Machine learning prediction of posttraumatic stress disorder trajectories following traumatic injury: Identification and validation in two independent samples.

Due to its heterogeneity, the prediction of posttraumatic stress disorder (PTSD) development after traumtic injury is difficult. Recent machine learning approaches have yielded insight into predicting PTSD symptom trajectories. Using data collected within 1 month of traumatic injury, we applied eXtreme Gradient Boosting (XGB) to classify admitted and discharged patients (hospitalized, n = 192; nonhospitalized, n = 214), recruited from a Level 1 trauma center, according to PTSD symptom trajectories. Trajectories were identified using latent class mixed models on PCL-5 scores collected at baseline, 1-3 months posttrauma, and 6 months posttrauma. In both samples, nonremitting, remitting, and resilient PTSD symptom trajectories were identified. In the admitted patient sample, a unique delayed trajectory emerged. Machine learning classifiers (i.e., XGB) were developed and tested on the admitted patient sample and externally validated on the discharged sample with biological and clinical self-report baseline variables as predictors. For external validation sets, prediction was fair for nonremitting versus other trajectories, areas under the curve (AUC = .70); good for nonremitting versus resilient trajectories, AUCs = .73-.76; and prediction failed for nonremitting versus remitting trajectories, AUCs = .46-.48. However, poor precision (< .57) across all models suggests limited generalizability of nonremitting symptom trajectory prediction from admitted to discharged patient samples. Consistency in symptom trajectory identification across samples supports prior studies on the stability of PTSD symptom trajectories following trauma exposure; however, continued work and replication with larger samples are warranted to understand overlapping and unique predictive features of PTSD in different traumatic injury populations.

Principal component analysis and brain-based predictors of emotion regulation in anxiety and depression.

BACKGROUND: Reappraisal, an adaptive emotion regulation strategy, is associated with frontal engagement. In internalizing psychopathologies (IPs) such as anxiety and depression frontal activity is atypically reduced suggesting impaired regulation capacity. Yet, successful reappraisal is often demonstrated at the behavioral level. A data-driven approach was used to clarify brain and behavioral relationships in IPs. METHODS: During functional magnetic resonance imaging, anxious [general anxiety disorder (n = 43), social anxiety disorder (n = 72)] and depressed (n = 47) patients reappraised negative images to reduce negative affect ('ReappNeg') and viewed negative images ('LookNeg'). After each trial, the affective state was reported. A cut-point (i.e. values <0 based on ΔReappNeg-LookNeg) demarcated successful reappraisers. Neural activity for ReappNeg-LookNeg, derived from 37 regions of interest, was submitted to Principal Component Analysis (PCA) to identify unique components of reappraisal-related brain response. PCA factors, symptom severity, and self-reported habitual reappraisal were submitted to discriminant function analysis and linear regression to examine whether these data predicted successful reappraisal (yes/no) and variance in reappraisal ability. RESULTS: Most patients (63%) were successful reappraisers according to the behavioral criterion (values<0; ΔReappNeg-LookNeg). Discriminant function analysis was not significant for PCA factors, symptoms, or habitual reappraisal. For regression, more activation in a factor with high loadings for frontal regions predicted better reappraisal facility. Results were not significant for other variables. CONCLUSIONS: At the individual level, more activation in a 'frontal' factor corresponded with better reappraisal facility. However, neither brain nor behavioral variables classified successful reappraisal (yes/no). Findings suggest individual differences in regions strongly implicated in reappraisal play a role in on-line reappraisal capability.

Transdiagnostic neural correlates of volitional emotion regulation in anxiety and depression.

