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.

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.

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.

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.

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.

A Virtual Reality Meditative Intervention Modulates Pain and the Pain Neuromatrix in Patients with Opioid Use Disorder.

OBJECTIVE: Standard of care for opioid use disorder (OUD) includes medication and counseling. However, there is an unmet need for complementary approaches to treat OUD patients coping with pain; furthermore, few studies have probed neurobiological features of pain or its management during OUD treatment. This preliminary study examines neurobiological and behavioral effects of a virtual reality-based meditative intervention in patients undergoing methadone maintenance treatment (MMT). DESIGN: Prospective, non-blinded, single-arm, 12-week intervention with standardized assessments. SETTING: Academic research laboratory affiliated with an on-site MMT clinic. METHODS: Fifteen (11 female) MMT patients completed a virtual reality, therapist-guided meditative intervention that included breathing and relaxation exercisessessions were scheduled twice weekly. Assessments included functional magnetic resonance imaging (fMRI) of pain neuromatrix activation and connectivity (pre- and post-intervention), saliva cortisol and C-reactive protein (CRP) at baseline and weeks 4, 8 and 12; and self-reported pain and affective symptoms before and after each intervention session. RESULTS: After each intervention session (relative to pre-session), ratings of pain, opioid craving, anxiety and depression (but not anger) decreased. Saliva cortisol (but not CRP) levels decreased from pre- to post-session. From pre- to post-intervention fMRI assessments, pain task-related left postcentral gyrus (PCG) activation decreased. At baseline, PCG showed positive connectivity with other regions of the pain neuromatrix, but this pattern changed post-intervention. CONCLUSIONS: These preliminary findings demonstrate feasibility, therapeutic promise, and brain basis of a meditative intervention for OUD patients undergoing MMT.

Community and household-level socioeconomic disadvantage and functional organization of the salience and emotion network in children and adolescents.

Socioeconomic disadvantage (SED) during childhood has been linked to disparities in physical and mental health. A growing body of research has focused on identifying neurodevelopmental consequences of SED, commonly measured using within-household factors (e.g., household income), to better understand the processes underlying SED-related disparities. These studies suggest that childhood SED has a widespread impact on brain development, altering development of multiple brain regions simultaneously. These findings also raise the possibility that childhood SED impacts development of key brain systems, such as the salience and emotion network (SEN), which is positioned at the intersection of brain systems involved in cognitive and emotion-related functioning and is thought to mediate information flow within and between these networks. The present study tests for associations between household- and community-level SED, as well as their interaction, and measures of SEN-based functional neural organization in 57 children and adolescents (ages 6-17). We applied graph theoretical analyses to resting-state functional magnetic resonance imaging (fMRI) data to examine SEN-based functional network topology. Results showed that youth residing in more distressed communities demonstrate lower hub-like properties (i.e., less efficient global information transfer and fewer connections) of two core SEN nodes - the anterior cingulate cortex and the left supramarginal gyrus. Similarly, lower household income was associated with lower efficiency of the anterior cingulate, but had no effect on the supramarginal gyrus. There was, however, an interaction between income and community SED in the rostral prefrontal cortex, such that higher income was associated with higher clustering coefficient and lower betweenness centrality, suggesting greater local processing and lower influence of this region on information flow across the network. These effects were significant only among youth living in low (but not high) SED communities, suggesting that within-household SED factors may not protect against the detrimental effects of a disadvantaged community context. Similarly, the age-related increase in average path length of the left rostral prefrontal cortex was only significant among youth living in low (but not high) SED communities. Given that maturation of the SEN is considered to be a critical functional backbone supporting the development of more flexible cognitive and emotional processes into adulthood, we tested for links between SEN graph metrics and measures of cognitive and emotion-related functioning. We found that higher community SED and lower income were both associated with lower IQ. Lower IQ, in turn, was associated with global efficiency of the left supramarginal gyrus. Observed effects of SED on SEN-based functional neural organization may help to explain the strong and pervasive link between childhood SED and disparities in cognitive and emotional outcomes.

Emotion-related brain organization and behavioral responses to socioemotional stimuli in pediatric cancer survivors with posttraumatic stress symptoms.

BACKGROUND: Pediatric cancer is a life-changing, stressful experience for children and their families. Although most children adjust well, psychologically, a significant subset report posttraumatic stress symptoms (PTSS), with nearly 75% reexperiencing traumatic parts of cancer and/or its treatment. However, little research has examined the effects of pediatric cancer and related PTSS on emotional processing, and on functional properties of key emotional centers in the brain (e.g., amygdala). PROCEDURE: We examined cancer-related PTSS, behavioral responses during an emotion-processing task, and resting-state functional connectivity of the amygdala in 17 pediatric cancer survivors (ages 6-11) and 17 age- and sex-matched controls. RESULTS: Cancer survivors, relative to controls, were more likely to rate ambiguous (i.e., neutral) faces as negative (i.e., "negativity bias"). Higher reexperiencing PTSS was associated with faster responses to neutral faces. Although there were no group differences in amygdala centrality, within survivors, both higher reexperiencing PTSS and faster reaction times were associated with increased centrality of the amygdala-a functional property associated with hubs of information processing in the brain. In an exploratory mediation analysis, we found that amygdala centrality mediated the link between reaction time and PTSS, suggesting that changes in the brain may be a proximal marker of the expression of emotion-related symptomology. CONCLUSIONS: Negativity bias in cancer survivors may reflect their stressful experiences with cancer and/or its treatment. This negativity bias may represent a susceptibility to changes in emotion-related brain functioning, which may, in turn, lead to PTSS.

