Trauma-exposed Control Subjects Research Articles

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium

BackgroundPosttraumatic 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). MethodsNeuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < 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 with the mean SC of 5000 randomly generated n-region networks. ResultsPatients with PTSD, relative to non-PTSD control subjects, 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. ConclusionsCovariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Evaluation of gray matter reduction in patients with typhoon-related posttraumatic stress disorder using causal network analysis of structural MRI.

The structural changes recent-onset posttraumatic stress disorder (PTSD) subjects were rarely investigated. This study was to compare temporal and causal relationships of structural changes in recent-onset PTSD with trauma-exposed control (TEC) subjects and non-TEC subjects. T1-weighted magnetic resonance images of 27 PTSD, 33 TEC and 30 age- and sex-matched healthy control (HC) subjects were studied. The causal network of structural covariance was used to evaluate the causal relationships of structural changes in PTSD patients. Volumes of bilateral hippocampal and left lingual gyrus were significantly smaller in PTSD patients and TEC subjects than HC subjects. As symptom scores increase, reduction in gray matter volume began in the hippocampus and progressed to the frontal lobe, then to the temporal and occipital cortices (p < 0.05, false discovery rate corrected). The hippocampus might be the primary hub of the directional network and demonstrated positive causal effects on the frontal, temporal and occipital regions (p < 0.05, false discovery rate corrected). The frontal regions, which were identified to be transitional points, projected causal effects to the occipital lobe and temporal regions and received causal effects from the hippocampus (p < 0.05, false discovery rate corrected). The results offer evidence of localized abnormalities in the bilateral hippocampus and remote abnormalities in multiple temporal and frontal regions in typhoon-exposed PTSD patients.

A prospective natural history study of Krabbe disease in a patient cohort with onset between 0 and 12 months

Posttraumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (single nucleotide polymorphism–based heritability) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, fewer than 10 large-scale genome-wide association studies of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group has brought together more than 200 scientists with the goal to increase sample size for genome-wide association studies and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes more than 32,000 PTSD cases and 100,000 trauma-exposed control subjects, and collection is ongoing. The first results found a significant shared genetic risk of PTSD with other psychiatric disorders and sex-biased heritability estimates with higher heritability in female individuals compared with male individuals. This review describes the scope and current focus of the Psychiatric Genomics Consortium PTSD group and its expansion from the initial genome-wide association study group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of “omics”-based studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.

Amygdala Nuclei Volume and Shape in Military Veterans With Posttraumatic Stress Disorder

BackgroundThe amygdala is a subcortical structure involved in socioemotional and associative fear learning processes relevant for understanding the mechanisms of posttraumatic stress disorder (PTSD). Research in animals indicates that the amygdala is a heterogeneous structure in which the basolateral and centromedial divisions are susceptible to stress. While the amygdala complex is implicated in the pathophysiology of PTSD, little is known about the specific contributions of the individual nuclei that constitute the amygdala complex. MethodsMilitary veterans (n = 355), including military veterans with PTSD (n = 149) and trauma-exposed control subjects without PTSD (n = 206), underwent high-resolution T1-weighted anatomical scans. Automated FreeSurfer segmentation of the amygdala yielded 9 structures: basal, lateral, accessory basal, anterior amygdaloid, and central, medial, cortical, and paralaminar nuclei, along with the corticoamygdaloid transition zone. Subregional volumes were compared between groups using ordinary-least-squares regression with relevant demographic and clinical regressors followed by 3-dimensional shape analysis of whole amygdala. ResultsPTSD was associated with smaller left and right lateral and paralaminar nuclei, but with larger left and right central, medial, and cortical nuclei (p < .05, false discovery rate corrected). Shape analyses revealed lower radial distance in anterior bilateral amygdala and lower Jacobian determinant in posterior bilateral amygdala in PTSD compared with control subjects. ConclusionsAlterations in select amygdala subnuclear volumes and regional shape distortions are associated with PTSD in military veterans. Volume differences of the lateral nucleus and the centromedial complex associated with PTSD demonstrate a subregion-specific pattern that is consistent with their functional roles in fear learning and fear expression behaviors.

Increased right amygdala metabolite concentrations in the absence of atrophy in children and adolescents with PTSD.

