The adhesion G-protein coupled receptors (aGPCRs) are a family of 33 G-protein receptors consisting of ADGRA1-3, ADGRB1-3, ADGRC1-3, ADGRD1-2, ADGRE1-5, ADGRF1-5, ADGRG1-7, ADGRL1-4, and ADGRV1. Recent studies have unveiled the role of aGPCRs in numerous brain functions, including in neurodevelopment, synapse formation and maintenance, establishment of the blood-brain barrier, and myelination. Further, dysfunction of aGPCRs have been associated with disorders such as gliomas, depression, and epilepsy, among many others. Herein, we review generalized properties of aGPCRs, their brain-specific expression, associations with neurological and psychiatric diseases, and potential as future pharmacological targets.
Gait assessments have been performed in several murine models of Parkinson's Disease (PD), but the M83+/- mouse model of PD has been relatively understudied in this context. Metrics of gait swing, stride length and frequency, and ataxia were collected in M83+/- mice with peripheral injections of α-syn preformed fibrils (PFF) and in aged M83+/- mice without fibrils using the DigiGait™ system. PFF-mice showed significantly decreased swing in all limbs (0.11 ± 0.02 vs. 0.13 ± 0.03, p = 0.007) compared to age-matched controls. Stride frequency was significantly increased in all limbs (3.9 ± 0.4 vs. 3.0 ± 0.5, p = 0.010) of PFF-treated mice. Swing was significantly greater in the hindlimbs of young M83+/-+PFF mice compared to aged M83+/- mice (0.11(0.5) vs. 0.08 (0.3), p = 0.015). Ataxia was significantly higher in young M83+/-+PFF mice compared to control for forelimbs (1.1 ± 1.0 vs. 0.6 ± 0.5, p = 0.027), hindlimbs (0.9 ± 1.0 vs. 0.3 ± 0.2, p = 0.016), and all limbs (1.0 ± 1.0 vs. 0.3 ± 0.5, p = 0.015). M83+/- mice demonstrate significant gait abnormalities consistent with features of PD. This study supports the utility of the M83+/- murine model for preclinical gait analyses in PD.
Anxiety disorders are among the most prevalent and debilitating mental illnesses worldwide. While environmental factors such as early-life stress contribute to their etiology, genetics also plays a crucial role, with a family history increasing susceptibility. Unlike Mendelian traits driven by single gene variants, anxiety disorders appear to follow polygenic inheritance in which multiple genetic variants collectively shape risk. Genome-wide association studies (GWAS) have identified numerous loci linked to anxiety, yet individual variants have small effect sizes and leave much of the heritability unexplained. A clue to resolving this conundrum may lie in the fact that most GWAS hits reside in non-coding regions with characteristics of gene-regulatory elements. This observation raises the possibility that altered expression of otherwise normal genes contributes to susceptibility. Gene-regulatory elements control when and where genes are expressed. Disruption of these elements may contribute to anxiety disorders by subtly altering neuronal signaling and stress-response pathways. Unraveling the role of gene regulation in anxiety disorders presents a promising avenue for improved diagnosis and targeted treatments. This review explores recent advances in the field and their potential for understanding the genetic architecture of anxiety disorders.
Background:Chronic pain (CP) and substance use disorders (SUDs) frequently co-occur. This brief review highlights environmental, neurobiological, and genetic sources of comorbidity of CP and SUDs, focused on alcohol, nicotine, cannabis, and opioids. Methods:A literature search on CP and SUDs was performed using Google Scholar and PubMed. Relevant literature was summarized in a narrative review. Results:Recent genomic studies reveal that SUDs and CP share a significant portion of genetic variance, and causal inference methods suggest that CP and SUDs have bidirectional effects on one another. CP and SUDs share multiple neurobiological pathways such as the reward and stress systems, with studies implicating important regions such as the insular and anterior cingulate cortex, the ventral tegmental area, and the nucleus accumbens. Environmental risk factors for CP and SUDs include socioeconomic background, education, and broader environmental factors such as neighborhood resources, air quality and greenspace. Social support is also a protective factor against CP and SUD diagnoses and crucial for their successful treatment and remission. Conclusions:Promising new areas of research underlying CP and SUD comorbidity include female-specific CP conditions and substance use patterns, the role of the immune system in both SUDs and CP, and the rise of large biobanks that will further precision medicine by allowing researchers to jointly model genetic, neurobiological, and socioenvironmental factors underlying their co-occurrence. In summary, CP and SUDs are debilitating conditions with far-ranging consequences for both individuals and communities; investigating their shared etiology will result in better treatments for both.
Childhood attention-deficit/hyperactivity disorder (ADHD) symptoms prospectively predict the development of borderline personality disorder (BPD) symptoms in adolescence and adulthood; adult women with BPD, in particular, often retrospectively report childhood ADHD symptoms. However, little is known about specific developmental pathways and mechanisms that contribute to this sequential comorbidity. Herein we outline a call for multi-method developmental research examining altered social processing as a potential mechanism underlying risk for BPD in girls with ADHD. We review relevant developmental psychopathology theory, describe recent empirical work, and outline steps for future work with the goal of promoting continued research focused on reducing the personal and societal burden associated with ADHD and BPD.
