Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

KCNQ2/3 Gain-of-Function Variants and Cell Excitability: Differential Effects in CA1 versus L2/3 Pyramidal Neurons.

Gain-of-function (GOF) pathogenic variants in the potassium channels KCNQ2 and KCNQ3 lead to hyperexcitability disorders such as epilepsy and autism spectrum disorders. However, the underlying cellular mechanisms of how these variants impair forebrain function are unclear. Here, we show that the R201C variant in KCNQ2 has opposite effects on the excitability of two types of mouse pyramidal neurons of either sex, causing hyperexcitability in layer 2/3 (L2/3) pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. Similarly, the homologous R231C variant in KCNQ3 leads to hyperexcitability in L2/3 pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. However, the effects of KCNQ3 gain-of-function on excitability are specific to superficial CA1 pyramidal neurons. These findings reveal a new level of complexity in the function of KCNQ2 and KCNQ3 channels in the forebrain and provide a framework for understanding the effects of gain-of-function variants and potassium channels in the brain.SIGNIFICANCE STATEMENT KCNQ2/3 gain-of-function (GOF) variants lead to severe forms of neurodevelopmental disorders, but the mechanisms by which these channels affect neuronal activity are poorly understood. In this study, using a series of transgenic mice we demonstrate that the same KCNQ2/3 GOF variants can lead to either hyperexcitability or hypoexcitability in different types of pyramidal neurons [CA1 vs layer (L)2/3]. Additionally, we show that expression of the recurrent KCNQ2 GOF variant R201C in forebrain pyramidal neurons could lead to seizures and SUDEP. Our data suggest that the effects of KCNQ2/3 GOF variants depend on specific cell types and brain regions, possibly accounting for the diverse range of phenotypes observed in individuals with KCNQ2/3 GOF variants.

The DIAMOND-KID: Psychometric Properties of a Structured Diagnostic Interview for DSM-5 Anxiety, Mood, and Obsessive-Compulsive and Related Disorders in Children and Adolescents.

The objective of the present study was to examine the reliability and validity of a new semi-structured interview for pediatric psychiatric disorders, which is needed as existing interviews do not cover the full range of anxiety, mood, and obsessive-compulsive disorder (OCD)-related disorders. Three hundred eleven child patients (aged 10-17) were administered the Diagnostic Interview for Anxiety, Mood, and OCD and Related Neuropsychiatric Disorders-Child and Adolescent Version (DIAMOND-KID). Of these, 65 provided interrater reliability data and 59 provided test-retest reliability data. Participants also completed self-report measures that assessed symptoms of anxiety, mood, and OCD and related disorders. Although parents/guardians could participate in the interview at the clinician's discretion, most of the initial interviews and all of the reliability interviews were based on the child's self-report. Test-retest reliability ranged from very good to excellent. Interrater reliability was more variable, with estimates for generalized anxiety disorder and major depressive disorder in the questionable range; the other interrater reliability estimates ranged from good to very good. Convergent validity was established by significant between-group comparisons on applicable self-report measures for all diagnoses. The results of the present study indicate that the DIAMOND-KID is a promising semi-structured diagnostic interview for 5th edition of the Diagnostic and Statistical Manual of Mental Disorders in pediatric populations.

Social withdrawal in Parkinson's disease: A scoping review.