Previous studies have shown that posttraumatic stress disorder (PTSD) is associated with dysfunction of the limbic system, in which the amygdala plays an important role. The purpose of this study was to evaluate whether the neurochemical concentrations assessed by proton magnetic resonance spectroscopy (1H-MRS) in the amygdala are abnormal in children and adolescents with PTSD. Twenty-eight pediatric PTSD patients (11 boys, 17 girls) and 24 matched trauma-exposed control subjects (9 boys, 15 girls) underwent magnetic resonance brain imaging and 1H-MRS of the bilateral amygdalae. The concentrations of N-acetylaspartate (NAA), myo-inositol (mI), total creatine (tCr) and total choline (tCho) in the right amygdala were significantly increased in PTSD patients compared with trauma-exposed control subjects. There were significant group-by-age interactions in the left amygdala NAA and right amygdala mI concentrations: older pediatric patients with PTSD had higher left amygdala NAA concentration and younger patients had higher right amygdala mI concentration than trauma-exposed control subjects. There was also a significant correlation between right mI concentration and time since trauma in PTSD patients. Finally, there was significant group-by-age interaction in the left amygdala volume; intragroup analysis revealed that the right amygdala volume was significantly lower than the left in the PTSD group, but not in the control group. These neurochemical abnormalities of the amygdala may indicate that dysfunctions of both neurons and glial cells are involved in the pathology of pediatric PTSD.

Diffusion Tensor Imaging Analysis of Mild Traumatic Brain Injury and Posttraumatic Stress Disorder

BackgroundDebate exists over the extent to which dysfunctions arising from mild traumatic brain injury (mTBI) are distinct from posttraumatic stress disorder (PTSD). MethodsThis study investigated 1) the white matter integrity of participants with either mTBI or PTSD, and 2) the relationship between white matter integrity and postconcussive syndrome. The sample comprised 110 civilians (mTBI group = 40; PTSD group = 32; age- and sex-matched trauma-exposed control subjects = 38) recruited from community advertising. Indicators of white matter abnormalities were fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. PTSD symptoms were indexed by the Clinician-Administered PTSD Scale, and postconcussive symptoms were assessed using the Somatic and Psychological Health Report measure. ResultsFractional anisotropy was reduced in mTBI participants in the corpus callosum, tracts of the brainstem, projection fibers, association fibers, and limbic fibers compared with both PTSD and trauma-exposed control subjects. This decrease in fractional anisotropy was observed in the context of concurrent changes in radial diffusivity, axial diffusivity, and mean diffusivity. Postconcussive symptoms were largely explained by PTSD severity rather than by changes in brain white matter. mTBI appears to be characterized by distinct reductions in white matter integrity, and this cannot be attributed to PTSD. ConclusionsPTSD symptoms appear to be more strongly associated with postconcussive syndrome than with white matter compromise. These findings extend epidemiological evidence of the relative associations of PTSD and mTBI with postconcussive syndrome.

Regional Prefrontal Resting-State Functional Connectivity in Posttraumatic Stress Disorder

BackgroundPrefrontal subregions, including the ventromedial prefrontal cortex (PFC), dorsomedial PFC, and dorsolateral PFC (DLPFC), are differentially implicated in the pathophysiology of posttraumatic stress disorder (PTSD), though few existing studies have examined subregional differences in resting-state functional connectivity (rsFC). We hypothesized that PTSD would involve weaker positive rsFC between ventromedial PFC, dorsomedial PFC, and other default mode network regions and increased negative rsFC between DLPFC and posterior default mode network regions. Additionally, we hypothesized that prefrontal regions exhibiting group differences in rsFC would be characterized by alterations in cortical thickness. MethodsParticipants included 36 healthy control subjects, 30 trauma-exposed control subjects, and 21 individuals with current DSM-IV PTSD resulting from community-acquired trauma. Participants completed the Clinician Administered PTSD Scale, questionnaires (Childhood Trauma Questionnaire, Adverse Childhood Events, Life Events Checklist, Beck Depression Inventory), structural neuroimaging, and resting-state functional magnetic resonance imaging. rsFC of DLPFC, ventromedial PFC, and dorsomedial PFC seeds was evaluated in SPM12 and CONN. Cortical thickness for regions with significant rsFC findings was assessed using FreeSurfer. ResultsRelative to both healthy control and trauma-exposed control subjects, individuals with PTSD showed increased negative rsFC between the DLPFC and a region of precuneus. This finding was associated with increased overall symptom severity but not with trauma load or childhood trauma exposure. Greater negative DLPFC-precuneus connectivity was associated with greater bilateral precuneus thickness. ConclusionsGiven participation of precuneus subregions in the central executive network, increased anticorrelation between right DLPFC and precuneus in this sample may reflect increased opposition between anterior and posterior central executive network hubs in PTSD.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

BackgroundMany 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. MethodsWe 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. ResultsIn 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 < .0063). ConclusionsOur 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.

Changes in FKBP5 expression and memory functions during cognitive–behavioral therapy in posttraumatic stress disorder: A preliminary study

Posttraumatic stress disorder (PTSD) is characterized by hyperarousal, flashbacks, avoidance, and memory dysfunctions. Although psychotherapy improves the clinical symptoms, its effect on memory has not been explored. In addition, there is no information about gene expression changes related to hippocampal functions. We assessed PTSD patients (n=20) using the Wechsler Memory Scale-Revised (WAIS-R) and a paired associates learning (PAL) test, as well as changes in blood FK506 binding protein (FKBP5) mRNA expression before and after cognitive behavioral therapy (CBT). Results revealed that before CBT PTSD patients were impaired on WAIS-R delayed recall, attention/concentration, and PAL compared with trauma-exposed control subjects (n=20). These memory dysfunctions showed a significant improvement after CBT. Better performance on the PAL test correlated with enhanced blood FKBP5 mRNA expression. These results suggest that elevated FKBP5 expression during CBT is related to improved associative memory linked to the hippocampal formation.

