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Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GADepartment of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA
Institute for Technology in Psychiatry, McLean Hospital, Belmont, MAThe Many Brains Project, Belmont, MADepartment of Psychiatry, Harvard Medical School, Boston, MA
Institute for Technology in Psychiatry, McLean Hospital, Belmont, MADepartment of Psychiatry, McLean Hospital, Belmont, MADepartment of Psychiatry, Harvard Medical School, Boston, MA
Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, ALDepartment of Surgery, Division of Acute Care Surgery, University of Alabama School of Medicine, Birmingham, ALCenter for Injury Science, University of Alabama at Birmingham, Birmingham, AL
Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PAPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PAPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MADepartment of Psychiatry, Boston University School of Medicine, Boston, MA
National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CTDepartment of Psychiatry, Yale School of Medicine, New Haven, CT
Division of Biosciences, Ohio State University College of Dentistry, Columbus, OHInstitute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH
Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MAStanley Center for Psychiatric Research, Broad Institute, Cambridge, MA
Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MIDepartment of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI
Kolling Institute, University of Sydney, St Leonards, New South WalesFaculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, New South WalesPhysical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL
Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NCInstitute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC
Jennifer S. Stevens, Ph.D. Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 69 Jesse Hill Jr. Dr., Atlanta, GA 30303, TEL: (404) 778-1698
Address correspondence to: Nathaniel G. Harnett, Ph.D. Division of Depression and Anxiety McLean Hospital, Mailstop 212 115 Mill St, Belmont MA 02478 TEL: 617-855-3526
Prior sexual trauma is associated with greater risk for PTSD after a subsequent traumatic event; however, underlying neurobiological mechanisms remain opaque. We investigated longitudinal posttraumatic dysfunction and amygdala functional dynamics following admission to an Emergency Department for new primarily non-sexual trauma in participants with and without previous sexual trauma.
Methods
Participants (n=2,178) were recruited following acute trauma exposure (primarily motor vehicle collision). A subset (n=242) completed MR imaging that included a fearful faces task and resting-state scan two weeks after trauma. We investigated associations between prior sexual trauma with several dimensions of posttraumatic symptoms over six months. We further assessed amygdala activation and connectivity differences between groups with or without prior sexual trauma.
Results
Prior sexual trauma was associated with greater posttraumatic depression (F(1,1120)=28.35, p=1.22x10–7, ηp2=.06), anxiety (F(1,1113)=17.43, p=3.21x10–5, ηp2=.05), and PTSD (F(1,1027)=11.34, p=7.85x10–4, ηp2=.04) severity and more maladaptive beliefs about pain (F(1,1113)=8.51, p=.004, ηp2=.02) but was not related to amygdala reactivity to fearful versus neutral faces (all p>0.05). A secondary analysis revealed an interaction between sexual trauma and lifetime trauma load on left amygdala to visual cortex connectivity (peak Z-value: –4.41, corrected p<0.02).
Conclusion
Findings suggest that prior sexual trauma is associated with heightened posttraumatic dysfunction following a new trauma exposure but not increased amygdala activity. Additionally, sexual trauma may interact with lifetime trauma load to alter neural circuitry in visual processing regions following acute trauma exposure. Further research should probe the relationship between trauma type and visual circuitry in the acute aftermath of trauma.
Approximately 1 in 3 women and 1 in 8 men in the United States (U.S.) have experienced rape, sexual assault, or childhood sexual abuse in their lifetime (
). Sexually traumatic events carry the greatest conditional risk for posttraumatic stress disorder (PTSD) development compared to all other types of trauma (
). Furthermore, sexual trauma (ST) may compound risk for psychopathology after a new subsequent trauma (e.g., motor vehicle collision; 13,14). Given that 50-90% of the population will experience a traumatic event in their lifetime (
), the likelihood of experiencing a subsequent traumatic event after prior ST is high. Although recent neuroimaging studies in the early aftermath of trauma have revealed several neural predictors of posttraumatic dysfunction, if and how prior ST may modulate these effects in individuals is still unknown. Understanding the interplay between prior ST and subsequent trauma may contribute to more accurate predictive models of individual susceptibility to PTSD.
