network during passive viewing of negative images may reflect disengagement of regulatory responses from vmPFC in situations eliciting strong amygdala reactivity, potentially due to stronger appraisals of threat in children exposed to early threatening environments. This pattern may be adaptive in the short term but place adolescents at higher risk of psychopathology later in life.

3. Altered development of hippocampus-dependent associative learning following early-life adversity

   Lambert, Hilary K.,  Peverill, Matthew, Sambrook, Kelly A., Rosen, Maya L., Sheridan, Margaret A., and McLaughlin, Katie A.

   Developmental Cognitive Neuroscience Aug 2019

   Abs

   Little is known about how childhood adversity influences the development of learning and memory and underlying neural circuits. We examined whether violence exposure in childhood influenced hippocampus-dependent associative learning and whether differences: a) were broad or specific to threat cues, and b) exhibited developmental variation. Children (n = 59; 8–19 years, 24 violence-exposed) completed an associative learning task with angry, happy, and neutral faces paired with objects during fMRI scanning. Outside the scanner, participants completed an associative memory test for face-object pairings. Violence-exposed children exhibited broad associative memory difficulties that became more pronounced with age, along with reduced recruitment of the hippocampus and atypical recruitment of fronto-parietal regions during encoding. Violence-exposed children also showed selective disruption of associative memory for threat cues regardless of age, along with reduced recruitment of the intraparietal sulcus (IPS) during encoding in the presence of threat. Broad associative learning difficulties may be a functional consequence of the toxic effects of early-life stress on hippocampal and fronto-parietal cortical development. Difficulties in the presence of threat cues may result from enhanced threat processing that disrupts encoding and short-term storage of associative information in the IPS. These associative learning difficulties may contribute to poor life outcomes following childhood violence exposure.

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

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

   Nature Communications Oct 2019

   Abs

   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.

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

   Dennis, Emily L., Disner, Seth G., Fani, Negar, Salminen, Lauren E., Logue, Mark, Clarke, Emily K., Haswell, Courtney C., Averill, Christopher L., Baugh, Lee A., Bomyea, Jessica, Bruce, Steven E., Cha, Jiook, Choi, Kyle, Davenport, Nicholas D., Densmore, Maria, Plessis, Stefan, Forster, Gina L., Frijling, Jessie L., Gonenc, Atilla, Gruber, Staci, Grupe, Daniel W., Guenette, Jeffrey P., Hayes, Jasmeet, Hofmann, David, Ipser, Jonathan, Jovanovic, Tanja, Kelly, Sinead, Kennis, Mitzy, Kinzel, Philipp, Koch, Saskia B. J., Koerte, Inga, Koopowitz, Sheri, Korgaonkar, Mayuresh, Krystal, John, Lebois, Lauren A. M., Li, Gen, Magnotta, Vincent A., Manthey, Antje, May, Geoff J., Menefee, Deleene S., Nawijn, Laura, Nelson, Steven M., Neufeld, Richard W. J., Nitschke, Jack B., O’Doherty, Daniel,  Peverill, Matthew, Ressler, Kerry J., Roos, Annerine, Sheridan, Margaret A., Sierk, Anika, Simmons, Alan, Simons, Raluca M., Simons, Jeffrey S., Stevens, Jennifer, Suarez-Jimenez, Benjamin, Sullivan, Danielle R., Théberge, Jean, Tran, Jana K., Heuvel, Leigh, Werff, Steven J. A., Rooij, Sanne J. H., Zuiden, Mirjam, Velez, Carmen, Verfaellie, Mieke, Vermeiren, Robert R. J. M., Wade, Benjamin S. C., Wager, Tor, Walter, Henrik, Winternitz, Sherry, Wolff, Jonathan, York, Gerald, Zhu, Ye, Zhu, Xi, Abdallah, Chadi G., Bryant, Richard, Daniels, Judith K., Davidson, Richard J., Fercho, Kelene A., Franz, Carol, Geuze, Elbert, Gordon, Evan M., Kaufman, Milissa L., Kremen, William S., Lagopoulos, Jim, Lanius, Ruth A., Lyons, Michael J., McCauley, Stephen R., McGlinchey, Regina, McLaughlin, Katie A., Milberg, William, Neria, Yuval, Olff, Miranda, Seedat, Soraya, Shenton, Martha, Sponheim, Scott R., Stein, Dan J., Stein, Murray B., Straube, Thomas, Tate, David F., Wee, Nic J. A., Veltman, Dick J., Wang, Li, Wilde, Elisabeth A., Thompson, Paul M., Kochunov, Peter, Jahanshad, Neda, and Morey, Rajendra A.

