Browsing by Author "Morey, Rajendra A"

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Open Access
A case of frontal neuropsychological and neuroimaging signs following multiple primary-blast exposure.
(Neurocase, 2012-06) Hayes, Jasmeet Pannu; Morey, Rajendra A; Tupler, Larry A
Blast-related traumatic brain injury (TBI) from the Afghanistan and Iraq wars represents a significant medical concern for troops and veterans. To better understand the consequences of primary-blast injury in humans, we present a case of a Marine exposed to multiple primary blasts during his 14-year military career. The neuropsychological profile of this formerly high-functioning veteran suggested primarily executive dysfunction. Diffusion-tensor imaging revealed white-matter pathology in long fiber tracks compared with a composite fractional-anisotropy template derived from a veteran reference control group without TBI. This study supports the existence of primary blast-induced neurotrauma in humans and introduces a neuroimaging technique with potential to discriminate multiple-blast TBI.
Open Access
A Pilot Study of Neurocognitive Function and Brain Structures in Adolescents With Alcohol Use Disorders: Does Maltreatment History Matter?
(Child Maltreatment) De Bellis, Michael D; Morey, Rajendra A; Nooner, Kate B; Woolley, Donald P; Haswell, Courtney C; Hooper, Stephen R
Open Access
Acute effects of trauma-focused research procedures on participant safety and distress
(Psychiatry Research, 2014-01-30) Brown, Vanessa M; Strauss, Jennifer L; LaBar, Kevin S; Gold, Andrea L; McCarthy, Gregory; Morey, Rajendra A
The ethical conduct of research on posttraumatic stress disorder (PTSD) requires assessing the risks to study participants. Some previous findings suggest that patients with PTSD report higher distress compared to non-PTSD participants after trauma-focused research. However, the impact of study participation on participant risk, such as suicidal/homicidal ideation and increased desire to use drugs or alcohol, has not been adequately investigated. Furthermore, systematic evaluation of distress using pre- and post-study assessments, and the effects of study procedures involving exposure to aversive stimuli, are lacking. Individuals with a history of PTSD (n=68) and trauma-exposed non-PTSD controls (n=68) responded to five questions about risk and distress before and after participating in research procedures including a PTSD diagnostic interview and a behavioral task with aversive stimuli consisting of mild electrical shock. The desire to use alcohol or drugs increased modestly with study participation among the subgroup (n=48) of participants with current PTSD. Participation in these research procedures was not associated with increased distress or participant risk, nor did study participation interact with lifetime PTSD diagnosis. These results suggest some increase in distress with active PTSD but a participant risk profile that supports a favorable risk-benefit ratio for conducting research in individuals with PTSD. © 2013.
Open Access
Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.
(Human brain mapping, 2022-06) Bouchard, Heather C; Sun, Delin; Dennis, Emily L; Newsome, Mary R; Disner, Seth G; Elman, Jeremy; Silva, Annelise; Velez, Carmen; Irimia, Andrei; Davenport, Nicholas D; Sponheim, Scott R; Franz, Carol E; Kremen, William S; Coleman, Michael J; Williams, M Wright; Geuze, Elbert; Koerte, Inga K; Shenton, Martha E; Adamson, Maheen M; Coimbra, Raul; Grant, Gerald; Shutter, Lori; George, Mark S; Zafonte, Ross D; McAllister, Thomas W; Stein, Murray B; Thompson, Paul M; Wilde, Elisabeth A; Tate, David F; Sotiras, Aristeidis; Morey, Rajendra A
Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.
Open Access
Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics.
(Pain Med, 2016-01) Naylor, Jennifer C; Kilts, Jason D; Szabo, Steven T; Dunn, Charlotte E; Keefe, Francis J; Tupler, Larry A; Shampine, Lawrence J; Morey, Rajendra A; Strauss, Jennifer L; Hamer, Robert M; Wagner, H Ryan; MIRECC Workgroup; Marx, Christine E
BACKGROUND AND OBJECTIVES: Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. METHODS: The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. RESULTS: Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann–Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P = 0.0028], chest pain [P = 0.032], and aggregate total pain (sum of all four pain items) [P = 0.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P = 0.001]. CONCLUSIONS: These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.
Open Access
Altered resting-state functional connectivity of basolateral and centromedial amygdala complexes in posttraumatic stress disorder.
