Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Feasibility of tracking invasive Escherichia coli disease among older adults in a community setting: A prospective observational study.

PURPOSE: Invasive Escherichia coli disease (IED) encompasses a diverse range of sterile site infections. This study evaluated the feasibility of capturing IED among community-dwelling older adults to inform the implementation of a phase 3 efficacy trial of a novel vaccine against IED (NCT04899336). METHODS: EXPECT-1 (NCT04087681) was a prospective, multinational, observational study conducted in medically stable participants aged ≥ 60 years. At least 50% of participants were selected based on a history of urinary tract infection (UTI) in the previous 10 years. The main outcomes were the incidence of IED and the number of hospitalisations reported by the site vs participant. The length of follow-up was 12 months. In a US-based substudy, a smartphone-based geofencing was evaluated to track hospital entries. RESULTS: In total, 4470 participants were enrolled (median age, 70.0 years); 59.5% (2657/4469) of participants had a history of UTI in the previous 10 years. Four IED events were captured through deployment of different tracking methods: a self-report, a general practitioner (GP) report, and a follow-up call. The incidence rate of IED was 98.6 events per 100,000 person-years. The number of reported hospitalisations was 2529/4470 (56.6%) by the site and 2177/4470 (48.7%) by participants; 13.8% of hospitalisations would have been missed if utilising only site reports. Geofencing detected 72 hospital entries. CONCLUSION: Deployment of multiple tracking methods can optimise detection of IED among community-dwelling older adults. Older adults with a history of UTI could be feasibly targeted for a phase 3 vaccine efficacy trial through a network of GPs.

Clinical presentation and antimicrobial resistance of invasive Escherichia coli disease in hospitalized older adults: a prospective multinational observational study.

BACKGROUND: Clinical data characterizing invasive Escherichia coli disease (IED) are limited. We assessed the clinical presentation of IED and antimicrobial resistance (AMR) patterns of causative E. coli isolates in older adults. METHODS: EXPECT-2 (NCT04117113) was a prospective, observational, multinational, hospital-based study conducted in patients with IED aged ≥ 60 years. IED was determined by the microbiological confirmation of E. coli from blood; or by the microbiological confirmation of E. coli from urine or an otherwise sterile body site in the presence of requisite criteria of systemic inflammatory response syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick SOFA (qSOFA). The primary outcomes were the clinical presentation of IED and AMR rates of E. coli isolates to clinically relevant antibiotics. Complications and in-hospital mortality were assessed through 28 days following IED diagnosis. RESULTS: Of 240 enrolled patients, 80.4% had bacteremic and 19.6% had non-bacteremic IED. One-half of infections (50.4%) were community-acquired. The most common source of infection was the urinary tract (62.9%). Of 240 patients, 65.8% fulfilled ≥ 2 SIRS criteria, and 60.4% had a total SOFA score of ≥ 2. Investigator-diagnosed sepsis and septic shock were reported in 72.1% and 10.0% of patients, respectively. The most common complication was kidney dysfunction (12.9%). The overall in-hospital mortality was 4.6%. Of 299 E. coli isolates tested, the resistance rates were: 30.4% for trimethoprim-sulfamethoxazole, 24.1% for ciprofloxacin, 22.1% for levofloxacin, 16.4% for ceftriaxone, 5.7% for cefepime, and 4.3% for ceftazidime. CONCLUSIONS: The clinical profile of identified IED cases was characterized by high rates of sepsis. IED was associated with high rates of AMR to clinically relevant antibiotics. The identification of IED can be optimized by using a combination of clinical criteria (SIRS, SOFA, or qSOFA) and culture results.

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.

Amygdala responses to threat in violence-exposed children depend on trauma context and maternal caregiving.

Early life adversity (ELA) has been linked with increased arousal responses to threat, including increased amygdala reactivity. Effects of ELA on brain function are well recognized, and emerging evidence suggests that caregivers may influence how environmental stressors impact children's brain function. We investigated the hypothesis that positive interaction between mother and child can buffer against ELA effects on children's neural responses to threat, and related symptoms. N = 53 mother-child pairs (children ages 8-14 years) were recruited from an urban population at high risk for violence exposure. Maternal caregiving was measured using the Parenting Questionnaire and in a cooperation challenge task. Children viewed fearful and neutral face stimuli during functional magnetic resonance imaging. Children who experienced greater violence at home showed amygdala sensitization, whereas children experiencing more school and community violence showed amygdala habituation. Sensitization was in turn linked with externalizing symptoms. However, maternal warmth was associated with a normalization of amygdala sensitization in children, and fewer externalizing behaviors prospectively up to 1 year later. Findings suggested that the effects of violence exposure on threat-related neural circuitry depend on trauma context (inside or outside the home) and that primary caregivers can increase resilience.

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

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 < 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 < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 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.

Successful treatment of post-traumatic stress disorder reverses DNA methylation marks.

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = -0.84, t = -2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.