   Molecular Psychiatry Dec 2019

   Abs

   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.

6. Association of Economic Status and Educational Attainment With Posttraumatic Stress Disorder: A Mendelian Randomization Study

   Polimanti, Renato, Ratanatharathorn, Andrew, Maihofer, Adam X., Choi, Karmel W., Stein, Murray B., Morey, Rajendra A., Logue, Mark W., Nievergelt, Caroline M., Stein, Dan J., Koenen, Karestan C., Gelernter, Joel, and for the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group,

   JAMA Network Open May 2019

   Abs

   There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood.To investigate the association of PTSD with traits related to EA.Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018.Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR.Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (rg = −0.26; SE = 0.05; P = 4.60 × 10−8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (β = −0.23; 95% CI, −0.07 to −0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA (trauma exposure: β = 0.37; 95% CI, 0.19 to 0.52; P = 2.57 × 10−5; risk-taking: β = 0.76; 95% CI, 0.38 to 1.13; P = 1.13 × 10−4), while income may mediate the association of EA with PSTD (MR income: β = −0.18; 95% CI, −0.29 to −0.07; P = .001; MR EA: β = −0.23; 95% CI, −0.39 to −0.07; P = .004; multivariable MR income: β = −0.32; 95% CI, −0.57 to 0.07; P = .02; multivariable MR EA: β = −0.04; 95% CI, −0.29 to 0.21; SE, 0.13; P = .79).Large-scale genomic data sets add further evidence to the negative association of EA with PTSD, also supporting the role of economic status as a mediator in the association observed.

2018

1. Smaller hippocampal volume in posttraumatic stress disorder: a multisite ENIGMA-PGC study: subcortical volumetry results from posttraumatic stress disorder consortia

   Logue, M.W., van, Rooij, Dennis, E.L., Davis, S.L., Hayes, J.P., Stevens, J.S., Densmore, M., Haswell, C.C., Ipser, J., Koch, S.B.J., Korgaonkar, M., Lebois, L.A.M., Peverill, M., Baker, J.T., Boedhoe, P.S.W., Frijling, J.L., Gruber, S.A., Harpaz-Rotem, I., Jahanshad, N., Koopowitz, S., Levy, I., Nawijn, L., O’Connor, L., Olff, M., Salat, D.H., Sheridan, M.A., Spielberg, J.M., van, Zuiden, Winternitz, S.R., Wolff, J.D., Wolf, E.J., Wang, X., Wrocklage, K., Abdallah, C.G., Bryant, R.A., Geuze, E., Jovanovic, T., Kaufman, M.L., King, A.P., Krystal, J.H., Lagopoulos, J., Bennett, M., Lanius, R., Liberzon, I., McGlinchey, R.E., McLaughlin, K.A., Milberg, W.P., Miller, M.W., Ressler, K.J., Veltman, D.J., Stein, D.J., Thomaes, K., Thompson, P.M., and Morey, R.A.

   Biological Psychiatry May 2018

   Abs

   Background Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. Methods We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. Results In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p =.00054), and smaller amygdalae (d = −0.11, p =.025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p \textless.0063). Conclusions Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma. © 2017

2. Structural covariance network centrality in maltreated youth with posttraumatic stress disorder

   Sun, Delin, Peverill, Matthew R., Swanson, Chelsea S., McLaughlin, Katie A., and Morey, Rajendra A.

