Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

Stress and trauma profoundly influence psychiatric biobehavioral outcomes. The identification of treatment and biomarker targets would be accelerated by a broad understanding of the biological responses to these events. The goal of this study was to determine genes responsive to auditory fear conditioning (FC), a well-characterized amygdala-dependent rodent model of threat-exposure, in the presence or absence of prior stress history, providing insight into the physiological processes underlying response to trauma. RNA-sequencing was performed in blood and amygdala from mice that underwent fear conditioning with (Immo+FC) and without (FC) prior immobilization stress, a paradigm that induces HPA axis, and behavioral stress sensitization. In the amygdala, 607 genes were regulated by FC vs. home-cage (HC) controls, and 516 genes differed in stress-sensitized mice (Immo+FC vs. FC). In the former, we observed an enhancement of specific biological processes involved in learning and synaptic transmission, and in the latter processes associated with cell proliferation and the cellular response to drugs. In the blood of stress-sensitized animals, 468 genes were dynamically regulated when compared to FC, and were enriched for the biological pathways of inflammation and cytokine signaling. This study identified genes and pathways that respond to threat in the amygdala and blood of mice with and without a prior stress history and reveals the impact of stress history on subsequent inflammation. Future studies will be needed to examine the role of these dynamically regulated genes may play in human clinical stress and trauma-related disorders

Effect of Childhood Trauma on Adult Depression and Neuroendocrine Function: Sex-Specific Moderation by CRH Receptor 1 Gene

Variations of the corticotropin-releasing hormone receptor 1 (CRHR1) gene appear to moderate the development of depression after childhood trauma. Depression more frequently affects women than men. We examined sex differences in the effects of the CRHR1 gene on the relationship between childhood trauma and adult depression. We recruited 1,063 subjects from the waiting rooms of a public urban hospital. Childhood trauma exposure and symptoms of depression were assessed using dimensional rating scales. Subjects were genotyped for rs110402 within the CRHR1 gene. An independent sample of 78 subjects underwent clinical assessment, genotyping, and a dexamethasone/CRH test. The age range at recruitment was 18–77 years and 18–45, for the two studies respectively. In the hospital sample, the protective effect of the rs110402 A-allele against developing depression after childhood trauma was observed in men (N = 424), but not in women (N = 635). In the second sample, the rs110402 A-allele was associated with decreased cortisol response in the dexamethasone/CRH test only in men. In A-allele carriers with childhood trauma exposure women exhibited increased cortisol response compared men; there were no sex differences in A-allele carriers without trauma exposure. This effect may, however, not be related to gender differences per se, but to differences in the type of experienced abuse between men and women. CRHR × environment interactions in the hospital sample were observed with exposure to physical, but not sexual or emotional abuse. Physical abuse was the most common type of abuse in men in this cohort, while sexual abuse was most commonly suffered by women. Our results suggest that the CRHR1 gene may only moderate the effects of specific types of childhood trauma on depression. Gender differences in environmental exposures could thus be reflected in sex-specific CRHR1 × child abuse interactions

Polygenic risk associated with post-traumatic stress disorder onset and severity.

Post-traumatic stress disorder (PTSD) is a psychiatric illness with a highly polygenic architecture without large effect-size common single-nucleotide polymorphisms (SNPs). Thus, to capture a substantial portion of the genetic contribution, effects from many variants need to be aggregated. We investigated various aspects of one such approach that has been successfully applied to many traits, polygenic risk score (PRS) for PTSD. Theoretical analyses indicate the potential prediction ability of PRS. We used the latest summary statistics from the largest published genome-wide association study (GWAS) conducted by Psychiatric Genomics Consortium for PTSD (PGC-PTSD). We found that the PRS constructed for a cohort comprising veterans of recent wars (n = 244) explains a considerable proportion of PTSD onset (Nagelkerke R2 = 4.68%, P = 0.003) and severity (R2 = 4.35%, P = 0.0008) variances. However, the performance on an African ancestry sub-cohort was minimal. A PRS constructed with schizophrenia GWAS also explained a significant fraction of PTSD diagnosis variance (Nagelkerke R2 = 2.96%, P = 0.0175), confirming previously reported genetic correlation between the two psychiatric ailments. Overall, these findings demonstrate the important role polygenic analyses of PTSD will play in risk prediction models as well as in elucidating the biology of the disorder

