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.

A test of pre-exposure spacing and multiple context pre-exposure on the mechanisms of latent inhibition of dental fear: A study protocol.

BACKGROUND: Latent inhibition occurs when exposure to a stimulus prior its direct associative conditioning impairs learning. Results from naturalistic studies suggest that latent inhibition disrupts the learning of dental fear from aversive associative conditioning and thereby reduces the development of dental phobia. Although theory suggests latent inhibition occurs because pre-exposure changes the expected relevance and attention directed to the pre-exposed stimulus, evidence supporting these mechanisms in humans is limited. The aim of this study is to determine if two variables, pre-exposure session spacing and multiple context pre-exposure, potentiate the hypothesized mechanisms of expected relevance and attention and, in turn, increase latent inhibition of dental fear. METHODS: In a virtual reality simulation, child and adult community members (ages 6 to 35) will take part in pre-exposure and conditioning trials, followed by short- and long-term tests of learning. A 100ms puff of 60 psi air to a maxillary anterior tooth will serve as the unconditioned stimulus. Pre-exposure session spacing (no spacing vs. sessions spaced) and multiple context pre-exposure (single context vs. multiple contexts) will be between-subject factors. Stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial will serve as within-subject factors. Baseline pain sensitivity will also be measured as a potential moderator. DISCUSSION: It is hypothesized that spaced pre-exposure and pre-exposure in multiple contexts will increase the engagement of the mechanisms of expected relevance and attention and increase the latent inhibition of dental fear. It is expected that the findings will add to theory on fear learning and provide information to aid the design of future interventions that leverage latent inhibition to reduce dental phobia.

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.

A study protocol testing pre-exposure dose and compound pre-exposure on the mechanisms of latent inhibition of dental fear.

BACKGROUND: Dental stimuli can evoke fear after being paired - or conditioned - with aversive outcomes (e.g., pain). Pre-exposing the stimuli before conditioning can impair dental fear learning via a phenomenon known as latent inhibition. Theory suggests changes in expected relevance and attention are two mechanisms responsible for latent inhibition. In the proposed research, we test whether pre-exposure dose and degree of pre-exposure novelty potentiate changes in expected relevance and attention to a pre-exposed stimulus. We also assess if the manipulations alter latent inhibition and explore the possible moderating role of individual differences in pain sensitivity. METHODS: Participants will be healthy individuals across a wide range of ages (6 to 35 years), from two study sites. Participants will undergo pre-exposure and conditioning followed by both a short-term and long-term test of learning, all in a novel virtual reality environment. The unconditioned stimulus will be a brief pressurized puff of air to a maxillary anterior tooth. Pre-exposure dose (low vs. high) and pre-exposure novelty (element stimulus vs. compound stimuli) will be between-subject factors, with stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial as within-subject factors. Pain sensitivity will be measured through self-report and a cold pressor test. It is hypothesized that a larger dose of pre-exposure and compound pre-exposure will potentiate the engagement of the target mechanisms and thereby result in greater latent inhibition in the form of reduced fear learning. Further, it is hypothesized that larger effects will be observed in participants with greater baseline pain sensitivity. DISCUSSION: The proposed study will test whether pre-exposure dose and compound stimulus presentation change expected relevance and attention to the pre-exposed stimulus, and thereby enhance latent inhibition of dental fear. If found, the results will add to our theoretical understanding of the latent inhibition of dental fear and inform future interventions for dental phobia prevention.

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.

Violence Exposure and Mental Health Consequences Among Urban Youth.

Urban residents are disproportionately affected by violence exposure and mental health consequences as compared to non-urban residents. The present study examined the prevalence of violence exposure and associated mental health consequences among urban and non-urban youth. Urban participants were drawn from Detroit, Michigan, a city that has led the nation for most of the last decade as one of the most violent big cities in the U.S. Participants included 32 Detroit youth and 32 youth recruited from the surrounding non-urban areas, matched on age (M=10.4±2.8 years) and sex (49% male). Youth completed validated measures of violence exposure, anxiety, and depression symptoms. Urban youth reported more violence exposures than their non-urban counterparts, including hearing gunshots (69% vs. 19%, respectively), witnessing a shooting (24% vs. 6%), and witnessing an arrest (58% vs. 27%). Overall, greater violence exposure was associated with more anxiety symptoms, particularly among urban youth. Although violence exposure was not associated with depressive symptoms overall, urban youth reported significantly higher depressive symptoms than non-urban youth. Exposure to specific violence types, particularly hearing gunshots, was associated with higher anxiety and depressive symptoms among urban but not non-urban youth. Being beat up predicted depressive symptoms among non-urban but not urban youth. Household income and community distress did not predict mental health outcomes. Taken together, urban youth have more exposure to violence, particularly firearm violence, and associated mental health problems than their non-urban counterparts. Targeted community-wide initiatives to prevent violence and identify exposed youth are needed to improve mental health in at-risk communities.

Getting a Good Night's Sleep: Associations Between Sleep Duration and Parent-Reported Sleep Quality on Default Mode Network Connectivity in Youth.