BACKGROUND: Individuals who suffer from anxiety and/or depression face difficulty in adaptively managing emotional responses, while accumulating evidence suggests impaired emotion regulation is a transdiagnostic feature of psychopathology. Effectual regulation in the context of negative stimuli is characterized by engagement of the prefrontal cortex (PFC) coupled with reduced amygdala reactivity. In anxiety disorders and major depression, PFC underengagement and atypical PFC-amygdala connectivity has been observed, although patient findings based on case-control studies have been mixed with regard to magnitude, locality, and extent of dysfunction. As anxiety disorders and major depression are heterogeneous disorders and frequently comorbid with one another, delineating relationships between reappraise-related substrates and symptoms may advance our understanding of emotion dysregulation in these populations. METHODS: We examined PFC activation and its functional connectivity (FC) to the amygdala using functional magnetic resonance imaging in a large sample of patients (N = 174) with primary generalized anxiety disorder (n = 47), social anxiety disorder (n = 78), or major depressive disorder (n = 49) during a reappraisal-based emotion regulation task. Comorbidity was permitted and the majority of participants had a concurrent psychiatric illnesses. RESULTS: Across participants, whole-brain results showed that (1) greater anxiety and depression symptom severity was related to less engagement of the dorsal anterior cingulate cortex (ACC) and (2) less FC between the amygdala and ventrolateral PFC. Results were driven by anxiety, while depression symptoms were not significant. CONCLUSION: These findings demonstrate that individual differences in anxiety and depression may help explain ACC and PFC dysfunction during emotion regulation observed across anxiety and depressive disorders.

Neuroimaging Predictors and Mechanisms of Treatment Response in Social Anxiety Disorder: an Overview of the Amygdala.

PURPOSE OF REVIEW: Aberrant amygdala activity is implicated in the neurobiology of social anxiety disorder (SAD) and is, therefore, a treatment target. However, the extent to which amygdala predicts clinical improvement or is impacted by treatment has not been critically examined. This review highlights recent neuroimaging findings from clinical trials and research that test links between amygdala and mechanisms of action. RECENT FINDINGS: Neuropredictor studies largely comprised psychotherapy where improvement was foretold by amygdala activity and regions beyond amygdala such as frontal structures (e.g., anterior cingulate cortex, medial prefrontal cortex) and areas involved in visual processes (e.g., occipital regions, superior temporal gyrus). Pre-treatment functional connectivity between amygdala and frontal areas was also shown to predict improvement signifying circuits that support emotion processing and regulation interact with treatment. Pre-to-post studies revealed decreases in amygdala response and altered functional connectivity in amygdala pathways regardless of treatment modality. In analogue studies of fear exposure, greater reduction in anxiety was predicted by less amygdala response to a speech challenge and amygdala activity decreased following exposures. Yet, studies have also failed to detect amygdala effects reporting instead treatment-related changes in regions and functional systems that support sensory, emotion, and regulation processes. An array of regions in the corticolimbic subcircuits and extrastriate cortex appear to be viable sites of action. The amygdala and amygdala pathways predict treatment outcome and are altered following treatment. However, further study is needed to establish the role of the amygdala and other candidate regions and brain circuits as sites of action.

Individual differences in cognitive reappraisal use and emotion regulatory brain function in combat-exposed veterans with and without PTSD.

BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) exhibit marked deficits in emotion regulation. Past research has demonstrated underengagement of the prefrontal cortex during regulation of negative affect in those with PTSD, but has been unable to find evidence of impaired downregulation of the amygdala. One possibility is that there exists variability in amygdala reactivity that cuts across diagnostic status and which can be characterized using a continuous measure of individual differences. In healthy/nontraumatized volunteers, individual variability in amygdala engagement during emotion processing and regulation has been shown to relate to habitual use of regulation strategies. METHODS: The current study examined whether self-reported use of cognitive reappraisal and expressive suppression regulation strategies correlated with brain activation during cognitive reappraisal in combat-exposed veterans with (n = 28) and without PTSD (combat-exposed controls, CEC; n = 20). RESULTS: Results showed that greater self-reported use of cognitive reappraisal was associated with less activation in the right amygdala during volitional attempts to attenuate negative affect using reappraisal, irrespective of PTSD diagnosis. CONCLUSIONS: This finding is in line with prior work and extends evidence of an association between habitual use of regulation strategies and amygdala engagement during emotion regulation to a trauma-exposed sample of individuals both with and without PTSD. Furthermore, by providing evidence of individual differences in regulation-related amygdala response in a traumatized sample, this result may increase understanding of the neural mechanisms that support variability in symptom manifestation observed across individuals with PTSD.

