Cognitive and Social-Emotional Development in Girls With Fragile X Syndrome.

OBJECTIVES: To evaluate the developmental trajectory of key cognitive, social, and emotional features in girls with fragile X syndrome (FXS). METHODS: This longitudinal, parallel cohort study collected data between January 2018 and December 2022. Participants were evaluated 3 times with ∼12-18 months between visits. Participants included 65 girls with FXS, 6 to 16 years, and 52 age- and developmentally-matched girls without FXS. Participants' scores from direct assessment and caregiver report evaluated 3 cognitive domains (verbal abilities, nonverbal abilities, executive function) and 4 social-emotional domains (depression, general anxiety, social behavior, and social anxiety). RESULTS: Participants included 117 girls (mean [M] [SD] age at study entry: FXS M = 10.59 [3.00]; comparison M = 10.45 [2.40])). Omnibus tests showed 4 domains with significant group differences: Verbal (P < .0001, eg, Differential Abilities Scale-II(DAS-II), Picture Vocabulary (-6.25 [1.87])), nonverbal (P < .0001, eg, Kaufman Test of Educational Achievement, Third Edition, Brief Form, Math (-8.56 [2.90])), executive function (P < .0001, eg, NIH Toolbox List Sorting (-6.26 [1.48])), and social anxiety (P < .03, eg, Anxiety, Depression, and Mood Scale (ADAMS) Social Avoidance (1.50 [0.65])). Three domains had significant group by age interaction: Verbal (P < .04, eg, DAS-II, Word Definitions (-1.33 [0.55])), social behavior (P < .01, eg, Social Responsiveness Scale-2 Social Communication (1.57 [0.51])), and social anxiety (P < .01, eg, ADAMS Social Avoidance (0.46 [0.19])). CONCLUSIONS: These findings support the development of early, disorder specific interventions for girls with FXS targeting verbal and nonverbal skills, executive function, social behavior, and social anxiety.

Cost-effectiveness of train-the-trainer versus expert consultation training models for implementing interpersonal psychotherapy in college mental health settings: evidence from a national cluster randomized trial.

BACKGROUND: This study is a cost-effectiveness study of two implementation strategies designed to train therapists in college and university counseling centers to deliver interpersonal psychotherapy. Costs of implementing a train-the-trainer (TTT) strategy versus an expert consultation strategy were estimated, and their relative effects upon therapist outcomes were calculated and compared. METHODS: Twenty four counseling centers were recruited across the United States. These centers were randomized to either a TTT (experimental) condition, in which an in-house therapist trained other center therapists, or an expert consultation condition, in which center therapists participated in a workshop and received 12 months of ongoing supervision. The main outcome was therapist fidelity (adherence and competence) to interpersonal psychotherapy, assessed via audio recordings of therapy sessions, and analyzed using linear mixed models. Costs of each condition were quantified using time-driven activity-based costing methods, and involved a costing survey administered to center directors, follow up interviews and validation checks, and comparison of time tracking logs of trainers in the expert condition. Mean costs to produce one therapist were obtained for each condition. The costs to produce equivalent improvements in therapist-level outcomes were then compared between the two conditions. RESULTS: Mean cost incurred by counseling centers to train one therapist using the TTT strategy was $3,407 (median = $3,077); mean cost to produce one trained therapist in the control condition was $2,055 (median = $1,932). Therapists in the TTT condition, on average, demonstrated a 0.043 higher adherence score compared to therapists in the control condition; however, this difference was not statistically significant. For the competence outcome, effect size for therapists in the TTT condition was in the large range (1.16; 95% CI: 0.85-1.46; p < .001), and therapists in this condition, on average, demonstrated a 0.073 higher competence score compared to those in the expert consultation condition (95% CI, 0.008-0.14; p = .03). Counseling centers that used the TTT model incurred $353 less in training costs to produce equivalent improvements in therapist competence. CONCLUSIONS: Despite its higher short run costs, the TTT implementation strategy produces greater increases in therapist competence when compared to expert consultation. Expanding resources to support this platform for service delivery can be an effective way to enhance the mental health care of young people seeking care in college and university counseling centers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02079142.

