Nightmares and sleep disruption are hallmarks of posttraumatic stress disorder (PTSD), cause significant distress, and often persist after the remission of other symptoms. Autonomic dysregulation, including tachycardia, excessive sweating, and panic, have been implicated in the pathophysiology of PTSD. Existing self-report measures for nightmares and disrupted sleep primarily focus on subsets of the relevant clinical features, with relatively little emphasis on symptoms of autonomic dysregulation during sleep, restricting their ability to quantitatively assess the impact of trauma on sleep or to track treatment response. Here, we describe a new 11-item self-report measure, the Seattle Trauma and Autonomic Reactivity Sleep Symptoms Scale (STARSS), which assesses commonly encountered clinical symptomatology of trauma-associated sleep disruptions including nightmares, autonomic symptoms during sleep, and sleep-related hypervigilance. Items of the scale were derived from a series of clinician assessments of sleep-related symptoms observed in practice and research settings of PTSD treatment to respond to prazosin, an alpha-1 adrenoceptor antagonist. Psychometric validation of the STARSS was conducted in a sample of 830 healthcare workers and first responders working during the COVID-19 pandemic. Measures of internal consistency, discriminant and convergent validity, sensitivity, specificity, and factor structure were conducted in the study sample. The STARSS was positively correlated with self-report measures covering symptom domains additional to nightmares and commonly elevated following trauma exposure, including PTSD (PCL-5; r=0.76), anxiety (GAD7; r=0.67), depression (PHQ9; r=0.63), and insomnia (ISI; r=0.54), and displayed strong internal consistency (α=0.88; ω=0.93). Underlying factors included sleep-related hyperarousal, partner/self-reported activity in sleep, and trauma dream intensity. The STARSS is a brief, clinically informed questionnaire assessing autonomic and trauma-related symptoms during sleep, with strong psychometric validity. The scale is more highly correlated to PTSD symptom burden than are existing measures of insomnia and anxiety, suggesting specificity for trauma-related sleep disruption. Future work will explore the utility of the STARSS in clinical and research contexts for identifying treatment targets and tracking treatment response, as well as testing the potential for the measure to identify individuals likely to respond to specific interventions, supporting a precision medicine approach. VA Puget Sound R&D Seed Grant

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Abstract ID 95469Poster Board 523Mild traumatic brain injury (mTBI), commonly called the "hallmark injury" of the Iraq/Afghanistan wars, is an established risk factor for Alzheimer’s Disease and related dementias (ADRD). Alcohol use disorder (AUD) can also increase the risk of ADRD, and is often comorbid with mTBI. However, the interaction of mTBI and AUD in contributing to ADRD remains understudied. The current study investigates how chronic alcohol after blast-induced mTBI affects development of ADRD and aging related behaviors and biomarkers. Male mice were exposed to repetitive (3x) blast or sham using a translationally relevant shock tube. Following recovery from blast, group-housed mice were allowed intermittent access to multiple doses of alcohol (2-20%) in our novel Socially Integrated Polysubstance cages for three separate four week periods. Behavioral outcomes (spatial working memory, thermal sensitivity, blast-conditioned aversion, hyperreactivity) were assessed prior to alcohol exposure and again three days after each access period. Fluid and imaging-based biomarkers were also assessed, including brain glucose metabolism (FDG-PET), peripheral cytokines, gut microbiome, liver health, and glymphatic function (3D histology). Initial behavioral results show escalation of alcohol intake between exposures, a potential negative effect of alcohol on spatial working memory, higher alcohol intake for blast-exposed mice, and a combined effect of blast-exposure and alcohol on hyperreactivity. Early biomarker analyses suggest high alcohol intake impairs brain glucose metabolism and glymphatic clearance in both sham and blast-exposed mice, while only blast-exposed mice show impairments after low amounts of chronic alcohol. These results provide a holistic characterization of how aging is affected by trauma and alcohol over the lifespan, highlight new biomarkers to predict adverse outcomes, and ultimately provide potential clinical targets to combat adverse comorbid outcomes in the aging population.