(Neuropsychopharmacology, 2014-01) Brown, Vanessa M; LaBar, Kevin S; Haswell, Courtney C; Gold, Andrea L; Mid-Atlantic MIRECC Workgroup; McCarthy, Gregory; Morey, Rajendra A
The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD.
Open Access
Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.
(Molecular psychiatry, 2021-08) 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; du 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 BJ; Koerte, Inga; Koopowitz, Sheri; Korgaonkar, Mayuresh; Krystal, John; Lebois, Lauren AM; Li, Gen; Magnotta, Vincent A; Manthey, Antje; May, Geoff J; Menefee, Deleene S; Nawijn, Laura; Nelson, Steven M; Neufeld, Richard WJ; 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; van den Heuvel, Leigh; van der Werff, Steven JA; van Rooij, Sanne JH; van Zuiden, Mirjam; Velez, Carmen; Verfaellie, Mieke; Vermeiren, Robert RJM; Wade, Benjamin SC; 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; van der Wee, Nic JA; Veltman, Dick J; Wang, Li; Wilde, Elisabeth A; Thompson, Paul M; Kochunov, Peter; Jahanshad, Neda; Morey, Rajendra A
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.
Open Access
Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group.
(Arch Gen Psychiatry, 2012-11) Morey, Rajendra A; Gold, Andrea L; LaBar, Kevin S; Beall, Shannon K; Brown, Vanessa M; Haswell, Courtney C; Nasser, Jessica D; Wagner, H Ryan; McCarthy, Gregory; Mid-Atlantic MIRECC Workgroup
CONTEXT: Smaller hippocampal volumes are well established in posttraumatic stress disorder (PTSD), but the relatively few studies of amygdala volume in PTSD have produced equivocal results. OBJECTIVE: To assess a large cohort of recent military veterans with PTSD and trauma-exposed control subjects, with sufficient power to perform a definitive assessment of the effect of PTSD on volumetric changes in the amygdala and hippocampus and of the contribution of illness duration, trauma load, and depressive symptoms. DESIGN: Case-controlled design with structural magnetic resonance imaging and clinical diagnostic assessments. We controlled statistically for the important potential confounds of alcohol use, depression, and medication use. SETTING: Durham Veterans Affairs Medical Center, which is located in proximity to major military bases. PATIENTS: Ambulatory patients (n = 200) recruited from a registry of military service members and veterans serving after September 11, 2001, including a group with current PTSD (n = 99) and a trauma-exposed comparison group without PTSD (n = 101). MAIN OUTCOME MEASURE: Amygdala and hippocampal volumes computed from automated segmentation of high-resolution structural 3-T magnetic resonance imaging. RESULTS: Smaller volume was demonstrated in the PTSD group compared with the non-PTSD group for the left amygdala (P = .002), right amygdala (P = .01), and left hippocampus (P = .02) but not for the right hippocampus (P = .25). Amygdala volumes were not associated with PTSD chronicity, trauma load, or severity of depressive symptoms. CONCLUSIONS: These results provide clear evidence of an association between a smaller amygdala volume and PTSD. The lack of correlation between trauma load or illness chronicity and amygdala volume suggests that a smaller amygdala represents a vulnerability to developing PTSD or the lack of a dose-response relationship with amygdala volume. Our results may trigger a renewed impetus for investigating structural differences in the amygdala, its genetic determinants, its environmental modulators, and the possibility that it reflects an intrinsic vulnerability to PTSD.
Open Access
Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.
(Neuropsychopharmacology, 2016-02) Morey, Rajendra A; Haswell, Courtney C; Hooper, Stephen R; De Bellis, Michael D
Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.
Open Access
Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan.
(Human Brain Mapping, 2014-06) Li, Wei; Wu, Bing; Batrachenko, Anastasia; Bancroft-Wu, Vivian; Morey, Rajendra A; Shashi, Vandana; Langkammer, Christian; De Bellis, Michael D; Ropele, Stefan; Song, Allen W; Liu, Chunlei
As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing.
Open Access
Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans.
(Human Brain Mapping, 2013-11) Morey, Rajendra A; Haswell, Courtney C; Selgrade, Elizabeth S; Massoglia, Dino; Liu, Chunlei; Weiner, Jonathan; Marx, Christine E; MIRECC Work Group; Cernak, Ibolja; McCarthy, Gregory
Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events.
Open Access
ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.