BACKGROUND: Parkinson's disease (PD) can interfere with individuals' social functioning and lead to social withdrawal. Social withdrawal may result in negative outcomes for persons with PD and their caregivers, such as decreased quality of life. It is necessary to understand the nature of social withdrawal in PD in order to develop strategies to address this issue and prevent negative outcomes. OBJECTIVE: The purpose of this scoping review was to synthesize existing evidence regarding social withdrawal in PD. METHODS: We searched PubMed, CINAHL, and PsycINFO for studies of social withdrawal in individuals living with PD. Findings were organized according to study characteristics, measurement and description of social withdrawal, prevalence, associated factors, and interventions. RESULTS: Fifty-eight studies were included. We found that persons with PD reduced social activities voluntarily and involuntarily, and social withdrawal was related to various factors including physical, cognitive, and psychiatric symptoms and perceived stigma. Community-based social activity programs appeared to improve social participation. Few studies employed longitudinal methods or tested interventions to reduce social withdrawal. CONCLUSIONS: Social withdrawal is associated with various negative outcomes in PD, though more research is needed to understand the true scope of this problem. Limitations in social withdrawal research include vague conceptualization and methodological limitations (i.e., instrumentation and study design), as well as a paucity of interventional studies. The findings of this review can be used to guide hypothesis generation and future study design, with the ultimate goal of mitigating social withdrawal and improving quality of life for people with PD.

KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3.

KCNQ2 and KCNQ3 channels are associated with multiple neurodevelopmental disorders and are also therapeutic targets for neurological and neuropsychiatric diseases. For more than two decades, it has been thought that most KCNQ channels in the brain are either KCNQ2/3 or KCNQ3/5 heteromers. Here, we investigated the potential heteromeric compositions of KCNQ2-containing channels. We applied split-intein protein trans-splicing to form KCNQ2/5 tandems and coexpressed these with and without KCNQ3. Unexpectedly, we found that KCNQ2/5 tandems form functional channels independent of KCNQ3 in heterologous cells. Using mass spectrometry, we went on to demonstrate that KCNQ2 associates with KCNQ5 in native channels in the brain, even in the absence of KCNQ3. Additionally, our functional heterologous expression data are consistent with the formation of KCNQ2/3/5 heteromers. Thus, the composition of KCNQ channels is more diverse than has been previously recognized, necessitating a re-examination of the genotype/phenotype relationship of KCNQ2 pathogenic variants.

Social Withdrawal in Huntington's Disease: A Scoping Review.

BACKGROUND: Huntington's disease (HD) commonly presents with impaired social functioning. Specifically, many patients exhibit social withdrawal, or decreased engagement in social activities. Despite the frequency of social withdrawal in HD, no review has been previously published on this subject. OBJECTIVE: The aim of this study was to conduct a scoping review of social withdrawal in HD. METHODS: Two searches were conducted to identify relevant literature. The articles were screened by title and abstract, followed by full text review for all remaining articles. Consistent with scoping review methodology, data extraction focused on identification of broad themes and knowledge gaps. RESULTS: Eight articles were identified that described social withdrawal in HD. Social withdrawal was exhibited by individuals with varying disease severity, and it occurred both within and outside of the home. Social withdrawal was associated with increased caregiver burden, behavioral issues, and psychiatric, cognitive, and physiological changes. Only one case study described an intervention that increased social participation in a previously withdrawn patient. CONCLUSION: Although social withdrawal is commonly encountered in clinical settings, this review highlights the need for prospective studies to systematically evaluate social withdrawal in HD. These studies should be designed to consider disease stage and associated HD features as well as caregiver burden and potential interventions. Additionally, objective measures of social withdrawal should be used when possible, as existing instruments measure perceptions of participation levels rather than actual withdrawal behavior. Such studies will lay the groundwork to improve social functioning and quality of life for people with HD.

Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders.

KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.

Cellular taxonomy and spatial organization of the murine ventral posterior hypothalamus.

The ventral posterior hypothalamus (VPH) is an anatomically complex brain region implicated in arousal, reproduction, energy balance, and memory processing. However, neuronal cell type diversity within the VPH is poorly understood, an impediment to deconstructing the roles of distinct VPH circuits in physiology and behavior. To address this question, we employed a droplet-based single-cell RNA sequencing (scRNA-seq) approach to systematically classify molecularly distinct cell populations in the mouse VPH. Analysis of >16,000 single cells revealed 20 neuronal and 18 non-neuronal cell populations, defined by suites of discriminatory markers. We validated differentially expressed genes in selected neuronal populations through fluorescence in situ hybridization (FISH). Focusing on the mammillary bodies (MB), we discovered transcriptionally-distinct clusters that exhibit neuroanatomical parcellation within MB subdivisions and topographic projections to the thalamus. This single-cell transcriptomic atlas of VPH cell types provides a resource for interrogating the circuit-level mechanisms underlying the diverse functions of VPH circuits.