That ST is likely to result in PTSD is well-established by existing literature. Prior work found ∼94% of female rape survivors met symptomatic criteria for PTSD two weeks post-trauma, with ∼50% continuing to meet criteria three months later (
). Significant associations between childhood sexual abuse (CSA) and psychological distress in adults have been described, including anxiety, depression, PTSD, and dissociation (
). The apparent pre-existing elevated risk for psychopathology in survivors of ST may affect the course of posttraumatic dysfunction after a new trauma and may be better elucidated through the identification of neural signatures. In particular, identifying neural signatures of risk for PTSD through functional neuroimaging may contribute to the ability to implement targeted early interventions for those most at risk.
Prior research suggests that the amygdala, a region critical to threat learning and expression, may be a major neural substrate of PTSD vulnerability (
). Earlier functional neuroimaging studies of PTSD in small samples have shown that the amygdala is hyperactive in response to emotional stimuli, leading to symptoms of hyperarousal, heightened fear, and impairments in emotional regulation in individuals with the disorder (
Stevens JS, Harnett NG, Lebois LAM, van Rooij SJH, Ely TD, Roeckner A, et al. (2021): Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma. Am J Psychiatry appi.ajp.2021.20101526.
), suggesting that childhood adversity (e.g., CSA) may be predictive of a more blunted than hyperactive response. In prospective studies, amygdala reactivity to emotional stimuli has emerged as predictive of PTSD when MRI scans occurred both prior to exposure to a traumatic event (
). Alterations in amygdala connectivity to regions including the prefrontal cortex (PFC) and dorsal anterior cingulate cortex (dACC) have also been demonstrated in those with PTSD (
). In women, decreased functional connectivity (FC) between right amygdala and left ventromedial PFC (vmPFC) during threat processing was associated with PTSD (
). In the early aftermath of trauma, greater resting state FC (rsFC) between dorsal lateral PFC (dlPFC) and an arousal network, which encompassed the amygdala, hippocampus, mamillary bodies, midbrain, and pons, was associated with reduced PTSD symptoms three months later (
Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.
). Further, the interconnections between amygdala and visual circuitry are particularly relevant for processing of threat-relevant visual stimuli in PTSD, and recent work, including in the AURORA study, has identified the role of the structure of the ventral visual stream in PTSD symptoms over time (
Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis [no. 1].
Acute Posttraumatic Symptoms Are Associated With Multimodal Neuroimaging Structural Covariance Patterns: A Possible Role for the Neural Substrates of Visual Processing in Posttraumatic Stress Disorder.
). For example, a study comparing visual processing in those with and without PTSD found that activity in response to visual scenes was lower in those with PTSD in the ventral stream of the visual system (
). Prior research thus suggests that amygdala reactivity and connectivity to other brain regions, which are important for the appraisal and regulation of threat, may play an important role in the development of posttraumatic psychopathology.
Despite the importance of the previous imaging work, lack of consideration for potential effects of prior ST is a critical limitation of the current literature. Understanding the modulatory effects of prior ST on future PTSD symptom development and amygdala function in the acute aftermath of a new trauma may help inform more targeted clinical and neuromodulatory interventions. ST has previously been linked to alterations in amygdala function that may be important for understanding PTSD vulnerability. Specifically, prior work found adolescent girls who had experienced physical or sexual assault and had greater amygdala reactivity to faces showed less symptom improvement after therapy (
). However, these studies examined the effects of a single trauma episode and did not consider previous life events or subsequent traumatic events. The lack of neuroimaging studies of ST survivors after later trauma, particularly longitudinal neuroimaging studies, represents a gap in knowledge that must be filled to elucidate potential mechanisms of vulnerability in ST survivors to adverse neural sequelae following other traumatic events.
In the current study, we investigated the impact of prior ST on posttraumatic pathology including PTSD, depression, anxiety, and dissociation following an acute traumatic event requiring an emergency department (ED) evaluation in a multisite, longitudinal study. We further assessed differences in amygdala reactivity to fearful compared to neutral faces and amygdala rsFC between those with and without prior history of ST. We hypothesized that individuals with prior history of ST would show greater symptoms of posttraumatic dysfunction persisting through six months following the acute trauma. We also hypothesized that those with ST would have greater activation in amygdala to fearful compared to neutral faces than the group without ST. We anticipated that ST would modulate rsFC of the amygdala to other regions involved in threat processing (i.e., PFC, hippocampus, visual cortex). The study findings demonstrate that prior ST exacerbates the psychological impact of subsequent trauma and contributes to variability in the neural circuitry of PTSD in the early aftermath of trauma, making it an important consideration in the evaluation of recent trauma victims.