Translational approaches to the neurobiological study of conditional discrimination and inhibition: Implications for psychiatric disease.

There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses. The objective of this review is to give an overview of the conditional discrimination and inhibition findings reported in both animal models and human neuropsychiatric disorders. Both behavioral and neural findings are reviewed among human and rodent studies that include conditional fear discrimination via conditional stimuli with and without reinforcement (CS+ vs. CS-, respectively) and/or conditional inhibition of fear through assessment of the fear response to a compound CS-/CS+ cue versus CS+. There are several parallels across species in behavioral fear expression as well as neural circuits promoting fear reduction in response to a CS- and/or CS-/CS+ compound cue. Continued and increased efforts to compare similar behavioral fear inhibition paradigms across species are needed to make breakthrough advances in our understanding and treatment approaches to individuals with fear disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Childhood Maltreatment and Amygdala-Mediated Anxiety and Posttraumatic Stress Following Adult Trauma.

Background: Childhood abuse (physical, emotional, and sexual) is associated with aberrant connectivity of the amygdala, a key threat-processing region. Heightened amygdala activity also predicts adult anxiety and posttraumatic stress disorder (PTSD) symptoms, as do experiences of childhood abuse. The current study explored whether amygdala resting-state functional connectivity may explain the relationship between childhood abuse and anxiety and PTSD symptoms following trauma exposure in adults. Methods: Two weeks posttrauma, adult trauma survivors (n = 152, mean age [SD] = 32.61 [10.35] years; women = 57.2%) completed the Childhood Trauma Questionnaire and underwent resting-state functional magnetic resonance imaging. PTSD and anxiety symptoms were assessed 6 months posttrauma. Seed-to-voxel analyses evaluated the association between childhood abuse and amygdala resting-state functional connectivity. A mediation model evaluated the potential mediating role of amygdala connectivity in the relationship between childhood abuse and posttrauma anxiety and PTSD. Results: Childhood abuse was associated with increased amygdala connectivity with the precuneus while covarying for age, gender, childhood neglect, and baseline PTSD symptoms. Amygdala-precuneus resting-state functional connectivity was a significant mediator of the effect of childhood abuse on anxiety symptoms 6 months posttrauma (B = 0.065; 95% CI, 0.013-0.130; SE = 0.030), but not PTSD. A secondary mediation analysis investigating depression as an outcome was not significant. Conclusions: Amygdala-precuneus connectivity may be an underlying neural mechanism by which childhood abuse increases risk for anxiety following adult trauma. Specifically, this heightened connectivity may reflect attentional vigilance for threat or a tendency toward negative self-referential thoughts. Findings suggest that childhood abuse may contribute to longstanding upregulation of attentional vigilance circuits, which makes one vulnerable to anxiety-related symptoms in adulthood.

Experiences of childhood abuse are related to long-term mental health outcomes, but the mechanisms of this relationship have been unclear. In this study of adult trauma survivors, Harb et al. found that experiences of childhood abuse are related to abnormal connectivity patterns of the amygdala, a key region for fear and threat processing, and precuneus. These connectivity patterns were identified as a mechanism through which experiences of child abuse are related to adult anxiety symptoms posttrauma. These findings advance our understanding of the specific downstream impacts of experiencing childhood abuse and can inform targeted assessment and intervention methods, especially in an adult trauma sample.

The Dichotomy of Threat and Deprivation as Subtypes of Childhood Maltreatment: Differential Functional Connectivity Patterns of Threat and Reward Circuits in an Adult Trauma Sample.