   Journal of Psychiatric Research Mar 2018

   Abs

   Childhood maltreatment is associated with posttraumatic stress disorder (PTSD) and elevated rates of adolescent and adult psychopathology including major depression, bipolar disorder, substance use disorders, and other medical comorbidities. Gray matter volume changes have been found in maltreated youth with (versus without) PTSD. However, little is known about the alterations of brain structural covariance network topology derived from cortical thickness in maltreated youth with PTSD. High-resolution T1-weighted magnetic resonance imaging scans were from demographically matched maltreated youth with PTSD (N = 24), without PTSD (N = 64), and non-maltreated healthy controls (n = 67). Cortical thickness data from 148 cortical regions was entered into interregional partial correlation analyses across participants. The supra-threshold correlations constituted connections in a structural brain network derived from four types of centrality measures (degree, betweenness, closeness, and eigenvector) estimated network topology and the importance of nodes. Between-group differences were determined by permutation testing. Maltreated youth with PTSD exhibited larger centrality in left anterior cingulate cortex than the other two groups, suggesting cortical network topology specific to maltreated youth with PTSD. Moreover, maltreated youth with versus without PTSD showed smaller centrality in right orbitofrontal cortex, suggesting that this may represent a vulnerability factor to PTSD following maltreatment. Longitudinal follow-up of the present results will help characterize the role that altered centrality plays in vulnerability and resilience to PTSD following childhood maltreatment.

2017

1. Child Abuse, Neural Structure, and Adolescent Psychopathology: A Longitudinal Study

   Busso, Daniel S., McLaughlin, Katie A., Brueck, Stephanie,  Peverill, Matthew, Gold, Andrea L., and Sheridan, Margaret A.

   Journal of the American Academy of Child & Adolescent Psychiatry Apr 2017
2. Neural Correlates of Emotion Regulation and Adolescent Suicidal Ideation

   Miller, Adam Bryant, McLaughlin, Katie A., Busso, Daniel S., Brueck, Stephanie,  Peverill, Matthew, and Sheridan, Margaret A.

   Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Sep 2017

   Abs

   Research on the neural correlates associated with risk for suicidal ideation (SI) has been limited, particularly in one increasingly at-risk group—adolescents. Previous research with adolescents indicates that poor emotion regulation skills are linked with SI, but these studies have not previously examined neural activation in service of emotion regulation between those with and without SI histories. Here we examine whether SI is associated with neural responses during an emotion regulation functional magnetic resonance imaging task in a group of adolescents (N = 49) 13 to 20 years of age (mean = 16.95). While there were no differences between youths with and without SI in self-reported emotional responses to negative pictures, youths with SI activated the dorsolateral prefrontal cortex more than youths without SI on trials in which they attempted to regulate their emotional responses compared with trials in which they passively viewed negative pictures. In contrast, during passive viewing of negative stimuli, youths with SI activated the dorsolateral prefrontal cortex, temporoparietal junction, and cerebellum less than same-age control subjects. These findings were robust to control subjects for depression and adversity exposure and are consistent with the idea that youths with SI have disrupted emotion regulation, potentially related to differences in recruitment of top-down control regions. In contrast, youths without SI activated regions implicated in emotion regulation even when not directed to effortfully control their emotional response. This is the first study to examine neural function during emotion regulation as a potential neural correlate of risk for SI in adolescents.

3. The Role of Visual Association Cortex in Associative Memory Formation across Development

   Rosen, Maya L., Sheridan, Margaret A., Sambrook, Kelly A., Peverill, Matthew R., Meltzoff, Andrew N., and McLaughlin, Katie A.

