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Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of children and having a genetic contribution, the underlying causes remain poorly understood. In this study, we leverage dense phenotype information to identify features (i.e., symptoms and comorbid diagnoses) of tic disorders within the context of a clinical biobank. Using de-identified electronic health records (EHRs), we identified individuals with tic disorder diagnosis codes. We performed a phenome-wide association study (PheWAS) to identify the EHR features enriched in tic cases versus controls (n = 1406 and 7030; respectively) and found highly comorbid neuropsychiatric phenotypes, including: obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety (p < 7.396 × 10-5). These features (among others) were then used to generate a phenotype risk score (PheRS) for tic disorder, which was applied across an independent set of 90,051 individuals. A gold standard set of tic disorder cases identified by an EHR algorithm and confirmed by clinician chart review was then used to validate the tic disorder PheRS; the tic disorder PheRS was significantly higher among clinician-validated tic cases versus non-cases (p = 4.787 × 10-151; ß = 1.68; SE = 0.06). Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex and underdiagnosed conditions, such as tic disorders.
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Bancos de Muestras Biológicas , Registros Electrónicos de Salud , Fenotipo , Trastornos de Tic , Humanos , Trastornos de Tic/genética , Trastornos de Tic/diagnóstico , Trastornos de Tic/epidemiología , Masculino , Femenino , Comorbilidad , Niño , Adulto , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/diagnóstico , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/diagnóstico , Estudios de Casos y Controles , Factores de RiesgoRESUMEN
Hoarding disorder (HD) and obsessive-compulsive disorder (OCD) are highly comorbid and genetically related, but their similarities and differences at the neural level are not well characterized. The present study examined the time-frequency information contained in stimulus-related EEG data as participants worked on a visual flanker task. Three groups were included: participants diagnosed with HD (N = 33), OCD (N = 26), and healthy controls (N = 35). Permutation-controlled mass-univariate analyses found no differences between groups in terms of the magnitude of the oscillatory responses. Differences between groups were found selectively for phase-based measures (phase-locking across trials and across sensors) in time ranges well after those consistent with initial visuocortical processes, in the alpha (10 Hz) as well as theta and beta frequency bands, centered around 6 Hz and 15 Hz, respectively. Specifically, HD showed attenuated phase locking in theta and alpha compared to OCD and HC, while OCD showed heightened inter-site phase locking in alpha/beta. Including age as a covariate attenuated, but did not eliminate, the group differences. These findings point to signatures of cortical dynamics and cortical communication task processing that are unique to HD, and which are specifically present during higher-order visual cognition such as stimulus-response mapping, response selection, and action monitoring.
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Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.
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Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Depresión , Pruebas de Farmacogenómica , Inhibidores Selectivos de la Recaptación de Serotonina , Adulto , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/diagnóstico , Variantes Farmacogenómicas , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Despite the high prevalence of anxiety disorders in children and adolescents and the existence of effective evidence-based treatments for them, access to psychological care remains a major public health concern. Summer camps may provide an effective treatment avenue for youth who might not otherwise have access to care. This study describes the design and implementation of Fear Facers, a semistructured, 5-day, daytime exposure-therapy-based summer camp designed for youth with a primary diagnosis of obsessive-compulsive disorder (OCD), social anxiety, separation anxiety, or a specific phobia. Preliminary data regarding feasibility and patient outcomes is also reported. Among 52 children and adolescents aged 7 to 16 who attended one of six camp sessions between 2018 and 2021, significant reductions in anxiety (dâ¯=â¯0.54) and OCD symptoms (dâ¯=â¯0.57) were observed from pre-camp to immediately post-camp. A subset of campers who were followed for an additional 3 months post-camp (nâ¯=â¯22) showed maintenance of treatment gains. Retention rates for the intervention were high. Our investigation provides further support for the use of a camp-based design for cognitive-behavioral approaches, and may provide a unique setting to maximize elements of inhibitory learning in exposures. We also discuss a number of elements regarding feasibility that need consideration for those hoping to develop similar interventions.