(Translational psychiatry, 2020-03) Thompson, Paul M; Jahanshad, Neda; Ching, Christopher RK; Salminen, Lauren E; Thomopoulos, Sophia I; Bright, Joanna; Baune, Bernhard T; Bertolín, Sara; Bralten, Janita; Bruin, Willem B; Bülow, Robin; Chen, Jian; Chye, Yann; Dannlowski, Udo; de Kovel, Carolien GF; Donohoe, Gary; Eyler, Lisa T; Faraone, Stephen V; Favre, Pauline; Filippi, Courtney A; Frodl, Thomas; Garijo, Daniel; Gil, Yolanda; Grabe, Hans J; Grasby, Katrina L; Hajek, Tomas; Han, Laura KM; Hatton, Sean N; Hilbert, Kevin; Ho, Tiffany C; Holleran, Laurena; Homuth, Georg; Hosten, Norbert; Houenou, Josselin; Ivanov, Iliyan; Jia, Tianye; Kelly, Sinead; Klein, Marieke; Kwon, Jun Soo; Laansma, Max A; Leerssen, Jeanne; Lueken, Ulrike; Nunes, Abraham; Neill, Joseph O'; Opel, Nils; Piras, Fabrizio; Piras, Federica; Postema, Merel C; Pozzi, Elena; Shatokhina, Natalia; Soriano-Mas, Carles; Spalletta, Gianfranco; Sun, Daqiang; Teumer, Alexander; Tilot, Amanda K; Tozzi, Leonardo; van der Merwe, Celia; Van Someren, Eus JW; van Wingen, Guido A; Völzke, Henry; Walton, Esther; Wang, Lei; Winkler, Anderson M; Wittfeld, Katharina; Wright, Margaret J; Yun, Je-Yeon; Zhang, Guohao; Zhang-James, Yanli; Adhikari, Bhim M; Agartz, Ingrid; Aghajani, Moji; Aleman, André; Althoff, Robert R; Altmann, Andre; Andreassen, Ole A; Baron, David A; Bartnik-Olson, Brenda L; Marie Bas-Hoogendam, Janna; Baskin-Sommers, Arielle R; Bearden, Carrie E; Berner, Laura A; Boedhoe, Premika SW; Brouwer, Rachel M; Buitelaar, Jan K; Caeyenberghs, Karen; Cecil, Charlotte AM; Cohen, Ronald A; Cole, James H; Conrod, Patricia J; De Brito, Stephane A; de Zwarte, Sonja MC; Dennis, Emily L; Desrivieres, Sylvane; Dima, Danai; Ehrlich, Stefan; Esopenko, Carrie; Fairchild, Graeme; Fisher, Simon E; Fouche, Jean-Paul; Francks, Clyde; Frangou, Sophia; Franke, Barbara; Garavan, Hugh P; Glahn, David C; Groenewold, Nynke A; Gurholt, Tiril P; Gutman, Boris A; Hahn, Tim; Harding, Ian H; Hernaus, Dennis; Hibar, Derrek P; Hillary, Frank G; Hoogman, Martine; Hulshoff Pol, Hilleke E; Jalbrzikowski, Maria; Karkashadze, George A; Klapwijk, Eduard T; Knickmeyer, Rebecca C; Kochunov, Peter; Koerte, Inga K; Kong, Xiang-Zhen; Liew, Sook-Lei; Lin, Alexander P; Logue, Mark W; Luders, Eileen; Macciardi, Fabio; Mackey, Scott; Mayer, Andrew R; McDonald, Carrie R; McMahon, Agnes B; Medland, Sarah E; Modinos, Gemma; Morey, Rajendra A; Mueller, Sven C; Mukherjee, Pratik; Namazova-Baranova, Leyla; Nir, Talia M; Olsen, Alexander; Paschou, Peristera; Pine, Daniel S; Pizzagalli, Fabrizio; Rentería, Miguel E; Rohrer, Jonathan D; Sämann, Philipp G; Schmaal, Lianne; Schumann, Gunter; Shiroishi, Mark S; Sisodiya, Sanjay M; Smit, Dirk JA; Sønderby, Ida E; Stein, Dan J; Stein, Jason L; Tahmasian, Masoud; Tate, David F; Turner, Jessica A; van den Heuvel, Odile A; van der Wee, Nic JA; van der Werf, Ysbrand D; van Erp, Theo GM; van Haren, Neeltje EM; van Rooij, Daan; van Velzen, Laura S; Veer, Ilya M; Veltman, Dick J; Villalon-Reina, Julio E; Walter, Henrik; Whelan, Christopher D; Wilde, Elisabeth A; Zarei, Mojtaba; Zelman, Vladimir; ENIGMA Consortium
This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Open Access
ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide.