Neural Correlates of Attention Bias to Threat in Post-traumatic Stress Disorder

Attention bias has been proposed to contribute to symptom maintenance in Posttraumatic Stress Disorder (PTSD), although the neural correlates of these processes have not been well defined. When engaging in tasks that require attention, individuals with PTSD have demonstrated altered activity in brain regions such as the dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (vlPFC), and amygdala; however, few PTSD neuroimaging studies have employed tasks that both measure attentional strategies being engaged and included emotionally-salient information, which was the goal of the present study. We administered a modified attention bias task, the dot probe, which is equipped to measure direction and magnitude of bias, to a sample of 37 (19 trauma control, 18 PTSD+) traumatized African-American adults during functional magnetic resonance imaging. Compared to traumatized participants without PTSD, PTSD+ participants demonstrated increased activation in the dlPFC in response to trials including angry/threatening expressions. In addition, attentional avoidance of threat cues corresponded with increased vlPFC and dorsal ACC (dACC) activation in the PTSD group, a pattern that was not observed in controls. These data provide some evidence to suggest that relative increases in dlPFC, dACC and vlPFC activation to threat cues in the context of heightened attentional demands represent neural markers of attentional bias for threat in individuals with PTSD, reflecting selective disruptions in attentional control and emotion processing networks in this disorder

Mobile assessment of heightened skin conductance in posttraumatic stress disorder

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137606/1/da22610.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137606/2/da22610_am.pd

Attention Bias Toward Threat is Associated with Exaggerated Fear Expression and Impaired Extinction in PTSD

Background: Post-traumatic stress disorder (PTSD) develops in a minority of traumatized individuals. Attention biases to threat and abnormalities in fear learning and extinction are processes likely to play a critical role in the creation and/or maintenance of PTSD symptomatology. However, the relationship between these processes has not been established, particularly in highly traumatized populations; understanding their interaction can help inform neural network models and treatments for PTSD. Method: Attention biases were measured using a dot probe task modified for use with our population; task stimuli included photographs of angry facial expressions, which are emotionally salient threat signals. A fear-potentiated startle paradigm was employed to measure atypical physiological response during acquisition and extinction phases of fear learning. These measures were administered to a sample of 64 minority (largely African American), highly traumatized individuals with and without PTSD. Results: Participants with PTSD demonstrated attention biases toward threat ; this attentional style was associated with exaggerated startle response during fear learning and early and middle phases of extinction, even after accounting for the effects of trauma exposure. Conclusions: Our findings indicate that an attentional bias toward threat is associated with abnormalities in ‘fear load’ in PTSD, providing seminal evidence for an interaction between these two processes. Future research combining these behavioral and psychophysiological techniques with neuroimaging will be useful toward addressing how one process may modulate the other and understanding whether these phenomena are manifestations of dysfunction within a shared neural network. Ultimately, this may serve to inform PTSD treatments specifically designed to correct these atypical processes

Are all threats equal? Associations of childhood exposure to physical attack versus threatened violence with preadolescent brain structure

