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.

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).

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 (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).

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.

To better understand clinicians’ rationale for ordering testing for C. difficile infection (CDI) for patients receiving laxatives and the impact of the implementation of a clinical decision support (CDS) intervention.

A mixed-methods, case series was performed from March 2, 2017 to December 31, 2018.

Yale New Haven Hospital, a 1,541 bed tertiary academic medical center.

Hospitalized patients ≥ 18 years old, and clinicians who were alerted by the CDS.

CDS was triggered in real-time when a clinician sought to order testing for CDI for a patient who received one or more doses of laxatives within the preceding 24 hours.

A total of 3,376 CDS alerts were triggered during the 21-month study period from 2,567 unique clinician interactions. Clinicians bypassed the CDS alert 74.5% of the time, more frequent among residents (48.3% bypass vs. 39.9% accept) and advanced practice providers (APPs) (34.9% bypass vs. 30.6% accept) than attendings (11.3% bypass vs. 22.5% accept). Ordering clinicians noted increased stool frequency/output (48%), current antibiotic exposure (34%), and instructions by an attending physician to test (28%) were among the most common reasons for overriding the alert and proceeding with testing for CDI.

Testing for CDI despite patient laxative use was associated with an increased clinician concern for CDI, patient risk for CDI, and attending physician instruction for testing. Attendings frequently accepted CDS guidance while residents and APPs often reinstated CDI test orders, suggesting a need for greater empowerment and discretion when ordering tests.

Identifying persons with HIV (PWH) at increased risk for Alzheimer’s disease (AD) is complicated because memory deficits are common in HIV-associated neurocognitive disorders (HAND) and a defining feature of amnestic mild cognitive impairment (aMCI; a precursor to AD). Recognition memory deficits may be useful in differentiating these etiologies. Therefore, neuroimaging correlates of different memory deficits (i.e., recall, recognition) and their longitudinal trajectories in PWH were examined.

We examined 92 PWH from the CHARTER Program, ages 45–68, without severe comorbid conditions, who received baseline structural MRI and baseline and longitudinal neuropsychological testing. Linear and logistic regression examined neuroanatomical correlates (i.e., cortical thickness and volumes of regions associated with HAND and/or AD) of memory performance at baseline and multilevel modeling examined neuroanatomical correlates of memory decline (average follow-up = 6.5 years).

At baseline, thinner pars opercularis cortex was associated with impaired recognition (p = 0.012; p = 0.060 after correcting for multiple comparisons). Worse delayed recall was associated with thinner pars opercularis (p = 0.001) and thinner rostral middle frontal cortex (p = 0.006) cross sectionally even after correcting for multiple comparisons. Delayed recall and recognition were not associated with medial temporal lobe (MTL), basal ganglia, or other prefrontal structures. Recognition impairment was variable over time, and there was little decline in delayed recall. Baseline MTL and prefrontal structures were not associated with delayed recall.

Episodic memory was associated with prefrontal structures, and MTL and prefrontal structures did not predict memory decline. There was relative stability in memory over time. Findings suggest that episodic memory is more related to frontal structures, rather than encroaching AD pathology, in middle-aged PWH. Additional research should clarify if recognition is useful clinically to differentiate aMCI and HAND.

Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.

As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.

Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.

Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Among people with HIV (PWH), the apolipoprotein e4 (APOE-e4) allele, a genetic marker associated with Alzheimer’s disease (AD), and self-reported family history of dementia (FHD), considered a proxy for higher AD genetic risk, are independently associated with worse neurocognition. However, research has not addressed the potential additive effect of FHD and APOE-e4 on global and domain-specific neurocognition among PWH. Thus, the aim of the current investigation is to examine the associations between FHD, APOE-e4, and neurocognition among PWH.

283 PWH (Mage=50.9; SDage=5.6) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed comprehensive neuropsychological and neuromedical evaluations and underwent APOE genotyping. APOE status was dichotomized into APOE-e4+ and APOE-e4-. APOE-e4+ status included heterozygous and homozygous carriers. Participants completed a free-response question capturing FHD of a first- or second-degree relative (i.e., biologic parent, sibling, children, grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling). A dichotomized (yes/no), FHD variable was used in analyses. Neurocognition was measured using global and domain-specific demographically corrected (i.e., age, education, sex, race/ethnicity) T-scores. t-tests were used to compare global and domain-specific demographically-corrected T-scores by FHD status and APOE-e4 status. A 2x2 factorial analysis of variance (ANOVA) was used to model the interactive effects of FHD and APOE-e4 status. Tukey’s HSD test was used to follow-up on significant ANOVAs.