Methods and Materials
Participants
Participants were recruited from EDs across the United States as part of a longitudinal, multisite parent study of adverse neuropsychiatric sequalae (The AURORA Study; see 43). Participants ages 18-65 were recruited from an ED after a qualifying traumatic event including motor vehicle collision, sexual assault, physical assault, fall greater than ten feet, or a mass casualty incident. Other traumatic events were also qualifying if the event involved actual or threatened death, serious injury, or sexual violence exposure, either by direct exposure, witnessing, or learning about it, as endorsed by the individual and agreed upon by the assessing research assistant. Full details of the recruitment protocol are described previously (
A total of 2,626 participants recruited for the AURORA study between September 2017 and July 31, 2020 were included in this investigation (see Supplemental Materials for details on overall sample). A subset of participants (n=436) were invited to complete a magnetic resonance imaging (MRI) data collection session. Additional MRI exclusion criteria included history of seizures, epilepsy, Alzheimer’s Disease, dementia, or Parkinson’s Disease, and any MRI contraindication (e.g., metal or ferromagnetic implants, pregnancy, claustrophobia). MRI participants were scanned within two weeks of their ED visit for acute trauma at one of five imaging sites. Of the invited participants, 54 participants did not provide task or resting-state fMRI data and were therefore excluded. Further, we excluded an additional 92 participants for incomplete scan data, motion criteria, or other behavioral, anatomical, and technical reasons (complete criteria are detailed in Supplemental Materials). Complete data on ST, our primary variable of interest, were missing for an additional 48 participants and we thus excluded these participants from analyses (see details below for classification of ST). The final imaging sample consisted of 242 participants (Table 1). Most participants were recruited after a motor vehicle collision (70.3%), and slightly more than half (55.4%) endorsed at least one instance of prior ST as indexed from the Life Events Checklist for DSM-5 and Childhood Trauma Questionnaire (see details below). Among the final sample, only two participants (.83%) were recruited from the ED following a sexual assault, and index trauma type did not differ for the prior ST group vs. the group without prior ST (p=.61, see Table 1). We were thus unable to consider the polyvictimization aspect of prior ST on posttraumatic dysfunction. Participants provided written informed consent and all study procedures were approved by each site’s Institutional Review Board.
Table 1Participant demographics and sample characteristics in imaging sample (n=242)
Table 1Participant demographics and sample characteristics in imaging sample (n=242)
Measures
Detailed information on the included psychometric measures is provided in the supplementary material and prior AURORA work (
Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.
). In the current study, ST was defined as endorsing having personally experienced at least one instance of 1) CSA, 2) rape or sexual assault, or 3) another unwanted sexual experience. CSA was assessed using an abbreviated form of the Childhood Trauma Questionnaire—Short Form (CTQ-SF; 47). Prior rape, sexual assault, or other unwanted sexual experience was determined by the Life Events Checklist for DSM-5 (LEC-5; 48,49). If a participant answered affirmatively to any one of these three questions, then they were coded as “yes” for ST, regardless of whether they were missing data for either or both of the other questions. However, given the potential for individuals not to report prior ST (
), participants must have denied all three experiences to be coded as “no” for ST. Otherwise, they were coded as “missing.” This method achieved good internal reliability (Cronbach’s α=.74). We further calculated total CTQ-SF and LEC-5 scores without the ST items for additional analyses.
Participants reported posttraumatic symptoms across several domains retrospectively (past 30 days) in the ED, 2-weeks (past 14 days), 8-weeks, 3-months, and 6-months (past 30 days) after trauma. PTSD symptoms were assessed using the PTSD Symptom Checklist for DSM-5 (PCL-5; 52). Baseline (i.e., pre-trauma) PTSD symptoms or probable diagnosis were not exclusionary criteria. Anxiety symptoms were assessed with the Participant-Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale Short Form 7a and depression symptoms with the PROMIS Depression Short Form 8b scale (
PROMIS Cooperative Group Item banks for measuring emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS®): depression, anxiety, and anger.
