Endocannabinoids and Stress-Related Neurospsychiatric Disorders: A Systematic Review and Meta-Analysis of Basal Concentrations and Response to Acute Psychosocial Stress.

Background: Dysregulation of the endocannabinoid (eCB) system is implicated in various stress-related neuropsychiatric disorders (SRDs), including anxiety, depression, and post-traumatic stress disorder (PTSD). In this systematic review and meta-analysis, our objectives were to characterize circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations at rest and in response to acute laboratory-based psychosocial stress in individuals with SRDs and without (controls). Our primary aims were to assess the effects of acute psychosocial stress on eCB concentrations in controls (Aim 1), compare baseline (prestress) eCB concentrations between individuals with SRDs and controls (Aim 2), and explore differential eCB responses to acute psychosocial stress in individuals with SRDs compared with controls (Aim 3). Methods: On June 8, 2023, a comprehensive review of the MEDLINE (PubMed) database was conducted to identify original articles meeting inclusion criteria. A total of 1072, 1341, and 400 articles were screened for inclusion in Aims 1, 2, and 3, respectively. Results: Aim 1, comprised of seven studies in controls, revealed that most studies reported stress-related increases in AEA (86%, with 43% reporting statistical significance) and 2-AG (83%, though none were statistically significant except for one study in saliva). However, meta-analyses did not support these patterns (p's>0.05). Aim 2, with 20 studies, revealed that most studies reported higher baseline concentrations of both AEA (63%, with 16% reporting statistical significance) and 2-AG (60%, with 10% reporting statistical significance) in individuals with SRDs compared with controls. Meta-analyses confirmed these findings (p's<0.05). Aim 3, which included three studies, had only one study that reported statistically different stress-related changes in 2-AG (but not AEA) between individuals with PTSD (decrease) and controls (increase), which was supported by the meta-analysis (p<0.001). Meta-analyses showed heterogeneity across studies and aims (I2=14-97%). Conclusion: Despite substantial heterogeneity in study characteristics, samples, and methodologies, consistent patterns emerged, including elevated baseline AEA and 2-AG in individuals with SRDs compared with controls, as well as smaller stress-related increases in 2-AG in individuals with SRDs compared with controls. To consider eCBs as reliable biomarkers and potential intervention targets for SRDs, standardized research approaches are needed to clarify the complex relationships between eCBs, SRDs, and psychosocial stress.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence.

BACKGROUND: The endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)-an enzyme that regulates endocannabinoid signaling-to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. METHODS: This study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9-11 years at Baseline, 11-13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. RESULTS: A significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p's<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p's>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p's>0.05). CONCLUSIONS: Our findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

Smaller Hippocampal Volume Is Associated With Reduced Posttraumatic Stress Symptoms in Children With Cancer and Survivors Following a Brief Novel Martial Arts-Based Intervention.

PURPOSE: Children with cancer and survivors frequently report posttraumatic stress symptoms (PTSS), which are associated with volumetric changes in stress-sensitive brain regions, including the hippocampus. METHODS: We examined the impact of a novel, 4-week martial-arts-based meditative intervention on cancer-related PTSS in 18 pediatric patients and survivors and whether baseline hippocampal volumes correlate with PTSS severity and/or PTSS changes over time. RESULTS: Overall, PTSS did not significantly change from baseline to post-intervention. Smaller hippocampal volume was correlated with more severe re-experiencing PTSS at baseline, and greater reductions in PTSS post-intervention. CONCLUSIONS: Together, hippocampal volume may be a biomarker of PTSS severity and intervention response. Identifying hippocampal volume as a potential biomarker for PTSS severity and intervention response may allow for more informed psychosocial treatments.

The First "Hit" to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children.

Background: Cannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). Methods: This study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). Results: PCE was associated with lower fractional anisotropy of the right (ß = -0.005, p < .001) and left (ß = -0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. Conclusions: In sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Attention, attention! Posttraumatic stress disorder is associated with altered attention-related brain function.