Protocol for a randomized clinical trial to confirm the effectiveness of online guided self-help family-based treatment for adolescent anorexia nervosa.

BACKGROUND: The leading evidence-based treatment for anorexia nervosa (AN) in adolescents is Family-based Treatment (FBT). However, due to the intensive training requirements and lack of practitioners, it is often difficult for families to access FBT. Thus, innovations that improve access to care are needed. A pilot randomized study of a guided self-help version of Family-based Treatment (GSH-FBT) that utilized approximately 1/4 the amount of therapist time compared to FBT found that the approach was acceptable and appeared to achieve similar outcomes. The study protocol detailed in this manuscript compares the efficiency (clinician time) of GSH-FBT to Family-based Treatment via Videoconferencing (FBT-V) in a fully powered study in achieving clinical outcomes through a multi-site randomized clinical trial across the US and Ontario, Canada. METHODS: This study will randomize the families of adolescents ages 12-18 (n = 200) who meet DSM-5 criteria for AN to receive either GSH-FBT or FBT-V. Participants will be randomized to 15 sixty-minute sessions of FBT-V or to 10 twenty-minute sessions of online GSH-FBT. Major assessments will be conducted by a masked assessor at baseline, within treatment, at the end of treatment (EOT), and 6 and 12 months after the end of treatment (EOT). The primary outcomes of this study are changes to body weight and eating disorder cognitions relative to clinician time used (relative efficiency of treatment modality). CONCLUSIONS: The findings of this study may help increase access to care by providing a time efficient, affordable, more scalable intervention for adolescent AN compared to standard FBT.

Randomized waitlist-controlled trial of buried in treasures facilitated support groups and in-home uncluttering (BIT+) for hoarding disorder.

OBJECTIVE: The Buried in Treasures (BIT) workshop is a promising treatment for hoarding disorder (HD), though many participants struggle with home uncluttering. This randomized waitlist-controlled trial investigated the efficacy of a version of BIT, augmented with in-home uncluttering practice (BIT+). METHOD: Adults (N = 41) with hoarding disorder were recruited from the community and randomly assigned to BIT+ or waitlist. BIT+ consisted of 16 sessions of the BIT workshop and 10 uncluttering home visits over 18 weeks. Outcome measures included the Saving Inventory-Revised (self-report) and the Clutter Image Rating Scale (self and independent evaluator rated). Between group repeated measures analyses using general linear modeling examined the effect of BIT+ vs waitlist control on hoarding symptoms after 18 weeks. Within group analyses examined pre-post effects for all BIT+ participants combined after 18 weeks. RESULTS: After 18 weeks, BIT+ participants benefited significantly more than waitlist controls on hoarding severity with large effect size (Cohen's d = 1.5, p < .001). BIT+ was also associated with improvement reductions in hoarding symptoms, clutter, and functional impairment. CONCLUSIONS: The BIT+ intervention offers promise as a treatment option for hoarding. Adding in-home uncluttering practice may incrementally improve discarding practices. Future controlled trials are warranted.

Teleyoga for Patients With Alzheimer's Disease and Chronic Musculoskeletal Pain and Their Caregivers: A Feasibility Study.