IntroductionCannabis use disorder (CUD) is prevalent in ~2–5% of adults in the United States and is anticipated to increase as restrictions to cannabis decrease and tetrahydrocannabinol (THC) content in cannabis products increase. No FDA-approved medications for CUD are currently available, despite trials of dozens of re-purposed and novel drugs. Psychedelics have garnered interest as a therapeutic class in other substance use disorders, and self-report surveys suggest they may result in positive outcomes for CUD. Herein, we review the existing literature pertaining to psychedelic use in persons with or at risk for CUD and consider the potential rationale underpinning psychedelics as a treatment for CUD.MethodsA systematic search was performed in several databases. Inclusion criteria were primary research reporting use of psychedelics or related substances and CUD for treatment in human subjects. Exclusion criteria were results including psychedelics or related substances without changes in cannabis use or risks associated with CUD.ResultsThree hundred and five unique results were returned. One article was identified using the non-classical psychedelic ketamine in CUD; three articles were identified as topically relevant based on their secondary data or consideration of mechanism. Additional articles were reviewed for purposes of background, review of safety considerations, and formulating rationale.ConclusionLimited data and reporting are available on the use of psychedelics in persons with CUD, and more research is needed given the anticipated increase in CUD incidence and increasing interest in psychedelic use. While psychedelics, broadly, have a high therapeutic index with infrequent serious adverse effects, particular adverse effects at risk in the CUD population, such as psychosis and cardiovascular events, should be considered. Possible mechanisms by which psychedelics have therapeutic potential in CUD are explored.

Substance use disorders (SUDs) have significant morbidity and mortality, and few effective treatment methods are available. Fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide, has become an attractive target for research in SUD. Genetic variations in FAAH due to a single-nucleotide polymorphism might confer increased risk of developing an SUD. As well, exposure to toxic or addictive substances may result in differential activity and concentration of FAAH in brain regions salient to SUD. Therapeutically, pharmacological inhibition of FAAH may decrease some negative aspects of withdrawal from addictive substances, facilitate reversal learning of aversive experiences, and decrease drug-seeking behavior during abstinence. However, it may also lead to changes in preference for and sensitivity to these substances. Therefore, the efficacy of FAAH inhibition in SUD may be limited to selective stages of addiction. As the research is promising but not conclusive, more is needed.

BACKGROUND:Excessive noradrenergic signaling contributes to aversive symptoms of alcohol withdrawal that interfere with abstinence or reductions in harmful use. METHODS:To address this aspect of alcohol use disorder, 102 active-duty soldiers participating in command-mandated Army outpatient alcohol treatment were randomized to also receive the brain-penetrant alpha-1 adrenergic receptor antagonist prazosin or placebo for 13 weeks. Primary outcomes were scores on the Penn Alcohol Craving Scale (PACS), standard drink units (SDUs) per day averaged over each week, % days of any drinking per week, and % days of heavy drinking per week. RESULTS:PACS declines did not differ significantly between the prazosin and placebo groups in the overall sample. In the subgroup with comorbid PTSD (n = 48), PACS declines were significantly greater in the prazosin than in the placebo condition (p < 0.05). Baseline alcohol consumption was markedly reduced by the pre-randomization outpatient alcohol treatment program, but the addition of prazosin treatment produced a greater slope of decline in SDUs per day compared to placebo (p = 0.01). Preplanned subgroup analyses were performed in soldiers with elevated baseline cardiovascular measures consistent with increased noradrenergic signaling. In soldiers with elevated standing heart rate (n = 15), prazosin reduced SDUs per day (p = 0.01), % days drinking (p = 0.03), and % days heavy drinking (p = 0.001) relative to placebo. In soldiers with elevated standing systolic blood pressure (n = 27), prazosin reduced SDUs per day (p = 0.04) and tended to reduce % days drinking (p = 0.056). Prazosin also reduced depressive symptoms and the incidence of emergent depressed mood more than placebo (p = 0.05 and p = 0.01, respectively). During the final 4 weeks of prazosin vs. placebo treatment that followed completion of Army outpatient AUD treatment, alcohol consumption in soldiers with elevated baseline cardiovascular measures increased in those receiving placebo but remained suppressed in those receiving prazosin. CONCLUSIONS:These results extend reports that higher pretreatment cardiovascular measures predict beneficial effects of prazosin, which may be useful for relapse prevention in patients with AUD.