Spousal Breadwinning Across 30 Years of Marriage and Husbands' Health: A Gendered Life Course Stress Approach.

OBJECTIVE: Wives increasingly outearn their husbands, and gender relations theory suggests this arrangement may undermine men's well-being. We explore how long-term histories of spousal breadwinning may be associated with older men's self-rated mental and physical health, and risk of nine health diagnoses. METHOD: Using 30 years of couple-level income data from the Health and Retirement Study ( n = 1,095 couples), we use latent class analyses to identify six classes that differ with respect to the timing and level of wife breadwinning. We link these classes to older husbands' later-life health. RESULTS: Classes that transitioned from husband breadwinning to wife breadwinning in early or later adulthood were associated with husbands' poorer overall physical health and risk of cardiometabolic and stress-related diseases. Patterns persist net of sociodemographics, depressive symptoms, health behaviors, and adolescent health. DISCUSSION: Violating cultural expectations, such as the masculinity ideal of male breadwinning, is associated with older men's poorer health.

Deletion of KCNQ2/3 potassium channels from PV+ interneurons leads to homeostatic potentiation of excitatory transmission.

KCNQ2/3 channels, ubiquitously expressed neuronal potassium channels, have emerged as indispensable regulators of brain network activity. Despite their critical role in brain homeostasis, the mechanisms by which KCNQ2/3 dysfunction lead to hypersychrony are not fully known. Here, we show that deletion of KCNQ2/3 channels changed PV+ interneurons', but not SST+ interneurons', firing properties. We also find that deletion of either KCNQ2/3 or KCNQ2 channels from PV+ interneurons led to elevated homeostatic potentiation of fast excitatory transmission in pyramidal neurons. Pvalb-Kcnq2 null-mice showed increased seizure susceptibility, suggesting that decreases in interneuron KCNQ2/3 activity remodels excitatory networks, providing a new function for these channels.

Beyond sex and gender difference in funding and reporting of health research.

BACKGROUND: Understanding sex and gender in health research can improve the quality of scholarship and enhance health outcomes. Funding agencies and academic journals are two key gatekeepers of knowledge production and dissemination, including whether and how sex/gender is incorporated into health research. Though attention has been paid to key issues and practices in accounting for sex/gender in health funding agencies and academic journals, to date, there has been no systematic analysis documenting whether and how agencies and journals require attention to sex/gender, what conceptual explanations and practical guidance are given for such inclusion, and whether existing practices reflect the reality that sex/gender cannot be separated from other axes of inequality. METHODS: Our research systematically examines official statements about sex/gender inclusion from 45 national-level funding agencies that fund health research across 36 countries (covering the regions of the EU and associated countries, North America, and Australia) and from ten top-ranking general health (the top five in "science" and the top five in "social science") and ten sex- and/or gender-related health journals. We explore the extent to which agencies and journals require inclusion of sex/gender considerations and to what extent existing strategies reflect state of the art understandings of sex/gender, including intersectional perspectives. RESULTS: The research highlights the following: (a) there is no consistency in whether sex/gender are mentioned in funding and publishing guidelines; (b) there is wide variation in how sex/gender are conceptualized and how researchers are asked to address the inclusion/exclusion of sex/gender in research; (c) funding agencies tend to prioritize male/female equality in research teams and funding outcomes over considerations of sex/gender in research content and knowledge production; and (d) with very few exceptions, agency and journal criteria fail to recognize the complexity of sex/gender, including the intersection of sex/gender with other key factors that shape health. CONCLUSIONS: The conceptualization and integration of sex/gender needs to better capture the interacting and complex factors that shape health-an imperative that can be informed by an intersectional approach. This can strengthen current efforts to advance scientific excellence in the production and reporting of research. We provide recommendations and supporting questions to strengthen consideration of sex/gender in policies and practices of health journals and funding agencies.