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Terapia Implosiva , Trastorno Obsesivo Compulsivo , Humanos , Niño , Adolescente , Femenino , Masculino , Trastorno Obsesivo Compulsivo/terapia , Trastorno Obsesivo Compulsivo/psicología , Terapia Implosiva/métodos , Resultado del Tratamiento , Trastornos de Ansiedad/terapia , Trastornos de Ansiedad/psicología , Acampada , Ansiedad/terapia , Ansiedad/psicología , Trastornos Fóbicos/terapia , Trastornos Fóbicos/psicologíaRESUMEN
BACKGROUND: To examine the association between race, ethnicity, and parental educational attainment on tic-related outcomes among Tourette Syndrome (TS) participants in the Tourette Association of America International Consortium for Genetics (TAAICG) database. METHODS: 723 participants in the TAAICG dataset aged ≤21 years were included. The relationships between tic-related outcomes and race and ethnicity were examined using linear and logistic regressions. Parametric and nonparametric tests were performed to examine the association between parental educational attainment and tic-related outcomes. RESULTS: Race and ethnicity were collapsed as non-Hispanic white (N=566, 88.0%) versus Other (N=77, 12.0%). Tic symptom onset was earlier by 1.1 years (P < 0.0001) and TS diagnosis age was earlier by 0.9 years (P = 0.0045) in the Other group (versus non-Hispanic white). Sex and parental education as covariates did not contribute to the differences observed in TS diagnosis age. There were no significant group differences observed across the tic-related outcomes in parental education variable. CONCLUSIONS: Our study was limited by the low number of nonwhite or Hispanic individuals in the cohort. Racial and ethnic minoritized groups experienced an earlier age of TS diagnosis than non-Hispanic white individuals. Tic severity did not differ between the two groups, and parental educational attainment did not affect tic-related outcomes. There remain significant disparities and gaps in knowledge regarding TS and associated comorbid conditions. Our study suggests the need for more proactive steps to engage individuals with tic disorders from all racial and ethnic minoritized groups to participate in research studies.
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Determinantes Sociales de la Salud , Síndrome de Tourette , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Escolaridad , Etnicidad , Padres , Estados Unidos , Blanco , Grupos RacialesRESUMEN
To establish a patient-centered agenda for research that will lead to effective, widespread availability, adoption, and utilization of evidence-based behavioral treatment of Tourette syndrome and other tic disorders (TDs), we planned and executed a multistage, collaborative "Treating Tourette Together" research planning project with researchers, clinicians, patients, families, and other interested parties. Priorities for future behavioral treatment research were solicited from these parties via anonymous community surveys, a 2-day research planning summit with 46 individuals representing key stakeholder groups, and community response to summit reports. Four high-priority research domains were identified: (a) expanding treatment access, (b) improving treatment outcomes, (c) optimizing treatment within a broader care model, and (d) evaluating outcomes beyond tic severity. Community-engaged participatory research models can efficiently delineate clear and actionable priorities for clinical research. This approach holds promise for improving the impact of clinical research in TDs and other neuropsychiatric disorders.
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Trastornos de Tic , Tics , Síndrome de Tourette , Humanos , Tics/terapia , Trastornos de Tic/psicología , Síndrome de Tourette/terapia , Síndrome de Tourette/psicología , Terapia Conductista , Atención Dirigida al PacienteRESUMEN
Background and Objective: Tourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/Methods: Data from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. Results: Females with TS (25.5% of the sample) had a later age of symptom onset (6.5±2.8 vs. 6.0±2.7; p=0.001), later age at diagnosis (13.3±11.2 vs. 10.7±8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4±9.1 vs. 30.7±8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9±3.3 vs. 8.9±3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). Conclusion: Females with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.