Posttraumatic stress disorder (PTSD) is a debilitating condition characterized by altered arousal, mood, and cognition. Studies report attentional alterations such as threat bias in individuals with PTSD, though this work has largely been conducted within emotionally-charged contexts (e.g., threatening stimuli). Emerging behavioral evidence suggests that PTSD-related attention deficits exist even in the absence of threatening cues or anxiety triggers. However, the role and functioning of attention brain circuits as they relate to PTSD remains underexplored. In this mini review, we highlight recent work using non-emotional stimuli to investigate the neurobiology of attention and disruptions to attention-related brain function among individuals with PTSD. We then discuss gaps in the current literature, including questions pertaining to the neural circuitry of attentional alterations in PTSD, as well as the contributions that trauma exposure, PTSD symptoms, comorbidities, and pre-existing vulnerabilities may have in this relationship. Finally, we suggest future directions for this emerging area of research, which may further inform knowledge surrounding the neurobiological underpinnings of PTSD and potential treatments.

Impact of prenatal cannabis exposure on functional connectivity of the salience network in children.

Cannabis use among pregnant people has increased over the past decade. This is of concern as prenatal cannabis exposure (PCE) is associated with cognitive, motor, and social deficits among offspring. Here, we examined resting-state functional connectivity (rsFC) of the salience network (SN)-a core neurocognitive network that integrates emotional and sensory information-in children with (vs. without) PCE. Using neuroimaging and developmental history data collected from 10,719 children (M ± SD = 9.92 ± 0.62 years; 47.9% female) from the Adolescent Brain Cognitive Development study, we assessed the impact of parent-reported PCE (before or after knowledge of pregnancy) on rsFC within and between the SN and five other core neurocognitive networks. We also evaluated whether SN rsFC mediated the association between PCE and child psychopathology. Results showed that PCE before (but not after) knowledge of pregnancy was associated with lower SN-ventral attention network (VAN) rsFC. Furthermore, psychotic-like experiences mediated the association between PCE and SN-VAN rsFC, and reversal of the model was also significant, such that SN-VAN rsFC mediated the association between PCE and psychotic-like symptoms. However, these mediation effects were no longer significant after the inclusion of covariates. Taken together, these findings suggest that developmental alterations in SN-VAN interactions may explain the previously reported association between PCE and elevated risk of child psychopathology.

Air pollution, depressive and anxiety disorders, and brain effects: A systematic review.

Accumulating data suggest that air pollution increases the risk of internalizing psychopathology, including anxiety and depressive disorders. Moreover, the link between air pollution and poor mental health may relate to neurostructural and neurofunctional changes. We systematically reviewed the MEDLINE database in September 2021 for original articles reporting effects of air pollution on 1) internalizing symptoms and behaviors (anxiety or depression) and 2) frontolimbic brain regions (i.e., hippocampus, amygdala, prefrontal cortex). One hundred and eleven articles on mental health (76% human, 24% animals) and 92 on brain structure and function (11% human, 86% animals) were identified. For literature search 1, the most common pollutants examined were PM2.5 (64.9%), NO2 (37.8%), and PM10 (33.3%). For literature search 2, the most common pollutants examined were PM2.5 (32.6%), O3 (26.1%) and Diesel Exhaust Particles (DEP) (26.1%). The majority of studies (73%) reported higher internalizing symptoms and behaviors with higher air pollution exposure. Air pollution was consistently associated (95% of articles reported significant findings) with neurostructural and neurofunctional effects (e.g., increased inflammation and oxidative stress, changes to neurotransmitters and neuromodulators and their metabolites) within multiple brain regions (24% of articles), or within the hippocampus (66%), PFC (7%), and amygdala (1%). For both literature searches, the most studied exposure time frames were adulthood (48% and 59% for literature searches 1 and 2, respectively) and the prenatal period (26% and 27% for literature searches 1 and 2, respectively). Forty-three percent and 29% of studies assessed more than one exposure window in literature search 1 and 2, respectively. The extant literature suggests that air pollution is associated with increased depressive and anxiety symptoms and behaviors, and alterations in brain regions implicated in risk of psychopathology. However, there are several gaps in the literature, including: limited studies examining the neural consequences of air pollution in humans. Further, a comprehensive developmental approach is needed to examine windows of susceptibility to exposure and track the emergence of psychopathology following air pollution exposure.

