Treating Tourette Together: An Agenda for Patient-Centered Research Focused on Comprehensive Behavioral Intervention for Tics.

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.

Long-term follow-up of acceptance-enhanced behavior therapy for trichotillomania.

Acceptance-enhanced behavior therapy for trichotillomania (AEBT-TTM) is effective in reducing trichotillomania (TTM) symptoms, but the durability of treatment effects remains in question. This study analyzed 6-month follow-up data from a large randomized clinical trial comparing AEBT-TTM to an active psychoeducation and supportive therapy control (PST). Adults with TTM (N=85; 92% women) received 10 sessions of AEBT-TTM or PST across 12 weeks. Independent evaluators assessed participants at baseline, post-treatment, and 6 months follow-up. For both AEBT-TTM and PST, self-reported and evaluator-rated TTM symptom severity decreased from baseline to follow-up. TTM symptoms did not worsen from post-treatment to follow-up. At follow-up, AEBT-TTM and PST did not differ in rates of treatment response, TTM diagnosis, or symptom severity. High baseline TTM symptom severity was a stronger predictor of high follow-up severity for PST than for AEBT-TTM, suggesting AEBT-TTM may be a better option for more severe TTM. Results support the efficacy of AEBT-TTM and show that treatment gains were maintained over time. Although AEBT-TTM yielded lower symptoms at post-treatment, 6-month follow-up outcomes suggest AEBT-TTM and PST may lead to similar symptom levels in the longer term. Future research should examine mechanisms that contribute to long-term gain maintenance.

Caregiver Perspectives on the Health Care System for Tic Disorders: Utilization and Barriers.

OBJECTIVE: This study aimed to understand health care experiences among a sample of caregivers of children with TDs to inform future directions for improving the health care system. METHODS: We conducted a survey of caregivers of youth with TDs and used descriptive statistics and quantitative analyses to characterize the health care utilization practices of the sample. RESULTS: The majority (70%) of families first consulted their pediatrician/primary care provider, and caregivers reported receiving care in line with current best practice guidelines. However, caregivers in the current sample perceived a lack of knowledgeability on the part of their first providers, which significantly predicted more providers seen and also reported difficulty finding specialty providers (63% of the sample reported difficulty finding a treatment provider who understood tics). CONCLUSION: Results suggest that improving caregiver satisfaction with early health care experiences for their child's TD may help to relieve the burden on families and the health care system more broadly, along with continued efforts to increase the number of specialty providers available.

Evaluating the feasibility, acceptability, and preliminary effectiveness of tele-comprehensive behavior therapy for tics (teleCBIT) for Tourette syndrome in youth and adults.

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.

Optimizing Individual Targeting of Fronto-Amygdala Network with Transcranial Magnetic Stimulation (TMS): Biophysical, Physiological and Behavioral Variations in People with Methamphetamine Use Disorder.