PURPOSE: Sleep plays an important role in healthy neurocognitive development, and poor sleep is linked to cognitive and emotional dysfunction. Studies in adults suggest that shorter sleep duration and poor sleep quality may disrupt core neurocognitive networks, particularly the default mode network (DMN)-a network implicated in internal cognitive processing and rumination. Here, we examine the relationships between sleep and within- and between-network resting-state functional connectivity (rs-FC) of the DMN in youth. METHODS: This study included 3,798 youth (11.9 ± 0.6 years, 47.5% female) from the Adolescent Brain Cognitive Development cohort. Sleep duration and wake after sleep onset (WASO) were quantified using Fitbit watch recordings, and parent-reported sleep disturbances were measured using the Sleep Disturbance Scale for Children. We focused on rs-FC between the DMN and anticorrelated networks (i.e., dorsal attention network [DAN], frontoparietal network, salience network). RESULTS: Both shorter sleep duration and greater sleep disturbances were associated with weaker within-network DMN rs-FC. Shorter sleep duration was also associated with weaker anticorrelation (i.e., higher rs-FC) between the DMN and two anticorrelated networks: the DAN and frontoparietal network. Greater WASO was also associated with DMN-DAN rs-FC, and the effects of WASO on rs-FC were most pronounced among children who slept fewer hours/night. DISCUSSION: Together, these data suggest that different aspects of sleep are associated with distinct and interactive alterations in resting-state brain networks. Alterations in core neurocognitive networks may confer increased risk for emotional psychopathology and attention-related vulnerabilities. Our findings contribute to the growing number of studies demonstrating the importance of healthy sleep practices in youth.

Study protocol of an investigation of attention and prediction error as mechanisms of action for latent inhibition of dental fear in humans.

BACKGROUND: Evidence suggests that dental anxiety and phobia are frequently the result of direct associative fear conditioning but that pre-exposure to dental stimuli prior to conditioning results in latent inhibition of fear learning. The mechanisms underlying the pre-exposure effect in humans, however, are poorly understood. Moreover, pain sensitivity has been linked to dental fear conditioning in correlational investigations and theory suggests it may moderate the latent inhibition effect, but this hypothesis has not been directly tested. These gaps in our understanding are a barrier to the development of evidence-based dental phobia prevention efforts. METHODS: Healthy volunteers between the ages of 6 and 35 years will be enrolled across two sites. Participants will complete a conditioning task in a novel virtual reality environment, allowing for control over pre-exposure and the examination of behaviour. A dental startle (a brief, pressurized puff of air to a tooth) will serve as the unconditioned stimulus. Using a within-subjects experimental design, participants will experience a pre-exposed to-be conditioned stimulus, a non-pre-exposed to-be conditioned stimulus, and a neutral control stimulus. Two hypothesized mechanisms, changes in prediction errors and attention, are expected to mediate the association between stimulus condition and fear acquisition, recall, and retention. To ascertain the involvement of pain sensitivity, this construct will be measured through self-report and the cold pressor task. DISCUSSION: Dental phobia negatively affects the dental health and overall health of individuals. This study aims to determine the mechanisms through which pre-exposure retards conditioned dental fear acquisition, recall, and retention. A randomized control trial will be used to identify these mechanisms so that they can be precisely targeted and maximally engaged in preventative efforts.

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.

Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality Pavlovian fear extinction paradigm in healthy adults.

Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.

Impact of Childhood Trauma Exposure, Genetic Variation in Endocannabinoid Signaling, and Anxiety on Frontolimbic Pathways in Children.

Introduction: The endocannabinoid (eCB) system plays a key role in modulating brain development, including myelination processes. Recent studies link a common variant (C385A, rs324420) in the fatty acid amide hydrolase (FAAH) gene to higher circulating eCB levels, lower anxiety, and altered frontolimbic development. Frontolimbic pathways, which demonstrate a protracted maturational course across childhood and adolescence, are associated with anxiety, and are vulnerable to environmental stressors such as trauma exposure. Here, we examined the impact of trauma exposure, FAAH genotype, and anxiety on frontolimbic white matter microstructure in children. Materials and Methods: We leveraged baseline data from the Adolescent Brain Cognitive Development (ABCD) study (n=9969; mean±standard deviation age=9.92±0.62 years; 47.1% female). Saliva samples were used for genotyping, and caregivers reported on their child's anxiety symptoms and trauma exposure. Fractional anisotropy (FA), a nonspecific measure of white matter integrity, was estimated for frontolimbic tracts. Results: Thirty-six percent of youth experienced one or more potentially traumatic events according to DSM-5 Criterion A (64% controls), and 45% were FAAH A-allele carriers (55% noncarriers). Relative to controls, trauma-exposed youth demonstrated higher anxiety and higher FA of the left uncinate. The FAAH A-allele (vs. CC) was associated with lower FA in the left fornix and left parahippocampal cingulum, and there was an indirect effect of FAAH genotype on anxiety through FA of the left fornix. Moreover, genotype moderated the association between FA of the left cingulum and anxiety. Conclusions: Our findings demonstrate distinct effects of trauma exposure and the FAAH C385A variant on frontolimbic pathways and subsequent anxiety risk in preadolescent children. This line of work may provide important insights into neurodevelopmental mechanisms leading to anxiety risk, and potential targets for intervention.