BACKGROUND: Childhood maltreatment is associated with reduced activation of the nucleus accumbens, a central region in the reward network, and overactivity in the amygdala, a key region in threat processing. However, the long-lasting impact of these associations in the context of later-life stress is not well understood. The current study explored the association between childhood threat and deprivation and functional connectivity of threat and reward regions in an adult trauma sample. METHODS: Trauma survivors (N = 169; mean age [SD] = 32.2 [10.3] years; female = 55.6%) were recruited from a level I trauma center. Two weeks after injury, participants completed the Childhood Trauma Questionnaire (measuring experiences of threat and deprivation) and underwent resting-state functional magnetic resonance imaging. Seed-to-voxel analyses evaluated the effect of childhood threat and deprivation on amygdala and nucleus accumbens resting-state connectivity. RESULTS: Higher levels of threat were associated with increased connectivity between the right nucleus accumbens with temporal fusiform gyrus/parahippocampal gyrus and the left amygdala and the precuneus (false discovery rate-corrected p < .05). After controlling for posttraumatic symptoms 2 weeks posttrauma and lifetime trauma exposure, only the nucleus accumbens findings survived. There were no significant relationships between experiences of childhood deprivation and amygdala or nucleus accumbens connectivity. CONCLUSIONS: Experiences of threat are associated with increased nucleus accumbens and amygdala connectivity, which may reflect a preparedness to detect salient and visual stimuli. This may also reflect a propensity toward dysregulated reward processing. Overall, these results suggest that childhood threat may be contributing to aberrant neural baseline reward and threat sensitivity later in life in an adult trauma sample.

Negative emotion interference during a synonym matching task in pediatric bipolar disorder with and without attention deficit hyperactivity disorder.

This study examined whether processing of emotional words impairs cognitive performance in acutely ill patients with pediatric bipolar disorder (PBD), with or without comorbid attention-deficit hyperactivity disorder (ADHD), relative to healthy controls (HC). Forty youths with PBD without ADHD, 20 youths with PBD and ADHD, and 29 HC (mean age = 12.97 ± 3.13) performed a Synonym Matching task, where they decided which of two probe words was the synonym of a target word. The three words presented on each trial all had the same emotional valence, which could be negative, positive, or neutral. Relative to HC both PBD groups exhibited worse accuracy for emotional words relative to neutral ones. This effect was greater with negative words and observed regardless of whether PBD patients had comorbid ADHD. In the PBD group without ADHD, manic symptoms correlated negatively with accuracy for negative words, and positively with reaction time (RT) for all word types. Our findings suggest a greater disruptive effect of emotional valence in both PBD groups relative to HC, reflecting the adverse effect of altered emotion processing on cognitive function in PBD. Future studies including an ADHD group will help clarify how ADHD symptoms may affect emotional interference independently of PBD.

Relationship between heart rate variability and differential patterns of cortisol response to acute stressors in mid-life adults: A data-driven investigation.

Cortisol and heart rate variability (HRV) are well-established biomarkers of the human stress response system. While a relationship between cortisol and HRV is assumed, few studies have found evidence of their correlation within single study designs. One complication for isolating such a relationship may lie in individual variability in the cortisol response to stress such that atypical cortisol responding (i.e., elevated or blunted) occurs. To-date, studies on the cortisol response have employed traditional mean-difference-based approaches to examine average magnitude change in cortisol over time. Alternatively, data-driven trajectory modelling, such as latent growth mixture modelling, may be advantageous for quantifying cortisol based on patterns of response over time. Latent growth mixture modelling was used in N = 386 adults to identify subgroups based on trajectories of cortisol responses to stress. The relationship between cortisol and HRV was tested within subgroups. Results revealed a 'prototypical' subgroup characterised by expected rise and fall in cortisol response to stress (n = 309), a 'decline' subgroup (n = 28) that declined in cortisol after stress, and a 'rise' subgroup (n = 49) that increased in cortisol after stress. Within the 'prototypical' subgroup, greater HRV during stress was associated with decline in cortisol after stress from its maximum (r (306) = 0.19, p < 0.001). This relationship failed to emerge in the 'decline' and 'rise' subgroups (p > 0.271). Results document different patterns of cortisol response to stress; among those who exhibit a 'prototypical' response, changes in HRV during stress are related to changes in cortisol after stress.