(Neuroimage, 2017-01-15) Thompson, Paul M; Andreassen, Ole A; Arias-Vasquez, Alejandro; Bearden, Carrie E; Boedhoe, Premika S; Brouwer, Rachel M; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cannon, Dara M; Cohen, Ronald A; Conrod, Patricia J; Dale, Anders M; Deary, Ian J; Dennis, Emily L; de Reus, Marcel A; Desrivieres, Sylvane; Dima, Danai; Donohoe, Gary; Fisher, Simon E; Fouche, Jean-Paul; Francks, Clyde; Frangou, Sophia; Franke, Barbara; Ganjgahi, Habib; Garavan, Hugh; Glahn, David C; Grabe, Hans J; Guadalupe, Tulio; Gutman, Boris A; Hashimoto, Ryota; Hibar, Derrek P; Holland, Dominic; Hoogman, Martine; Hulshoff Pol, Hilleke E; Hosten, Norbert; Jahanshad, Neda; Kelly, Sinead; Kochunov, Peter; Kremen, William S; Lee, Phil H; Mackey, Scott; Martin, Nicholas G; Mazoyer, Bernard; McDonald, Colm; Medland, Sarah E; Morey, Rajendra A; Nichols, Thomas E; Paus, Tomas; Pausova, Zdenka; Schmaal, Lianne; Schumann, Gunter; Shen, Li; Sisodiya, Sanjay M; Smit, Dirk JA; Smoller, Jordan W; Stein, Dan J; Stein, Jason L; Toro, Roberto; Turner, Jessica A; van den Heuvel, Martijn P; van den Heuvel, Odile L; van Erp, Theo GM; van Rooij, Daan; Veltman, Dick J; Walter, Henrik; Wang, Yalin; Wardlaw, Joanna M; Whelan, Christopher D; Wright, Margaret J; Ye, Jieping; ENIGMA Consortium
In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others(1), ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.
Open Access
International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.
(Nature communications, 2019-10) Nievergelt, Caroline M; Maihofer, Adam X; Klengel, Torsten; Atkinson, Elizabeth G; Chen, Chia-Yen; Choi, Karmel W; Coleman, Jonathan RI; 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; Caldas-de-Almeida, José M; 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 MJ; 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 AM; 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 PF; 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; van den 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; Koenen, Karestan C
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.
Open Access
Neural systems for cognitive and emotional processing in posttraumatic stress disorder.
(Front Psychol, 2012) Brown, Vanessa M; Morey, Rajendra A
Individuals with posttraumatic stress disorder (PTSD) show altered cognition when trauma-related material is present. PTSD may lead to enhanced processing of trauma-related material, or it may cause impaired processing of trauma-unrelated information. However, other forms of emotional information may also alter cognition in PTSD. In this review, we discuss the behavioral and neural effects of emotion processing on cognition in PTSD, with a focus on neuroimaging results. We propose a model of emotion-cognition interaction based on evidence of two network models of altered brain activation in PTSD. The first is a trauma-disrupted network made up of ventrolateral PFC, dorsal anterior cingulate cortex (ACC), hippocampus, insula, and dorsomedial PFC that are differentially modulated by trauma content relative to emotional trauma-unrelated information. The trauma-disrupted network forms a subnetwork of regions within a larger, widely recognized network organized into ventral and dorsal streams for processing emotional and cognitive information that converge in the medial PFC and cingulate cortex. Models of fear learning, while not a cognitive process in the conventional sense, provide important insights into the maintenance of the core symptom clusters of PTSD such as re-experiencing and hypervigilance. Fear processing takes place within the limbic corticostriatal loop composed of threat-alerting and threat-assessing components. Understanding the disruptions in these two networks, and their effect on individuals with PTSD, will lead to an improved knowledge of the etiopathogenesis of PTSD and potential targets for both psychotherapeutic and pharmacotherapeutic interventions.
Open Access
Neural systems for guilt from actions affecting self versus others.