Socioeconomic disadvantage and altered corticostriatal circuitry in urban youth.

Socioeconomic disadvantage (SED) experienced in early life is linked to a range of risk behaviors and diseases. Neuroimaging research indicates that this association is mediated by functional changes in corticostriatal reward systems that modulate goal-directed behavior, reward evaluation, and affective processing. Existing research has focused largely on adults and within-household measures as an index of SED, despite evidence that broader community-level SED (e.g., neighborhood poverty levels) has significant and sometimes distinct effects on development and health outcomes. Here, we test effects of both household- and community-level SED on resting-state functional connectivity (rsFC) of the ventral striatum (VS) in 100 racially and economically diverse children and adolescents (ages 6-17). We observed unique effects of household income and community SED on VS circuitry such that higher community SED was associated with reduced rsFC between the VS and an anterior region of the medial prefrontal cortex (mPFC), whereas lower household income was associated with increased rsFC between the VS and the cerebellum, inferior temporal lobe, and lateral prefrontal cortex. Lower VS-mPFC rsFC was also associated with higher self-reported anxiety symptomology, and rsFC mediated the link between community SED and anxiety. These results indicate unique effects of community-level SED on corticostriatal reward circuitry that can be detected in early life, which carries implications for future interventions and targeted therapies. In addition, our findings raise intriguing questions about the distinct pathways through which specific sources of SED can affect brain and emotional development.

Poor between-session recall of extinction learning and hippocampal activation and connectivity in children.

BACKGROUND: In healthy adults, successful between-session recall of extinction learning depends on the hippocampus and ventromedial prefrontal cortex (vmPFC), especially when tested in the extinction context. Poor extinction recall and dysfunction within hippocampal-vmPFC circuitry are associated with fear-based disorders (e.g., anxiety, posttraumatic stress disorder). Despite the early age of onset of virtually all fear-based disorders and the protracted development of the hippocampus and vmPFC across the first two decades of life, little is known about extinction recall and the underlying neural correlates in children. METHODS: Here, we tested extinction recall in 43 pre-adolescent children (ages 6-11 yrs) by coupling functional magnetic resonance imaging and virtual reality with a novel interpersonal threat-related two-day (ABBA) fear-extinction paradigm. Conditioned fear responding was assessed at behavioral, subjective, physiological, and neural levels. RESULTS: Although children demonstrated intact within-session extinction, there was poor between-session recall of extinction learning (retention index: 13.56%), evidenced by elevations in skin conductance, avoidant behavioral responses, and subjective ratings. Elevations in conditioning fear responding were accompanied by activation in the hippocampus and insula, and increased connectivity of the hippocampus with the insula and dorsal anterior cingulate cortex - regions implicated in the return of fear in adult studies. Children who kept more distance from the extinguished cue during extinction subsequently demonstrated heightened hippocampal-cingulate coupling during recall, suggesting that avoidant behavior interferes with extinction retention. CONCLUSIONS: Poor extinction recall in children may have implications for developmental vulnerability to fear-based disorders, and for the application of therapeutic strategies that rely on principles of extinction (e.g., exposure therapy) to pediatric samples.

Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes.

Today, children are surviving pediatric cancer at unprecedented rates, making it one of modern medicine's true success stories. However, we are increasingly becoming aware of several deleterious effects of cancer and the subsequent "cure" that extend beyond physical sequelae. Indeed, survivors of childhood cancer commonly report cognitive, emotional, and psychological difficulties, including attentional difficulties, anxiety, and posttraumatic stress symptoms (PTSS). Cognitive late- and long-term effects have been largely attributed to neurotoxic effects of cancer treatments (e.g., chemotherapy, cranial irradiation, surgery) on brain development. The role of childhood adversity in pediatric cancer - namely, the presence of a life-threatening disease and endurance of invasive medical procedures - has been largely ignored in the existing neuroscientific literature, despite compelling research by our group and others showing that exposure to more commonly studied adverse childhood experiences (i.e., domestic and community violence, physical, sexual, and emotional abuse) strongly imprints on neural development. While these adverse childhood experiences are different in many ways from the experience of childhood cancer (e.g., context, nature, source), they do share a common element of exposure to threat (i.e., threat to life or physical integrity). Therefore, we argue that the double hit of early threat and cancer treatments likely alters neural development, and ultimately, cognitive, behavioral, and emotional outcomes. In this paper, we (1) review the existing neuroimaging research on child, adolescent, and adult survivors of childhood cancer, (2) summarize gaps in our current understanding, (3) propose a novel neurobiological framework that characterizes childhood cancer as a type of childhood adversity, particularly a form of early threat, focusing on development of the hippocampus and the salience and emotion network (SEN), and (4) outline future directions for research.

