BACKGROUND:Childhood maltreatment (CM), encompassing abuse and neglect, is highly prevalent and associated with elevated risk for major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and other related conditions. However, the extent to which neuroanatomical alterations in MDD and PTSD are attributable to CM is uncertain. METHODS:Here, we analyzed CM and whole-brain magnetic resonance imaging (MRI) data from 3711 participants in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) MDD and PTSD Working Groups (25 sites; mean age = 33.3 ± 13.0 years; 59.9% female). Normative modeling estimated deviation z scores for 14 subcortical volume, 68 cortical thickness (CT), and 68 surface area (SA) measures. To identify transdiagnostic effects, associations between CM and brain deviation scores were evaluated across all participants (patients and healthy control participants) stratified by sex and 3 age bins (pediatric, young adult, older adult). RESULTS:In young adults (ages 18-35), abuse was associated with larger volumes in the thalamus and pallidum, thinner isthmus cingulate and middle frontal regions, and thicker medial orbitofrontal cortex; there were no significant effects in pediatric (≤18 years) participants. The strongest effects were observed in young female adults (|β| = 0.07-0.22, q < .05): Greater abuse and neglect were correlated with smaller hippocampus and putamen volumes, thinner entorhinal cortex, and smaller SA in fusiform/inferior parietal regions and with larger SA in the orbitofrontal and occipital cortices. In males, abuse had widespread effects on CT and SA (|β| = 0.1-0.18, q < .05); effects for neglect were minimal. CONCLUSIONS:Our findings of age- and sex-specific instantiations of CM on brain morphometry highlight the importance of developmental context in understanding how adverse experiences shape neurobiological vulnerability to MDD and PTSD.

Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = -0.26, pBON = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = -1.01, pBON = 0.04) and arousal (β = -0.9, pBON = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = -0.1, pBON = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = -0.31, pBON = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, pBON = 9 × 10-3) and neglect (β = 0.29, pBON = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.

BACKGROUND:Estradiol (E2) is associated with enhanced alcohol-related reward. Childhood maltreatment may potentiate its effects, particularly in women. There is a gap in the literature exploring the mechanistic effects of E2 on alcohol use and reward neurocircuitry, particularly in trauma-exposed women. We hypothesized that women would show an increase in alcohol use and craving immediately before ovulation, reduced by childhood maltreatment, and stronger effects of exogenous E2 on reward circuits. METHODS:Participants (n = 91) were largely trauma exposed, naturally cycling women characterized by low alcohol use and craving, recruited from the greater Atlanta area, enrolled in a randomized, double-blind, within-subjects, crossover clinical trial of transdermal E2 as part of the GTP (Grady Trauma Project). Participants rated their alcohol use and craving nightly over the course of a full menstrual cycle, using ecological momentary assessment (1765 responses). Interacting effects of childhood maltreatment and menstrual cycle phase on alcohol use and craving were modeled using zero-inflated Poisson regressions. A subset was then randomized to receive transdermal E2 or placebo during resting-state functional magnetic resonance imaging and crossed over to the other condition on a subsequent cycle (n = 49). RESULTS:Findings supported a preovulatory increase in alcohol craving (β = 0.63, p = .03). An increase around ovulation was blunted in women with higher childhood maltreatment, among whom ovulatory alcohol craving decreased (β = -0.05, p = .02). Exogenous E2 administration produced changes in resting-state functional connectivity between the ventral tegmental area and insula among participants who exhibited cycle-dependent alcohol craving. CONCLUSIONS:Findings suggest that the endogenous preovulatory E2 peak enhances alcohol craving but that childhood maltreatment may blunt this effect.

Background:Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation therapy that is applied across psychiatric conditions to modulate specific neural circuits and improve clinical symptoms. While functional magnetic resonance imaging (fMRI)-guided personalized TMS targets are increasingly used, there are critical unresolved methodological, neurobiological, and clinical questions. Addressing topographic variability, stability, and associations with clinical outcomes is essential for advancing clinical development and scalable precision neuromodulation. Methods:A precision neurocircuitry-based fMRI-guided TMS approach was developed to treat disorders of the amygdala. In a randomized clinical trial for posttraumatic stress disorder (PTSD; n=50), topographic variability and stability of patient-specific right dorsolateral prefrontal cortex (rDLPFC) targets with the strongest functional connectivity to the right amygdala were analyzed. Results:There was significant target variability between participants and between targeting methods, but target stability was observed after engaging the amygdala circuitry with behavioral threat-related tasks. Target topography did not change after 20 sessions of sham TMS. However, after active TMS (1Hz, 36,000 pulses) target topography was significantly different. A larger change in the medial-anterior direction correlated with greater PTSD symptom improvement. Conclusions:Target variability and stability for fMRI-guided TMS of the amygdala circuitry is demonstrated, supporting the use of patient-specific targeting strategies for TMS. A clinical change in PTSD symptoms was associated with greater change in target topography, which suggests neuroplastic adaptations in the targeted networks and a possible treatment-dependent shift towards more medial prefrontal control over amygdala regulation. These findings are important for fMRI-guided precision neuromodulation therapy development, particularly for the amygdala circuitry.

