Persistent brain fog is common in adults with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), in whom it causes distress and in many cases interferes with performance of instrumental activities of daily living (IADL) and return-to-work. There are no interventions with rigorous evidence of efficacy for this new, often disabling condition. The purpose of this pilot is to evaluate the efficacy, on a preliminary basis, of a new intervention for this condition termed Constraint-Induced Cognitive therapy (CICT). CICT combines features of two established therapeutic approaches: cognitive speed of processing training (SOPT) developed by the laboratory of K. Ball and the Transfer Package and task-oriented training components of Constraint-Induced Movement therapy developed by the laboratory of E. Taub and G. Uswatte.

Participants were > 3 months after recovery from acute COVID symptoms and had substantial brain fog and impairment in IADL. Participants were randomized to CICT immediately or after a 3-month delay. CICT involved 36 hours of outpatient therapy distributed over 4-6 weeks. Sessions had three components: (a) videogamelike training designed to improve how quickly participants process sensory input (SOPT), (b) training on IADLs following shaping principles, and (c) a set of behavioral techniques designed to transfer gains from the treatment setting to daily life, i.e., the Transfer Package. The Transfer Package included (a) negotiating a behavioral contract with participants and one or more family members about the responsibilities of the participants, family members, and treatment team; (b) assigning homework during and after the treatment period; (c) monitoring participants’ out-of-session behavior; (d) supporting problem-solving by participants and family members about barriers to performance of IADL; and (e) making follow-up phone calls. IADL performance, brain fog severity, and cognitive impairment were assessed using validated, trans-diagnostic measures before and after treatment and three months afterwards in the immediate-CICT group and on parallel occasions in the delayed-CICT group (aka waitlist controls).

To date, five were enrolled in the immediate-CICT group; four were enrolled in the wait-list group. All had mild cognitive impairment, except for one with moderate impairment in the immediate-CICT group. Immediate-CICT participants, on average, had large reductions in brain fog severity on the Mental Clutter Scale (MCS, range = 0 to 10 points, mean change = -3.7, SD = 2.0); wait-list participants had small increases (mean change = 1.0, SD = 1.4). Notably, all five in the immediate-CICT group had clinically meaningful improvements (i.e., changes > 2 points) in performance of IADL outside the treatment setting as measured by the Canadian Occupational Performance Measure (COPM) Performance scale; only one did in the wait-list group. The advantage for the immediate-CICT group was very large on both the MCS and COPM (d’s = 1.7, p’s < .05). In follow-up, immediate-CICT group gains were retained or built-upon.

These preliminary findings warrant confirmation by a large-scale randomized controlled trial. To date, CICT shows high promise as an efficacious therapy for brain fog due to PASC. CICT participants had large, meaningful improvements in IADL performance outside the treatment setting, in addition to large reductions in brain fog severity.

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.

Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.

One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.

A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.

Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock).

Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments.

Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging.

This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.