What's parenting got to do with it: emotional autonomy and brain and behavioral responses to emotional conflict in children and adolescents.

Healthy parenting may be protective against the development of emotional psychopathology, particularly for children reared in stressful environments. Little is known, however, about the brain and behavioral mechanisms underlying this association, particularly during childhood and adolescence, when emotional disorders frequently emerge. Here, we demonstrate that psychological control, a parenting strategy known to limit socioemotional development in children, is associated with altered brain and behavioral responses to emotional conflict in 27 at-risk (urban, lower income) youth, ages 9-16. In particular, youth reporting higher parental psychological control demonstrated lower activity in the left anterior insula, a brain area involved in emotion conflict processing, and submitted faster but less accurate behavioral responses-possibly reflecting an avoidant pattern. Effects were not replicated for parental care, and did not generalize to an analogous nonemotional conflict task. We also find evidence that behavioral responses to emotional conflict bridge the previously reported link between parental overcontrol and anxiety in children. Effects of psychological control may reflect a parenting style that limits opportunities to practice self-regulation when faced with emotionally charged situations. Results support the notion that parenting strategies that facilitate appropriate amounts of socioemotional competence and autonomy in children may be protective against social and emotional difficulties.

Dynamic functional connectivity of neurocognitive networks in children.

The human brain is highly dynamic, supporting a remarkable range of cognitive abilities that emerge over the course of development. While flexible and dynamic coordination between neural systems is firmly established for children, our understanding of brain functional organization in early life has been built largely on the implicit assumption that functional connectivity (FC) is static. Understanding the nature of dynamic neural interactions during development is a critical issue for cognitive neuroscience, with implications for neurodevelopmental pathologies that involve anomalies in brain connectivity. In this work, FC dynamics of neurocognitive networks in a sample of 146 youth from varied sociodemographic backgrounds were delineated. Independent component analysis, sliding time window correlation, and k-means clustering were applied to resting-state fMRI data. Results revealed six dynamic FC states that re-occur over time and that complement, but significantly extend, measures of static FC. Moreover, the occurrence and amount of time spent in specific FC states are related to the content of self-generated thought during the scan. Additionally, some connections are more variable over time than are others, including those between inferior parietal lobe and precuneus. These regions contribute to multiple networks and likely play a role in adaptive processes in childhood. Age-related increases in temporal variability of FC among neurocognitive networks were also found. Taken together, these findings lay the groundwork for understanding how variation in the developing chronnectome is related to risk for neurodevelopmental disorders. Understanding how brain systems reconfigure with development should provide insight into the ontogeny of complex, flexible cognitive processes. Hum Brain Mapp 38:97-108, 2017. © 2016 Wiley Periodicals, Inc.

Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood.

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

Particulate Matter Exposure and Default Mode Network Equilibrium During Early Adolescence.

Background: Air pollution exposure has been associated with adverse cognitive and mental health outcomes in children, adolescents, and adults, although youth may be particularly susceptible given ongoing brain development. However, the neurodevelopmental mechanisms underlying the associations among air pollution, cognition, and mental health remain unclear. We examined the impact of particulate matter (PM2.5) on resting-state functional connectivity (rsFC) of the default mode network (DMN) and three key attention networks: dorsal attention, ventral attention, and cingulo-opercular. Methods: Longitudinal changes in rsFC within/between networks were assessed from baseline (9-10 years) to the 2-year follow-up (11-12 years) in 10,072 youth (M ± SD = 9.93 + 0.63 years; 49% female) from the Adolescent Brain Cognitive Development (ABCD®) study. Annual ambient PM2.5 concentrations from the 2016 calendar year were estimated using hybrid ensemble spatiotemporal models. RsFC was estimated using functional neuroimaging. Linear mixed models were used to test associations between PM2.5 and change in rsFC over time while adjusting for relevant covariates (e.g., age, sex, race/ethnicity, parental education, and family income) and other air pollutants (O3, NO2). Results: A PM2.5 × time interaction was significant for within-network rsFC of the DMN such that higher PM2.5 concentrations were associated with a smaller increase in rsFC over time. Further, significant PM2.5 × time interactions were observed for between-network rsFC of the DMN and all three attention networks, with varied directionality. Conclusion: PM2.5 exposure was associated with alterations in the development and equilibrium of the DMN-a network implicated in self-referential processing-and anticorrelated attention networks, which may impact trajectories of cognitive and mental health symptoms across adolescence.

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.

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.

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.