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BACKGROUND: Anxiety disorders are the most frequently diagnosed psychiatric conditions in children and adolescents. Cognitive behavioural therapy (CBT) is a well-established and effective treatment for anxiety and related disorders across the lifespan. Expectations of psychotherapy have been demonstrated to affect outcomes, yet there is sparse existing literature on adolescent patient and parent perspectives of CBT prior to engagement with treatment. AIMS: This study aimed to qualitatively explore the expectations and perceptions of CBT for anxiety and related disorders among adolescent patients and parents. METHOD: Fourteen adolescent patients and 16 parents participated in semi-structured individual interviews or focus groups consisting of 2-3 participants. Interview transcripts were analysed using inductive analysis. RESULTS: Three themes were identified: worries about CBT, expectations and knowledge of the CBT process, and the role of parents and families. Overall, we found that adolescents and parents had generally positive views of CBT. The outset of CBT saw adolescents and parents express concern about stigma as well as the ambiguity of CBT. Parents continued to express a lack of understanding of what CBT entailed during their child's treatment course. CONCLUSION: These results suggest that both adolescents and parents would benefit from early discussion and reinforcement of expectations for CBT treatment. Further research efforts are warranted and should be directed towards determining appropriate expectations for parental involvement in a child's CBT course and effective communication of treatment expectations to both adolescents and parents.
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Terapia Cognitivo-Conductual , Motivación , Adolescente , Humanos , Niño , Trastornos de Ansiedad/terapia , Trastornos de Ansiedad/psicología , Padres/psicología , Terapia Cognitivo-Conductual/métodos , AnsiedadRESUMEN
OBJECTIVES: Late life depression (LLD) and hoarding disorder (HD) are common in older adults and characterized by executive dysfunction and disability. We aimed to determine the frequency of co-occurring HD in LLD and examine hoarding severity as an additional contributor to executive dysfunction, disability, and response to psychotherapy for LLD. DESIGN: Cross-sectional. SETTING: Outpatient psychiatry program. PARTICIPANTS: Eighty-three community-dwelling adults ages 65-90 with LLD. INTERVENTION: Problem-solving therapy. MEASUREMENTS: Measures of executive function, disability, depression, and hoarding severity were completed at post-treatment. Pearson's chi-squared tests evaluated group differences in rates of cognitive impairment, disability, and depression treatment response between participants with HD (LLD+HD) and LLD only. Separate linear regressions assessed associations between hoarding severity and executive function, disability, and psychotherapy response. Covariates included age, education, gender, and depression severity. RESULTS: 30.1% (25/83) of LLD participants met HD criteria. Relative to LLD, LLD+HD participants demonstrated greater impairment rates on measures of executive function (Letter-Number-Sequencing, X2(1)=4.0, p = 0.045; Stroop-Interference, X2(1) = 4.8, p = 0.028). Greater hoarding severity was associated with poorer executive functioning performance (Letter-Number-Sequencing (t[70] = -2.1, ß = -0.05, p = 0.044), Digit-Span (t[71] = -2.4, ß = -0.07, p = 0.019), Letter-Fluency (t[ 71] = -2.8, ß = -0.24, p = 0.006)). Rates of disability were significantly higher for LLD+HD (88.0%) than LLD (62.3%), (X2[1] = 5.41, p = 0.020) and higher hoarding severity was related to greater disability (t[72] = 2.97, ß = 0.13, p = 0.004). Depression treatment response rates were significantly lower for LLD+HD (24.0%) compared to LLD (48.3%), X2(1) = 4.26, p = 0.039, and HD status predicted psychotherapy response, t(67) = -2.15, ß = -15.6, p = 0.035. CONCLUSIONS: We found 30.1% co-occurrence of HD in LLD, which was accompanied by greater executive dysfunction, disability, and poorer response to depression treatment. Results underscore the need for increased screening of hoarding behaviors in LLD and tailored interventions for this LLD+HD group.