Background: Previous studies in people with substance use disorders (SUDs) have implicated both the frontopolar cortex and amygdala in drug cue reactivity and craving, and amygdala-frontopolar coupling is considered a marker of early relapse risk. Accumulating data highlight that the frontopolar cortex can be considered a promising therapeutic target for transcranial magnetic stimulation (TMS) in SUDs. However, one-size-fits-all approaches to TMS targets resulted in substantial variation in both physiological and behavioral outcomes. Individualized TMS approaches to target cortico-subcortical circuits like amygdala-frontopolar have not yet been investigated in SUDs. Objective: Here, we (1) defined individualized TMS target location based on functional connectivity of the amygdala-frontopolar circuit while people were exposed to drug-related cues, (2) optimized coil orientation based on maximizing electric field (EF) perpendicular to the individualized target, and (3) harmonized EF strength in targeted brain regions across a population. Method: MRI data including structural, resting-state, and task-based fMRI data were collected from 60 participants with methamphetamine use disorders (MUDs). Craving scores based on a visual analog scale were collected immediately before and after the MRI session. We analyzed inter-subject variability in the location of TMS targets based on the maximum task-based connectivity between the left medial amygdala (with the highest functional activity among subcortical areas during drug cue exposure) and frontopolar cortex using psychophysiological interaction (PPI) analysis. Computational head models were generated for all participants and EF simulations were calculated for fixed vs. optimized coil location (Fp1/Fp2 vs. individualized maximal PPI location), orientation (AF7/AF8 vs. orientation optimization algorithm), and stimulation intensity (constant vs. adjusted intensity across the population). Results: Left medial amygdala with the highest (mean ± SD: 0.31±0.29) functional activity during drug cue exposure was selected as the subcortical seed region. Amygdala-to-whole brain PPI analysis showed a significant cluster in the prefrontal cortex (cluster size: 2462 voxels, cluster peak in MNI space: [25 39 35]) that confirms cortico-subcortical connections. The location of the voxel with the most positive amygdala-frontopolar PPI connectivity in each participant was considered as the individualized TMS target (mean ± SD of the MNI coordinates: [12.6 64.23 -0.8] ± [13.64 3.50 11.01]). Individual amygdala-frontopolar PPI connectivity in each participant showed a significant correlation with VAS scores after cue exposure (R=0.27, p=0.03). Averaged EF strength in a sphere with r = 5mm around the individualized target location was significantly higher in the optimized (mean ± SD: 0.99 ± 0.21) compared to the fixed approach (Fp1: 0.56 ± 0.22, Fp2: 0.78 ± 0.25) with large effect sizes (Fp1: p = 1.1e-13, Hedges'g = 1.5, Fp2: p = 1.7e-5, Hedges'g = 1.26). Adjustment factor to have identical 1 V/m EF strength in a 5mm sphere around the individualized targets ranged from 0.72 to 2.3 (mean ± SD: 1.07 ± 0.29). Conclusion: Our results show that optimizing coil orientation and stimulation intensity based on individualized TMS targets led to stronger electric fields in the targeted brain regions compared to a one-size-fits-all approach. These findings provide valuable insights for refining TMS therapy for SUDs by optimizing the modulation of cortico-subcortical circuits.

Response Inhibition in Youth Undergoing Intensive Treatment for Obsessive Compulsive Disorder.

Response Inhibition (RI) is the ability to suppress behaviors that are inappropriate for a given context. Obsessive-compulsive disorder (OCD) has been associated with impaired RI in adults as measured by the Stop Signal Task (SST). Conflicting results have been found in terms of the relationship between OCD severity and SST performance, and no studies to date have examined the relationship between SST and response to OCD treatment. Also relatively unknown is whether RI performance in OCD is associated with developmental or gender differences. This naturalistic study examined the relationship between SST performance, OCD severity, and OCD treatment response in a pediatric sample undergoing intensive treatment involving exposure and response prevention and medication management (n = 36). The SST and Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS) were administered at admission and program discharge. OCD severity was not significantly related to stop signal reaction time (SSRT) in the whole sample and among subgroups divided by age and gender. Baseline SSRT and SSRT change did not predict CYBOCS change across treatment in the whole sample, but exploratory analyses indicated both were significant predictors among female adolescents. Results suggest there may be developmental gender differences in the relationship between RI and clinical improvement in pediatric OCD.

Differential extrinsic brain network connectivity and social cognitive task-specific demands in Autism Spectrum Disorder (ASD).

Few studies have used task-based functional connectivity (FC) magnetic resonance imaging to examine emotion-processing during the critical neurodevelopmental period of adolescence in Autism Spectrum Disorders (ASDs). Moreover, task designs with pervasive confounds (e.g., lack of appropriate controls) persist because they activate neural circuits of interest reliably. As an alternative approach to "subtracting" activity from putative control conditions, we propose examining FC across an entire task run. By pivoting our analysis and interpretation of existing paradigms, we may better understand neural response to non-focal instances of socially-relevant stimuli that approximate real-world experiences more closely. Hence, using two well-established affective tasks (face-viewing, face-matching) with diverging social-cognitive demands, we investigated extrinsic FC from amygdala (AMG) and fusiform gyrus (FG) seeds in typically-developing (TD; N = 17) and ASD (N = 17) male adolescents (10-18 yo) and clinical correlations (Social Communication Questionnaire; SCQ) of group FC differences. Participant data (4TD, 6ASD) with excessive head-motion were excluded from final analysis. Direct between-group comparisons revealed significant differences between groups for neural response but not task performance (accuracy, reaction time). During face-viewing, we found greater FC from AMG and FG seeds for ASD participants (ASD > TD) in regions involved in the Default Mode and Fronto-Parietal Task Control Networks. During face-matching, we found greater FC from AMG and FG seeds for TD participants (TD > ASD), in regions associated with the Salience, Dorsal Attention, and Somatosensory Networks. SCQ scores correlated positively with regions with group differences on the face-viewing task and negatively with regions identified for the face-matching task. Task-dependent group differences in FC despite comparable behavioral performance suggest that high-functioning ASD may wield compensatory strategies; clinically-correlated FC patterns may associate with differential task-demands, ecological validity, and context-dependent processing. Employing this novel approach may further the development of targeted therapeutic interventions informed by individual differences in the highly heterogeneous ASD population.