The impact of neurotoxicant exposures on posttraumatic stress disorder trajectories: The Ft. Devens Gulf War Veterans Cohort.

Gulf War veterans (GWVs) were exposed to neurotoxicants, including sarin nerve gas, anti-nerve agent pills, pesticides, oil well fires, and fumes from unvented tent heaters, all of which have been associated with subsequent adverse health. Posttraumatic stress disorder (PTSD) symptoms have also been associated with GW deployment; however, associations between exposures and PTSD symptoms have not been investigated. We assessed PTSD symptom trajectories and associations with neurotoxicant exposures in Ft. Devens Cohort (FDC) veterans (N = 259) who endorsed trauma exposure during deployment and completed the PTSD Checklist at three follow-ups (1992-1993, 1997-1998, 2013-2017). Results indicate that among veterans with more severe initial PTSD symptoms, symptoms remained significantly higher across follow-ups, Bs = -1.489-1.028, whereas among those with low initial PTSD symptoms, symptom severity increased significantly over time, Bs = 1.043-10.304. Additionally, neurotoxicant exposure was associated with a significant increase in PTSD symptoms, Bs = -1.870-9.003. Significant interactions between time and exposures were observed for PTSD symptom clusters, suggesting that among participants with high initial PTSD symptom, unexposed veterans experienced symptom alleviation, whereas exposed veterans' PTSD symptoms remained high. In GWVs with low initial PTSD symptoms, both unexposed and exposed veterans experienced PTSD symptom exacerbations over time; however, this occurred at a faster rate among exposed veterans. These findings suggest that in the years following deployment, GWVs who were exposed to both traumatic events and neurotoxicants may experience more severe and chronic PTSD symptoms than those without neurotoxicant exposures.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

Neurotoxicant exposures and rates of Chronic Multisymptom Illness and Kansas Gulf War Illness criteria in Gulf War deployed women veterans.

AIMS: This study analyzed deployment-related exposures and risk of Persian Gulf War Illness (GWI) in women veterans from the Veterans Affairs (VA) Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB CSP#585). MAIN METHODS: We examined the associations between GW deployment-related exposures and case definitions for GWI in deployed GW women. Multivariate regression analyses controlling for demographic outcomes were performed. KEY FINDINGS: Surveys were obtained from 202 GW deployed women veterans. Self-reported exposure to smoke from oil well fires as well as chemical and biological warfare were the only exposures significantly associated with the Center for Disease Control and Prevention (CDC) GWI criteria. Seventy-nine women were excluded from the rest of the analyses as they met Kansas GW illness exclusion criteria. Eligible women who self-reported deployment-related exposure to smoke from oil wells, pyridostigmine bromide (PB) pills, pesticide cream, pesticide treated uniforms, and insect baits were significantly more likely to meet the Kansas GWI criteria (n = 123) than those unexposed and exposures were related to Kansas symptom subdomain endorsements. SIGNIFICANCE: These results suggest that women GW veterans reporting deployment related exposures of pesticide, oil well fire and PB pills are significantly more likely to meet the Kansas GWI criteria in this national cohort of GW women suggesting its utility in future studies. In addition, based on these results it appears that women exposed to particular toxicants during the war may benefit from more targeted treatment strategies dependent upon the mechanism of exposure of their toxicant induced outcomes.

Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls.

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls. In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.

Changes in Health Status in the Ft. Devens Gulf War Veterans Cohort: 1997-2017.