Psychological and physiological correlates of stimulus discrimination in adults.

The discrimination of cues in the environment that signal danger ("fear cue") is important for survival but depends critically on the discernment of such cues from ones that pose no threat ("safety cues"). In rodents, we previously demonstrated the underlying neurobiological mechanisms that support fear versus safety discrimination and documented that these mechanisms extend to the discrimination of reward as well. While learning about reward is equally important for survival, it remains an under-studied area of research, particularly in human studies of conditional discrimination. In the present study, we translated our rodent task of fear reward and neutral discrimination (fear, reward, and neutral discrimination [FRND]) for use in humans. Undergraduate students (N = 53) completed the FRND while electrodermal activity was recorded. Skin conductance response (SCR) amplitude, a marker of arousal response, was derived for fear, reward, and neutral cues that signaled no outcome; critical trials assessed conditional discrimination using combined fear + neutral and reward + neutral cues. Participants provided likeability ratings for each cue type. Results demonstrated that participants rated reward cues the best, fear cues the worst, and neutral cues in between, while SCR amplitude was largest for fear and reward cues and lowest for neutral cues. SCR amplitudes were reduced for fear + neutral (compared to fear) and reward + neutral cues (compared to reward). Results demonstrate that the FRND is a useful paradigm for the assessment of psychological and physiological discrimination of fear and reward. Implications and directions for future work are discussed.

Neural Correlates of Reward Processing in the Onset, Maintenance, and Treatment of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and heterogeneous psychiatric condition marked by both exaggerated threat responding and diminished positive affect. While symptom profiles of PTSD differ across individuals, symptoms also vary within individuals over the course of illness. Functional magnetic resonance imaging studies have provided crucial insights into the neurobiology of heightened threat responsivity in PTSD, which has aided in identifying neurobiological risk factors and treatment targets for this disorder. Despite this demonstrated utility, the application of functional magnetic resonance imaging to understanding deficits in reward responsivity in PTSD remains underexplored. Significantly, over 60% of individuals with PTSD experience anhedonia, or an inability to feel pleasure, which may reflect reward processing deficits. To better understand the neural underpinnings of reward deficits and their relevance to the onset, maintenance, and treatment of PTSD, we reviewed the functional magnetic resonance imaging literature through the framework of disease prognosis. Here, we provide insights on whether reward deficits are central to PTSD or are better explained by comorbid major depressive disorder, and we clarify how reward-related deficiencies in PTSD fit into the context of more intensely studied threat-related deficits.

Endocannabinoids, cortisol, and development of post-traumatic psychopathological trajectories.

OBJECTIVE: Our prior published work using the 2-factor model of PTSD identified four subgroups of trauma survivors on average 6 months following trauma: Resilient, Dysphoria, High Comorbid, and Severe Comorbid. Some findings indicate that low and high cortisol responses may increase risk for the development of PTSD and depression respectively, yet ways in which cortisol interacts with other physiological systems to enhance risk is unclear. This study examined the role of circulating eCBs in the development of previously identified psychopathological trajectories that is differentiated by cortisol in traumatically injured adults (N = 169). METHODS: Circulating concentrations of eCBs, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA) were measured during post-injury hospitalization and on average 6 months following trauma. Differences in 2-AG and AEA among the subgroups were tested using multivariate ANCOVA. RESULTS: Dysphoria (with highest cortisol levels) and High Comorbid subgroups exhibited higher post-injury AEA compared to the Resilient group. Dysphoria subgroup showed a significant decline in AEA by 6 months compared to Resilient and High Comorbid subgroups. CONCLUSION: Change in AEA over time in individuals with high post-injury cortisol may serve as a buffer against risk for severe psychopathology. Assessing AEA and cortisol levels concurrently across time may serve as indicators of risk.

Neural processes of emotional conflict detection and prediction of posttraumatic stress disorder symptom clusters in traumatic injury survivors.