Background Transcranial Magnetic Stimulation (TMS) is a non-invasive intervention for treatment-resistant depression (TRD). Comorbid anxiety is common in TRD patients. We examined the effect of single-dose versus high-dose bilateral TMS on depression and anxiety. Methods: Seventy-eight patients received 1Hz right dorsolateral prefrontal cortex (DLPFC) stimulation combined with left single-dose or high-dose iTBS to the left DLPFC at a nonprofit clinic. Depression and anxiety symptoms were measured at baseline, after 10 and 20 sessions, and final (30-36) TMS sessions. Results: Bilateral TMS resulted in a significant decrease in depression (F(3,70)=9.670, p<.001; 74.4% response, 47.7% remission) and anxiety (F(3,70)=4.916, p=0.004, 52.6% response, 39.7% remission). The high-dose group showed a faster reduction in depression (F(3,70)=2.875, p=0.042), but not anxiety symptoms. There was no dose difference at the final session. Conclusion: Bilateral TMS improved depression and anxiety symptoms with a quicker reduction in depression symptoms with higher dosing, which highlights an important clinical consideration to reduce visits.

The thalamus is a heterogeneous structure crucial for corticocortical communication, affective-perceptual integration, motor preparation, and memory-related functions. Posttraumatic stress disorder (PTSD) is characterized by various symptoms that likely relate to thalamic functions. Group-level and individual differential structural covariance (SC) analyses were conducted on intrathalamic, thalamocortical, and thalamosubcortical volumetric networks by segmenting structural MRI data from 2,784 subjects (PTSD n = 1,306; controls n = 1,478) into 25 thalamic nuclei per hemisphere. We found that PTSD was associated with stronger intrathalamic and thalamocortical network strength and stronger SC between the limbic thalamus and the somatomotor and auditory thalamus. PTSD severity was related to specific regional alterations in the intrathalamic network involving the lateral pulvinar. Comorbid depression severity positively correlated with global intrathalamic alterations, while avoidance symptoms positively correlated with global thalamosubcortical alterations. Hyperarousal symptoms related to altered SC in the thalamocortical network between the reuniens, central medial, paratenial, centromedian, and limitans-suprageniculate nuclei and lateral cortical regions spanning the occipital, temporal, and orbitofrontal cortices. Differential associations between avoidance, hyperarousal, and comorbid depression symptoms and thalamic SC in PTSD suggest that specific thalamic covariance patterns may be involved in unique facets of PTSD symptomatology.

Negative interpretation bias - the tendency to perceive ambiguous stimuli as threatening - is a core cognitive distortion underlying post-traumatic stress disorder (PTSD). The amygdala, a key structure in fear processing, is implicated in PTSD-related hypervigilance and heightened fear perception, yet direct causal evidence linking amygdala function to negative interpretation bias remains limited. Here, we present a unique prospective case of a male patient with refractory epilepsy and comorbid chronic PTSD, who underwent stereoelectroencephalography-guided radiofrequency ablation (SEEG-guided RFA) targeting the right amygdala. Before ablation, the patient exhibited heightened negative interpretation bias, judging ambiguous faces as more fearful compared to control groups of epilepsy patients without PTSD. Intracranial SEEG recordings revealed that this cognitive bias was associated with increased late-phase event-related potential (L-ERP) differentiation between fearful and happy faces in the right amygdala. Immediately following focal right amygdala ablation, negative interpretation bias and PTSD symptom severity were significantly reduced, while seizure frequency remained unchanged. Notably, reductions in L-ERP amplitude after ablation closely tracked decreases in fear perception, highlighting L-ERP as a potential biomarker of negative interpretation bias and therapeutic response. Our findings provide causal evidence from an n-of-1 study that the right amygdala supports maladaptive negative interpretation bias in a patient with PTSD and that right amygdala ablation can contribute to the relief of PTSD symptomatology.