Background: Chronic musculoskeletal pain is common in patients with Alzheimer's disease (AD), and there is growing awareness that chronic pain has an impact on the progression of dementia. Yoga has shown promise in treating chronic pain. However, attending in-person yoga can be difficult for AD patients. Objective: To assess the feasibility, acceptability and preliminary efficacy of an online yoga (teleyoga) protocol suitable for AD patients with chronic pain, and their caregivers. Methods: Patients with comorbid mild AD and chronic musculoskeletal pain (n = 15, 57-95 y/o; 73% Female) and their caregivers (n = 15, 50-75 y/o; 67% Female) received 12-week of teleyoga individually (n = 5 dyads) or in groups (n = 10 dyads). Study measures included standard feasibility metrics, and secondary outcomes included the Brief Pain Inventory-Short Form (BPI-SF), Beck Depression Inventory-II (BDI-II), and cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Caregivers also completed measures of caregiver burden, and quality of life (Short Form Health Survey-36, SF-36). Results: Feasibility measures showed adequate treatment adherence (85.1% in patients and 86.3% in caregivers), acceptability (mean acceptability rating = 3.0 for patients and 3.3 for caregivers, indicating positive approval), recruitment rate (n = 16 dyads within 1-year), retention rate (87%), missing data rate (.03%), and fidelity of treatment delivery (87%). Preliminary efficacy findings in the AD group showed significant reductions in pain severity (BPI-SF mean Δ = -.93, P = .045) and depression (BDI-II; mean Δ = -9.85, P = .005). %). Preliminary efficacy findings in the caregiver group showed significant reductions in depression (BDI-II mean Δ = -6.88, P = .036) and fatigue (SF-36 mean Δ = 9.81, P = .021). Conclusion: Results show that teleyoga is a feasible treatment for patients with comorbid mild AD and chronic musculoskeletal pain. Results also provide preliminary evidence of health benefits of teleyoga for both AD patients and their caregivers.

Multimodal Exercise and Cognitive Training Program Improves Cognitive Function in Amnestic Mild Cognitive Impairment.

OBJECTIVE: To investigate the preliminary efficacy of a combined physical exercise + cognitive training intervention for older adults with amnestic mild cognitive impairment (aMCI). DESIGN: Randomized clinical trial. SETTING: Veteran Affairs Hospital, Palo Alto, CA. PARTICIPANTS: Sample included 72 community-dwelling volunteers (mean age 72.4 ± 9.5) diagnosed with aMCI. INTERVENTION: Participants were randomized to either a combined aerobic and resistance exercise + cognitive training (CARE+CT) or stretching exercise + CT (SE+CT). MEASUREMENTS: Primary outcomes included intervention specific assessments of word list and name-face recall. Secondary cognitive outcomes included standardized composite scores that reflect cognitive domains (e.g., learning and memory, executive function, processing speed, visuospatial ability, language). Secondary physiological outcomes included VO2 max and functional capacity (e.g., distance walked 6-minute walk test). APOE and BDNF were determined from whole blood samples. RESULTS: Controlling for age and employment status, linear mixed effects models revealed that all participants experienced significant improvement in the delayed recall of word list, learning and memory and executive function. Only the CARE+CT condition had significant improvement in processing speed and functional capacity. APOE4 status impacted cognitive benefits of those in the SE+CT condition. CONCLUSIONS: Results provide preliminary support for combined exercise and cognitive training interventions for older adults with aMCI. Further research is needed to understand the mechanisms involved as well as the impact of these interventions in diverse samples. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01962038.

Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence.

BACKGROUND: Exposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology. METHODS: Adolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9-18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology. RESULTS: Symptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions. CONCLUSIONS: NAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

Early life stress predicts trajectories of emotional problems and hippocampal volume in adolescence.

Exposure to early life stress (ELS) has been consistently associated with adverse emotional and neural consequences in youth. The development of brain structures such as the hippocampus, which plays a significant role in stress and emotion regulation, may be particularly salient in the development of psychopathology. Prior work has documented smaller hippocampal volume (HCV) in relation to both ELS exposure and risk for psychopathology. We used longitudinal k-means clustering to identify simultaneous trajectories of HCV and emotional problems in 155 youth across three assessments conducted approximately two years apart (mean baseline age = 11.33 years, 57% female). We also examined depressive symptoms and resilience approximately two years after the third timepoint. We identified three clusters of participants: a cluster with high HCV and low emotional problems; a cluster with low HCV and high emotional problems; and a cluster with low HCV and low emotional problems. Importantly, severity of ELS was associated with greater likelihood of belonging to the low HCV/high symptom cluster than to the low HCV/low symptom cluster. Further, low HCV/high symptom participants had more depressive symptoms and lower resilience scores than did participants in the low HCV/low symptom, but not than in the high HCV/low symptom cluster. Our findings suggest that smaller HCV indexes biological sensitivity to stress. This adds to our understanding of the ways in which ELS can affect hippocampal and emotional development in young people and points to hippocampal volume as a marker of susceptibility to context.