Background: Neurodevelopmental studies of childhood adversity often define threatening experiences as those involving harm or the threat of harm. Whether effects differ between experiences involving harm (“physical attack”) versus the threat of harm alone (“threatened violence”) remains underexplored. We hypothesized that while both types of experiences would be associated with smaller preadolescent global and corticolimbic brain volumes, associations with physical attack would be greater. Methods: Generation R Study researchers (the Netherlands) acquired T1-weighted scans from 2905 preadolescent children, computed brain volumes using FreeSurfer, and asked mothers whether their children ever experienced physical attack (n = 202) or threatened violence (n = 335). Using standardized global (cortical, subcortical, white matter) and corticolimbic (amygdala, hippocampus, anterior cingulate cortex, orbitofrontal cortex) volumes, we fit confounder-adjusted models. Results: Physical attack was associated with smaller global volumes (βcortical=−0.14; 95% CI: −0.26, −0.02); βwhite matter= −0.16; 95% CI: − 0.28, − 0.03) and possibly some corticolimbic volumes, e.g., βamygdala/ICV-adjusted= −0.10 (95% CI: −0.21, 0.01). We found no evidence of associations between threatened violence and smaller volumes in any outcome; instead, such estimates were small, highly uncertain, and positive in direction. Conclusions: Experiences of physical attack and threatened violence may have quantitively different neurodevelopmental effects. Thus, differences between types of threatening experiences may be neurodevelopmentally salient.</p

Behavioral and neurostructural correlates of childhood physical violence victimization:Interaction with family functioning

Violence victimization may cause child behavior problems and neurostructural differences associated with them. Healthy family environments may buffer these effects, but neural pathways explaining these associations remain inadequately understood. We used data from 3154 children (x̅age  = 10.1) to test whether healthy family functioning moderated possible associations between violence victimization, behavior problems, and amygdala volume (a threat-responsive brain region). Researchers collected data on childhood violence victimization, family functioning (McMaster Family Assessment Device, range 0-3, higher scores indicate healthier functioning), and behavior problems (Achenbach Child Behavior Checklist [CBCL] total problem score, range 0-117), and they scanned children with magnetic resonance imaging. We standardized amygdala volumes and fit confounder-adjusted models with "victimization × family functioning" interaction terms. Family functioning moderated associations between victimization, behavior problems, and amygdala volume. Among lower functioning families (functioning score = 1.0), victimization was associated with a 26.1 (95% confidence interval [CI]: 9.9, 42.4) unit higher CBCL behavior problem score, yet victimized children from higher functioning families (score = 3.0) exhibited no such association. Unexpectedly, victimization was associated with higher standardized amygdala volume among lower functioning families (ŷ = 0.5; 95% CI: 0.1, 1.0) but lower volume among higher functioning families (ŷ = -0.4; 95% CI: -0.7, -0.2). Thus, healthy family environments may mitigate some neurobehavioral effects of childhood victimization.</p

Reduced Neural Activation During an Inhibition Task is Associated with Impaired Fear Inhibition in a Traumatized Civilian Sample

Introduction: Impaired inhibition of fear in the presence of safety cues and a deficiency in the extinction of fear cues are increasingly thought to be important biological markers of Posttraumatic Stress Disorder (PTSD). Other studies have suggested that there may be altered neural activation during behavioral inhibition tasks in subjects with PTSD. The current study aimed to see whether neural activation during inhibition was reduced in a highly traumatized civilian population, and whether atypical activation was associated with impaired fear inhibition. Methods: The participants were 41 traumatized women (20 PTSD+, 21 PTSD-) recruited from Grady Memorial Hospital in Atlanta, GA. We used a Go/NoGo procedure with functional magnetic resonance imaging (fMRI) in a high-resolution 3T scanner. Participants were instructed to press a button whenever an “X” or “O” appeared on the screen, but not if a red square appeared behind the letter. Participants were assessed for trauma history and PTSD diagnosis, and completed a fear-potentiated startle and extinction paradigm. Results: We found stronger activation in the ventromedial prefrontal cortex (vmPFC) in traumatized subjects without PTSD compared to those with PTSD in the NoGo greater than Go contrast condition. Activation in the vmPFC was negatively correlated with fear-potentiated startle responses during safety signal learning (p=.02) and fear extinction (p=.0002). Conclusions: These results contribute to understanding of how the neural circuitry involved in inhibitory processes may be deficient in PTSD. Furthermore, the same circuits involved in behavioral inhibition appear to be involved in fear inhibition processes during differential fear conditioning and extinction