Distinguishing and Managing Acute-Onset Complex Tic-like Behaviors in Adolescence.

Consistent with international reports,1 this group of Tourette syndrome (TS) experts has noticed a recent increase in adolescents presenting with tic-like symptoms that show a markedly atypical onset and course. These sudden-onset motor movements and vocalizations are often associated with significant impairment and disability, resulting in emergency department visits and hospitalizations for some affected youths.

Considerations for Pairing Cognitive Behavioral Therapies and Non-invasive Brain Stimulation: Ignore at Your Own Risk.

Multimodal approaches combining cognitive behavioral therapies (CBT) with non-invasive brain stimulation (NIBS) hold promise for improving the treatment of neuropsychiatric disorders. As this is a relatively new approach, it is a critical time to identify guiding principles and methodological considerations to enhance research rigor. In the current paper, we argue for a principled approach to CBT and NIBS pairings based on synergistic activation of neural circuits and identify key considerations about CBT that may influence pairing with NIBS. Careful consideration of brain-state interactions and CBT-related nuances will increase the potential for these combinations to be positively synergistic.

Predictors and Prospective Course of PANS: A Pilot Study Using Electronic Platforms for Data Collection.

Objectives: Little is known about the longitudinal course of pediatric acute-onset neuropsychiatric syndrome (PANS) because existing literature is primarily cross-sectional. To begin to address this gap, two digital platforms were used to prospectively monitor neuropsychiatric symptoms in children with PANS. The aim was to identify baseline clinical characteristics that would predict the course of neuropsychiatric symptoms over 12 weeks. We compared relative compliance between two electronic data acquisition platforms and evaluated agreement between parent-child ratings of symptoms. Methods: For 12 weeks, 20 children with PANS and their parents completed weekly rating scales of neuropsychiatric symptoms on Research Electronic Data Capture (REDCap) and concurrently parents completed tri-weekly ratings on My Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Chart, a symptom monitoring website. Longitudinal data were analyzed by using regression analyses. Results: Greater duration of time between onset of PANS and study enrollment was associated with worsening of parent-rated neuropsychiatric symptoms over 12 weeks (p = 0.05). Higher scores on parents' Caregiver Burden Inventory at baseline predicted that children would report more severe symptoms over the 12-week period (p = 0.01). Compliance rates for parents were 86.3% for the weekly REDCap PANS Symptoms Rating Scale compared with 53.8% for the tri-weekly My PANDAS Chart ratings. There was moderate agreement between children and parents on the PANS Symptom Rating Scale (r = 0.55, p < 0.0001). Conclusion: Our study highlights the utility of electronic methods for tracking longitudinal symptoms in children with PANS and suggests that particular baseline characteristics (e.g., delay in identification and treatment of PANS, greater caregiver burden) may be indicative of a differential trajectory of PANS course, with more severe symptoms over the short term. clinicaltrials.gov NCT04382716.

Social Cognitive Interventions for Adolescents with Autism Spectrum Disorders: A Systematic Review.

INTRODUCTION: Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder, impacts social experience and functioning throughout the lifespan. Although the postnatal phase of neuroplasticity has been a focus for early interventions in ASD, a second critical period in adolescence has emerged as a promising target for experience-dependent remediation. Interventions addressing the multidimensional construct of social cognition have also shown potential as a therapeutic approach. Yet, to date, evidence-based social cognitive interventions (SCIs) designed for adolescents with ASD are still lacking. In this review, we aim to survey and synthesize the extant literature on SCIs for adolescents with ASD in order to inform next steps for treatment research. METHODS: Using the PRISMA guidelines, we limited our queries to peer-reviewed, English-language journal articles describing SCI trials for adolescents with ASD using a randomized controlled design. RESULTS: Eighteen articles in total met our inclusion/exclusion criteria. We present and discuss these trials using the non-exclusive categories of group-based social skills interventions, experiential-based interventions, and computer-assisted interventions. LIMITATIONS: To ensure a focus on adolescence, we excluded trials with teen-age participants if mean subject age was not between 12-18 years. Also, given the variability across studies in outcome measures, study designs, samples, and effect sizes, findings were incommensurable. CONCLUSIONS: Several reviewed SCIs reported post-treatment improvements in varied domains but findings were inconsistent. Further investigations of existing and novel interventions are warranted; attention to assessing and improving long-term skill transfer is essential. Technology-assisted augmentations may improve treatment efficacy and ecological validity of therapeutic gains.