OBJECTIVE: Given the prevalence and significant burden of posttraumatic stress disorder (PTSD), identifying early predictors of symptom development following trauma is critical. PTSD is a heterogeneous disorder comprised of distinct symptom clusters-reexperiencing, avoidance, negative mood, and hyperarousal-that contribute to the broad range of possible symptom profiles. Affective and attentional regulation processes, such as emotional conflict detection, are impaired in individuals with PTSD; however, the neural mechanisms underlying these alterations and their predictive utility for the development of PTSD symptoms remain unclear. METHOD: Traumatic injury survivors (N = 49) without traumatic brain injury were recruited from the emergency department of an urban, Level-1 trauma center. Within 1 month of trauma exposure, participants completed a well-characterized emotional conflict task during a functional magnetic resonance imaging scan. Participants returned 6-month later for a clinical assessment of PTSD symptoms. Using a region-of-interest mask derived from whole-brain voxelwise analyses during emotional conflict detection (vs. no emotional conflict detection) we examined whether differential neural activity predicted 6-month PTSD symptom cluster severity. RESULTS: Greater activation of the right middle frontal gyrus during emotional conflict detection prospectively predicted lower PTSD avoidance symptom severity 6 months later (above and beyond the effects of self-reported baseline PTSD and depressive symptoms, previous traumatic life events, racial discrimination, age, sex, and injury severity). CONCLUSIONS: Neural processes of emotion conflict detection measured in the early aftermath of a potentially traumatic event are useful as predictors for the development of PTSD symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A cluster analytic approach to examining the role of cortisol in the development of post-traumatic stress and dysphoria in adult traumatic injury survivors.

Identification of specific risk factors for posttraumatic stress disorder (PTSD) versus depression after trauma has been challenging, in part due to the high comorbidity of these disorders. As exposure to trauma triggers activation of the hypothalamic-pituitary-adrenal (HPA)-axis, examining atypical stress responses via HPA-axis hormones, namely cortisol, may help in the delineation of these disorders. Indeed, extant research demonstrates that, following stress, individuals with chronic PTSD exhibit hypocortisolism (e.g., lower cortisol response than controls), while those with chronic depression exhibit hypercortisolism (e.g., higher response than controls). Less is known about the role of cortisol and these seemingly disparate profiles immediately following traumatic injury as well as whether cortisol can be used as a predictor of future development of PTSD versus depression symptoms. In this study cortisol was measured blood from 172 traumatic injury survivors during hospitalization (on average 2.5 days post-injury). PTSD and depression severity were assessed from Clinician Assessed PTSD Scale (CAPS-5) six-eight months later using a two-factor dimensional approach that measures trauma-specific symptoms of PTSD versus dysphoria (akin to depression). Cluster analysis was used to group individuals based on post-injury cortisol, PTSD, and dysphoria. Results demonstrated that trauma survivors who only developed symptoms of dysphoria at six months (with minimal symptoms of PTSD) were differentiated by high post-injury cortisol compared to other groups. By contrast, individuals who developed symptoms of both PTSD and dysphoria were differentiated by low post-injury cortisol and most severe symptoms of PTSD. Findings provide support for the presence of subgroups of trauma survivors defined, in part, by post-trauma cortisol.

Psychophysiological predictors of change in emotion dysregulation 6 months after traumatic injury.