Results revealed significant differences by FHD status in executive functioning (t(281)=-2.3, p=0.03) and motor skills (t(278)=-2.0, p=0.03) such that FHD+ performed worse compared to FHD-. Differences in global neurocognition by FHD status approached significance (t(281)=-1.8, p=.069). Global and domain-specific neurocognitive performance were comparable among APOE-e4 carriers and noncarriers (ps>0.05). Results evaluating the interactive effects of FHD and APOE-e4 showed significant differences in motor skills (F(3)=2.7, p=0.04) between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups such that the FHD+/APOE-e4- performed worse than the FHD-/APOE-e4+ group (p=0.02).

PWH with FHD exhibited worse neurocognitive performance within the domains of executive functioning and motor skills, however, there were no significant differences in neurocognition between APOE-e4 carriers and noncarriers. Furthermore, global neurocognitive performance was comparable across FHD/APOE-e4 groups. Differences between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups in motor skills were likely driven by FHD status, considering there were no independent effects of APOE-e4 status. This suggests that FHD may be a predispositional risk factor for poor neurocognitive performance among PWH. Considering FHD is easily captured through self-report, compared to blood based APOE-e4 status, PWH with FHD should be more closely monitored. Future research is warranted to address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline and impairment over time among in an older cohort of PWH, where APOE-e4 status may have stronger effects.

Functional connectivity of the default mode network (DMN) during rest has been shown to be different among adults with Mild Cognitive Impairment (MCI) relative to aged-matched individuals without MCI and is predictive of transition to dementia. Post-traumatic stress disorder (PTSD) is also associated with aberrant connectivity of the DMN. Prior work from this group has demonstrated a higher rate of MCI and PTSD among World Trade Center (WTC) responders relative to the general population. The current study sought to investigate the main and interactive effects of MCI and PTSD on DMN functioning. Based on prior work, we hypothesized that MCI, but not PTSD, would predict aberrant connectivity in the DMN.

99 WTC responders aged 44–65 stratified by MCI status (yes/no) and PTSD status (yes/no) and matched for age in years, sex (male vs. female), race (white, black, and other), and educational attainment (high school or less, some college / technical school, and university degree), and occupation on September 11, 2001 (law enforcement vs. other) underwent fMRI using a 3T Siemens Biograph MR scanner. A single 10-minute continuous functional MR sequence was acquired while participants were at rest with their eyes open. Group-level analyses were conducted using SPM-12, with correction for multiple comparisons using AFNI's 3dClustSim. Based on this threshold, the number of comparisons in our imaging volume, and the smoothness of our imaging data as measured by 3dFWHMx-acf, a minimum cluster size of 1134 voxels was required to have a corrected p . .05 with 2-sided thresholding. Spherical 3 mm seeds were placed in the dorsal (4, -50, 26) and ventral (4, -60, 46) posterior cingulate cortex (PCC).

Individuals with PTSD demonstrated significantly less connectivity of the dorsal posterior cingulate cortex (PCC) with medial insula (T = 5.21), subthalamic nucleus (T = 4.66), and postcentral gyrus (T = 3.81). There was no difference found in this study for connectivity between groups stratified by MCI status. There were no significant results for the ventral PCC seed.

Contrary to hypotheses that were driven by a study of cortical thickness in WTC responders, the impact of PTSD appears to outweigh the impact of MCI on dorsal DMN connectivity among WTC responders stratified by PTSD and MCI status. This study is limited by several issues, including low number of female and minority participants, relatively small group cell sizes (n = 23–27 per cell), a brief resting state sequence (10 minutes), and lack of a non-WTC control group. Importantly, responders are a unique population so generalizability to other populations may be limited. Individuals in the current study are now being followed longitudinally to relate baseline resting state functional connectivity with cognitive changes and changes in connectivity over a four-year period.

We measured sex differences in emotion regulation (ER) abilities – relying on exercise of cognitive reappraisal – during an image rating task in adults over 55 years of age with varying degrees of depression symptom severity. We also collected a self-report measure on participants' views of their own ER capacities. Previous research by this group has demonstrated the importance of emotion processing in the context of sex and aging in depression. We hypothesized that females would (1) score higher on the Cognitive Reappraisal Facet of the ERQ, (2) be more successful in utilizing cognitive reappraisal skills in response to negative stimuli; and (3) have self-report scores on the ERQ that more closely match their success at cognitive reappraisal than would males.

capacities. Previous research by this group has demonstrated the importance of emotion processing in the context of sex and aging in depression. We hypothesized that females would (1) score higher on the Cognitive Reappraisal Facet of the ERQ, (2) be more successful in utilizing cognitive reappraisal skills in response to negative stimuli; and (3) have self-report scores on the ERQ that more closely match their success at cognitive reappraisal than would males.