(Neuroimage, 2012-03) Morey, Rajendra A; McCarthy, Gregory; Selgrade, Elizabeth S; Seth, Srishti; Nasser, Jessica D; LaBar, Kevin S
Guilt is a core emotion governing social behavior by promoting compliance with social norms or self-imposed standards. The goal of this study was to contrast guilty responses to actions that affect self versus others, since actions with social consequences are hypothesized to yield greater guilty feelings due to adopting the perspective and subjective emotional experience of others. Sixteen participants were presented with brief hypothetical scenarios in which the participant's actions resulted in harmful consequences to self (guilt-self) or to others (guilt-other) during functional MRI. Participants felt more intense guilt for guilt-other than guilt-self and guilt-neutral scenarios. Guilt scenarios revealed distinct regions of activity correlated with intensity of guilt, social consequences of actions, and the interaction of guilt by social consequence. Guilt intensity was associated with activation of the dorsomedial PFC, superior frontal gyrus, supramarginal gyrus, and anterior inferior frontal gyrus. Guilt accompanied by social consequences was associated with greater activation than without social consequences in the ventromedial and dorsomedial PFC, precuneus, posterior cingulate, and posterior superior temporal sulcus. Finally, the interaction analysis highlighted select regions that were more strongly correlated with guilt intensity as a function of social consequence, including the left anterior inferior frontal gyrus, left ventromedial PFC, and left anterior inferior parietal cortex. Our results suggest these regions intensify guilt where harm to others may incur a greater social cost.
Open Access
Neuroimaging assessment of early and late neurobiological sequelae of traumatic brain injury: implications for CTE.
(Front Neurosci, 2015) Sundman, Mark; Doraiswamy, P Murali; Morey, Rajendra A
Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research.
Open Access
Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.
(NeuroImage, 2023-12) Zhu, Xi; Kim, Yoojean; Ravid, Orren; He, Xiaofu; Suarez-Jimenez, Benjamin; Zilcha-Mano, Sigal; Lazarov, Amit; Lee, Seonjoo; Abdallah, Chadi G; Angstadt, Michael; Averill, Christopher L; Baird, C Lexi; Baugh, Lee A; Blackford, Jennifer U; Bomyea, Jessica; Bruce, Steven E; Bryant, Richard A; Cao, Zhihong; Choi, Kyle; Cisler, Josh; Cotton, Andrew S; Daniels, Judith K; Davenport, Nicholas D; Davidson, Richard J; DeBellis, Michael D; Dennis, Emily L; Densmore, Maria; deRoon-Cassini, Terri; Disner, Seth G; Hage, Wissam El; Etkin, Amit; Fani, Negar; Fercho, Kelene A; Fitzgerald, Jacklynn; Forster, Gina L; Frijling, Jessie L; Geuze, Elbert; Gonenc, Atilla; Gordon, Evan M; Gruber, Staci; Grupe, Daniel W; Guenette, Jeffrey P; Haswell, Courtney C; Herringa, Ryan J; Herzog, Julia; Hofmann, David Bernd; Hosseini, Bobak; Hudson, Anna R; Huggins, Ashley A; Ipser, Jonathan C; Jahanshad, Neda; Jia-Richards, Meilin; Jovanovic, Tanja; Kaufman, Milissa L; Kennis, Mitzy; King, Anthony; Kinzel, Philipp; Koch, Saskia BJ; Koerte, Inga K; Koopowitz, Sheri M; Korgaonkar, Mayuresh S; Krystal, John H; Lanius, Ruth; Larson, Christine L; Lebois, Lauren AM; Li, Gen; Liberzon, Israel; Lu, Guang Ming; Luo, Yifeng; Magnotta, Vincent A; Manthey, Antje; Maron-Katz, Adi; May, Geoffery; McLaughlin, Katie; Mueller, Sven C; Nawijn, Laura; Nelson, Steven M; Neufeld, Richard WJ; Nitschke, Jack B; O'Leary, Erin M; Olatunji, Bunmi O; Olff, Miranda; Peverill, Matthew; Phan, K Luan; Qi, Rongfeng; Quidé, Yann; Rektor, Ivan; Ressler, Kerry; Riha, Pavel; Ross, Marisa; Rosso, Isabelle M; Salminen, Lauren E; Sambrook, Kelly; Schmahl, Christian; Shenton, Martha E; Sheridan, Margaret; Shih, Chiahao; Sicorello, Maurizio; Sierk, Anika; Simmons, Alan N; Simons, Raluca M; Simons, Jeffrey S; Sponheim, Scott R; Stein, Murray B; Stein, Dan J; Stevens, Jennifer S; Straube, Thomas; Sun, Delin; Théberge, Jean; Thompson, Paul M; Thomopoulos, Sophia I; van der Wee, Nic JA; van der Werff, Steven JA; van Erp, Theo GM; van Rooij, Sanne JH; van Zuiden, Mirjam; Varkevisser, Tim; Veltman, Dick J; Vermeiren, Robert RJM; Walter, Henrik; Wang, Li; Wang, Xin; Weis, Carissa; Winternitz, Sherry; Xie, Hong; Zhu, Ye; Wall, Melanie; Neria, Yuval; Morey, Rajendra A
Background
Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.
