The effects of Shaoma Zhijing granules and its main components on Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) represents a neurodevelopmental disorder characterized by an uncertain etiology and influencing factors. Frequently, it co-occurs with conditions such as attention deficit hyperactivity disorder, obsessive-compulsive disorder, and sleep disturbances, which have garnered substantial attention from the research community in recent years. Clinical trials have demonstrated that Shaoma Zhijing Granules (SMZJG, 5-ling granule, also known as TSupport or T92 under U.S. development), a traditional Chinese medicine compound, is an effective treatment for TS. PURPOSE: To conduct scientometric analysis on developing trends, research countries and institutions, current status, hot spots of TS and discuss the underlying mechanisms of SMZJG and its main components on TS. The aim is to provide valuable reference for ongoing clinical and basic research on TS and SMZJG. STUDY DESIGN & METHODS: Using Tourette syndrome, SMZJG and its main components along with their synonyms as keywords, we conducted a comprehensive search across major scientific databases including the Web of Science Core Collection, PubMed and China National Knowledge Infrastructure (CNKI) databases. A total of 5952 references and 99 patents were obtained. Among these, 5039 articles and reviews, as well as 54 patents were analyzed by Citespace and VOSviewer software. RESULTS: The available evidence indicates that the SMZJG's components likely exert their mechanisms in treating TS by regulating the dopaminergic pathway system, neurotransmitter imbalances, reducing neuroinflammation, promoting the repair of nerve damage and improving sleep disorders. CONCLUSION: This comprehensive analysis lays the foundation for an extensive exploration of the feasibility and clinical applications of SMZJG in TS treatment.

Scoping Review: Digital Mental Health Interventions for Children and Adolescents Affected by War.

OBJECTIVE: More than 200 million children and adolescents live in countries affected by violent conflict, are likely to have complex mental health needs, and struggle to access traditional mental health services. Digital mental health interventions have the potential to overcome some of the barriers in accessing mental health support. We performed a scoping review to map existing digital mental health interventions relevant for children and adolescents affected by war, to examine the strength of the evidence base, and to inform the development of future interventions. METHOD: Based on a pre-registered strategy, we systematically searched MEDLINE, Embase, Global Health, APA PsychInfo, and Google Scholar from the creation of each database to September 30, 2022, identifying k = 6,843 studies. Our systematic search was complemented by extensive consultation with experts from the GROW Network. RESULTS: The systematic search identified 6 relevant studies: 1 study evaluating digital mental health interventions for children and adolescents affected by war, and 5 studies for those affected by disasters. Experts identified 35 interventions of possible relevance. The interventions spanned from universal prevention to specialist-guided treatment. Most interventions directly targeted young people and parents or carers/caregivers and were self-guided. A quarter of the interventions were tested through randomized controlled trials. Because most interventions were not culturally or linguistically adapted to relevant contexts, their implementation potential was unclear. CONCLUSION: There is very limited evidence for the use of digital mental health interventions for children and adolescents affected by war at present. The review provides a framework to inform the development of new interventions. DIVERSITY & INCLUSION STATEMENT: We actively worked to promote sex and gender balance in our author group. STUDY PREREGISTRATION INFORMATION: Digital mental health interventions for children and young people affected by war: a scoping review; https://osf.io/; hrny9.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Interneuron loss and microglia activation by transcriptome analyses in the basal ganglia of Tourette syndrome.

Tourette syndrome (TS) is a disorder of high-order integration of sensory, motor, and cognitive functions afflicting as many as 1 in 150 children and characterized by motor hyperactivity and tics. Despite high familial recurrence rates, a few risk genes and no biomarkers have emerged as causative or predisposing factors. The syndrome is believed to originate in basal ganglia, where patterns of motor programs are encoded. Postmortem immunocytochemical analyses of brains with severe TS revealed decreases in cholinergic, fast-spiking parvalbumin, and somatostatin interneurons within the striatum (caudate and putamen nuclei). Here, we performed single cell transcriptomic and chromatin accessibility analyses of the caudate nucleus from 6 adult TS and 6 control post-mortem brains. The data reproduced the known cellular composition of the adult human striatum, including a majority of medium spiny neurons (MSN) and small populations of GABAergic and cholinergic interneurons. Comparative analysis revealed that interneurons were decreased by roughly 50% in TS brains, while no difference was observed for other cell types. Differential gene expression analysis suggested that mitochondrial function, and specifically oxidative metabolism, in MSN and synaptic function in interneurons are both impaired in TS subjects. Furthermore, such an impairment was coupled with activation of immune response pathways in microglia. Also, our data explicitly link gene expression changes to changes in cis-regulatory activity in the corresponding cell types, suggesting de-regulation as a factor for the etiology of TS. These findings expand on previous research and suggest that impaired modulation of striatal function by interneurons may be the origin of TS symptoms.

Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome. METHODS: Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression. RESULTS: Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect. CONCLUSIONS: This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.

Efficient reconstruction of cell lineage trees for cell ancestry and cancer.

Mosaic mutations can be used to track cell ancestries and reconstruct high-resolution lineage trees during cancer progression and during development, starting from the first cell divisions of the zygote. However, this approach requires sampling and analyzing the genomes of multiple cells, which can be redundant in lineage representation, limiting the scalability of the approach. We describe a strategy for cost- and time-efficient lineage reconstruction using clonal induced pluripotent stem cell lines from human skin fibroblasts. The approach leverages shallow sequencing coverage to assess the clonality of the lines, clusters redundant lines and sums their coverage to accurately discover mutations in the corresponding lineages. Only a fraction of lines needs to be sequenced to high coverage. We demonstrate the effectiveness of this approach for reconstructing lineage trees during development and in hematologic malignancies. We discuss and propose an optimal experimental design for reconstructing lineage trees.

Increased Alpha-Band Connectivity During Tic Suppression in Children With Tourette Syndrome Revealed by Source Electroencephalography Analyses.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder involving chronic motor and phonic tics. Most individuals with TS can suppress their tics for at least a short period of time. Yet, the brain correlates of tic suppression are still poorly understood. METHODS: In the current study, high-density electroencephalography was recorded during a resting-state and a tic suppression session in 72 children with TS. Functional connectivity between cortical regions was assessed in the alpha band (8-13 Hz) using an electroencephalography source connectivity method. Graph theory and network-based statistics were used to assess the global network topology and to identify brain regions showing increased connectivity during tic suppression. RESULTS: Graph theoretical analyses revealed distinctive global network topology during tic suppression, relative to rest. Using network-based statistics, we found a subnetwork of increased connectivity during tic suppression (p < .001). That subnetwork encompassed many cortical areas, including the right superior frontal gyrus and the left precuneus, which are involved in the default mode network. We also found a condition-by-age interaction, suggesting age-mediated increases in connectivity during tic suppression. CONCLUSIONS: These results suggest that children with TS suppress their tics through a brain circuit involving distributed cortical regions, many of which are part of the default mode network. Brain connectivity during tic suppression also increases as youths with TS mature. These results highlight a mechanism by which children with TS may control their tics, which could be relevant for future treatment studies.

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Evaluation of EEG biomarkers of Comprehensive Behavioral Intervention for Tics in children with Tourette syndrome.

OBJECTIVE: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment of Tourette syndrome (TS). However, the brain mechanisms involved in CBIT are poorly understood. Enhanced frontomesial EEG coherence during a Go/NoGo task has been suggested as a mechanism involved in voluntary tic control. In the current study, we conducted a randomized controlled trial to assess whether EEG coherence during a Go/NoGo task was associated with CBIT outcome. METHODS: Thirty-two children with TS were randomly assigned to CBIT or to treatment-as-usual (TAU). Treatment outcome was assessed by a blinded evaluator with the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impression - Improvement Scale (CGI-I). EEG was recorded during a Go/NoGo task at baseline and endpoint. EEG coherence was computed in the alpha frequency band between a priori selected channel pairs spanning the frontal and motor areas. RESULTS: Tic severity decreased significantly in the CBIT group. However, CBIT did not impact EEG coherence and baseline EEG coherence did not predict treatment outcome. CONCLUSIONS: Although CBIT was superior to TAU on blinded clinical outcomes, EEG coherence during the Go/NoGo task was not associated with change in tic severity. SIGNIFICANCE: The brain processes involved in the inhibition of motor responses do not appear to be involved in CBIT.

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Parental perspectives on attention-deficit/hyperactivity disorder treatments for children.

This study investigated parental perspectives and experiences on the evaluation and treatment process associated with attention-deficit/hyperactivity disorder (ADHD). Five hundred sixty-eight parents of youth 2-28 years-old (M = 9.37; SD = 4.11) diagnosed with ADHD responded to a 14-item online survey about their child's diagnosis and treatment. Parents reported that they had tried an average of 4.49 interventions (SD = 2.63). Parents further shared factors in treatment selection, most helpful parenting strategies, and preferences for types of treatments and treatment targets. A majority of parents reported incorporating many non-traditional strategies (e.g., exercise, healthy eating, outdoor activities) with goals of improving their child's coping skills, study habits, and anger management. The findings show that treatment choices were often selected based on trust in the provider, research support, and the child's preference. Given parental preferences for non-traditional strategies, treatment development efforts should consider these strategies as a component of a broader multimodal treatment approach to ADHD.

Protocol for a randomized controlled trial comparing the Circle of Security-parenting (COS-P) with treatment as usual in child mental health services.