Emotion regulation (ER), or the ability to modulate the experience and expression of emotion, is critical to adaptive functioning and is a key feature of mood disorders. At the same time, normal aging is associated with changes in ER, though the interaction of aging with the presence of a mood disorder are unclear. Here, we review what is known about ER and its underlying neural mechanisms in late life mood disorders, specifically late life depression and bipolar disorder. We also review behavioral and neuromodulation therapies that seek to reduce negative affect and improve positive affect. We conclude with recommendations for future research into the nature and mechanisms of ER and interventions targeting ER in older adults with mood disorders.
Introduction:The post-acute phase of anorexia nervosa (AN) following discharge from higher-level care is a high-risk period in which relapse rates are high and many individuals lack access to effective treatment. Even after acute nutritional stabilization, AN is characterized by decreased biobehavioral sensitivity towards general rewards and elevated sensitivity towards weight-loss cues. These reward patterns may continue to maintain eating disorder and comorbid affective symptoms. To address these gaps in the treatment literature for post-acute AN, we propose a randomized controlled trial comparing Positive Affect Treatment for AN (PAT-AN), a neuroscience-informed therapy adapted to target these reward imbalances in AN, to more standard psychoeducational and behavioral treatment (PBT) for eating disorders following acute care. Method:Adult participants (N = 80) with broad AN, including atypical AN, discharged from intensive treatment (e.g., residential, partial hospitalization) for AN within the past 6 months will be randomly assigned to 24 weeks of remotely-delivered PAT-AN or PBT. We will compare the feasibility, acceptability, and efficacy of each treatment to augment post-acute outpatient care for AN. A multimodal neurocognitive and self-report battery will assess eating pathology, comorbid symptom, and putative reward mechanism changes over the course of treatment (i.e., baseline, mid-treatment, post-treatment, three-month follow-up) and on a week-to-week basis. Discussion:This trial will, for the first time, directly target observed reward disturbances in the post-acute period of AN. Thus, this investigation has the potential to simultaneously evaluate a novel, efficacious treatment for AN and to further evaluate the role of reward dysfunction in AN maintenance.
Attention deficit hyperactivity disorder (ADHD) is a disorder that is prevalent in children and adults, with significant impact on life outcomes. Common treatment strategies include a combination of pharmacological and psychosocial interventions which have recognized limits to their effectiveness. Consequently, there exists interest in additional non-pharmacological interventions. In the current minireview we aim to complement existing surveys by focusing on a complementary approach, namely rooted in metacognition or the training of awareness. We review programs that incorporate metacognitive training of awareness in skill-training, psychosocial interventions, and mindfulness, and discuss existing assessments of metacognitive ability in ADHD. Existing data suggest that metacognitive approaches have potential in supporting symptom management in ADHD, with gains in objective assessments in near and far transfer tasks in educational research and high satisfaction from parents. Further research is warranted in assessment of the relative contribution of metacognitive elements relative to other treatment components, objective assessments of outcomes in psychosocial interventions, and efficacy in adult interventions.
Perinatal mood and anxiety disorders (PMAD), which include depression and/or anxiety in the year before and/or after delivery, are common complications of pregnancy, affecting up to one in four perinatal individuals, with costs of over $15 billion per year in the US. In this paper, we provide an overview of the disparities in utilization and delivery outcomes for individuals with perinatal mood and anxiety disorders in the US. In addition, we discuss the current US screening and treatment guidelines as well as the high societal costs of illness of PMAD for both perinatal individuals and children. Finally, we outline opportunities for quality improvement of PMAD care in the US, including leveraging increased engagement with healthcare system during prenatal care, working toward a more cohesive national strategy to address PMAD, leaning into evidence-based policymaking through collaboration with a panel of experts, and generating state-level profiles focused on PMAD.
Digital health interventions are exploding in today's medical practice and have tremendous potential to support the treatment of substance use disorders (SUD). Developers and healthcare providers alike must be cognizant of the potential for digital interventions to exacerbate existing inequities in SUD treatment, particularly as they relate to Social Determinants of Health (SDoH). To explore this evolving area of study, this manuscript will review the existing concepts of the digital divide and digital inequities, and the role SDoH play as drivers of digital inequities. We will then explore how the data used and modeling strategies can create bias in digital health tools for SUD. Finally, we will discuss potential solutions and future directions to bridge these gaps including smartphone ownership, Wi-Fi access, digital literacy, and mitigation of historical, algorithmic, and measurement bias. Thoughtful design of digital interventions is quintessential to reduce the risk of bias, decrease the digital divide, and create equitable health outcomes for individuals with SUD.