Who Responds to an Adaptive Intervention for Adolescents With Anorexia Nervosa Being Treated With Family-Based Treatment? Outcomes From a Randomized Clinical Trial.

OBJECTIVE: Anorexia nervosa (AN) is a serious psychiatric disorder with high morbidity and mortality. The current evidence supports the use of family-based treatment (FBT), but recovery rates are only about 40%. Improving treatment outcomes among adolescents with AN will save lives, improve health, and prevent chronicity. This study examined the relative efficacy of adding intensive parental coaching (IPC) to standard FBT for patients who do not respond by weight gain of 2.4 kg by session 4, a clinical predictor of outcome at the end of treatment, to improve remission rates (>94% of expected mean body mass index). METHOD: The study recruited 107 participants and their families from across the United States; 69 participants failed to respond early and were randomly assigned to continue with standard FBT or to receive 3 sessions of IPC. Participants were adolescents (ages 12-18) meeting DSM-5 criteria for AN; 6.5% were male, and 11% were Hispanic. RESULTS: Main outcomes were mean body mass index >94% expected for age, height, and sex. Secondary outcomes included change in eating-related cognitions. Adding IPC to early nonresponders did not improve outcomes except for participants whose parents demonstrated low parental self-efficacy at baseline (moderator). Early weight gain of 2.4 kg by session 4 was replicated as a predictor of end of treatment remission. CONCLUSION: Parental self-efficacy moderates IPC as an adaptive treatment for adolescents with AN. Baseline parental self-efficacy assessment can be used to identify families most likely to benefit from adding IPC to FBT. Future studies should consider earlier interventions to improve early response rates. PLAIN LANGUAGE SUMMARY: Anorexia nervosa is a serious psychiatric disorder. While family-based treatment (FBT) has the largest evidence base for adolescents with anorexia, recovery rates are only about 40%. This study investigated the addition of 3 sessions of intensive parental coaching intervention (IPC) to FBT among youth with anorexia who did not gain adequate weight early in treatment, a predictor of recovery by the end of treatment. Youth with inadequate weight gain were randomized to either receive FBT with IPC or FBT as usual. Overall, adding IPC did not improve outcomes among youth with anorexia. However among those whose parents demonstrated low parental self-efficacy at baseline, youth who received FBT with IPC had higher remission rates than youth who received FBT alone. CLINICAL GUIDANCE: Intensive parental coaching shows promise for improving outcomes among youth with anorexia whose parents report low parental self-efficacy. CLINICAL TRIAL REGISTRATION INFORMATION: Adaptive Treatment for Adolescent Anorexia Nervosa; https://clinicaltrials.gov/; NCT03097874.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Adolescent brain development in girls with Turner syndrome.

Turner syndrome (TS) is a common sex chromosome aneuploidy in females associated with various physical, cognitive, and socio-emotional phenotypes. However, few studies have examined TS-associated alterations in the development of cortical gray matter volume and the two components that comprise this measure-surface area and thickness. Moreover, the longitudinal direct (i.e., genetic) and indirect (i.e., hormonal) effects of X-monosomy on the brain are unclear. Brain structure was assessed in 61 girls with TS (11.3 ± 2.8 years) and 55 typically developing girls (10.8 ± 2.3 years) for up to 4 timepoints. Surface-based analyses of cortical gray matter volume, thickness, and surface area were conducted to examine the direct effects of X-monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X-monosomy emerging after pubertal onset. Longitudinal analyses revealed that, whereas typically developing girls exhibited normative declines in gray matter structure during adolescence, this pattern was reduced or inverted in TS. Further, girls with TS demonstrated smaller total surface area and larger average cortical thickness overall. Regionally, the TS group exhibited decreased volume and surface area in the pericalcarine, postcentral, and parietal regions relative to typically developing girls, as well as larger volume in the caudate, amygdala, and temporal lobe regions and increased thickness in parietal and temporal regions. Surface area alterations were predominant by age 8, while maturational differences in thickness emerged by age 10 or later. Taken together, these results suggest the involvement of both direct and indirect effects of X-chromosome haploinsufficiency on brain development in TS.