Emotion dysregulation that occurs after trauma conveys risk for multiple disorders, including posttraumatic stress disorder, depression, and anxiety. Psychophysiological data (e.g., skin conductance level [SCL]) may be a useful biomarker for quantifying emotion dysregulation given that autonomic nervous system (ANS)-mediated arousal may underlie this feature. In this longitudinal study, we tested whether SCL collected following a single-incident traumatic injury could predict changes in emotion dysregulation over 6 months. Sixty-six adults were recruited from the emergency department; SCL was quantified during an active trauma narrative, in which participants re-told their traumatic event to a research staff member, as well as a neutral narrative for a control condition. Change in SCL (ΔSCL) was calculated using a maximum activation - minimum activation difference score. Multilevel linear modeling was used to test ΔSCL as a predictor of emotion dysregulation using the Emotion Dysregulation Scale (EDS) over time (3 timepoints over 6 months). Results showed that greater ΔSCL - indicative of increasing arousal- during both the trauma (p = 0.037) and neutral (p = 0.013) narratives was a significant predictor of greater emotion dysregulation at each subsequent timepoint. Further, we found a ΔSCL by time interaction, such that less ΔSCL during the neutral narrative predicted decreased emotion dysregulation over time (b = -1.26, SE = 0.43, t = -2.91, p = 0.004). Results validate the use of lab-based assessments of arousal to study emotion dysregulation in trauma survivors. That recovery from emotion dysregulation was predicted by less arousal during a neutral event underscores the importance of clinically targeting response to safety in trauma survivors.

Racial Discrimination and Resting-State Functional Connectivity of Salience Network Nodes in Trauma-Exposed Black Adults in the United States.

Importance: For Black US residents, experiences of racial discrimination are still pervasive and frequent. Recent empirical work has amplified the lived experiences and narratives of Black people and further documented the detrimental effects of racial discrimination on both mental and physical health; however, there is still a need for further research to uncover the mechanisms connecting experiences of racial discrimination with adverse health outcomes. Objective: To examine neurobiological mechanisms that may offer novel insight into the association of racial discrimination with adverse health outcomes. Design, Setting, and Participants: This cross-sectional study included 102 Black adults who had recently experienced a traumatic injury. In the acute aftermath of the trauma, participants underwent a resting-state functional magnetic resonance imaging scan. Individuals were recruited from the emergency department at a Midwestern level 1 trauma center in the United States between March 2016 and July 2020. Data were analyzed from February to May 2021. Exposures: Self-reported lifetime exposure to racial discrimination, lifetime trauma exposure, annual household income, and current posttraumatic stress disorder (PTSD) symptoms were evaluated. Main Outcomes and Measures: Seed-to-voxel analyses were conducted to examine the association of racial discrimination with connectivity of salience network nodes (ie, amygdala and anterior insula). Results: A total of 102 individuals were included, with a mean (SD) age of 33 (10) years and 58 (57%) women. After adjusting for acute PTSD symptoms, annual household income, and lifetime trauma exposure, greater connectivity between the amygdala and thalamus was associated with greater exposure to discrimination (t(97) = 6.05; false discovery rate (FDR)-corrected P = .03). Similarly, racial discrimination was associated with greater connectivity between the insula and precuneus (t(97) = 4.32; FDR-corrected P = .02). Conclusions and Relevance: These results add to the mounting literature that racial discrimination is associated with neural correlates of vigilance and hyperarousal. The study findings extend this theory by showing that this association is apparent even when accounting for socioeconomic position, lifetime trauma, and symptoms of psychological distress related to an acute trauma.

Neighborhood Socioeconomic Disadvantage and the Neurobiology of Uncertainty in Traumatically Injured Adults.

BACKGROUND: Individuals residing in more socioeconomically disadvantaged neighborhoods experience greater uncertainty through insecurity of basic needs such as food, employment, and housing, compared with more advantaged neighborhoods. Although the neurobiology of uncertainty has been less frequently examined in relation to neighborhood disadvantage, there is evidence that neighborhood disadvantage is associated with widespread neural alterations. METHODS: Recently traumatically injured participants (n = 90) completed a picture anticipation task in the magnetic resonance imaging scanner, in which they viewed images presented in a temporally predictable or unpredictable manner. We investigated how neighborhood disadvantage (via area deprivation index [ADI]) was related to neural activation during anticipation and presentation of negative and neutral images after accounting for individual factors (i.e., age, gender, income, acute posttraumatic stress symptoms). RESULTS: There was a significant interaction during the anticipation period such that higher ADI rankings were related to greater activation of the right anterior cingulate cortex to predictable versus unpredictable neutral stimuli. Although no other robust interactions emerged related to ADI, we note several novel simple effects of ADI during anticipation and presentation periods in the hippocampus and prefrontal, cingulate, and occipital cortices. CONCLUSIONS: Together, these results may represent an adaptive response to predictable and/or negative stimuli, stemming from chronic exposure to socioeconomic-based uncertainties. Although effects were modest, future work should continue to examine pretrauma context on posttrauma outcomes. To better understand trauma outcomes, it is imperative that researchers consider the broader context in which trauma survivors reside.