   Journal of Cognitive Neuroscience Oct 2017

   Abs

   Associative learning underlies the formation of new episodic memories. Associative memory improves across development, and this age-related improvement is supported by the development of the hippocampus and pFC. Recent work, however, additionally suggests a role for visual association cortex in the formation of associative memories. This study investigated the role of category-preferential visual processing regions in associative memory across development using a paired associate learning task in a sample of 56 youths (age 6-19 years). Participants were asked to bind an emotional face with an object while undergoing fMRI scanning. Outside the scanner, participants completed a memory test. We first investigated age-related changes in neural recruitment and found linear age-related increases in activation in lateral occipital cortex and fusiform gyrus, which are involved in visual processing of objects and faces, respectively. Furthermore, greater activation in these visual processing regions was associated with better subsequent memory for pairs over and above the effect of age and of hippocampal and pFC activation on performance. Recruitment of these visual processing regions mediated the association between age and memory performance, over and above the effects of hippocampal activation. Taken together, these findings extend the existing literature to suggest that greater recruitment of category-preferential visual processing regions during encoding of associative memories is a neural mechanism explaining improved memory across development.

4. Dimensions of childhood adversity have distinct associations with neural systems underlying executive functioning

   Sheridan, Margaret A.,  Peverill, Matthew, Finn, Amy S., and McLaughlin, Katie A.

   Development and Psychopathology Dec 2017

   Abs

   Childhood adversity is associated with increased risk for psychopathology. Neurodevelopmental pathways underlying this risk remain poorly understood. A recent conceptual model posits that childhood adversity can be deconstructed into at least two underlying dimensions, deprivation and threat, that are associated with distinct neurocognitive consequences. This model argues that deprivation (i.e., a lack of cognitive stimulation and learning opportunities) is associated with poor executive function (EF), whereas threat is not. We examine this hypothesis in two studies measuring EF at multiple levels: performance on EF tasks, neural recruitment during EF, and problems with EF in daily life. In Study 1, deprivation (low parental education and child neglect) was associated with greater parent-reported problems with EF in adolescents (N = 169; 13-17 years) after adjustment for levels of threat (community violence and abuse), which were unrelated to EF. In Study 2, low parental education was associated with poor working memory (WM) performance and inefficient neural recruitment in the parietal and prefrontal cortex during high WM load among adolescents (N = 51, 13-20 years) after adjusting for abuse, which was unrelated to WM task performance and neural recruitment during WM. These findings constitute strong preliminary evidence for a novel model of the neurodevelopmental consequences of childhood adversity.

5. Current methods and limitations for longitudinal fMRI analysis across development

   Madhyastha, Tara,  Peverill, Matthew, Koh, Natalie, McCabe, Connor, Flournoy, John, Mills, Kate, King, Kevin, Pfeifer, Jennifer, and McLaughlin, Katie A.

   Developmental Cognitive Neuroscience Nov 2017

   Abs

   The human brain is remarkably plastic. The brain changes dramatically across development, with ongoing functional development continuing well into the third decade of life and substantial changes occurring again in older age. Dynamic changes in brain function are thought to underlie the innumerable changes in cognition, emotion, and behavior that occur across development. The brain also changes in response to experience, which raises important questions about how the environment influences the developing brain. Longitudinal functional magnetic resonance imaging (fMRI) studies are an essential means of understanding these developmental changes and their cognitive, emotional, and behavioral correlates. This paper provides an overview of common statistical models of longitudinal change applicable to developmental cognitive neuroscience, and a review of the functionality provided by major software packages for longitudinal fMRI analysis. We demonstrate that there are important developmental questions that cannot be answered using available software. We propose alternative approaches for addressing problems that are commonly faced in modeling developmental change with fMRI data.

2016

1. Childhood abuse and reduced cortical thickness in brain regions involved in emotional processing

   Gold, Andrea L., Sheridan, Margaret A.,  Peverill, Matthew, Busso, Daniel S., Lambert, Hilary K., Alves, Sonia, Pine, Daniel S., and McLaughlin, Katie A.