Associations of maternal emotion regulation with child white matter connectivity in Black American mother-child dyads.

Parental emotion regulation plays a major role in parent-child interactions, and in turn, neural plasticity in children, particularly during sensitive developmental periods. However, little is known about how parental emotion dysregulation is associated with variation in children's brain structure, which was the goal of this study. Forty-five Black American mother-child dyads were recruited from an intergenerational trauma study; emotion regulation in mothers and their children (age 8-13 years) was assessed. Diffusion-weighted images were collected in children; deterministic tractography was used to reconstruct pathways of relevance to emotion regulation. Metrics of white matter connectivity [fractional anisotropy (FA), mean diffusivity (MD)] were extracted for pathways. Socio-economic variables were also included in statistical models. Maternal emotion dysregulation was the strongest predictor of child fornix MD (r = .35, p = .001), indicating that more severe emotion dysregulation in mothers corresponded with lower fornix connectivity in children. Maternal impulsivity was a strong predictor of child fornix MD (r = .51, p < .001). Maternal emotion dysregulation may adversely influence connectivity of the child.s fornix, a hippocampal-striatal pathway implicated in reward processes; these associations remained even after accounting for other socio-environmental factors. Dysregulated maternal emotions may uniquely impact children's adaptation to trauma/stress by affecting networks that support appetitive processing.

Multimodal structural neuroimaging markers of risk and recovery from posttrauma anhedonia: A prospective investigation.

BACKGROUND: Anhedonic symptoms of posttraumatic stress disorder (PTSD) reflect deficits in reward processing that have significant functional consequences. Although recent evidence suggests that disrupted integrity of fronto-limbic circuitry is related to PTSD development, including anhedonic PTSD symptoms (posttrauma anhedonia [PTA]), little is known about potential structural biomarkers of long-term PTA as well as structural changes in fronto-limbic pathways associated with recovery from PTA over time. METHODS: We investigated associations between white matter microstructure, gray matter volume, and PTA in 75 recently traumatized individuals, with a subset of participants (n = 35) completing follow-up assessment 12 months after trauma exposure. Deterministic tractography and voxel-based morphometry were used to assess changes in white and gray matter structure associated with changes in PTA. RESULTS: Reduced fractional anisotropy (FA) of the uncinate fasciculus at around the time of trauma predicted greater PTA at 12-months posttrauma. Further, increased FA of the fornix over time was associated with lower PTA between 1 and 12-months posttrauma. Increased gray matter volume of the ventromedial prefrontal cortex and precuneus over time was also associated with reduced PTA. CONCLUSIONS: The microstructure of the uncinate fasciculus, an amygdala-prefrontal white matter connection, may represent a biomarker of vulnerability for later PTA. Conversely, development and recovery from PTA appear to be facilitated by white and gray matter structural changes in a major hippocampal pathway, the fornix. The present findings shed new light on neuroanatomical substrates of recovery from PTA and characterize white matter biomarkers of risk for posttraumatic dysfunction.

White matter microstructure in trauma-exposed children: Associations with pubertal stage.

Puberty represents a critical period in maturation during which major changes in neural architecture emerge; these changes are shaped, in part, by environmental experiences, including exposure to psychological trauma. However, little is known about how trauma exposure affects white matter microstructure across pubertal stages. This was the goal of the present cross-sectional study. Forty-one male and female African-American children between ages 8-13 were recruited as part of a study of developmental trauma and received assessments of trauma exposure, including violence, and pubertal development as well as diffusion tensor imaging (DTI). Significant interactions of pubertal stage and violent trauma exposure were observed in association with a marker of white matter integrity (mean diffusivity, MD) in the corpus callosum, cingulum bundle and uncinate fasciculus. Greater violent trauma exposure was associated with lower MD in the hippocampal cingulum and uncinate fasciculus in girls, but not boys. These data from a sample of trauma-exposed children may reflect a pattern of accelerated maturation in pathways that are critical for emotion regulation as well as attention and memory processes. It appears that fronto-limbic and callosal connections are particularly sensitive to the effects of violent trauma, revealing a potential pathway through which trauma creates vulnerability for later psychiatric and neurological disorders.

Puberty drives fear learning during adolescence.

Risk for adverse outcomes, including the onset of mental illness, increases during adolescence. This increase may be linked to both new exposures, such as violence at home or in the community, or to physiological changes driven by puberty. There are significant sex differences in adolescent risk, for instance, anxiety disorders are significantly more prevalent in girls than boys. Fear learning is linked to mental health and may develop during adolescence, but the role of puberty in adolescent-specific change has not yet been systematically evaluated. We conducted a longitudinal study of fear learning that tested fear-potentiated startle (FPS) in 78 children (40 girls) aged 8-16 years. Participants completed two to three visits that included a differential fear conditioning task and self-report of both pubertal status and violence exposure. We tested for effects of sex, pubertal status, and violence exposure on FPS over time with latent growth curve models. We also examined the association between FPS and later anxiety symptoms. We found significant changes in FPS to the threat cue, but not the safety cue, across visits. Higher pubertal status was significantly associated with increased FPS to threat cues at each visit, whereas sex and violence exposure were not. FPS to threat during the baseline visit also predicted later anxiety symptoms. These findings suggest that puberty drives increased fear response to threat cues similarly for girls and boys, and that this effect may not be significantly impacted by individual differences in violence exposure during early adolescence.