Reorienting Latent Variable Modeling for Supervised Learning.

Despite its potentials benefits, using prediction targets generated based on latent variable (LV) modeling is not a common practice in supervised learning, a dominating framework for developing prediction models. In supervised learning, it is typically assumed that the outcome to be predicted is clear and readily available, and therefore validating outcomes before predicting them is a foreign concept and an unnecessary step. The usual goal of LV modeling is inference, and therefore using it in supervised learning and in the prediction context requires a major conceptual shift. This study lays out methodological adjustments and conceptual shifts necessary for integrating LV modeling into supervised learning. It is shown that such integration is possible by combining the traditions of LV modeling, psychometrics, and supervised learning. In this interdisciplinary learning framework, generating practical outcomes using LV modeling and systematically validating them based on clinical validators are the two main strategies. In the example using the data from the Longitudinal Assessment of Manic Symptoms (LAMS) Study, a large pool of candidate outcomes is generated by flexible LV modeling. It is demonstrated that this exploratory situation can be used as an opportunity to tailor desirable prediction targets taking advantage of contemporary science and clinical insights.

Neuropsychiatric phenotypes in children with Noonan syndrome.

AIM: We investigated neuropsychiatric outcomes in children with Noonan syndrome and addressed limitations in previous research with a focus on prepubertal children, comparison to typically developing children, comprehensive neuropsychiatric evaluation, and controlling for overall cognitive abilities. METHOD: Forty-five children with Noonan syndrome (mean = 8 years 6 months, SD = 2 years 2 months; 29 females) and 40 typically developing children (mean = 8 years 9 months, SD = 2 years; 22 females) were evaluated with objective, parent-report, and psychiatric interview measures. RESULTS: Children with Noonan syndrome demonstrated elevated symptoms across attention-deficit/hyperactivity disorder (ADHD) (attention, hyperactivity, and inhibition), autism spectrum disorder (ASD) (maintaining social relationships, behavioral rigidity, and sensory sensitivity), and oppositional defiant disorder (ODD) (aggression) symptom clusters relative to typically developing children (all p < 0.05). Group differences in nearly all parent-report measures were significant after accounting for variations in intellectual functioning, suggesting that increased neurodevelopmental symptoms are not simply driven by overall intelligence. Twenty out of 42 children with Noonan syndrome met criteria for ADHD, eight out of 42 for ODD, and 11 out of 43 demonstrated clinically significant symptoms seen in children with ASD. INTERPRETATION: Children with Noonan syndrome are at increased risk for a range of ADHD, ASD, and ODD associated symptoms. A dimensional approach reveals significant ASD symptoms in Noonan syndrome that do not emerge when using the currently accepted categorical diagnostic approach. WHAT THIS PAPER ADDS: Neuropsychiatric disorders occur in more than half of children with Noonan syndrome. Children with Noonan syndrome demonstrate highly variable neurodevelopmental symptom profiles. Children with Noonan syndrome display variable impairments in attention, hyperactivity, and inhibition. Specific social concerns include behavioral rigidity, transitions, and difficulties maintaining social relationships. Children with Noonan syndrome display variably elevated levels of aggression and emotional dysregulation.

Group trauma focused cognitive behavior therapy for parents of premature infants compared to individual therapy intervention.