Utility of the Outcome Questionnaire-45.2 in outpatient anxiety clinics: A comparison between anxiety patients with and without co-occurring depression.

OBJECTIVE: The Outcome Questionnaire-45.2 (OQ-45) is a self-report measure of general psychological distress. Although intended to be transdiagnostic, the OQ-45 may be best conceptualized as a measure of depression; as such, its utility in assessing other symptoms such as anxiety is unclear. METHOD: We examined scores on the OQ-45 in a sample of 329 patients with anxiety and related disorders, half of whom had co-occurring depression. RESULTS: Eighty-two percent of patients scored above the OQ-45 cutoff, whereas 18% were incorrectly screened out. Patients with co-occurring depression were more likely to score above the OQ-45 cutoff than nondepressed patients. Depression severity predicted many of the OQ-45 scales, even after controlling for anxiety severity. By contrast, most of the anxiety-specific measures failed to predict the OQ-45 after controlling for depression severity. CONCLUSIONS: Findings suggest that the OQ-45 may not adequately capture anxiety symptoms and are discussed in terms of diagnostic screening and assessment.

Remission in CBT for adult anxiety disorders: A meta-analysis.

Currently there is no universally accepted definition of remission in anxiety disorders. This may be causing significantly different estimates of treatment efficacy across anxiety disorders. The aim of this paper was to determine not only the overall remission rate in cognitive-behavioral therapy (CBT) for anxiety disorders, but also to examine whether the different definitions of remission lead to significantly different remission rates. From the initial 228 abstracts reviewed by the authors, 100 articles were retained. The overall mean remission rate was 51.0%. Remission rates were highest when remission was defined as good end state functioning or no longer meeting criteria for the primary diagnosis. Studies of posttraumatic stress disorder had the highest remission rates, while those of obsessive-compulsive disorder and social anxiety disorder had the lowest remission rates. Rates of remission differed by certain demographic (e.g., older age) and clinical (e.g., medication use) characteristics. Although CBT is an empirically supported treatment for anxiety disorders, it is clear that there is room for improvement, as many patients do not achieve remission status.

Psychometric Properties of the Hoarding Rating Scale-Interview.

The present study tested the psychometric properties of an expanded version of the Hoarding Rating Scale (HRS-I), a semistructured interview for hoarding disorder (HD). Eighty-seven adults with HD and 44 healthy control (HC) participants were assessed using the HRS-I and completed a battery of self-report measures of HD severity, negative affect, and functional impairment. All interviews were audio recorded. From the HD participants, 21 were randomly selected for inter-rater reliability (IRR) analysis and 11 for test-retest reliability (TRR) analysis. The HRS-I showed excellent internal consistency (α = 0.87). IRR and TRR in the HD sample were good (intra-class coefficients = 0.81 and 0.85, respectively). HRS-I scores correlated strongly with scores on the self-report Saving Inventory-Revised (SI-R); partial correlations indicated that the HRS-I clutter, difficulty discarding, and acquiring items correlated significantly and at least moderately with corresponding SI-R subscales, when controlling for the other SI-R subscales. The HD group scored significantly higher on all items than did the HC group, with large effect sizes (d = 1.28 to 6.58). ROC analysis showed excellent sensitivity (1.00) and specificity (1.00) for distinguishing the HD and HC groups with a cutoff score of 11. Results and limitations are discussed in light of prior research.

Getting to the Heart of Masculinity Stressors: Masculinity Threats Induce Pronounced Vagal Withdrawal During a Speaking Task.

