ABSTRACTDevelopment of digital biomarkers holds promise for enabling scalable, time-sensitive, and cost-effective strategies to monitor symptom severity among those with major depressive disorder ...(MDD). The current study examined the use of passive movement and light data from wearable devices to assess depression severity in 15 patients with MDD. Using over 1 week of movement data, we were able to significantly assess depression severity with high precision for self-reported (r = 0.855; 95% confidence interval CI, 0.610–0.950; p = 4.95 × 10) and clinician-rated (r = 0.604; 95% CI, 0.133–0.894; p = 0.017) symptom severity. Pending replication, the present data suggest that the use of passive wearable sensors to inform healthcare decisions holds considerable promise.
Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and ...effectors. Mammalian cells express four Rag proteins (RagA-D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Here, by using genetically modified cell lines that express single Rag heterodimers, we uncover a Rag dimer code that determines how amino acids regulate mTORC1. First, RagC/D differentially define the substrate specificity downstream of mTORC1, with RagD promoting phosphorylation of its lysosomal substrates TFEB/TFE3, while both Rags are involved in the phosphorylation of non-lysosomal substrates such as S6K. Mechanistically, RagD recruits mTORC1 more potently to lysosomes through increased affinity to the anchoring LAMTOR complex. Furthermore, RagA/B specify the signalling response to amino acid removal, with RagB-expressing cells maintaining lysosomal and active mTORC1 even upon starvation. Overall, our findings reveal key qualitative differences between Rag paralogues in the regulation of mTORC1, and underscore Rag gene duplication and diversification as a potentially impactful event in mammalian evolution.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although effective treatments are available, most individuals with body dysmorphic disorder (BDD) do not receive an appropriate diagnosis or treatment. We aimed to examine treatment utilization and ...barriers to treatment, and to identify associated socio-demographic and clinical characteristics.
German individuals completed an online self-report survey of appearance concerns. A sample of N = 429 individuals met criteria for BDD. We examined the frequency of treatment utilization and barriers, analyzed comparisons between treated and untreated individuals and assessed the relationships of socio-demographic and clinical features with mental health treatment utilization and treatment barriers, respectively.
Only 15.2% of the individuals with BDD had been diagnosed with BDD, and lifetime rates of mental health treatment were low (39.9%). Individuals endorsed multiple barriers to mental health treatment, especially shame, low perceived need and a preference for cosmetic and medical treatments. Associated features were identified, including age, a BDD diagnosis, body dysmorphic symptom severity, a likely major depressive disorder, prior cosmetic surgery, and insight.
The results of this largest study to date highlight that BDD is still underrecognized and undertreated even in a country with extensive mental health care and few financial barriers. We discuss modifiable factors and strategies to foster awareness of BDD in sufferers and professionals to improve treatment dissemination and to reduce treatment barriers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cognitive (CT) and behavioral treatments (BT) for OCD are efficacious separately and in combination. Tailoring treatment to patient-level predictors and moderators of outcome has the potential to ...improve outcomes. The present study combined data from eight treatment clinics to examine the benefits of BT (n = 125), CT (n = 108), and CBT (n = 126), and study predictors across all treatments and moderators of outcome by treatment type. All three methods led to large benefits for OCD and depression symptoms. Residual gain scores for OCD symptoms were marginally smaller for BT compared to treatments containing CT. For depression, significantly more gains were evident for CBT than BT, and CT did not differ from either. Significantly fewer BT participants (36%) achieved clinically significant improvement compared to CT (56%), and this was marginally evident for CBT (48%). For all treatments combined, no predictors were identified in residual gain analyses, but clinically improved patients had lower baseline depression and stronger beliefs about responsibility/threat and importance/control of thoughts. Moderator analyses indicated that higher baseline scores on depression adversely affected outcomes for BT but not CT or CBT, and lower OCD severity and more education were associated with positive outcomes for CT only. A trend was evident for higher responsibility/threat beliefs to moderate clinical improvement outcomes for those receiving cognitive (CT and CBT), but not behavioral (BT) treatment. Medication status and comorbidity did not predict or moderate outcomes. Findings are discussed in light of models underlying behavioral and cognitive treatments for OCD.
•Behavior therapy, cognitive therapy and their combination showed benefits for OCD and depression•Improvements in OCD symptoms were somewhat greater for treatments containing cognitive therapy•Lower initial depression predicted more benefit, especially for behavior therapy•Stronger beliefs about responsibility and harm and more education may influence cognitive therapy benefits•Medication status and comorbidity did not predict treatment outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The ...neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population. OBJECTIVE To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD. DESIGN Cross-sectional, case-control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty-one patients with OCD and 21 healthy participants. MAIN OUTCOMES AND MEASURES Skin conductance responses and blood oxygenation level–dependent responses. RESULTS The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity. CONCLUSIONS AND RELEVANCE As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.