BACKGROUND: The current study compares results of a group-based intervention developed to reduce symptoms of posttraumatic stress, depression, and anxiety in parents of premature infants with a prior study using an individual version of the treatment manual. METHODS: 26 mothers of preterm infants (25-34 weeks' gestational age; >600 g) received 6 sessions of trauma-focused cognitive behavior therapy (CBT). Outcomes were compared with those of a previously published RCT, which tested an individual therapy based on the same model in a group of 62 mothers. Results were also compared across in-person and telehealth treatment. RESULTS: From baseline to follow up, the individual intervention showed greater improvement in trauma symptoms assessed with the Davidson Trauma Scale (d = 0.48, p = 0.016), although both conditions showed clinically significant improvement. Similar patterns were found for maternal depression and anxiety. In-person treatment was found to be superior to telehealth treatment administered during the COVID-19 pandemic, although the difference was not significant. CONCLUSIONS: Group-based trauma focused CBT is an effective treatment modality for parents of premature infants with symptoms of psychological distress but not as effective as individual therapy using the same treatment model.

Emotion regulation and choice of bilateral mastectomy for the treatment of unilateral breast cancer.

BACKGROUND: There has been steadily increasing use of bilateral mastectomy (BMX) in the treatment of primary breast cancer (BC). In this study, we utilized functional magnetic resonance imaging (fMRI) to examine the influence of emotion regulation on the decision of newly diagnosed BC patients to choose BMX rather than non-BMX treatments. METHODS: We recruited 123 women with unilateral BC, 61 of whom received BMX and 62 of whom received non-BMX treatments, and 39 healthy controls. While participants were in the fMRI scanner, we showed them BC-related and non-BC-negative images. In one condition, they were instructed to watch the images naturally. In another, they were instructed to regulate their negative emotion. We compared the fMRI signal during these conditions throughout the brain. RESULTS: With non-BC-negative images as the baseline, BC patients showed greater self-reported reactivity and neural reactivity to BC-related images in brain regions associated with self-reflection than did controls. Among the BC patients, the BMX group showed weaker activation in prefrontal emotion regulation brain regions during emotion regulation than did the non-BMX group. CONCLUSIONS: BC patients are understandably emotionally hyper-reactive to BC-related stimuli and those who ultimately received BMX experience more difficulty in regulating BC-related negative emotion than non-BMX BC patients. These findings offer neuropsychological evidence that difficulty in managing anxiety related to the possibility of cancer recurrence is a factor in surgical treatment decision-making and may be an intervention target with the goal of strengthening the management of cancer-related anxiety by nonsurgical means. TRIAL REGISTRATION: NCT03050463.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: 1. How Ras-MAPK activating variants of PTPN11 / SOS1 protein-coding genes affect brain anatomy. 2. The relationship between PTPN11 gene expression levels and brain anatomy, and 3. The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 ( n = 30) or SOS1 ( n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA) and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area ( d 's<-0.8), and extensive effects on SA ( d 's>|0.8|) and CT ( d 's>|0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Beyond maintaining safety: Examining the benefit of emotion-centered problem solving therapy added to safety planning for reducing late life suicide risk.

Few clinical trials have examined brief non-pharmacological treatments for reducing suicide risk in older Veterans, a high-risk group. Problem Solving Therapy (PST) is a promising psychosocial intervention for reducing late life suicide risk by increasing adaptive coping to problems through effective problem solving and related coping skills. The current randomized clinical trial will compare the efficacy of six telephone-delivered sessions of Safety Planning (enhanced usual care; EUC) only or an updated version of PST (emotion-centered PST [EC-PST]) + EUC to determine the added clinical benefit of EC-PST for reducing severity of suicidal ideation and for increasing reasons for living, a critical protective factor. Participants randomized to EC-PST + EUC or EUC only will be 150 Veterans (75 each) with active suicidal ideation who are aged 60 or older; have a current DSM-5 anxiety, depressive, and/or trauma-related disorder; and without significant cognitive impairment. Primary outcomes (Geriatric Suicide Ideation Scale and Reasons for Living-Older Adults scale) will be assessed at 11 timepoints: baseline, after each of 6 treatment sessions, posttreatment, and at follow-up at 1, 3, and 6 months posttreatment, and analyzed using mixed effects modeling. Additionally, moderators and mediators of primary outcomes will be examined-functional disability, executive dysfunction, and problem-solving ability. Qualitative feedback from participants will identify potential Veteran-centric changes to the EC-PST protocol and to EUC. Ultimately, the goal of this study is to inform the evidence-based clinical practice guidelines for treatments to reduce suicide risk in older Veterans and specifically to inform clinical decision-making regarding the merit of adding EC-PST to EUC.