Purpose: Recent research has suggested that chronic alcohol exposure induces changes in the endocannabinoid system within the central nervous system and therefore could be an attractive target for better understanding and treating alcohol use disorder (AUD). Much of this research has centered around the CB1 receptor and its endogenous partial agonist, the endocannabinoid anandamide, as the CB1 receptor is densely expressed in brain regions involved in development and maintenance of addictive behaviors. In addition, recent evidence has suggested that chronic alcohol exposure induces changes in the modulation of endocannabinoid concentration and suggests that these changes may contribute to the motivation to abuse alcohol. Therefore, we performed a systematic literature review to evaluate how fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, relates to the characteristics and biology of AUD, as well as how modulating FAAH through pharmacologic inhibition or genetic manipulation affects outcomes related to alcohol use and consumption. Method: A search strategy was developed using the terms "endocannabinoids" or "drug delivery systems" and "alcohol dependence" or "alcohol use disorder" or "alcoholism" and "Fatty Acid Amide Hydrolase" and "FAAH" as text words and Medical Subject Headings (i.e., MeSH and EMTREE). We then used this search strategy on the electronic databases PubMed, Embase, and Web of Science. Results: We found 224 records; after removing repeated records (37%), articles that did not fit the topic question (47%), or were not primary research (4%), we included 26 for qualitative synthesis (12%). Discussion: The literature clearly suggests that FAAH has a role in the biology and characteristics of AUD. FAAH inhibition seems especially promising as a target for alcohol withdrawal as it may lead to a reduction in symptoms, including anxiety and a reduction of alcohol intake reinstatement. However, decreased FAAH may also lead to reduced sensitivity to alcohol along with increased preference and intake. Conclusions: Modulation of FAAH is promising for therapeutic intervention of AUD, but requires more research. Pre-clinical studies have indicated that FAAH inhibition may reduce withdrawal characteristics, but may also exacerbate other characteristics of AUD outside of that period.

Repetitive mild traumatic brain injury (mTBI) has been called the “signature injury” of military service members in the Iraq and Afghanistan wars and is highly comorbid with post-traumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Pre-clinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction—but only to the degree by which such models reflect the human experience. Avoidance of trauma reminders is a hallmark of PTSD. Here, we sought to understand whether a mouse model of blast reproduces this phenomenon, in addition to blast-induced physical injuries. Drawing on well-established work from the chronic stress and Pavlovian conditioning literature, we hypothesized that even while one is anesthetized during blast exposure, environmental cues encountered in the peri-blast environment could be conditioned to evoke aversion/dysphoria and re-experiencing of traumatic stress. Using a pneumatic shock tube that recapitulates battlefield-relevant open-field blast forces, we provide direct evidence that stress is inherent to repetitive blast exposure, resulting in chronic aversive/dysphoric-like responses to previous blast-paired cues. The results in this report demonstrate that, although both single and repetitive blast exposures produce acute stress responses (weight loss, corticosterone increase), only repetitive blast exposure also results in co-occurring aversive/dysphoric-like stress responses. These results extend appreciation of the highly complex nature of repetitive blast exposure; and lend further support for the potential translational relevance of animal modeling approaches currently used by multiple laboratories aimed at elucidating the mechanisms (both molecular and behavioral) of repetitive blast exposure.

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.