Methods
We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.
Results
We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.
Conclusion
These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.
Open Access
Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD.
(J Psychiatr Res, 2011-05) Hayes, Jasmeet Pannu; LaBar, Kevin S; McCarthy, Gregory; Selgrade, Elizabeth; Nasser, Jessica; Dolcos, Florin; VISN 6 Mid-Atlantic MIRECC workgroup; Morey, Rajendra A
Neurobiological models of posttraumatic stress disorder (PTSD) suggest that altered activity in the medial temporal lobes (MTL) during encoding of traumatic memories contribute to the development and maintenance of the disorder. However, there is little direct evidence in the PTSD literature to support these models. The goal of the present study was to examine MTL activity during trauma encoding in combat veterans using the subsequent memory paradigm. Fifteen combat veterans diagnosed with PTSD and 14 trauma-exposed control participants viewed trauma-related and neutral pictures while undergoing event-related fMRI. Participants returned one week after scanning for a recognition memory test. Region-of-interest (ROI) and voxel-wise whole brain analyses were conducted to examine the neural correlates of successful memory encoding. Patients with PTSD showed greater false alarm rates for novel lures than the trauma-exposed control group, suggesting reliance on gist-based representations in lieu of encoding contextual details. Imaging analyses revealed reduced activity in the amygdala and hippocampus in PTSD patients during successful encoding of trauma-related stimuli. Reduction in left hippocampal activity was associated with high arousal symptoms on the Clinician-Administered PTSD Scale (CAPS). The behavioral false alarm rate for traumatic stimuli co-varied with activity in the bilateral precuneus. These results support neurobiological theories positing reduced hippocampal activity under conditions of high stress and arousal. Reduction in MTL activity for successfully encoded stimuli and increased precuneus activity may underlie reduced stimulus-specific encoding and greater gist memory in patients with PTSD, leading to maintenance of the disorder.
Open Access
Scan-rescan reliability of subcortical brain volumes derived from automated segmentation.
(Hum Brain Mapp, 2010-11) Morey, Rajendra A; Selgrade, Elizabeth S; Wagner, Henry Ryan; Huettel, Scott A; Wang, Lihong; McCarthy, Gregory
Large-scale longitudinal studies of regional brain volume require reliable quantification using automated segmentation and labeling. However, repeated MR scanning of the same subject, even if using the same scanner and acquisition parameters, does not result in identical images due to small changes in image orientation, changes in prescan parameters, and magnetic field instability. These differences may lead to appreciable changes in estimates of volume for different structures. This study examined scan-rescan reliability of automated segmentation algorithms for measuring several subcortical regions, using both within-day and across-day comparison sessions in a group of 23 normal participants. We found that the reliability of volume measures including percent volume difference, percent volume overlap (Dice's coefficient), and intraclass correlation coefficient (ICC), varied substantially across brain regions. Low reliability was observed in some structures such as the amygdala (ICC = 0.6), with higher reliability (ICC = 0.9) for other structures such as the thalamus and caudate. Patterns of reliability across regions were similar for automated segmentation with FSL/FIRST and FreeSurfer (longitudinal stream). Reliability was associated with the volume of the structure, the ratio of volume to surface area for the structure, the magnitude of the interscan interval, and the method of segmentation. Sample size estimates for detecting changes in brain volume for a range of likely effect sizes also differed by region. Thus, longitudinal research requires a careful analysis of sample size and choice of segmentation method combined with a consideration of the brain structure(s) of interest and the magnitude of the anticipated effects.

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