Only the first of our three outcome measures was successfully predicted by the model including age, MADRS scores, and sex as predictors. Scores on the ERQ cognitive reappraisal facet with sex accounted for 11.3% of the variance (F=7.344, p=.009). Age and depression symptom severity did not reach significance. Performance on the ERT itself and the correlation between the two were not meaningfully modeled.

Women showed both better cognitive reappraisal abilities overall and more insight into the level of those abilities, findings that fall in line with most ER literature. However, we found that females were also more likely than males to be skewed in the positive or “overconfident” direction; to overestimate those same abilities. This information is useful for clinicians interpreting self-report information in the emotion regulation domain. These findings may not generalize to a more diverse (racially and socioeconomically) population and given the cognitive nature of the reappraisal strategy; these results may not extend to a less educated population. These data will be useful to inform the interpretation of fMRI images from this same experiment.

Many people with HIV (PWH) are at risk for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Studies on the association between cognition, neuroimaging outcomes, and the Apolipoprotein E4 (APOE4) genotype, which is associated with greater risk of AD, have yielded mixed results in PWH; however, many of these studies have examined a wide age range of PWH and have not examined APOE by race interactions that are observed in HIV-negative older adults. Thus, we examined how APOE status relates to cognition and medial temporal lobe (MTL) structures (implicated in AD pathogenesis) in mid- to older-aged PWH. In exploratory analyses, we also examined race (African American (AA)/Black and non-Hispanic (NH) White) by APOE status interactions on cognition and MTL structures.

The analysis included 88 PWH between the ages of 45 and 68 (mean age=51±5.9 years; 86% male; 51% AA/Black, 38% NH-White, 9% Hispanic/Latinx, 2% other) from the CNS HIV Antiretroviral Therapy Effects Research multi-site study. Participants underwent APOE genotyping, neuropsychological testing, and structural MRI; APOE groups were defined as APOE4+ (at least one APOE4 allele) and APOE4- (no APOE4 alleles). Eighty-nine percent of participants were on antiretroviral therapy, 74% had undetectable plasma HIV RNA (<50 copies/ml), and 25% were APOE4+ (32% AA/Black/15% NH-White). Neuropsychological testing assessed seven domains, and demographically-corrected T-scores were calculated. FreeSurfer 7.1.1 was used to measure MTL structures (hippocampal volume, entorhinal cortex thickness, and parahippocampal thickness) and the effect of scanner was regressed out prior to analyses. Multivariable linear regressions tested the association between APOE status and cognitive and imaging outcomes. Models examining cognition covaried for comorbid conditions and HIV disease characteristics related to global cognition (i.e., AIDS status, lifetime methamphetamine use disorder). Models examining the MTL covaried for age, sex, and

relevant imaging covariates (i.e., intracranial volume or mean cortical thickness).

APOE4+ carriers had worse learning (ß=-0.27, p=.01) and delayed recall (ß=-0.25, p=.02) compared to the APOE4- group, but APOE status was not significantly associated with any other domain (ps>0.24). APOE4+ status was also associated with thinner entorhinal cortex (ß=-0.24, p=.02). APOE status was not significantly associated with hippocampal volume (ß=-0.08, p=0.32) or parahippocampal thickness (ß=-0.18, p=.08). Lastly, race interacted with APOE status such that the negative association between APOE4+ status and cognition was stronger in NH-White PWH as compared to AA/Black PWH in learning, delayed recall, and verbal fluency (ps<0.05). There were no APOE by race interactions for any MTL structures (ps>0.10).

Findings suggest that APOE4 carrier status is associated with worse episodic memory and thinner entorhinal cortex in mid- to older-aged PWH. While APOE4+ groups were small, we found that APOE4 carrier status had a larger association with cognition in NH-White PWH as compared to AA/Black PWH, consistent with studies demonstrating an attenuated effect of APOE4 in older AA/Black HIV-negative older adults. These findings further highlight the importance of recruiting diverse samples and suggest exploring other genetic markers (e.g., ABCA7) that may be more predictive of AD in some races to better understand AD risk in diverse groups of PWH.

Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.

In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.

Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.

Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.