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.

Study protocol for a pilot clinical trial to understand neural mechanisms of response to a psychological treatment for pain and anxiety in pediatric functional abdominal pain disorders (FAPD).

BACKGROUND: Functional abdominal pain disorders (FAPD) are the most common chronic pain conditions of childhood and are made worse by co-occurring anxiety. Our research team found that the Aim to Decrease Pain and Anxiety Treatment (ADAPT), a six-session coping skills program using cognitive behavioral therapy strategies, was effective in improving pain-related symptoms and anxiety symptoms compared to standard care. In follow-up, this current randomized clinical trial (RCT) aims to test potential neural mechanisms underlying the effect of ADAPT. Specifically, this two-arm RCT will explore changes in amygdalar functional connectivity (primary outcome) following the ADAPT protocol during the water loading symptom provocation task (WL-SPT). Secondary (e.g., changes in regional cerebral blood flow via pulsed arterial spin labeling MRI) and exploratory (e.g., the association between the changes in functional connectivity and clinical symptoms) outcomes will also be investigated. METHODS: We will include patients ages 11 to 16 years presenting to outpatient pediatric gastroenterology care at a midwestern children's hospital with a diagnosis of FAPD plus evidence of clinical anxiety based on a validated screening tool (the Generalized Anxiety Disorder-7 [GAD-7] measure). Eligible participants will undergo baseline neuroimaging involving the WL-SPT, and assessment of self-reported pain, anxiety, and additional symptoms, prior to being randomized to a six-week remotely delivered ADAPT program plus standard medical care or standard medical care alone (waitlist). Thereafter, subjects will complete a post assessment neuroimaging visit similar in nature to their first visit. CONCLUSIONS: This small scale RCT aims to increase understanding of potential neural mechanisms of response to ADAPT. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT03518216.

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.

A multi-site pilot randomized clinical trial of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) program: study design and COVID-19 adaptations.

BACKGROUND: Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. METHODS: This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12-22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. CONCLUSIONS: Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. CLINICAL TRIALS: gov registration: NCT04335643.

Child-Focused Cognitive Behavioral Therapy for Pediatric Abdominal Pain Disorders Reduces Caregiver Anxiety in Randomized Clinical Trial.

Pediatric functional abdominal pain disorders (FAPD) are associated with elevated anxiety in youth and their caregivers, both contributing to an adverse impact on functioning in youth with FAPD. While a CBT approach (ie, Aim to Decrease Anxiety and Pain Treatment [ADAPT]) is known to improve health outcomes for youth, it is unknown if child-focused treatment improves caregiver anxiety. This secondary analysis of a larger randomized clinical trial examined if child-focused CBT (ADAPT) for pain and anxiety also impacts caregiver anxiety and explored the relation between caregiver anxiety and child symptoms (ie, pain, disability, anxiety) after treatment. A total of 79 caregiver-child dyads were randomized to ADAPT plus treatment as usual (TAU) or TAU only. Caregiver anxiety and child outcomes (pain, disability, anxiety) were assessed at baseline and approximately 8 weeks later. Caregivers of children who completed ADAPT+TAU demonstrated lower anxiety compared to those who only received TAU. Moreover, regardless of treatment assignment, caregivers with greater anxiety had children who reported more pain and anxiety, but not functional disability at post-assessment. Results suggest a brief, child-focused intervention targeting pain and anxiety may also improve caregiver anxiety. As such, suggestions to improve future treatments are offered. PERSPECTIVE: Caregiver anxiety symptoms diminished after their child with functional abdominal pain completed a course of child-focused CBT targeting pain and anxiety. Further, caregiver anxiety was related to child-reported symptoms (pain and anxiety) after treatment. Therefore, improved caregiver mental health via a child-focused CBT may also improve pediatric outcomes.

Engagement during a Mixed In-Person and Remotely Delivered Psychological Intervention for Youth with Functional Abdominal Pain Disorders and Anxiety.