Increased activation of the fear neurocircuitry in children exposed to violence.

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8- to 14-year-old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long-term costs or consequences of these adaptations are largely unknown and an area for future investigations.

Association between posttraumatic stress disorder severity and amygdala habituation to fearful stimuli.

BACKGROUND: Amygdala hyperreactivity to threat has been proposed to be a causal contributor to posttraumatic stress disorder (PTSD). However, emerging literature in healthy samples shows higher test-retest reliability for amygdala habituation (the change over time in response to repeated stimuli) than for its reactivity to threat. Amygdala habituation has received relatively little attention in relationship to PTSD, despite the key role of this region in the etiology of the disorder. Thus, we investigated habituation to repeated fearful face stimuli and PTSD, in a large sample of trauma exposed African American women. METHODS: African American women (N = 100) were recruited from a nonprofit hospital serving a largely low-income population with a high risk of trauma exposure. Participants underwent functional magnetic resonance imaging, passively viewing fearful and neutral face stimuli, and reported their history of trauma exposure and current PTSD symptoms. We examined associations between PTSD symptom severity and amygdala reactivity (fearful > neutral) and habituation (early > late) to fearful faces. Secondary analyses tested whether amygdala habituation to fearful faces mediated the association between childhood trauma and PTSD. RESULTS: PTSD symptom severity and PTSD status (based on self-report measure) were both positively associated with amygdala habituation to repeated fearful face stimuli. Whole-brain analysis showed that this association extended to the bilateral hippocampus and left fusiform gyrus. The association held when controlling for trauma history and depressive symptoms. Amygdala habituation to fearful faces partially mediated the association between childhood trauma severity and PTSD symptom severity. CONCLUSION: Individuals with greater PTSD symptom severity showed greater amygdala habituation to social threat cues (fearful faces), and greater habituation may partly explain the association between childhood trauma exposure and current PTSD symptoms. Further examination of the dynamics of the amygdala response to threat cues may lead to new insights in the understanding and treatment of stress-related disorders.

The effect of aging on fronto-striatal reactive and proactive inhibitory control.

Inhibitory control, like most cognitive processes, is subject to an age-related decline. The effect of age on neurofunctional inhibition processing remains uncertain, with age-related increases as well as decreases in activation being reported. This is possibly because reactive (i.e., outright stopping) and proactive inhibition (i.e., anticipation of stopping) have not been evaluated separately. Here, we investigate the effects of aging on reactive as well as proactive inhibition, using functional MRI in 73 healthy subjects aged 30-70years. We found reactive inhibition to slow down with advancing age, which was paralleled by increased activation in the motor cortex. Behaviorally, older adults did not exercise increased proactive inhibition strategies compared to younger adults. However, the pattern of activation in the right inferior frontal gyrus (rIFG) showed a clear age-effect on proactive inhibition: rather than flexibly engaging the rIFG in response to varying stop-signal probabilities, older subjects showed an overall hyperactivation. Whole-brain analyses revealed similar hyperactivations in various other frontal and parietal brain regions. These results are in line with the neural compensation hypothesis of aging: processing becomes less flexible and efficient with advancing age, which is compensated for by overall enhanced activation. Moreover, by disentangling reactive and proactive inhibition, we can show for the first time that the age-related increase in activation during inhibition that is reported generally by prior studies may be the result of compensation for reduced neural flexibility related to proactive control strategies.

Resting state functional connectivity of the anterior cingulate cortex in veterans with and without post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is an anxiety disorder that is associated with structural and functional alterations in several brain areas, including the anterior cingulate cortex (ACC). Here, we examine resting state functional connectivity of ACC subdivisions in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from male veterans with (n = 31) and without (n = 25) PTSD, and healthy male civilian controls (n = 25). Veterans with and without PTSD (combat controls) had reduced functional connectivity compared to healthy controls between the caudal ACC and the precentral gyrus, and between the perigenual ACC and the superior medial gyrus and middle temporal gyrus. Combat controls had increased connectivity between the rostral ACC and precentral/middle frontal gyrus compared to PTSD patients and healthy civilian controls. The resting state functional connectivity differences in the perigenual ACC network reported here indicate that veterans differ from healthy controls, potentially due to military training, deployment, and/or trauma exposure. In addition, specific alterations in the combat controls may potentially be related to resilience. These results underline the importance of distinguishing trauma-exposed (combat) controls from healthy civilian controls when studying PTSD.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.

BACKGROUND: Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. METHODS: Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). RESULTS: We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. LIMITATIONS: Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. CONCLUSION: Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.