BACKGROUND: Previous work has found that traditional masculinity ideals and behaviors play a crucial role in higher rates of morbidity and mortality for men. Some studies also suggest that threatening men's masculinity can be stressful. Over time, this stress can weigh on men's cardiovascular and metabolic systems, which may contribute to men's higher rates of cardiometabolic health issues. PURPOSE: The purpose of this study is to explore how masculinity threats affect men's heart rate and heart rate variability reactivity (i.e., vagal withdrawal) to masculinity feedback on a social speaking task. METHODS: Two hundred and eighty-five undergraduate males were randomly assigned to one of six conditions during a laboratory-based speech task. They received one of two feedback types (masculinity or control) and one of three feedback levels (low, high, or dropping) in order to assess whether masculinity threats influence heart rate reactivity and vagal withdrawal patterns during the speech task. RESULTS: Men who receive low masculinity feedback during the speech task experienced more pronounced vagal withdrawal relative to those who received the control. CONCLUSION: Masculinity threats can induce vagal withdrawal that may accumulate over the life course to contribute to men's relatively worse cardiometabolic health.

The Development of a Technology-Based Hierarchy to Assess Chronic Low Back Pain and Pain-Related Anxiety From a Fear-Avoidance Model.

UNLABELLED: Previous studies have not examined the assessment of chronic low back pain (CLBP) and pain-related anxiety from a fear avoidance model through the use of motion-capture software and virtual human technologies. The aim of this study was to develop and assess the psychometric properties of an interactive, technologically based hierarchy that can be used to assess patients with pain and pain-related anxiety. We enrolled 30 licensed physical therapists and 30 participants with CLBP. Participants rated 21 video clips of a 3-D animated character (avatar) engaging in activities that are typically feared by patients with CLBP. The results of the study indicate that physical therapists found the virtual hierarchy clips acceptable and depicted realistic patient experiences. Most participants with CLBP reported at least 1 video clip as being sufficiently anxiety-provoking for use clinically. Therefore, this study suggests a hierarchy of fears can be created out of 21 virtual patient video clips paving the way for future clinical use in patients with CLBP. PERSPECTIVE: This report describes the development of a computer-based virtual patient system for the assessment of back pain-related fear and anxiety. Results show that people with back pain as well as physical therapists found the avatar to be realistic, and the depictions of behavior anxiety- and fear-provoking.

Independent review of social and population variation in mental health could improve diagnosis in DSM revisions.

At stake in the May 2013 publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), are billions of dollars in insurance payments and government resources, as well as the diagnoses and treatment of millions of patients. We argue that the most recent revision process has missed social determinants of mental health disorders and their diagnosis: environmental factors triggering biological responses that manifest themselves in behavior; differing cultural perceptions about what is normal and what is abnormal behavior; and institutional pressures related to such matters as insurance reimbursements, disability benefits, and pharmaceutical marketing. In addition, the experts charged with revising the DSM lack a systematic way to take population-level variations in diagnoses into account. To address these problems, we propose the creation of an independent research review body that would monitor variations in diagnostic patterns, inform future DSM revisions, identify needed changes in mental health policy and practice, and recommend new avenues of research. Drawing on the best available knowledge, the review body would make possible more precise and equitable psychiatric diagnoses and interventions.

Beyond a catalogue of differences: a theoretical frame and good practice guidelines for researching sex/gender in human health.

Extensive medical, public health, and social science research have focused on cataloguing male-female differences in human health. Unfortunately, much of this research unscientifically and unquestionably attributes these differences to biological causes--as exemplified in the Institute of Medicine's conclusion that "every cell has a sex." In this manuscript we theorize the entanglement of sex and gender in human health research and articulate good practice guidelines for assessing the role of biological processes--along with social and biosocial processes--in the production of non-reproductive health differences between and among men and women. There are two basic tenets underlying this project. The first is that sex itself is not a biological mechanism and the second is that "sex" and "gender" are entangled, and analyses should proceed by assuming that measures of sex are not pristine, but include effects of gender. Building from these tenets--and using cardiovascular disease as a consistent example--we articulate a process that scientists and researchers can use to seriously and systematically assess the role of biology and social environment in the production of health among men and women. We hope that this intervention will be one further step toward understanding the complexity and nuance of health outcomes, and that this increased knowledge can be used to improve human health.