). Dissociative symptoms were measured with a modified version of the Brief Dissociative Experiences Scale (DES-B–Modified; 55,56). Symptoms that may be considered consistent within a cognitive domain (i.e., maladaptive beliefs about one’s pain; 57) were assessed with the Rumination subscale of the Pain Catastrophizing Scale (PCS; 58).
MRI Procedures
MRI data were obtained from participants within approximately 2 weeks after trauma exposure as described in our prior reports (
Stevens JS, Harnett NG, Lebois LAM, van Rooij SJH, Ely TD, Roeckner A, et al. (2021): Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma. Am J Psychiatry appi.ajp.2021.20101526.
Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.
Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis [no. 1].
). Detailed information on acquisition parameters by site and imaging processing are available in the supplement. Briefly, fMRIPrep was used to preprocess task and resting-state fMRI data. During the fMRI task, participants passively viewed fearful and neutral faces in block presentations with a fixation cross presented between each block. Group level statistical modeling was completed on the Fearful > Neutral faces contrast extracted for the amygdala using the CIT168 atlas (
). The rs-fMRI data were further processed within the Analysis for Functional NeuroImages (AFNI) program 3dTproject to perform linear detrending, censoring of non-steady state volumes identified by fMRIPrep, bandpass filtering (0.01 – 0.1 Hz), and regression of white matter, corticospinal fluid, and global signal to account for potential physiological noise. The mean fMRI signal time-course was extracted separately from the left and right medial amygdala defined by the Brainnetome atlas (
), and Z-transformed Pearson correlation coefficients were calculated between each ROI and the rest of the brain (i.e., two voxelwise connectivity maps for left/right amygdala per participant). Group-level statistical modeling was completed in AFNI using the separate voxelwise connectivity maps.
Statistical Analyses
Statistical analyses were completed in R 4.1.1 through R Studio 2021.09.0+351 and AFNI. Hypotheses related to effects of prior ST on posttraumatic stress, depression, anxiety, dissociation, and maladaptive beliefs about pain symptoms were assessed with repeated-measures analyses of covariance (ANCOVAs) with timepoint (i.e., pre-trauma, week 2, week 8, month 3, and month 6 follow-up sessions) as our within-subjects factor and prior ST (i.e., yes/no) as our between-subjects factor. ANCOVAs were first conducted with demographic covariates (age at time of ED admission, yearly income, education level) and were Bonferroni corrected at a corrected alpha level of .05 for significance (five models per comparison, thus critical p-value=.05/5). Secondary ANCOVAs included covariates for trauma variables (CTQ total score without sexual abuse variable and LEC-5 standard total score without sexual assault variables) to account for effects of other trauma exposures and were also Bonferroni corrected at a corrected alpha level of .05 for significance.
Hypotheses related to ROI activation to fearful > neutral faces were assessed with one-way ANCOVAs utilizing the same covariates as previous models (primary models included only demographic covariates, secondary models included both demographic and trauma-related covariates, Bonferroni corrected at a corrected alpha level of .05 for significance, two models per comparison, thus critical p-value=.05/2). To assess hypotheses related to seed-based rsFC, we utilized AFNI’s 3dttest++, assessing voxelwise FC for our a priori ROIs (left and right amygdala) as a function of prior history of ST. Analyses included covariates for scanner site, age, income level, and education level for primary models. We again covaried for overall prior trauma as well as PCL-5 scores at week 2 in secondary models with a corrected alpha level of .05 maintained by setting a cluster-forming threshold of p<.005. Gender was not included as a covariate given the high known multicollinearity of sex/gender with prevalence of ST (in the current sample, prior history of ST for n=32 men (23.9%) and n=102 women (76.1%)). Exploratory analyses investigated the interaction between other lifetime trauma and prior ST on amygdala reactivity and rsFC.
Results
Participant demographics and psychological characteristics
Sample characteristics including participant demographics and trauma history are presented in Table 1. Childhood trauma (excluding CSA) and lifetime trauma (excluding rape or sexual assault and other unwanted sexual experience) levels were significantly higher among those who also endorsed prior history of ST. There were significantly more women compared to men among the individuals who experienced ST than among those who did not have ST (p=.001). The samples did not significantly differ in age, race/ethnicity, income, educational attainment, or index trauma event type.