Functional abdominal pain disorders (FAPD) are common disabling pain conditions frequently associated with co-occurring mental health problems such as anxiety. Psychological therapies such as cognitive behavioral therapy (CBT) have been shown to be effective. Therefore, it is important to understand participant engagement (i.e., use of intervention tools) to such approaches, and if engagement impacts treatment response. The Aim to Decrease Anxiety and Pain Treatment (ADAPT) is an effective psychological treatment approach using a blend of in-person sessions and interventionist phone support with self-paced web modules to manage pain and anxiety. The current study used a mixed-methods approach to investigate micro-level and macro-level participant engagement during the ADAPT program. In-person/phone session attendance was high (>95%) although scheduling adjustments were common (25.5%). Varied levels of engagement with web tools were observed. Thematic analysis also revealed variability in patterns of use. Additionally, while participants indicated they generally understood how to use certain skills (e.g., problem solving, detective thinking), and these skills were effective in managing symptoms during treatment, these activities were generally underutilized. Further, participant engagement did not predict response to the ADAPT intervention. These findings are important as the demand for accessible psychotherapeutic tools to manage pain and anxiety is likely to remain high.

The Utility of an Anxiety Screening Measure in Youth With Functional Abdominal Pain Disorders and Clinical Characteristics Associated With Presence of Anxiety.

OBJECTIVES: Anxiety is common in youth with functional abdominal pain disorders (FAPD) and is related to increased pain-related impairment. However, it is unknown if self-reported anxiety on a clinical screener represents a true anxiety disorder diagnosis in youth with FAPD. Further, little is known about clinical characteristics in youth with FAPD and comorbid anxiety (ANX). Therefore, we evaluated whether the clinical cutoff on the Screen for Anxiety and Related Disorders (SCARED) corresponded with the presence of an anxiety disorder. We predicted a more clinically complex profile (eg, increased pain-related impairment, psychological problems, and family risk factors) in youth with FAPD+ANX compared with youth with FAPD alone. MATERIALS AND METHODS: Participants completed measures of anxiety, functional disability, pain intensity, pain catastrophizing, and mood, and underwent a semistructured diagnostic interview to assess for psychological disorders. Caregivers completed family characteristics and caregiver distress measures. Analyses of group differences were conducted using χ2 and multivariate tests. RESULTS: The SCARED appears to be a good proxy for an anxiety disorder in youth with FAPD, particularly for generalized anxiety disorder and social anxiety disorder. Youth with FAPD+ANX reported higher rates of pain-related disability and depressive symptoms compared with those with FAPD alone, but other clinical characteristics and family risk factors were comparable across groups. DISCUSSION: Findings support the use of the SCARED as a proxy for an anxiety disorder diagnosis in youth with FAPD and suggest youth with FAPD+ANX may have a more complex clinical profile categorized by greater mental health and health-related impairment as compared with youth with FAPD alone.

Addressing Pediatric Mental Health Using Telehealth During Coronavirus Disease-2019 and Beyond: A Narrative Review.

The pediatrician serves as a frontline provider addressing patients' medical and mental health needs, yet coronavirus disease-2019 (COVID-19) is reshaping the way physicians deliver care. Pediatricians are increasingly faced with the challenge of delivering care, including mental health care, remotely. Given the rapidly evolving literature, we performed a narrative review of the use of telehealth for mental health care for pediatric populations during the COVID-19 pandemic. Areas of focus included 1) pediatric primary care settings, 2) special pediatric populations (eg, eating disorders, autism), 3) access and engagement in telehealth care, and 4) training opportunities available for mental health providers. Themes that emerged across studies included the importance of meeting patients' needs (eg, access to technological resources) to optimize success in using telehealth tools and challenges around provider access to support tools for use during telehealth. Thus, we provided a summary of evidence-based tools (including COVID-19 specific resources) for improving the remote delivery of mental health care by pediatricians. We also reviewed future directions including trials currently underway to enhance understanding of future telehealth applications for pediatric mental health care.