Gulf War veterans (GWVs) were exposed to numerous neurotoxicants during deployment. Upon returning home, many reported a multitude of symptoms including fatigue, pain, gastrointestinal and respiratory issues, and neurological, cognitive, and mood complaints, collectively termed "Gulf War Illness (GWI)." Now, nearly 30 years post-war, many GWVs continue to suffer from these symptoms, in addition to health concerns associated with normal aging. While most research on GWVs has been cross-sectional, it is important to evaluate the progression and onset of new GWI symptoms longitudinally. The current study investigated the health of GWVs 25+ years after the war by resurveying the Ft. Devens Cohort and comparing their current health to their health reported 15 to 20 years earlier. The sample consists of 317 GWVs (~54 years old at the latest survey, 38 women) who responded to both surveys (1997-1998 and 2013-2017). Multivariable regression analyses were used to assess changes in GWI symptomatology and prevalence of medical conditions. The rates of 12 of 25 health symptoms increased significantly from the prior 1997-1998 survey. Anxiety, numbness in extremities, depressed mood, and joint pain had the greatest increase in endorsement. The rates of 7 of 16 medical conditions increased significantly from the prior 1997-1998 survey. High blood pressure, diabetes, and cancer had the greatest increase in prevalence. In summary, this study demonstrates that both symptoms and physician-diagnosed medical conditions associated with GW deployment/exposure increased in prevalence. For GWVs, focus by providers on the treatment of cognitive and mental health issues as well as cardiovascular and cerebrovascular risk factors is warranted. Targeting symptom alleviation would help improve the quality of life in these veterans until treatments addressing the entire illness become available.

Longitudinal Assessment of Health Symptoms in Relation to Neurotoxicant Exposures in 1991 Gulf War Veterans: The Ft. Devens Cohort.

OBJECTIVE: This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans. METHODS: Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates. RESULTS: Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily. CONCLUSION: This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.

Adolescent substance use and functional connectivity between the ventral striatum and hippocampus.

Neurodevelopmental explanations for adolescent substance use have focused on heightened sensitivity of mesolimbic circuitry, centered on the ventral striatum (VS). Recent evidence suggests that, relative to adults, adolescents show a stronger link between reinforcement learning and episodic memory for rewarding outcomes and greater functional connectivity between the VS and hippocampus, which may reflect a heightened reward modulation of memory. However, a link between VS-hippocampal circuitry and adolescent substance use has yet to be established. Two separate studies were conducted to evaluate whether variation in VS-hippocampal resting-state functional connectivity (rs-FC) predicts subsequent adolescent substance use exposure. A pilot study (Study 1) was conducted in 19 youth recruited from a high sociodemographic risk population (N = 19; mean age = 13.3 SD = 1.4; 14 females; 47% Black Non-Hispanic, 32% White Non-Hispanic). To replicate results of Study 1, Study 2 utilized data from the National Consortium on Adolescent Neurodevelopment and Alcohol (N = 644; mean age = 16.3 SD = 2.5; 339 females; 11% Black Non-Hispanic, 11% Hispanic/Latino, 66% White Non-Hispanic). Resting-state fMRI data were collected at a baseline time point and lifetime and past year self-reported substance use was collected at a follow up visit. Regression models tested whether baseline VS-hippocampal rs-FC predicted substance use exposure at follow up, as measured by an index score reflecting the number of substance classes (e.g., alcohol, marijuana) tried and overall frequency of use. Across both studies, higher VS-hippocampal rs-FC at baseline predicted greater substance use exposure at follow up (pFWE < 0.05). These data provide the first evidence linking increased VS-hippocampal connectivity with greater adolescent substance use exposure. Results fit with the emerging idea that variation in adolescent substance use may relate to not only individual differences in mesolimbic sensitivity to reward, but also to an individuals' memory sensitivity to reward as measured by connectivity between canonical memory and reward regions.

Rates of Chronic Medical Conditions in 1991 Gulf War Veterans Compared to the General Population.

Prevalence of nine chronic medical conditions in the population-based Ft. Devens Cohort (FDC) of GW veterans were compared with the population-based 2013⁻2014 National Health and Nutrition Examination Survey (NHANES) cohort. Excess prevalence was calculated as the difference in prevalence estimates from the Ft. Devens and NHANES cohorts; and confidence intervals and p-values are based on the standard errors for the two prevalence estimates. FDC males were at increased risk for reporting seven chronic medical conditions compared with NHANES males. FDC females were at decreased risk for high blood pressure and increased risk for diabetes when compared with NHANES females. FDC veterans reporting war-related chemical weapons exposure showed higher risk of high blood pressure; diabetes; arthritis and chronic bronchitis while those reporting taking anti-nerve gas pills had increased risk of heart attack and diabetes. GW veterans are at higher risk of chronic conditions than the general population and these risks are associated with self-reported toxicant exposures.