Facing ambiguity: Social threat sensitivity mediates the association between peer victimization and adolescent anxiety.

Peer victimization is a developmentally salient stressor that elevates adolescents' risk for anxiety disorders. However, modifiable mechanisms that explain this link and can be targeted via therapeutic interventions remain poorly understood. Drawing from psychobiological models implicating aberrant threat sensitivity in the development and maintenance of psychopathology, the current study investigated sensitivity to peer-related social threats as a mechanism underlying the association between peer victimization and anxiety. A sample of 197 dyads of early adolescents (M age = 12.02; 46% female) and parents/guardians (M age = 41.46; 90% female) completed online surveys assessing peer victimization, sensitivity to potential (i.e., ambiguous) social threats, and anxiety. Controlling for potentially confounding demographic and psychosocial factors, both self- and parent-reported peer victimization were positively associated with adolescent anxiety symptoms. Additionally, there were significant indirect effects from self- and parent-reported peer victimization to anxiety via social threat sensitivity. Supplemental analyses indicated unique effects of covert, but not overt, peer victimization on social threat sensitivity and anxiety. The findings provide initial evidence that peer victimization experiences lower adolescents' threshold for interpreting threats in ambiguous social situations, which contributes to heightened anxiety. These results implicate social threat sensitivity as a potential therapeutic target for interrupting links from peer victimization to psychological distress.

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.

Meditation reduces brain activity in the default mode network in children with active cancer and survivors.

BACKGROUND: Mounting evidence demonstrates that meditation can lower pain and emotional distress in adults, and more recently, in children. Children may benefit from meditation given its accessibility across a variety of settings (e.g., surgical preparation). Recent neuroimaging studies in adults suggest that meditation techniques are neurobiologically distinct from other forms of emotion regulation, such as distraction, that rely on prefrontal control mechanisms, which are underdeveloped in youth. Rather, meditation techniques may not rely on "top-down" prefrontal control and may therefore be utilized across the lifespan. PROCEDURE: We examined neural activation in children with cancer, a potentially distressing diagnosis. During neuroimaging, children viewed distress-inducing video clips while using martial arts-based meditation (focused attention, mindful acceptance) or non-meditation (distraction) emotion regulation techniques. In a third condition (control), participants passively viewed the video clip. RESULTS: We found that meditation techniques were associated with lower activation in default mode network (DMN) regions, including the medial frontal cortex, precuneus, and posterior cingulate cortex, compared to the control condition. Additionally, we found evidence that meditation techniques may be more effective for modulating DMN activity than distraction. There were no differences in self-reported distress ratings between conditions. CONCLUSION: Together, these findings suggest that martial arts-based meditation modulates negative self-referential processing associated with the DMN, and may have implications for the management of pediatric pain and negative emotion.

Martial arts-based curriculum reduces stress, emotional, and behavioral problems in elementary schoolchildren during the COVID-19 pandemic: A pilot study.

This exploratory study examined the impact of Heroes Circle, a martial arts-based curriculum on stress, emotional, and behavioral problems in elementary school children. While students completed classroom surveys at baseline, post-curriculum surveys were collected from teachers, students, and parents/guardians two and five months after COVID-19-related school shutdowns. Satisfaction with the curriculum was high among those who received the intervention. Children reported increased mindfulness and decreased stress over the school year. Most children (77%) were still using the program's techniques and reporting benefits five months later, including lower internalizing symptoms and COVID-19-related fears. These patterns were not observed at the control school.

Editorial: Growing up in a High-Stigma Context: An Unseen Driver of Neurodevelopment, Health, and Pathology.

Growing research establishes that stigma can play a key role in driving population health inequalities, particularly among minority groups.1 Indeed, stigma related to gender, race/ethnicity, sexual orientation, mental illness, or disability has been linked to elevated risk of mental and physical health problems ranging from depression to cardiovascular disease. Recent neuroimaging studies point to changes in brain structure and function-particularly in stress-responsive brain networks-in mediating the link between stigma and risk of mental disorders. For example, recent neuroimaging research links racial discrimination to elevated neural response to threat in Black women in the United States.2 Importantly, stigma can occur at multiple levels, and most research to date has focused on stigma experienced at individual or interpersonal levels (eg, identity concealment, victimization). However, structural stigma (eg, laws and social norms) is increasingly recognized as a critical social determinant of health for people in marginalized groups. However, structural stigma is methodologically challenging to study at the level of neurobiology because relatively large, multisite studies are needed that span different sociopolitical contexts. An innovative study by Hatzenbuehler et al.3 in this issue of the Journal examines for the first time the impact of structural stigma on neurodevelopment in children. This study paves the way for future studies examining how contexts-particularly stigmatizing contexts-can act as unseen drivers of neurodevelopment, health, or pathology.

A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults.

Poor fear extinction learning and recall are linked to the development of fear-based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear-related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat-related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma-related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive-reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear-related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N = 59; C/C = 35, A-carrier = 24). We found lesser amygdala activation in A-allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A-carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.

A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System.

Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.