Participants with a prior history of ST in the imaging subsample had significantly greater posttraumatic dysfunction across time points (Figure 1; Table 2). Main effects of ST were largest for depression (F(1,1068)=64.11, p=3.06x10–15, ηp2=.06) followed by anxiety (F(1,1062)=50.49, p=2.20x10–12, ηp2=.05), PTSD (F(1,981)=36.17, p=2.55x10–9, ηp2=.04), dissociation (F(1,1063)=17.55, p=3.03x10–5, ηp2=.02), and maladaptive beliefs about pain (F(1,1055)=16.01, p=6.73x10–5, ηp2=.02) after adjusting for demographic covariates (age, income, and education level). After including additional trauma-related covariates to control for all previous lifetime trauma excluding ST, we observed smaller main effects of ST, but these remained significant except for dissociation (p=.14; Table 2). There was a significant effect of time point (i.e., pre-trauma, week 2, week 8, month 3, and month 6) on all symptoms when adjusting for demographic and trauma covariates, such that symptoms generally increased from pre-trauma to week 2 before decreasing over time. The interaction between time point and ST was not significant for any of the models. When we assessed effects of ST in the overall sample (n=2,178), effects varied slightly but overall, the same findings were observed (see Supplemental Results and Tables S1, S3, S4). These data suggest that prior ST exacerbates severity of posttraumatic symptoms across domains over at least 6 months from a new trauma exposure.
Figure 1Posttraumatic dysfunction and prior ST in the six months following acute trauma in imaging sample (n=242). (a) Total depression symptoms (PROMIS Short Form) (b) Total anxiety symptoms (PROMIS Short Form) (c) Total PTSD symptoms (PCL-5). (d) Total dissociation symptoms (DES-B). (e) Total symptoms of maladaptive beliefs about pain (PCS Pain Rumination Subscale). For all symptom types, the group with prior history of ST presented with higher symptoms when adjusting for demographic covariates. When trauma-related covariates were included in models, only the effect of ST on dissociation symptoms became non-significant (p=.14). Plots are presented without adjustment for covariates. Lines indicate mean scores, and error bars indicate +/– 1 standard error (SE).
Table 2Prior sexual trauma and posttraumatic dysfunction in first 6 months following trauma in imaging sample (n=242)
Table 2Prior sexual trauma and posttraumatic dysfunction in first 6 months following trauma in imaging sample (n=242)
PCL-5, PTSD Checklist for DSM-5, PROMIS, Participant-Reported Outcomes Measurement Information System Anxiety Scale Short Form 7a and Depression Short Form 8b, DES-B, Dissociative Experiences Scale – Modified, PCS, Pain Catastrophizing Scale Rumination subscale
Given the observed main effect of prior ST on total PCL-5 scores, we further explored effects of ST on PCL-5 symptom clusters, with previously used covariates (primary models included only demographic covariates, secondary models included both demographic and trauma-related covariates). In primary models, the effect of ST was significant on each symptom cluster (see Table 3), with the largest effect observed for Criterion D (negative alterations in cognition and mood). In secondary models controlling for overall lifetime trauma, the effect of ST remained significant only for Criterion D. These follow-up results suggest that the effect of prior ST on post-traumatic stress may be driven by symptoms of negative thoughts and feelings.
Table 3Prior sexual trauma and types of PCL-5 symptom clusters in imaging sample (n=242)
Table 3Prior sexual trauma and types of PCL-5 symptom clusters in imaging sample (n=242)
PCL-5, PTSD Checklist for DSM-5 Symptom clusters: Criterion B Intrusion (items 1-5), Criterion C Avoidance (items 6-7), Criterion D Negative alterations in cognition and mood (items 8-14), Criterion E Hyperarousal (items 15-20)
Reactivity to fearful and neutral faces and ST
We did not observe statistically significant effects of prior ST on neural reactivity to fearful faces within the left (F(1,218)=1.61, p=.21) or right amygdala (F(1,218)=1.91, p=.17) in primary or secondary models (F(1,205)=.55, p=.46 and F(1,205)=1.28, p=.26, respectively). Further ROIs were explored and are detailed in Supplemental Materials (Table S5). The current findings suggest prior ST does not affect neural reactivity to fearful faces after a recent trauma within these brain regions.