Residential segregation is associated with differential exposure to air pollution. Hippocampus structure and function are highly susceptible to pollutants and associated with posttraumatic stress disorder (PTSD) development. Therefore, we investigated associations between residential segregation, air pollutants, hippocampal neurobiology, and PTSD in recent trauma survivors. Participants (N = 278; 34% non-Hispanic white, 46% Non-Hispanic Black, 16% Hispanic) completed multimodal neuroimaging two weeks after trauma. Yearly averages of air pollutants (PM2.5 and NO2) and racial/economic segregation (Index of Concentration at the Extremes) were derived from each participant's address. Linear models assessed if air pollutants mediated associations between segregation and hippocampal volume, threat reactivity, or parahippocampal cingulum fractional anisotropy (FA) after covarying for age, sex, income, and 2-week PTSD symptoms. Further models evaluated if pollutants or segregation prospectively predicted PTSD symptoms six months post-trauma. We found that non-Hispanic Black participants lived in neighborhoods with significantly greater segregation and air pollution compared to Hispanic and non-Hispanic white participants (ps < 0.001). PM2.5 concentration was positively correlated with threat reactivity (r(276) = 0.16, p < 0.006), while NO2 concentration was positively correlated with hippocampus volume (r(276) = 0.17, p < 0.005) and negatively correlated with white matter tract FA (r(276) = -0.18, p < 0.003). There was a significant indirect effect of NO2 between segregation and FA values (β = 0.08, 95% CI[0.01, 0.15]), and an indirect effect of PM2.5 between segregation and threat reactivity (β = -0.08, 95% CI[-0.14, -0.01]). There was no direct effect of segregation on hippocampal features. Pollutants and segregation were not associated with PTSD symptoms. In conclusion, residential segregation is associated with greater air pollution exposure, which is in turn associated with variability in hippocampal features among recent trauma survivors. Further research is needed to assess relationships between other environmental factors and trauma and stress-related disorders.

Background:While social impairment is a hallmark of increasing severity of post-traumatic stress disorder (PTSD), the dynamics between social support and trauma recovery are less clear. Current theories suggest either social support is responsible for reducing PTSD severity (social causation), or worsening PTSD ultimately degrades supportive networks (social erosion). Furthermore, there is a paucity of research on social support and longitudinal trauma recovery within the civilian population. We hypothesized a bidirectional relationship exists between social support and PTSD, such that both social causation and erosion impact the trajectory of recovery at different times post-trauma. Methods:A total of n = 2943 participants were recruited following a traumatic event leading to Emergency Department visit in the AURORA study, reported perceived emotional support (PROMIS) and severity of PTSD symptoms (PCL-5) at 2 weeks, 8 weeks, 3 months, 6 months, and 12 months post trauma. PTSD symptom severity overall and within symptom criteria (B-E) were assessed. Results:A 5-wave cross-lagged panel model showed a statistically significant negative association between emotional support and subsequent PTSD symptoms across the majority of timepoints in the year following trauma. Concurrently, we observed a negative association between PTSD severity and subsequent perceived emotional support. Additional analyses showed emotional support was mainly correlated with subsequent negative mood and feelings, whereas avoidant behavior was most correlated with lower emotional support. Conclusion:Our analyses emphasize the importance of initiating social interventions and establishing robust social networks immediately after a traumatic event.

Objective: Transcranial magnetic stimulation (TMS) has shown promise in reducing posttraumatic stress disorder (PTSD) symptoms, with varied clinical results. A mechanistic understanding is needed to personalize treatment and improve response rates. The threat neurocircuitry, specifically the right amygdala, has consistently been implicated in PTSD pathophysiology. This neuroscience-informed trial aimed to modulate the threat neurocircuitry using functional MRI (fMRI)-guided TMS to treat PTSD. Methods: In a double-blind clinical trial, 50 adults with PTSD symptoms were randomized to 10 twice-daily sessions of either 1-Hz TMS or sham TMS. TMS was delivered to an fMRI-guided target within the right dorsolateral prefrontal cortex with the strongest functional connection to the right amygdala. The primary outcomes were right amygdala threat reactivity, assessed by fMRI, and skin conductance reactivity during trauma recall, measured pre-and post-TMS. The secondary outcomes were hyperarousal and total PTSD symptoms (based on the PTSD Checklist for DSM-5), measured pre-and post-TMS and at a follow-up assessment between 3 and 6 months after TMS. Results: Active TMS significantly reduced right amygdala threat reactivity compared with sham TMS. No significant effect of TMS was observed on skin conductance reactivity. From pre-to post-TMS, significant reductions in hyperarousal and total PTSD symptoms were observed across groups, but no significant differences between groups were observed. From pre-TMS to follow-up, active TMS compared with sham TMS significantly reduced hyperarousal and total PTSD symptoms. Clinical findings were found to be robust in sensitivity analyses. Conclusions: This is the first clinical trial to demonstrate that personalized fMRI-guided TMS targeting the threat neurocircuitry reduces amygdala threat reactivity and improves long-term PTSD symptoms at follow-up. These findings suggest the potential for a personalized approach to neuromodulation in individuals with PTSD.