   Journal of Child Psychology and Psychiatry Oct 2016

   Abs

   Background Alterations in gray matter development represent a potential pathway through which childhood abuse is associated with psychopathology. Several prior studies find reduced volume and thickness of prefrontal (PFC) and temporal cortex regions in abused compared with nonabused adolescents, although most prior research is based on adults and volume-based measures. This study tests the hypothesis that child abuse, independent of parental education, predicts reduced cortical thickness in prefrontal and temporal cortices as well as reduced gray mater volume (GMV) in subcortical regions during adolescence. Methods Structural MRI scans were obtained from 21 adolescents exposed to physical and/or sexual abuse and 37 nonabused adolescents (ages 13–20). Abuse was operationalized using dichotomous and continuous measures. We examined associations between abuse and brain structure in several a priori-defined regions, controlling for parental education, age, sex, race, and total brain volume for subcortical GMV. Significance was evaluated at p \textless .05 with a false discovery rate correction. Results Child abuse exposure and severity were associated with reduced thickness in ventromedial prefrontal cortex (PFC), right lateral orbitofrontal cortex, right inferior frontal gyrus, bilateral parahippocampal gyrus (PHG), left temporal pole, and bilateral inferior, right middle, and right superior temporal gyri. Neither abuse measure predicted cortical surface area or subcortical GMV. Bilateral PHG thickness was inversely related to externalizing symptoms. Conclusions Child abuse, an experience characterized by a high degree of threat, is associated with reduced cortical thickness in ventromedial and ventrolateral PFC and medial and lateral temporal cortex in adolescence. Reduced PHG thickness may be a mediator linking abuse with externalizing psychopathology, although prospective research is needed to evaluate this possibility.

2. Working memory filtering continues to develop into late adolescence

   Peverill, Matthew, McLaughlin, Katie A., Finn, Amy S., and Sheridan, Margaret A.

   Developmental Cognitive Neuroscience Oct 2016

   Abs

   While most measures of working memory (WM) performance have been shown to plateau by mid-adolescence and developmental changes in fronto-parietal regions supporting WM encoding and maintenance have been well characterized, little is known about developmental variation in WM filtering. We investigated the possibility that the neural underpinnings of filtering in WM reach maturity later in life than WM function without filtering. Using a cued WM filtering task (McNab and Klingberg, 2008), we investigated neural activity during WM filtering in a sample of 64 adults and adolescents. Regardless of age, increases in WM activity with load were concentrated in the expected fronto-parietal network. For adults, but not adolescents, recruitment of the basal ganglia during presentation of a filtering cue was associated with neural and behavioral indices of successful filtering, suggesting that WM filtering and related basal ganglia function may still be maturing throughout adolescence and into adulthood.

3. Neurobehavioral markers of resilience to depression amongst adolescents exposed to child abuse

   Dennison, Meg J., Sheridan, Margaret A., Busso, Daniel S., Jenness, Jessica L.,  Peverill, Matthew, Rosen, Maya L., and McLaughlin, Katie A.

   Journal of Abnormal Psychology Oct 2016

   Abs

   Childhood maltreatment is strongly associated with depression, which is characterized by reduced reactivity to reward. Identifying factors that mitigate risk for depression in maltreated children is important for understanding etiological links between maltreatment and depression as well as improving early intervention and prevention. We examine whether high reward reactivity at behavioral and neurobiological levels is a marker of resilience to depressive symptomology in adolescence following childhood maltreatment. A sample of 59 adolescents (21 with a history of maltreatment; Mean Age = 16.95 years, SD = 1.44) completed an fMRI task involving passive viewing of emotional stimuli. BOLD signal changes to positive relative to neutral images were extracted in basal ganglia regions of interest. Participants also completed a behavioral reward-processing task outside the scanner. Depression symptoms were assessed at the time of the MRI and again 2 years later. Greater reward reactivity across behavioral and neurobiological measures moderated the association of maltreatment with baseline depression. Specifically, faster reaction time (RT) to cues paired with monetary reward relative to those unpaired with reward and greater BOLD signal in the left pallidum was associated with lower depression symptoms in maltreated youth. Longitudinally, greater BOLD signal in the left putamen moderated change in depression scores over time, such that higher levels of reward response were associated with lower increases in depression over time among maltreated youths. Reactivity to monetary reward and positive social images, at both behavioral and neurobiological levels, is a potential marker of resilience to depression among adolescents exposed to maltreatment. These findings add to a growing body of work highlighting individual differences in reactivity to reward as a core neurodevelopmental mechanism in the etiology of depression. (PsycINFO Database Record

4. Using Make for reproducible and parallel neuroimaging workflow and quality-assurance

   Askren, Mary K., McAllister-Day, Trevor K., Koh, Natalie, Mestre, Zoé, Dines, Jennifer N., Korman, Benjamin A., Melhorn, Susan J., Peterson, Daniel J.,  Peverill, Matthew, Qin, Xiaoyan, Rane, Swati D., Reilly, Melissa A., Reiter, Maya A., Sambrook, Kelly A., Woelfer, Karl A., Grabowski, Thomas J., and Madhyastha, Tara M.