Seed-based rsFC and ST
We did not observe a significant effect of prior ST on amygdala connectivity to other brain regions (all p>0.05). However, in exploratory post-hoc tests, we found that there was an interaction between ST and lifetime trauma on amygdala to visual cortex connectivity (peak Z-value: –4.41, corrected p<0.01, X=–6.5, Y=–104.5, Z=13.5; Fig. 2). Specifically, the non-ST group showed a positive relationship between lifetime trauma and amygdala to visual cortex connectivity (r(100)=.20, p=.04) while the ST group showed a negative relationship (r(110)= –.25, p=.01). Of note, the prior models of reactivity to fearful faces did not show a significant interaction between lifetime trauma and ST on left or right amygdala reactivity (p=.73 and p=.41, respectively). These data suggest the past occurrence of ST alters the influence of prior traumatic experiences on neural connectivity patterns after a recent trauma.
Figure 2Left amygdala to visual cortex connectivity and prior ST in imaging sample (n=242). (a) After accounting for both demographic and trauma-related covariates, we found that the effect of prior ST on left amygdala to visual cortex connectivity in a resting state had an interaction with overall lifetime trauma load. (b) In the group with ST, stronger connectivity was negatively associated with overall lifetime trauma load, and in the group without ST, the opposite pattern was found.
ST is a known risk factor for the development of adverse neuropsychiatric sequalae, but how it may modulate the impact of a subsequent trauma is unclear. In this investigation, symptoms of PTSD, depression, anxiety, dissociation, and maladaptive beliefs about pain in the early aftermath of acute trauma were significantly higher in those with a prior history of ST than those without a history of ST. Contrary to our hypotheses, prior history of ST was not associated with differences in amygdala reactivity to fearful faces. However, there was an interaction between prior history of ST and exposure to other traumas on amygdala to visual cortex rsFC. The current findings suggest a need to consider prior history of ST in the development of predictive models of adverse neuropsychiatric sequalae and treatment in the early aftermath of trauma.
Of particular note in this study is the interaction effect of ST on lifetime trauma exposure with amygdala to visual cortex rsFC. Emerging work has begun to highlight the importance of visual circuitry and extrinsic connectivity of visual systems in relation to trauma and stress-related disorders (
Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.
Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis [no. 1].
Acute Posttraumatic Symptoms Are Associated With Multimodal Neuroimaging Structural Covariance Patterns: A Possible Role for the Neural Substrates of Visual Processing in Posttraumatic Stress Disorder.
). Specifically, hyperactivity of amygdala and associated enhancement of visual perceptual processing of trauma-related stimuli may be related to visual re-experiencing and intrusive symptoms such as flashbacks, and may partially support hypervigilance and attention to threat-related cues (
). A study of mood and anxiety disorder patients found that BOLD activity in the amygdala and ventral visual cortex co-varied significantly with trauma such that those with high trauma showed the smallest BOLD changes in response to emotional versus neutral scenes in these regions (
). Given that highly traumatized participants with prior ST in this study showed reduced amygdala-visual cortex rsFC, this pattern may reflect a posttraumatic outcome more tied to negative cognition/depression. Prior research found decreased rsFC of amygdala to visual cortex in major depressive disorder (
). Further, the largest effects of prior ST were on criterion D components of PTSD (i.e., negative cognitions/mood) and depression symptoms. These results may also be interpreted in light of other findings of lower activity in ventral visual stream in a picture-viewing task in those with PTSD versus non-PTSD trauma-exposed controls (
), given that the group with ST in our sample was significantly more likely to meet probable diagnostic criteria for PTSD. One speculative hypothesis in light of these findings is that high polytrauma that includes ST promotes avoidant behaviors to minimize exposure to trauma-related cues, which in turn inhibits extinction memory processes and promotes more frequent negative thoughts about the trauma. Future research involving specifically testing visual threat memory processes in trauma survivors with ST is needed to fully elucidate this potential mechanism.