Moderators and mediators of a digital cognitive behavior therapy-guided self-help intervention for eating disorders: Informing future design efforts.

OBJECTIVE: The Student Bodies-Eating Disorders intervention (SB-ED), a digital cognitive behavior therapy-guided self-help intervention for college women with an eating disorder, is effective for reducing eating disorder psychopathology. The purpose of this study was to evaluate moderators and mediators of the SB-ED intervention. To our knowledge, this is the first evaluation of clinical mediators of a digital intervention for women with eating disorders. METHOD: This is an exploratory secondary analysis of a cluster randomized trial comparing the SB-ED intervention to referral to usual care among 690 women at 27 United States colleges. Moderators included body mass index (BMI), race, ethnicity, weight/shape concerns, eating disorder impairment, thin ideal internalization, depression, anxiety, and motivation for treatment, assessed at baseline. Thin ideal internalization and depressive symptoms were tested as predictors at postintervention and mediators at 2-year follow-up. Outcome was change in global eating disorder psychopathology. RESULTS: BMI moderated the effect of the intervention at follow-up (but not posttreatment), with individuals with a lower BMI experiencing more continued improvements in eating disorder psychopathology following the intervention than individuals with a higher BMI. Thin ideal internalization mediated the effect of the intervention at follow-up, and depression partially mediated the effect of the intervention at follow-up. CONCLUSIONS: Results of the mediator analyses suggest that helping college women reduce inflated internalization of the thin ideal and improve depressive symptoms leads to improvements in eating disorder psychopathology. Results also suggest opportunities to optimize the intervention so individuals across the BMI spectrum experience ongoing improvements over time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Longitudinal investigation of cognition, social competence, and anxiety in children and adolescents with Turner syndrome.

Turner syndrome (TS), a common neurogenetic disorder caused by complete or partial absence of an X chromosome in females, is characterized by distinct physical, cognitive, and social-emotional features. Girls with TS typically display average overall intellectual functioning with relative strength in verbal abilities and weaknesses in visuospatial processing, executive function (EF), and social cognition. This study was designed to better understand longitudinal trajectories of cognitive and social-emotional domains commonly affected in TS. Participants included 57 girls with monosomic 45,X TS and 55 age- and verbal-IQ matched girls who completed behavioral, child-report, and parent-report measures across four timepoints. Group differences in visuospatial processing, EF, social cognition, and anxiety were assessed longitudinally. Potential effects of estrogen replacement therapy (ERT) were assessed cross-sectionally on an exploratory basis. The TS group showed poorer performance on measures of visuospatial processing, EF, and social cognition, but not anxiety, compared to controls throughout childhood and adolescence. There were no significant group differences in the trajectory of skill development over time. Exploratory analyses within the TS group revealed that girls who were receiving ERT showed better performance on measures of overall IQ, expressive vocabulary, and visuospatial processing compared to those not receiving ERT. Consistent with existing literature, weaknesses in visuospatial processing, EF, and social competence among girls with TS persisted throughout childhood and adolescence. Exploratory analyses suggest that ERT may help improve some aspects of cognitive function in TS, although other pre-existing, nonhormonal differences between the two TS subgroups may alternatively explain these findings, given our study design. Future studies are needed to examine potential impacts of ERT on cognitive and social-emotional development in TS.

Brief structured respiration practices enhance mood and reduce physiological arousal.

Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.