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Disfunción Cognitiva , Trastorno de Acumulación , Acaparamiento , Humanos , Anciano , Depresión/complicaciones , Depresión/epidemiología , Depresión/terapia , Estudios Transversales , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/terapia , Conducta Compulsiva , Trastorno de Acumulación/terapia , Trastorno de Acumulación/psicologíaRESUMEN
Hoarding disorder (HD) is a debilitating neuropsychiatric condition that affects 2%-6% of the population and increases in incidence with age. Major depressive disorder (MDD) co-occurs with HD in approximately 50% of cases and leads to increased functional impairment and disability. However, only one study to date has examined the rate and trajectory of hoarding symptoms in older individuals with a lifetime history of MDD, including those with current active depression (late-life depression; LLD). We therefore sought to characterize this potentially distinct phenotype. We determined the incidence of HD in two separate cohorts of participants with LLD (n = 73) or lifetime history of MDD (n = 580) and examined the reliability and stability of hoarding symptoms using the Saving Inventory-Revised (SI-R) and Hoarding Rating Scale-Self Report (HRS), as well as the co-variance of hoarding and depression scores over time. HD was present in 12% to 33% of participants with MDD, with higher rates found in those with active depressive symptoms. Hoarding severity was stable across timepoints in both samples (all correlations >0.75), and fewer than 30% of participants in each sample experienced significant changes in severity between any two timepoints. Change in depression symptoms over time did not co-vary with change in hoarding symptoms. These findings indicate that hoarding is a more common comorbidity in LLD than previously suggested, and should be considered in screening and management of LLD. Future studies should further characterize the interaction of these conditions and their impact on outcomes, particularly functional impairment in this vulnerable population.
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Trastorno Depresivo Mayor , Trastorno de Acumulación , Acaparamiento , Humanos , Anciano , Depresión/psicología , Trastorno Depresivo Mayor/epidemiología , Acaparamiento/epidemiología , Reproducibilidad de los Resultados , Conducta Compulsiva , Trastorno de Acumulación/diagnósticoRESUMEN
Past research has shown that healthcare workers (HCWs) experience high levels of psychological distress during epidemics and pandemics, resulting in cascading effects that have led to chronically understaffed hospitals and healthcare centers. Due to the nature of their responsibilities and workplace stress, HCWs are among vulnerable groups especially during global health crises. During COVID-19 many healthcare workers reported greater symptoms of anxiety, depression, and COVID-19 related worries. Furthermore, adverse childhood experiences increase vulnerability for psychological conditions, especially during pandemics. This study sets out to (1) investigate the moderating effects of adverse childhood experiences on healthcare workers' COVID-19 related stressors and depression/anxiety symptoms, and (2) investigate the moderating effects of adverse childhood experiences on proximity to the COVID-19 virus and depression/anxiety symptoms. Participants included 438 employed HCWs recruited from academic medical centers and smaller healthcare agencies in northcentral Florida between October to December 2020. Mean age of participants was 38.23 (SD = 11.5) with most of the HCWs being white (72.1%), non-Hispanic (86.8%) and female (82%). Healthcare workers completed several online questionnaires, including the Adverse Childhood Experiences scale, Patient Health Questionnaire, Generalized Anxiety Disorder Scale, a COVID-19 specific worries scale, and a Social Proximity to COVID-19 scale. Healthcare workers experiencing specific COVID-19 worries reported experiencing anxiety and depressive symptoms. A significant positive interaction was seen between childhood adverse experiences globally and COVID-19 worries on anxiety symptoms. A significant positive interaction was observed between childhood maltreatment specifically and COVID-19 worries on depressive symptoms. Additionally, a positive interaction effect was seen between childhood adverse experiences and COVID-19 social proximity for both depression symptoms and anxiety symptoms. Findings from the present study indicate that adverse childhood experiences strengthen the relationship between COVID-19 worry/proximity and negative psychological symptoms. Vulnerable populations such as individuals who have experienced ACEs could benefit from targeted and specific interventions to cope with the collective trauma experienced globally due to COVID-19. As COVID-19 becomes endemic, hospital leadership and authorities should continue addressing COVID-19 worries and HCWs' psychological symptoms through mental health support and organizational interventions.