These findings are consistent with a large body of previous literature that demonstrate ST as a risk factor for later mental health disorders. As in prior work (
), the current study found that individuals with a prior history of ST have increased posttraumatic symptom severity across a number of domains (e.g., PTSD, depression, and anxiety). The group with prior ST had higher symptoms prior to the new trauma as well as elevated symptoms after the acute traumatic event, suggesting that the acute phase after a new trauma may be an especially vulnerable period for this population and that ST may thus have especially deleterious effects on mental health. In general, interpersonal traumas result in higher rates of PTSD than non-interpersonal traumas such as motor vehicle collisions or natural disasters (
Trauma at the Hands of Another: Longitudinal Study of Differences in the Posttraumatic Stress Disorder Symptom Profile Following Interpersonal Compared With Noninterpersonal Trauma.
Trauma at the Hands of Another: Distinguishing PTSD Patterns Following Intimate and Nonintimate Interpersonal and Noninterpersonal Trauma in a Nationally Representative Sample.
). Further, prior literature suggests that, by its nature, sexual assault is unique even to other types of interpersonal trauma as it is a crime that violates and “disrupts the sense of autonomy, control, and mastery over one’s body” (
). This unique nature of ST may explain why it is a singularly serious risk factor for later psychopathology, and taken together with prior literature, the present results suggest that prior history of ST exacerbates posttraumatic dysfunction following a new trauma. Care providers should thus be especially sensitive to the possibility of heightened distress both in the short- and long-term following events such as motor vehicle collisions in those with prior ST.
We did not observe differences in amygdala reactivity to fearful faces between individuals with and without a prior history of ST. We initially hypothesized that ST would be associated with greater amygdala reactivity given that a large body of prior work has found amygdala hyperactivity in those with PTSD (e.g., 28,80). Further, in prior analyses of the AURORA study, amygdala reactivity to fearful faces was related to PTSD symptom presentations (
Stevens JS, Harnett NG, Lebois LAM, van Rooij SJH, Ely TD, Roeckner A, et al. (2021): Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma. Am J Psychiatry appi.ajp.2021.20101526.
). In the current study, although some participants were exposed to prior ST and others were not, all participants in the current study were recently exposed to a traumatic event. It is possible that trauma-exposed individuals, regardless of prior ST, exhibit comparably high levels of reactivity to threat-related/emotional stimuli due to the recency of their traumatic event. It may also be that prior ST modulates amygdala reactivity at a later timescale than was assessed in the present study. Further longitudinal studies are required to assess if prior ST may modulate amygdala reactivity to threat in the months after trauma exposure.
Several limitations should be noted for the present study. First, we are unable to determine whether observed neurobiological alterations are pre-existing risk factors or the result of the acute trauma because MRIs could not be obtained prior to the ED visit. Though our study design allows for greater understanding of the possible neurobiological mechanisms present in the early aftermath of acute trauma, it remains impractical and expensive to implement a fully prospective longitudinal design of acute trauma. Without preexisting knowledge of who will go on to experience a traumatic event that brings them to the ED, scanning individuals as early as 2 weeks after such a trauma is likely one of the most practical ways of studying the progression of posttraumatic symptoms and possible biological alterations in the acute phase of trauma exposure. Second, we applied stringent exclusion criteria for categorizing ST that may be excluding certain individuals who experienced prior ST but chose to decline these questions due to distress or other concerns. Third, the available measure assessing dissociation was likely insufficient to comprehensively assess the range of dissociation symptoms that have been linked to traumatic sexual experiences (
). As noted in Methods and Materials, only two of the eight items of the DES-B were included, and both assessed derealization. It is possible that a more extensive measure which also assesses depersonalization could have revealed more strongly the hypothesized effects of ST on dissociation. Fourth, although we observed effects of prior sexual trauma on neural connectivity and posttraumatic symptoms, many of the effect sizes were small to moderate in size. Thus, although the differences are significant, it may be important to consider how these factors interact with one another as opposed to focusing on individual effects. Fifth, our connectivity analyses utilized resting-state data and our inferences are thus limited by a lack of concurrent behavioral/task-specific data. Future research should leverage task-related connectivity approaches to probe the relationship between amygdala and visual circuitry in participants of different trauma backgrounds. Finally, it is possible that the developmental timing (e.g., in childhood, adolescence or adulthood) of prior ST may impact the present findings. Information on the timing of prior trauma exposure was not available and thus we are unable to fully disentangle the impact of ST timing on posttraumatic reactions.