The aging population of the world is increasing at an unprecedented rate which is expected to lead to a corresponding unparalleled increase in age related diseases. Of particular concern are the large number of older adults expected to develop Alzheimer's disease (AD), which will require extraordinary local, national and worldwide healthcare resources. In this context, innovative interventions are needed urgently to delay AD onset and thereby give our healthcare systems time to prepare and provide meaningful care to our aging populations. This focused review discusses the crucial role of frontal gamma oscillations as a therapeutic target to delay or ameliorate cognitive decline in AD. Frontal gamma oscillations, including from prefrontal cortical areas, serve as a biomarker for working memory and other cognitive functions, and their impairment is observed before clinical symptoms manifest. This review evaluates evidence from animal models and human subjects to highlight the correlation between gamma wave abnormalities and cognitive deterioration. Furthermore, the review summarizes 11 clinical studies using neuromodulation techniques designed to stimulate gamma oscillations in mild cognitive impairment (MCI) and AD patients, including transcranial electrical stimulation, transcranial magnetic stimulation, and rhythmic sensory stimulation. These interventions have shown promise in mitigating early-stage cognitive decline, as evidenced by improved performance on memory tests, increased gamma oscillatory responses, and some have even shown reduced brain atrophy. These early studies suggest that treatments that strengthen frontal gamma oscillatory responses through neuromodulation are a promising approach to delay cognitive decline, that may serve as an adjunct to other therapies or as a standalone treatment in some populations.
Background: Despite the growing focus on transgender individuals, there is still a paucity of coherent research on the association between self-reported gender identity and the diagnosis of gender dysphoria (GD). This study explores the gap between the self-reported gender identity and the diagnosed condition. Methods: Data from high school and college in Hunan, China, were collected from September 2019 to December 2019. Students who self-reported as gender minority (including transgender and other gender minorities) were interviewed by psychiatrists to confirm their GD diagnosis. Rates of the self-identified gender minority and GD clinical diagnosis were the present study’s primary outcomes. Depression, social avoidance and distress, social support, and suicidal ideation were measured with the Beck Depression Inventory (BDI), Social Avoidance and Distress Scale (SAD), Social Support Rating Scale (SSRS), and Beck Scale for Suicide Ideation (BSI), respectively. Results: Despite the relatively high rate of self-reported gender minorities in the sample (6.5%), none of them matched the clinical diagnosis of GD, as confirmed by psychiatrists. Nevertheless, even with the absence of GD diagnosis
Background:Despite the effectiveness and growing availability of treatment for opioid use disorder (OUD) with buprenorphine, many people with OUD do not access treatment services. This article describes the rationale, methodological design, evolution, and progress of an ongoing clinical trial of treatment linkage strategies for people with untreated OUD.Methods:The study, titled Opioid Use Disorder Treatment Linkage at Strategic Touchpoints using Buprenorphine (OUTLAST-B), uses "strategic touchpoints", initially sexual health clinics and subsequently broadened to other service venues and participant social networks, for recruitment and screening. Adults with untreated OUD (target N = 360) are randomized to one of the three arms: Usual Care (UC, enhanced with overdose education and naloxone distribution), Patient Navigation (PN), or Patient Navigation with an immediate short-term bridge prescription for buprenorphine (PN + BUP). In the PN and PN + BUP arms, the Patient Navigator works with participants for 2 months to facilitate treatment entry and early retention, resolve barriers (e.g., ID cards, transportation), and provide motivational support.Results:The primary outcome is OUD treatment entry within 30 days of enrollment. Participants are assessed at baseline and followed at 3- and 6-months post-enrollment on measures of healthcare utilization, substance use, and general functioning. Challenges and recruitment adaptations pursuant to the COVID-19 pandemic are discussed.Conclusions:This study could provide insights on how to reach people with untreated OUD and link them to care through non-traditional routes.Trial Registration:The study is registered at ClinicalTrials.gov (NCT04991974).
It is important to consider reciprocal associations between maternal and offspring mental health problems during early childhood. Existing interventions often focus narrowly on either adult or child mental health, missing the opportunity for holistic care. We describe the rationale and development of a pilot randomized clinical trial that explores their integration, combining an evidence-based parenting intervention with depression treatment to improve both maternal and child outcomes. Our approach is part of a growing field of two-generation interventions that offer a promising approach to enhance mental health support for caregivers and their young children.
Endogenous neuropeptide Oxytocin (OXT) plays a crucial role in modulating pro-social behavior and the neural response to social/emotional stimuli. Intranasal administration is the most common method of delivering OXT. Intranasal OXT has been implemented in clinical studies of various psychiatric disorders with mixed results, mainly related to lack of solid pharmacodynamics and pharmacokinetics model. Due to intranasal OXT's mechanism of reducing the activation of neural areas implicated in emotional responding and emotion regulation, a psychopathology with this target mechanism could be potentially excellent candidate for future clinical trial. In this regard, irritability in youth may be a very promising target for clinical studies of intranasal OXT. Here we provide a mini-review of fifteen randomized controlled trials in pediatric patients with diagnoses of autism spectrum disorder (ASD), Prader-Willi syndrome (PWS), or Phelan-McDermid syndrome (PMS). Most studies had small sample sizes and varying dosages, with changes in irritability, mainly as adverse events (AEs). Neuroimaging results showed modulation of the reward processing system and the neural areas implicated in social-emotional information processing by intranasal OXT administration. Further research is needed to determine the most effective dose and duration of OXT treatment, carefully select target psychopathologies, verify target engagement, and measure adverse event profiles.