Objective: Studies investigating resting-state functional connectivity of the amygdala and hippocampus have produced inconsistent findings. The authors' objective was to conduct the largest systematic comparison of alterations in functional connectivity of the amygdala and hippocampus in individuals with posttraumatic stress disorder (PTSD) using a multicohort mega-analysis with uniform processing steps and parameters across all cohorts. Methods: Resting-state functional MRI data from 1,017 PTSD patients and 1,702 control participants from 32 international sites were centrally preprocessed with HALFpipe and analyzed using the Image-Based Meta- and Mega-Analysis (IBMMA) package for neuroimaging processing. Group-level seed-based whole-brain analyses were completed for the right and left amygdala and hippocampus. Additional correlation analyses were conducted between PTSD norm-severity scores and resting-state functional connectivity (rs-FC). Results: Compared to control participants, individuals with PTSD showed stronger rs-FC between the left amygdala seed and right hippocampus and amygdala and the left and right lingual gyri. Greater PTSD total norm-severity scores were significantly associated with rs-FC between the left amygdala and right hippocampus/amygdala and rs-FC between the right amygdala and left hippocampus/amygdala. Conclusions: Greater connectivity between subcortical threat centers involved in fear processing, memory, and extinction learning characterizes the resting state in PTSD. Future directions include investigating how different interventions, such as brain stimulation, neurofeedback, and psychotherapy, might modulate the aberrant neural networks in PTSD.

Individuals with post-traumatic stress disorder (PTSD) are at higher risk for age-related physical comorbidities, such as cardiovascular disorders, and exhibit accelerated epigenetic and brain aging. The present study examined PTSD as a moderator of the association between DNA methylation (DNAm)-based systemic aging (GrimAge, PhenoAge) and brain aging, indexed by MRI-based and DNAm-derived BrainAge estimates, in 174 lifetime PTSD cases and 138 trauma-exposed controls from four cohorts. Peripheral DNAm assayed with the MethylationEPIC BeadChip was used to calculate epigenetic age acceleration (EAA), using multiple clocks (GrimAge, PC GrimAge, PC PhenoAge), and DNAm-based BrainAge acceleration. Neuroimaging-derived BrainAge estimates were calculated with T1-weighted MRI scans that were processed using FreeSurfer v5.3 and run on BrainageR. Meta-analysis of the four cohorts examined the interactions between lifetime PTSD and EAA on BrainAge acceleration. EAA measures were intercorrelated (0.43 < rmeta < 0.84), but MRI-based BrainAge acceleration was not correlated with any EAA estimate (rmeta = 0.03, p = 0.56). Lifetime PTSD moderated the association between PC GrimAge acceleration and DNAm-based BrainAge acceleration (Standardized Mean Difference [SMD] = 0.84 [95% CI: -1.51, -0.17], p = 0.01), and the association between GrimAge acceleration and MRI-based BrainAge acceleration (SMD = -0.40 [95% CI: -0.74, -0.07], p = 0.02). Stratified analyses confirmed that the positive associations between GrimAge acceleration and BrainAge acceleration were attenuated or absent in PTSD cases relative to trauma-exposed controls. Trauma-exposed individuals represent a vulnerable population who may benefit from personalized approaches guided by multi-modal measures of biological aging to prevent and manage modifiable medical disease processes.

BACKGROUND:Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group. METHODS:T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9). RESULTS:PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges' g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges' g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (p corrected  = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (p corrected  = .001). CONCLUSIONS:PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