Amygdala Volume Changes in Posttraumatic Stress Disorder in a Large Case-Controlled Veterans Group

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. 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. 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. Durham Veterans Affairs Medical Center, which is located in proximity to major military bases. 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). Amygdala and hippocampal volumes computed from automated segmentation of high-resolution structural 3-T magnetic resonance imaging. 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. 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.

Effects of psychotherapy on hippocampal volume in out-patients with post-traumatic stress disorder: a MRI investigation

Magnetic resonance imaging (MRI) studies have especially reported smaller hippocampal volume in patients with post-traumatic stress disorder (PTSD), most of them war or sexual abuse victims. The present study compares the hippocampal volumes of out-patients with PTSD who had low co-morbidity rates to those of trauma-exposed control subjects without PTSD, and measures hippocampal volume changes in these patients after brief eclectic psychotherapy. We hypothesized that smaller hippocampal volumes are specific to PTSD and that hippocampal volume changes after effective psychotherapy would be measurable. Eighteen patients with PTSD and 14 traumatized control subjects were examined with MRI. In a randomized clinical trial, the PTSD patients were assigned to treatment (n = 9) or waiting-list group (n = 9). After the former received psychotherapy for 4 months, the MRI was repeated on both PTSD groups. Three temporal lobe structures were manually segmented: hippocampus, amygdala, and parahippocampal gyrus. Volumetric analysis was used to measure grey matter, white matter, and cerebrospinal fluid. PTSD patients had significantly smaller hippocampal volumes at baseline (total 13.8%, right 13.5%, left 14.1%) compared to the control subjects. After effective psychotherapy, however, no volume changes were found in the smaller hippocampi. We confirmed previous findings of smaller hippocampal volume in PTSD in a new population made up of out-patients who experienced different types of traumas, reducing co-morbidity to a minimum. Smaller hippocampal volumes did not change after effective psychotherapy, even while symptoms resolved.

Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery

Functional neuroimaging experiments targeting personal recall of emotional events may help elucidate neural substrates underlying posttraumatic stress disorder (PTSD). Studies suggest that limbic and paralimbic function might be altered in PTSD, as compared with trauma-exposed control subjects; however, little is known about functional changes resulting from traumatic experience itself. The present study examined both PTSD-specific and trauma-specific regional cerebral blood flow (rCBF) patterns during script-driven imagery. Sixteen combat veterans with PTSD (PP); 15 combat veterans without PTSD (CC); and 14 healthy, aged-matched noncombat control subjects (NC) underwent [15O] H20 positron emission tomography (PET) scanning during script-driven imagery of emotionally evocative and neutral autobiographic events. Differential patterns of activation were detected in amygdala and medial frontal cortex. Past trauma experience was associated with decreased amygdala activity (i.e., less activity than healthy control subjects); however, combat control subjects deactivated this region (i.e., greater activity to neutral scripts). All subjects deactivated medial frontal cortex; PTSD patients had greater rostral anterior cingulate (rACC) deactivation compared with control groups, who deactivated ventromedial prefrontal cortex (vmPFC). Trauma-specific patterns may represent potential compensatory changes to traumatic reminders, while patterns observed only in the PTSD group may reflect neural substrates specific to PTSD pathophysiology.

Temporal instability of auditory and visual event-related potentials in posttraumatic stress disorder

Background We examined P300 measures in patients with posttraumatic stress disorder (PTSD) and control subjects at two different time points to determine event-related potential (ERP) stability over time and the relationship of changes in ERPs to changes in symptom levels. Methods Auditory and visual P300 was recorded in a three-condition novelty oddball task in 25 male subjects with combat-related PTSD and 15 male combat-exposed normal control subjects at two time points separated by 6–12 months. Regression analyses were conducted to compare the temporal stability of ERP measures in PTSD and control subjects. Variability in ERP measures over time within PTSD subjects was examined for association with changes in symptom levels. Results There were no significant differences in P300 amplitude or latency in PTSD versus control subjects at either time point, regardless of stimulus type (target, novel) or modality (auditory, visual). Nine of 24 P300 measures were significantly less predictable over time in the PTSD group compared to control subjects. Variability of P300 measures over time was not associated with fluctuations in symptoms of depression or PTSD. Conclusions P300 ERPs are more variable cross-sectionally and over time in PTSD subjects compared to trauma exposed control subjects. Measures of variability about the group mean appear to be more informative about the cognitive electrophysiology of PTSD than measures of central tendency.