In conclusion, the current study investigated the impact of prior ST on posttraumatic dysfunction and alterations in neural circuitry following an acute trauma. We found that prior ST was related to greater symptoms of depression, PTSD, anxiety, dissociation, and maladaptive beliefs about pain that persisted in the six months following acute trauma. Additionally, we found that there was an interaction between ST and other lifetime trauma on amygdala to visual cortex FC during a resting state MRI scan. These findings suggest that prior ST is an important determinant in the progression of symptoms following a later trauma and that it may also be related to alterations in visual circuitry modulated by amygdala activity. Particular care should be taken in the treatment of those with prior ST following traumatic events. Further, increased understanding of interactions between threat and visual processing brain regions after trauma may open new avenues for neuroscience-based interventions in the early aftermath of trauma.
The investigators wish to thank the trauma survivors participating in the AURORA Study. Their time and effort during a challenging period of their lives make our efforts to improve recovery for future trauma survivors possible. This project was supported by NIMH under K00MH119603 and U01MH110925, the US Army MRMC, One Mind, and The Mayday Fund. The content is solely responsibility of the authors and does not necessarily represent the official views of any of the funders. Data and/or research tools used in the preparation of this manuscript were obtained from the National Institute of Mental Health (NIMH) Data Archive (NDA). NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s): NIMH Data Archive Digital Object Identifier (DOI) 10.15154/1528118. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDA.
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Disclosures: Dr. Lebois reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD), grant support from the National Institute of Mental Health (NIMH), K01 MH118467, and the Julia Kasparian Fund for Neuroscience Research. Dr. Lebois also reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. In the last three years Dr Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, the Rett Research Foundation, and Samsung Research. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. Dr. Rauch reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (Veterans Administration) per diem for oversight committee, and other from Community Psychiatry/Mindpath Health paid board service, including equity outside the submitted work; other from National Association of Behavioral Healthcare for paid Board service; and Leadership roles on Board or Council for SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). SS has received funding from the Florida Medical Malpractice Joint Underwriter’s Association Dr. Alvin E. Smith Safety of Healthcare Services Grant; Allergan Foundation; the NIH/NIA-funded Jacksonville Aging Studies Center (JAX-ASCENT; R33AG05654); and the Substance Abuse and Mental Health Services Administration (1H79TI083101-01); and the Florida Blue Foundation. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. Joormann receives consulting payments from Janssen Pharmaceuticals. Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Concert Pharmaceuticals, Engrail Therapeutics, Neumora Therapeutics (former BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals; honoraria from the Psychonomic Society and the American Psychological Association (for editorial work) and Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, and Millennium Pharmaceuticals. In addition, he has received stock options from Neumora Therapeutics (former BlackThorn Therapeutics), Compass Pathways, Engrail Therapeutics, and Neuroscience Software. Dr. Harte has no competing interests related to this work, though in the last three years he has received research funding from Aptinyx and Arbor Medical Innovations, and consulting payments from Aptinyx, Heron Therapeutics, and Eli Lilly. Dr. Elliott reports support from the National Institutes of Health (NIH) through Grant Numbers R01HD079076 & R03HD094577: Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Center for Medical Rehabilitation Research. He also reports funding from New South Wales Health, Spinal Cord Injury Award (2020-2025) and consulting fees (< $15,000 per annum) from Orofacial Therapeutics, LLC. In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. Koenen’s research has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation, and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality, and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town, and Capita Ireland. She has had paid speaking engagements in the last three years with the American Psychological Association, European Central Bank. Sigmund Freud University – Milan, Cambridge Health Alliance, and Coverys. She receives royalties from Guilford Press and Oxford University Press. Dr. McLean served as a consultant for Walter Reed and for Arbor Medical Innovations. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, Takeda, and Jazz Pharma; serves on Scientific Advisory Boards for Sage and the Brain Research Foundation, and he has received sponsored research support from Takeda, Brainsway and Alto Neuroscience. Dr. Harnett reports grant support from the National Institute of Mental Health, K00 MH119603. All other authors report no biomedical financial interests or potential conflicts of interest.
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