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INTRODUCTION: Comprehensive behavioral intervention for tics (CBIT) is an efficacious, first-line treatment for Tourette syndrome (TS) and other chronic or persistent tic disorders. However, CBIT's public health impact has been limited by suboptimal treatment access. Preliminary research has shown that providing CBIT over videoconference (teleCBIT) is a promising delivery method for patients who cannot access in-person care. However, extant studies have been small efficacy trials focused only on pediatric patients. Replication of these studies is needed in additional treatment settings and across a wider age range of patients, especially in light of advances in telehealth technology and increasing telehealth adoption among practitioners. METHODS: We conducted a single-arm trial to evaluate the feasibility, acceptability, and effectiveness of teleCBIT embedded in comprehensive, medical tic specialty clinics. From October 2016 to September 2018, patients were offered teleCBIT at their usual care appointments. Those who were interested and met inclusion/exclusion criteria received 8 sessions of CBIT guided by a manualized protocol. An independent evaluator, masked to treatment progress, administered assessments at baseline, post-treatment, and 3 and 6 months after treatment. RESULTS: Twenty-five percent of patients who were offered treatment initiated teleCBIT through the study, and all treatment initiators completed treatment. From pre- to post-treatment, decreases in Yale Global Tic Severity Scale (YGTSS) total tic severity scores showed a large effect size among pediatric patients (n = 19; t = 5.72, P < 0.001, d = 1.31) and a medium-to-large effect size for adult patients (n = 10, t = 1.41, P = 0.096, d = 0.664). Thirteen of 19 pediatric patients (68%) and 6 of 10 adult patients (60%) had a positive global treatment response at post-treatment. Patients rated the treatment as highly satisfactory. Ninety-three percent of sessions were free of substantial technical problems. DISCUSSION: Within the context of medical tic specialty clinics, teleCBIT demonstrated strong evidence of feasibility, acceptability, and preliminary effectiveness comparable to in-person treatment for both pediatric and adult patients. TeleCBIT warrants study in future research on enhancing care systems for patients with TS. TRIAL REGISTRY: https://clinicaltrials.gov/ct2/keydates/NCT04007913.
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Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and ironsulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.
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Trastornos del Movimiento , Síndrome de Tourette , Humanos , Síndrome de Tourette/diagnóstico por imagen , Síndrome de Tourette/genética , Transcriptoma , Encéfalo/diagnóstico por imagen , HomeostasisRESUMEN
Introduction: Dispositional traits of wellbeing and stress-reaction are strong predictors of mood symptoms following stressful life events, and the COVID-19 pandemic introduced many life stressors, especially for healthcare workers. Methods: We longitudinally investigated the relationships among positive and negative temperament group status (created according to wellbeing and stress-reaction personality measures), burnout (exhaustion, interpersonal disengagement), COVID concern (e.g., health, money worries), and moral injury (personal acts, others' acts) as predictors of generalized anxiety, depression, and post-traumatic stress symptoms in 435 healthcare workers. Participants were employees in healthcare settings in North Central Florida who completed online surveys monthly for 8 months starting in October/November 2020. Multidimensional Personality Questionnaire subscale scores for stress-reaction and wellbeing were subjected to K-means cluster analyses that identified two groups of individuals, those with high stress-reaction and low wellbeing (negative temperament) and those with the opposite pattern defined as positive temperament (low stress-reaction and high wellbeing). Repeated measures ANOVAs assessed all time points and ANCOVAs assessed the biggest change at timepoint 2 while controlling for baseline symptoms. Results and Discussion: The negative temperament group reported greater mood symptoms, burnout, and COVID concern, than positive temperament participants overall, and negative participants' scores decreased over time while positive participants' scores increased over time. Burnout appeared to most strongly mediate this group-by-time interaction, with the burnout exhaustion scale driving anxiety and depression symptoms. PTSD symptoms were also related to COVID-19 health worry and negative temperament. Overall, results suggest that individuals with higher stress-reactions and more negative outlooks on life were at risk for anxiety, depression, and PTSD early in the COVID-19 pandemic, whereas individuals with positive temperament traits became more exhausted and thus more symptomatic over time. Targeting interventions to reduce mood symptoms in negative temperament individuals and prevent burnout/exhaustion in positive temperament individuals early in an extended crisis may be an efficient and effective approach to reduce the mental health burden on essential workers.