Background: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry post-trauma in humans. Neuroimaging markers may be particularly useful as they can provide insight into the underlying mechanisms that may make an individual more vulnerable to developing trauma-related psychopathologies. This study aimed to identify reward-related neural mechanisms associated with changes in alcohol use after trauma exposure. Methods: Participants were recruited from U.S. emergency departments (ED) for the AURORA study (N=286, 178 female). Trauma-related change in alcohol use at 8 weeks post-trauma relative to pre-trauma was quantified as a change in 30-day total drinking per the PhenX Toolkit Alcohol 30-Day Quantity and Frequency Measure. Reward-related neurocircuitry activation and functional connectivity (FC) were assessed 2 weeks post-trauma using fMRI during a monetary reward task using region of interest and whole-brain voxelwise analyses. Results: Greater increase in alcohol use from pre-trauma to 8 weeks post-trauma was predicted by (1) greater ventral tegmental area (VTA) and (2) greater cerebellum activation during Gain>Loss trials measured 2 weeks post-trauma and (3) greater seed-based FC between the VTA and lateral occipital cortex and precuneus. Conclusions: Altered VTA activation and FC early post-trauma could predict reward-seeking and processing, contributing to greater alcohol use post-trauma. These data provide novel evidence of neural mechanisms that underlie increased alcohol use early post-trauma that can be targeted via early interventions to the development of maladaptive alcohol use.

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA successfully analyzed a large-n dataset of several thousand participants and revealed findings in brain regions that some traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

BACKGROUND:Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) often co-occur. There is a lack of longitudinal studies measuring the naturalistic development of PTSD and alcohol use problems in individuals with recent trauma exposure. This study aimed to compare the temporal relationships between posttraumatic stress symptoms and alcohol use over 6 months following trauma exposure in males and females. METHODS:Large-scale longitudinal observational emergency department (ED)-based study of individuals with recent trauma exposure. Individuals with recent trauma exposure (n = 2942, 62% female) were recruited from 29 EDs across the United States within 72 h of trauma exposure from 2017 to 2021. PTSD symptoms, measured via the PTSD Checklist for the DSM-5, and alcohol use measured via the PhenX toolkit, were assessed at five time points: ED visit, 2 weeks, 8 weeks, 3 months, and 6 months following trauma. RESULTS:PTSD symptoms predicted lower future alcohol use between the pretrauma to two-week time points (b = -0.08, p = 0.01) and higher use between the 3- to 6-month time points (b = 0.06, p = 0.01). There were no time points in which alcohol use predicted future PTSD symptoms. When stratifying by sex, male participants showed reciprocal associations, with alcohol use early after trauma predicting PTSD symptoms between 2 and 8 weeks (b = 0.08, p = 0.01), while PTSD symptoms predicted alcohol use between the 3- to 6-month time points (b = 0.10, p = 0.01). Female participants showed a different reciprocal pattern, with pretrauma PTSD symptoms predicting lower alcohol use 2 weeks posttrauma (b = -0.08, p = 0.04), while alcohol use subsequently predicted greater PTSD symptoms from 8 weeks to 3 months (b = 0.04, p = 0.04); these findings did not survive Bonferroni correction. CONCLUSIONS:Males and females exhibit complex temporal development patterns of PTSD symptoms and alcohol use that align with the mutual maintenance hypothesis in males but the susceptibility hypothesis in females. These patterns are masked in analyses that do not stratify by sex.

Background:Depression, posttraumatic stress disorder (PTSD), and suicidality are more prevalent among people with seizures, but few studies exist in low-resourced minoritized populations. Existing knowledge of the overlapping neurocircuitry between seizure activity in limbic regions (eg, medial temporal lobe epilepsy) and PTSD also suggests that people with seizure histories may exhibit PTSD-like alterations in their fear-potentiated startle (FPS) responses. However, this hypothesis has yet to be systematically tested. Here, we leveraged a large study on stress and trauma to evaluate the prevalence of psychiatric conditions and FPS responses in a low-resourced minoritized population of individuals with a history of seizures. Methods:Prevalence of self-reported PTSD symptoms, depression symptoms, suicidality, and history of suicide attempt were compared between people with and without self-reported seizures among a sample of 3012 predominantly racially marginalized and low-resourced civilians. We compared FPS responses in 13 people with a history of seizures to 13 rigorously matched seizure-free controls. FPS responses were measured using eyeblink data collected during a fear conditioning acoustic startle task. Results:Participants with a history of seizures showed significantly higher prevalence of depression symptoms, suicidality, history of suicide attempt, PTSD symptoms, and probable PTSD diagnosis than seizure-free controls, even after controlling for trauma load. Those with a history of seizures displayed heightened FPS responses and impaired fear discrimination which mimics that of PTSD. Conclusion:These data concur with prior literature on people with a history of seizure activity being at higher risk for psychiatric symptomatology. Additionally, this study provides novel insights on the psychophysiological fear response in trauma-exposed people with a history of seizures, which could inform the identification and treatment of psychiatric vulnerability in these individuals.