Hippocampal Resting-State Functional Connectivity Forecasts Individual Posttraumatic Stress Disorder Symptoms: A Data-Driven Approach.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a debilitating disorder, and there is no current accurate prediction of who develops it after trauma. Neurobiologically, individuals with chronic PTSD exhibit aberrant resting-state functional connectivity (rsFC) between the hippocampus and other brain regions (e.g., amygdala, prefrontal cortex, posterior cingulate), and these aberrations correlate with severity of illness. Previous small-scale research (n < 25) has also shown that hippocampal rsFC measured acutely after trauma is predictive of future severity using a region-of-interest-based approach. While this is a promising biomarker, to date, no study has used a data-driven approach to test whole-brain hippocampal FC patterns in forecasting the development of PTSD symptoms. METHODS: A total of 98 adults at risk of PTSD were recruited from the emergency department after traumatic injury and completed resting-state functional magnetic resonance imaging (8 min) within 1 month; 6 months later, they completed the Clinician-Administered PTSD Scale for DSM-5 for assessment of PTSD symptom severity. Whole-brain rsFC values with bilateral hippocampi were extracted (using CONN) and used in a machine learning kernel ridge regression analysis (PRoNTo); a k-folds (k = 10) and 70/30 testing versus training split approach were used for cross-validation (1000 iterations to bootstrap confidence intervals for significance values). RESULTS: Acute hippocampal rsFC significantly predicted Clinician-Administered PTSD Scale for DSM-5 scores at 6 months (r = 0.30, p = .006; mean squared error = 120.58, p = .006; R2 = 0.09, p = .025). In post hoc analyses, hippocampal rsFC remained significant after controlling for demographics, PTSD symptoms at baseline, and depression, anxiety, and stress severity at 6 months (B = 0.59, SE = 0.20, p = .003). CONCLUSIONS: Findings suggest that functional connectivity of the hippocampus across the brain acutely after traumatic injury is associated with prospective PTSD symptom severity.

Circulating endocannabinoids and prospective risk for depression in trauma-injury survivors.

Biological mechanisms associated with response to trauma may impact risk for depression. One such mechanism is endocannabinoid signaling (eCB), a neuromodulatory system comprised of the CB1 subtype of cannabinoid receptors (CB1R), encoded by the CNR1 gene, and two primary endogenous ligands: 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolamine (AEA), hydrolyzed by monoacylglycerol lipase (gene name MGLL) and fatty acid amide hydrolase (gene name FAAH). Preclinical data suggest that eCB/CB1R signaling acts as a stress buffer and its loss or suppression increases depression-like behaviors. We examined circulating concentrations of the eCBs (2-AG and AEA) days and six months after a traumatic injury as a marker of eCB/CB1R signaling and as predictors of Center for Epidemiologic Studies of Depression Scale-Revised [CESD-R] scores as a measure of depression severity six months after injury. We also explored associations of CNR1, FAAH, and MGLL genetic variance with depression severity at six months. Results from hierarchical multiple linear regressions showed that higher 2-AG serum concentrations after trauma predicted greater depression at six months (ß = 0.23, p = 0.007); neither AEA after trauma, nor 2-AG and AEA at six months were significant predictors (p's > 0.305). Carriers of minor allele for the putative single nucleotide polymorphism in the CNR1 gene rs806371 (ß = 0.19, p = 0.024) experienced greater depression at six months. These data suggest that the eCB signaling system is highly activated following trauma and that eCB/CB1R activity contributes to long-term depression risk.