Body dysmorphic disorder (BDD) is associated with severe comorbidity and impairment. Muscle dysmorphia (MD) is a subtype of BDD which has rarely been assessed outside of undergraduate student ...samples. Further, there are limited data comparing MD to other psychiatric disorders, including BDD. Thus, the aim of the current study is to explore differences in symptom severity and conformity to masculine norms in men diagnosed with BDD or MD. Men from the greater Boston, Massachusetts area completed a one-time assessment, which included clinician-based structured interviews and self-report questionnaires assessing MD symptom severity, BDD symptom severity, and conformity to traditional masculine norms. The sample was N = 30 men (MD: n = 15; BDD: n = 15). Statistically significant medium to large effects emerged with the MD group experiencing greater MD and BDD symptom severity, and positive attitudes towards the use of violence to solve problems. Although not reaching statistical significance, additional medium-to-large effects also emerged with the MD group reporting greater emotional restriction/suppression, heterosexual self-presentation, and desired sexual promiscuity compared to the BDD group. Findings suggest that men diagnosed with MD may experience greater MD/BDD symptom severity and endorsement of some components of 'traditional' masculine norms, compared to men diagnosed with BDD. Results may suggest that addressing some forms of rigid masculine norms (e.g., use of violence) in therapy could be useful in treating MD; however, additional research comparing clinical samples of men with MD and BDD are needed to guide the nosology, assessment, and treatment of MD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders.
METHODS:Data from 2 10-week, multisite ...studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9–69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression–Improvement score assessed by masked evaluators.
RESULTS:The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction.
CONCLUSIONS:Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication.
CLINICALTRIALS.GOV IDENTIFIERS:The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively).
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup.
Body dysmorphic disorder (BDD) is associated with low self-esteem. The aim of this meta-analysis was to examine the strength of the cross-sectional relationship between BDD symptom severity and ...global self-esteem in individuals with BDD, mentally healthy controls, community or student samples, and cosmetic surgery patients. Moreover, the role of depressive symptom severity in this relationship and other moderating factors were investigated.
A keyword-based literature search was performed to identify studies in which BDD symptoms and global self-esteem were assessed. Random effects meta-analysis of Fisher's z-transformed correlations and partial correlations controlling for the influence of depressive symptom severity was conducted. In addition to meta-analysis of the observed effects, we corrected the individual correlations for variance restrictions to address varying ranges of BDD symptom severity across samples.
Twenty-five studies with a total of 6278 participants were included. A moderately negative relationship between BDD symptom severity and global self-esteem was found (r = -.42, CI = -.48, -.35 for uncorrected correlations, r = -.45, CI = -.51, -.39 for artifact-corrected correlations). A meta-analysis of partial correlations revealed that depressive symptom severity could partly account for the aforementioned relationship (pr = -.20, CI = -.25, -.15 for uncorrected partial correlations, pr = -.23, CI = -.28, -.17 for artifact-corrected partial correlations). The sample type (e.g., individuals with BDD, mentally healthy controls, or community samples) and diagnosis of BDD appeared to moderate the relationship only before artifact correction of effect sizes, whereas all moderators were non-significant in the meta-analysis of artifact-corrected correlations.
The findings demonstrate that low self-esteem is an important hallmark of BDD beyond the influence of depressive symptoms. It appears that negative evaluation in BDD is not limited to appearance but also extends to other domains of the self. Altogether, our findings emphasize the importance of addressing self-esteem and corresponding core beliefs in prevention and treatment of BDD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts ...with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P2, demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.
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•TSC1 contains a C-terminal coiled-coil domain that binds TSC2•A helical linker domain of TSC1 mediates formation of TSC complex oligomers•The N-terminal domain of TSC1 binds to PIP lipids•Lysosomal TSC complex recruitment and mTORC1 inhibition requires TSC1 and PI3,5P2
Fitzian et al. identify oligomerization and phosphoinositide (PIP) lipid binding as essential functions of the TSC1 subunit of the TSC tumor suppressor complex. The study furthermore establishes a mechanistic link between generation of the lysosomal marker lipid PI3,5P2 and regulation of cell growth by mTORC1 via TSC1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Smartphone app-based therapies offer clear promise for reducing the gap in available mental health care for people at risk for or people with mental illness. To this end, as smartphone ownership has ...become widespread, app-based therapies have become increasingly common. However, the research on app-based therapies is lagging behind. In particular, although experts suggest that human support may be critical for increasing engagement and effectiveness, we have little systematic knowledge about the role that human support plays in app-based therapy. It is critical to address these open questions to optimally design and scale these interventions.
The purpose of this study is to provide a scoping review of the use of human support or coaching in app-based cognitive behavioral therapy for emotional disorders, identify critical knowledge gaps, and offer recommendations for future research. Cognitive behavioral therapy is the most well-researched treatment for a wide range of concerns and is understood to be particularly well suited to digital implementations, given its structured, skill-based approach.
We conducted systematic searches of 3 databases (PubMed, PsycINFO, and Embase). Broadly, eligible articles described a cognitive behavioral intervention delivered via smartphone app whose primary target was an emotional disorder or problem and included some level of human involvement or support (coaching). All records were reviewed by 2 authors. Information regarding the qualifications and training of coaches, stated purpose and content of the coaching, method and frequency of communication with users, and relationship between coaching and outcomes was recorded.
Of the 2940 titles returned by the searches, 64 (2.18%) were eligible for inclusion. This review found significant heterogeneity across all of the dimensions of coaching considered as well as considerable missing information in the published articles. Moreover, few studies had qualitatively or quantitatively evaluated how the level of coaching impacts treatment engagement or outcomes. Although users tend to self-report that coaching improves their engagement and outcomes, there is limited and mixed supporting quantitative evidence at present.
Digital mental health is a young but rapidly expanding field with great potential to improve the reach of evidence-based care. Researchers across the reviewed articles offered numerous approaches to encouraging and guiding users. However, with the relative infancy of these treatment approaches, this review found that the field has yet to develop standards or consensus for implementing coaching protocols, let alone those for measuring and reporting on the impact. We conclude that coaching remains a significant hole in the growing digital mental health literature and lay out recommendations for future data collection, reporting, experimentation, and analysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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