   Frontiers in Neuroinformatics Oct 2016

   Abs

   The contribution of this paper is to describe how we can program neuroimaging workflow using Make, a software development tool designed for describing how to build executables from source files. A makefile (or a file of instructions for Make) consists of a set of rules that create or update target files if they have not been modified since their dependencies were last modified. These rules are processed to create a directed acyclic dependency graph that allows multiple entry points from which to execute the workflow. We show that using Make we can achieve many of the features of more sophisticated neuroimaging pipeline systems, including reproducibility, parallelization, fault tolerance, and quality assurance reports. We suggest that Make permits a large step toward these features with only a modest increase in programming demands over shell scripts. This approach reduces the technical skill and time required to write, debug, and maintain neuroimaging workflows in a dynamic environment, where pipelines are often modified to accommodate new best practices or to study the effect of alternative preprocessing steps, and where the underlying packages change frequently. This paper has a comprehensive accompanying manual with lab practicals and examples (see Supplemental Materials) and all data, scripts, and makefiles necessary to run the practicals and examples are available in the "makepipelines" project at NITRC.

5. Maltreatment exposure, brain structure, and fear conditioning in children and adolescents

   McLaughlin, Katie A., Sheridan, Margaret A., Gold, Andrea L., Duys, Andrea, Lambert, Hilary K.,  Peverill, Matthew, Heleniak, Charlotte, Shechner, Tomer, Wojcieszak, Zuzanna, and Pine, Daniel S.

   Neuropsychopharmacology Jul 2016

   Abs

   Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.Neuropsychopharmacology advance online publication, 13 January 2016; doi:10.1038/npp.2015.365.

2015

1. Child maltreatment and neural systems underlying emotion regulation

   McLaughlin, Katie A.,  Peverill, Matthew, Gold, Andrea L., Alves, Sonia, and Sheridan, Margaret A.

   Journal of the American Academy of Child and Adolescent Psychiatry Sep 2015

   Abs

   OBJECTIVE: The strong associations between child maltreatment and psychopathology have generated interest in identifying neurodevelopmental processes that are disrupted following maltreatment. Previous research has focused largely on neural response to negative facial emotion. We determined whether child maltreatment was associated with neural responses during passive viewing of negative and positive emotional stimuli and effortful attempts to regulate emotional responses. METHOD: A total of 42 adolescents aged 13 to 19 years, half with exposure to physical and/or sexual abuse, participated. Blood oxygen level-dependent (BOLD) response was measured during passive viewing of negative and positive emotional stimuli and attempts to modulate emotional responses using cognitive reappraisal. RESULTS: Maltreated adolescents exhibited heightened response in multiple nodes of the salience network, including amygdala, putamen, and anterior insula, to negative relative to neutral stimuli. During attempts to decrease responses to negative stimuli relative to passive viewing, maltreatment was associated with greater recruitment of superior frontal gyrus, dorsal anterior cingulate cortex, and frontal pole; adolescents with and without maltreatment down-regulated amygdala response to a similar degree. No associations were observed between maltreatment and neural response to positive emotional stimuli during passive viewing or effortful regulation. CONCLUSION: Child maltreatment heightens the salience of negative emotional stimuli. Although maltreated adolescents modulate amygdala responses to negative cues to a degree similar to that of non-maltreated youths, they use regions involved in effortful control to a greater degree to do so, potentially because greater effort is required to modulate heightened amygdala responses. These findings are promising, given the centrality of cognitive restructuring in trauma-focused treatments for children.