A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS

CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29-year-old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled-coil-helix-coiled-coil-helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild-type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N-terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide-bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway

Applying the Bifactor S-1 Model to Ratings of ADHD/ODD Symptoms: A Commentary on Burns et al. (2019) and a Re-Analysis

To examine the construct validity of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), the bifactor S-1 approach has been applied as an alternative to the fully symmetrical bifactor models in order to eliminate anomalous results and to allow for an unambiguous interpretation of g- and s-factors. We compared and contrasted our results with those of Burns et al. (2019) and extended their analyses by taking into account a two- vs. a three-factor structure of ADHD. Data from our previous research were reanalyzed and reinterpreted in accordance with the bifactor S-1 approach, constructing different models with hyperactivity (HY), impulsivity (IM) or hyperactivity/impulsivity (HI) as the general factor. No anomalous results were observed. All factor loadings were significant. Our results were comparable to those reported by Burns et al. (2019), although items from the specific subscales inattention (IN) and ODD accounted for more variance in our sample. Model fit for our HI model was comparable to that in Burns et al. (2019). In our sample, model fit was best when solely HY or IM was chosen as a general reference factor. However, in these cases, the remaining specific factor IM or HY was weakly defined. Overall, we were able to replicate the results found by Burns et al. 2019), although our factor loadings on the g-factor were slightly lower and our specificity regarding IN and ODD was slightly higher. Our results support a two-factor structure of ADHD/ODD in a clinical population

Dimensions of Autistic Traits Rated by Parents of Children and Adolescents with Suspected Autism Spectrum Disorders

To examine the factor structure of autism spectrum disorder (ASD) and the psychometric properties of the German Symptom Checklist for Autism Spectrum Disorders (SCL-ASD). Data were collected from 312 clinical referrals with suspected ASD (2-18 years). Confirmatory factor analyses and analyses of reliability, convergent and divergent validity were performed. A bifactor model with one general ASD factor and two specific factors (interaction-communication; restricted, repetitive behaviors) provided an adequate data fit. Internal consistencies of the SCL-ASD subscales and the total scale were > .70. Correlations with measures of ASD traits were higher than correlations with measures of externalizing and internalizing symptoms. The results support a factor structure consistent with DSM-5/ICD-11 criteria. The SCL-ASD has sound psychometric properties

Aversive state processing in the posterior insular cortex

Triggering behavioral adaptation upon the detection of adversity is crucial for survival. The insular cortex has been suggested to process emotions and homeostatic signals, but how the insular cortex detects internal states and mediates behavioral adaptation is poorly understood. By combining data from fiber photometry, optogenetics, awake two-photon calcium imaging and comprehensive whole-brain viral tracings, we here uncover a role for the posterior insula in processing aversive sensory stimuli and emotional and bodily states, as well as in exerting prominent top-down modulation of ongoing behaviors in mice. By employing projection-specific optogenetics, we describe an insula-to-central amygdala pathway to mediate anxiety-related behaviors, while an independent nucleus accumbens-projecting pathway regulates feeding upon changes in bodily state. Together, our data support a model in which the posterior insular cortex can shift behavioral strategies upon the detection of aversive internal states, providing a new entry point to understand how alterations in insula circuitry may contribute to neuropsychiatric conditions

Validation of a new emotion regulation self-report questionnaire for children

Objective: To examine and validate the self-report Questionnaire on the Regulation of Unpleasant Moods in Children (FRUST), which is a modified and shortened version of the Questionnaire for the Assessment of Emotion Regulation in Children and Adolescents (FEEL-KJ). Methods: The data comprised child and parent ratings of a community-screened sample with differing levels of affective dysregulation (AD) (N = 391, age: M = 10.64, SD = 1.33, 56% male). We conducted latent factor analyses to establish a factor structure. Subsequently, we assessed measurement invariance (MI) regarding age, gender, and AD level and evaluated the internal consistencies of the scales. Finally, we examined the convergent and divergent validity of the instrument by calculating differential correlations between the emotion regulation strategy (ERS) scales and self- and parent-report measures of psychopathology. Results: A four-factor model, with one factor representing Dysfunctional Strategies and the three factors Distraction, Problem-Solving and Social Support representing functional strategies provided the best fit to our data and was straightforward to interpret. We found strong MI for age and gender and weak MI for AD level. Differential correlations with child and parent ratings of measures of psychopathology supported the construct validity of the factors. Conclusions: We established a reliable and valid self-report measure for the assessment of ERS in children. Due to the reduced number of items and the inclusion of highly specific regulatory behaviors, the FRUST might be a valuable contribution to the assessment of ER strategies for diagnostic, therapeutic, and research purposes

Irritability and Emotional Impulsivity as Core Feature of ADHD and ODD in Children (May, 10.1007/s10862-022-09974-8, 2022)

The categorical approach of diagnosing mental disorders entails the problem of frequently occurring comorbidities, suggesting a more parsimonious structure of psychopathology. In this study, we therefore aim to assess how affective dysregulation (AD) is associated with attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) in children. To assess AD in children aged 8-12 years (n = 391), we employed the parent version of a newly constructed parent rating scale. Following item reduction, we conducted exploratory and confirmatory factor analyses to establish a factorial structure of AD. One core dimension was identified, comprising irritability and emotional impulsivity, and two smaller dimensions, comprising positive emotionality and exuberance. Subsequently, we examined five different latent factor models - a unidimensional model, a first-order correlated factor model, a second-order correlated factor model, a traditional bifactor model, and a bifactor S-1 model, in which the first-order factor AD-Irritability/Emotional Impulsivity (II) was modeled as the general reference factor. A bifactor S-1 model with the a priori defined general reference domain AD-II provided the best fit to our data and was straightforward to interpret. This model showed excellent model fit and no anomalous factor loadings. This still held true, when comparing it to bifactor S-1 models with ADHD/ODD-related reference factors. Differential correlations with emotion regulation skills and the established Parent Proxy Anger Scale validate the interpretation of the different dimensions. Our results suggest that irritability/emotional impulsivity might be a common core feature of ADHD and ODD

Disentangling Symptoms of Externalizing Disorders in Children Using Multiple Measures and Informants

The trait impulsivity theory suggests that a single, highly heritable externalizing liability factor, expressed as temperamental trait impulsivity, represents the core vulnerability for externalizing disorders. The present study sought to test the application of latent factor models derived from this theory to a clinical sample of children. Participants were 474 German children (age 6-12 years, 81% male) with symptoms of attention-deficit/hyperactivity disorder and externalizing behavior problems participating in an ongoing multicenter intervention study. Using confirmatory factor analyses (CFA) and exploratory structural equation modeling (ESEM), we evaluated several factor models of externalizing spectrum disorders (unidimensional; first-order correlated factors; higher-order factor; fully symmetrical bifactor; bifactor S-1 model). Furthermore, we assessed our prevailing factor models for measurement invariance across raters (clinicians, parents, teachers) and assessment modes (interview, questionnaires). While both CFA and ESEM approaches provided valuable insights into the multidimensionality, ESEM solutions were generally superior since they showed a substantially better model fit and less biased factor loadings. Among the models tested, the bifactor S-1 CFA/ESEM models, with a general hyperactivity-impulsivity reference factor, displayed a statistically sound factor structure and allowed for straightforward interpretability. Furthermore, these models showed the same organization of factors and loading patterns, but not equivalent item thresholds across raters and assessment modes, highlighting cross-situational variability in child behavior. Our findings are consistent with the assumption of the trait impulsivity theory that a common trait, presented as hyperactivity-impulsivity symptoms, underlies all externalizing disorders