Sertraline Effects on Striatal Resting-State Functional Connectivity in Youth With Obsessive-Compulsive Disorder: A Pilot Study.

OBJECTIVE: Foundational knowledge on neural circuitry underlying pediatric obsessive-compulsive disorder (OCD) and how it changes during standard treatment is needed to provide the basis for conceptualization and development of novel targeted treatments. This study explored the effects of sertraline, a selective serotonin reuptake inhibitor, on resting-state functional connectivity in cortico-striatal-thalamic-cortical circuits in pediatric OCD. METHOD: Medication-free youths with OCD (n = 14) and healthy controls (n = 14) were examined at baseline and 12 weeks with resting-state functional magnetic resonance imaging. Between scan sessions, participants with OCD received 12 weeks of sertraline. For each scan, seed-based whole-brain resting-state functional connectivity analyses were conducted with 6 striatal seeds. Analysis of variance examined the interaction between group and time on striatal connectivity, including cluster-based thresholding to correct for multiple tests. Connectivity changes within circuits identified in group analyses were correlated with clinical change. RESULTS: Two significant group-by-time effects in the OCD group showed increased striatal connectivity from baseline to 12 weeks compared with controls. Circuits demonstrating this pattern included the right putamen with the left frontal cortex and insula and the left putamen with the left frontal cortex and pre- and post-central cortices. Increase in connectivity in the left putamen circuit was significantly correlated with clinical improvement on the Children's Yale-Brown Obsessive-Compulsive Scale score (r = -0.58, p = .03). CONCLUSION: Sertraline appears to affect specific striatal-based circuits in pediatric OCD, and these changes in part could account for clinical improvement. Future work is needed to confirm these preliminary findings, which would facilitate identification of circuit-based targets for novel treatment development. CLINICAL TRIAL REGISTRATION INFORMATION: Effects of Sertraline on Brain Connectivity in Adolescents with OCD; https://clinicaltrials.gov/; NCT02797808.

Pediatric OCD in the era of RDoC.

The NIMH Research Domain Criteria (RDoC) initiative was established with the goal of developing an alternative research classification to further research efforts in mental health. While RDoC acknowledges that constructs should be considered within a developmental framework, developmental considerations have not yet been well integrated within the existing RDoC matrix. In this paper, we consider RDoC in relation to pediatric OCD, a paradigmatic example of a neuropsychiatric disorder that often has onset in childhood but is also present across the lifespan. We discuss three RDoC subdomains with relevance to OCD as exemplars, providing for each construct a brief review of normative developmental changes, the state of construct-relevant research in pediatric OCD, and challenges and limitations related to developmental considerations within each subdomain. Finally, we conclude with a brief discussion of how RDoC may continue to evolve with regard to developmental considerations in order to further research in pediatric OCD.

Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders.

Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression.

Sensory over-responsivity in trichotillomania (hair-pulling disorder).

OBJECTIVE: This study was an initial investigation of sensory-over responsivity (SOR) to external sensations among individuals with trichotillomania (TTM). METHODS: Adults endorsing DSM-5 TTM criteria (N = 609) and a non-affected comparison sample (N = 268) completed a self-report survey. RESULTS: The majority of the TTM group endorsed SOR symptoms; three-quarters endorsed at least mild tactile and auditory SOR. About 15% endorsed SOR symptoms in the severe to extreme range. TTM participants had significantly higher mean scores in both auditory (t (652.89) = -6.51, p < .001, d = .45) and tactile (t (655.24) = -8.38, p < .001, d = .58) modalities than comparison participants, with medium effect sizes. Greater levels of SOR were related to greater levels of perfectionism and by-proxy pulling urges. SOR was significantly and positively correlated with functional impairment when controlling for TTM severity. CONCLUSION: This study expands prior work in obsessive-compulsive related disorders by contributing the first data about associations between TTM and over-responsivity to external sensations. Findings collectively suggest SOR may be related to maladaptive emotion regulation processes in TTM. A novel measure of SOR was developed and administered in this study.