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Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patient cohort, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns extracted from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron-sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms that affect receptor expression and long-term potentiation. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.
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Importance: Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of young children and having a genetic contribution, the underlying causes remain poorly understood, likely due to the complex phenotypic and genetic heterogeneity among affected individuals. Objective: In this study, we leverage dense phenotype information from electronic health records to identify the disease features associated with tic disorders within the context of a clinical biobank. These disease features are then used to generate a phenotype risk score for tic disorder. Design: Using de-identified electronic health records from a tertiary care center, we extracted individuals with tic disorder diagnosis codes. We performed a phenome-wide association study to identify the features enriched in tic cases versus controls (N=1,406 and 7,030; respectively). These disease features were then used to generate a phenotype risk score for tic disorder, which was applied across an independent set of 90,051 individuals. A previously curated set of tic disorder cases from an electronic health record algorithm followed by clinician chart review was used to validate the tic disorder phenotype risk score. Main Outcomes and Measures: Phenotypic patterns associated with a tic disorder diagnosis in the electronic health record. Results: Our tic disorder phenome-wide association study revealed 69 significantly associated phenotypes, predominantly neuropsychiatric conditions, including obsessive compulsive disorder, attention-deficit hyperactivity disorder, autism, and anxiety. The phenotype risk score constructed from these 69 phenotypes in an independent population was significantly higher among clinician-validated tic cases versus non-cases. Conclusions and Relevance: Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex diseases, such as tic disorders. The tic disorder phenotype risk score provides a quantitative measure of disease risk that can be leveraged for the assignment of individuals in case-control studies or for additional downstream analyses.
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OBJECTIVE: Existing studies have shown changes in attention and emotion processing of disorder-relevant visual stimuli in those with obsessive compulsive disorder (OCD). However, early visual processing in OCD has not been assessed, as previous studies did not examine the entire time course of visual processing but instead assessed potential differences in pre-determined visual evoked potentials (VEPs). This study investigates the entire visual processing stream in OCD compared to healthy age-matched controls (HC) using emotionally-neutral visual stimuli and a data-driven rather than hypothesis-driven approach. METHODS: 35 HC and 26 participants with OCD underwent EEG recording while completing a modified Eriksen flanker task. Permutation-controlled t-tests were used to identify group differences in the data's full time course of visual evoked potentials. Baseline-corrected amplitudes at time points where the groups were significantly different were analyzed using ANCOVAs with BDI, BAI, and SNAP-inattentiveness scores included as covariates. RESULTS: This analysis identified enhanced P1 amplitudes to two visual stimuli (the initial flanker and the stimulus), corresponding to time windows of 65-93 ms and 157-187 ms post-flanker presentation in the OCD group compared to controls. Group (OCD vs. HC) was the strongest predictor of VEP amplitude during both time windows, with no significant influences of any covariates. CONCLUSIONS: This study showed an enhanced P1 component in people with OCD to neutral visual stimuli, potentially reflecting either inefficient or excessive early visual processing in this population. Additional inquiry is necessary to determine whether altered visual processing is associated with the sensory hypervigilance observed in those with OCD. SIGNIFICANCE: This work identifies early visual processing alterations in OCD using neutral stimuli and a data-driven approach.
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Electroencefalografía , Trastorno Obsesivo Compulsivo , Humanos , Potenciales Evocados Visuales , Percepción Visual , Atención/fisiología , Potenciales Evocados/fisiología , Tiempo de Reacción/fisiologíaRESUMEN
Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Diabetes Mellitus Tipo 2 , Síndrome de Tourette , Masculino , Femenino , Humanos , Síndrome de Tourette/genética , Trastorno del Espectro Autista/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Factores de RiesgoRESUMEN
BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.