1482 Objectives: Repetitive mild traumatic brain injuries (mTBIs) may lead to an increased risk of future neurodegeneration, but such processes have not been investigated systematically. The goal of this research is to characterize longitudinal alterations in regional neuronal activity among Veterans with previous repeat blast mTBIs using FDG PET. Methods: Positron emission tomography with [18F]-fluorodeoxyglucose (FDG PET) was used to assess brain metabolism in 10 Veterans with repetitive mTBI (age 38.0±10.8, range 25-59 yrs) and 4 deployed controls (DC) with no blast exposure (age 35.8±7.7, range 28-45 yrs). Community controls (n=9, 28.0±8.1, range 20-45 yrs) were used as reference normal data. Each subject received two FDG-PET scans with a mean scan interval of 3.3±0.8 and 3.0±0.29 years for the DC and mTBI groups, respectively that was not significantly different (t[12]=0.44, n.s.). Images were anatomically standardized, normalized to global uptake and compared to the normal database to produce individual Z-score maps where higher Z values represent hypometabolic pixels (HP) (3D-SSP, U. UTAH). A custom algorithm was applied to the individual Z-score maps for each paired image set that counted the number pixels of 26 brain regions with a Z-score above a set threshold (Z>1.64). Longitudinal changes in number of HPs exceeding the threshold within each region as well as total global (GBL) and total cortex (CTX) were counted and within and between group differences were assessed statistically. To overcome challenges from heterogeneous brain reorganization and differences in injury patterns, we calculated a ratio of the number of regions (RR) with decreased HPs divided by the number of regions indicating increased HPs as a very general assessment of decline ( 1.0). Results: Groupwise comparisons between mTBI and DC of scan 1, scan 2, and scan 2-1 differences showed scattered regional decreases in mTBI that did not achieve statistical significance after Bonferonni corrections for multiple comparisons. No between or within group differences were found among GBL or CTX groups, indicating that variability of individualized longitudinal changes (see figure) were obscuring group differences. One of four DC subjects had RR 1.0 (range 1.67 - 2.75) indicated improvement (DC RR=1.42±0.86, mn+sd). In mTBI, 8/10 subjects (80%) had RR 1.0 indicating FDG-PET improvement (RR=7 and 1.67 respectively, mTBI group RR=0.74±2.03). A Chi-square analysis indicated there was a significant difference between the number of subjects declining the mTBI versus DC group (p≤0.05). Conclusions: Although groupwise changes of longitudinal FDG-PET scans were not found, a ratio of regions showing reduced number of hypometabolic pixels compared to increased hypometabolic pixels was able to differentiate individuals that may be declining from those that may be recovering from mTBI. These results indicate that groupwise assessment in longitudinal imaging follow up may be inadequate to detect such individualized changes after repetitive mTBI. Comparison of individual patterns with clinical data is ongoing. Although currently no treatments exist to mitigate poor outcome after repetitive mTBI, it is important for future clinical trials to have an objective means to identify patients that may benefit from specific therapeutic interventions.

Background: Despite the high prevalence of blunt smoking among cannabis users, very few studies examine the clinical profile of blunt smokers relative to those using more common methods of cannabis use, such as joints. Methods: The current study uses baseline data from the ACCENT (Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment) study, a multi-site randomized pharmacotherapy clinical trial within the National Drug Abuse Treatment Clinical Trials Network, to predict the association between blunt and joint use frequency and cannabis use characteristics (e.g., grams of cannabis used) and consequences (e.g., withdrawal) among past month cannabis users (N = 377) who were screened for study participation. Results: After controlling for race, age, gender, other forms of cannabis use (including joint use) and nicotine dependence, multivariable linear regression models indicated that the number of days of blunt use in the past month was a significant predictor of the average amount of cannabis per using day (t = 3.04, p < .01), the estimated average cost of cannabis (t = 2.28, p < .05) and Cannabis Withdrawal Scale scores (t = 1.94, p < .05). Frequency of joint use did not significantly predict any of the cannabis use characteristics or consequences. Conclusions: Blunt smokers may present to treatment with greater amounts of cannabis smoked and more intense withdrawal symptoms, which may adversely impact their likelihood of successful abstinence. Cannabis-dependent blunt smokers may be more likely to benefit from treatment that targets physiological and mood-related withdrawal symptoms.