BACKGROUND: The quality of a child's attachment to its primary caregiver plays an important role for its long-term socioemotional development. While 'secure' attachment is associated with better outcomes, 'insecure' attachment is associated with a higher risk of externalizing and internalizing symptoms. Children referred to mental health services show much higher rates of insecure attachment than the general population, yet the parent-child relationship is rarely in treatment focus. Attachment quality is closely associated with parental sensitive responsiveness that is target of attachment-based interventions like Circle of Security (COS). COS has shown to improve attachment quality and the well-being of both children and parents. No randomized controlled trials have investigated the effect of COS on parental sensitivity and child psychiatric symptoms in child mental health services. OBJECTIVES: To investigate whether COS-Parenting (COS-P) can increase observed maternal sensitivity and decrease children's psychiatric symptoms as an add on to treatment as usual (TAU). METHODS: In a randomized controlled parallel superiority trial COS-P is compared with TAU for parents of children referred to child mental health services (n = 186). Families are randomized 2:1 to intervention or control group, if their child is between 3 and 8 years old and scores ≥ 93d percentile on both the CBCL total score and the oppositional defiant disorder or conduct disorder subscale. Primary outcome is maternal sensitivity, secondary and exploratory outcomes include, among others, child psychiatric symptoms, parental stress and coping with children's negative emotions. Outcomes and adverse events are assessed before (T0) and after 10 weeks of treatment (T1) and 6 months later (T2). Regression analysis and /or ANOVA will be used for all outcomes. PERSPECTIVES: Targeting the parent-child relation has the potential to reduce psychiatric symptoms in children. This trial will provide valuable information if attachment-based interventions like COS-P can enhance treatment as usual in child mental health services. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT03578016.

Premonitory Urges Reconsidered: Urge Location Corresponds to Tic Location in Patients With Primary Tic Disorders.

OBJECTIVE: In patients with Tourette syndrome and other primary tic disorders (PTDs), tics are typically preceded by premonitory urges (PUs). To date, only a few studies have investigated the location and frequency of PUs, and contrary to clinical experience, the results suggest that PUs are not located in the same anatomic region as the tics. This study aimed to further explore PU location and frequency in detail, differentiating the kind and complexity of the corresponding tics, in a large sample of patients with PTD. METHODS: A total of 291 adult (≥ 18 years) patients with a confirmed diagnosis of chronic PTD were included. The study was conducted online, assement included tics and the general characterization of PUs and a sophisticated body drawing for locating PUs. RESULTS: We found that PUs were located in the same body area as, or in direct proximity to, the corresponding tic. Most frequently, PUs were located in the face and at the head (62.1%). Compared with simple tics, complex (motor and vocal) tics were more often preceded by a PU; but there was no difference in PU frequency observed between motor tics and vocal tics. PUs were more often experienced at the front than at the back of the body (73% vs. 27%), while there was no difference between the right and left sides (41.6% vs. 41.3%). CONCLUSION: The strong association between PU and tic location further supports the hypothesis that PUs represent the core of PTD. Accordingly, future therapies should focus on treating PUs to achieve greater tic reduction.

Electrophysiological signatures of inhibitory control in children with Tourette syndrome and attention-deficit/hyperactivity disorder.

Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, especially in children. Reduced inhibitory control abilities have been suggested as a shared phenotype across both conditions but its neural underpinnings remain unclear. Here, we tested the behavioral and electrophysiological correlates of inhibitory control in children with TS, ADHD, TS+ADHD, and typically developing controls (TDC). One hundred and thirty-eight children, aged 7-14 years, performed a Go/NoGo task during dense-array EEG recording. The sample included four groups: children with TS only (n = 47), TS+ADHD (n = 32), ADHD only (n = 22), and matched TDC (n = 35). Brain activity was assessed with the means of frontal midline theta oscillations, as well as the N200 and P300 components of the event-related potentials. Our analyses revealed that both groups with TS did not differ from other groups in terms of behavioral performance, frontal midline theta oscillations, and event-related potentials. Children with ADHD-only had worse Go/NoGo task performance, decreased NoGo frontal midline theta power, and delayed N200 and P300 latencies, compared to typically developing controls. In the current study, we found that children with TS or TS+ADHD do not show differences in EEG during a Go/NoGo task compared to typically developing children. Our findings however suggest that children with ADHD-only have a distinct electrophysiological profile during the Go/NoGo task as indexed by reduced frontal midline theta power and delayed N200 and P300 latencies.

Towards a definitive symptom structure of obsessive-compulsive disorder: a factor and network analysis of 87 distinct symptoms in 1366 individuals.

BACKGROUND: The symptoms of obsessive-compulsive disorder (OCD) are highly heterogeneous and it is unclear what is the optimal way to conceptualize this heterogeneity. This study aimed to establish a comprehensive symptom structure model of OCD across the lifespan using factor and network analytic techniques. METHODS: A large multinational cohort of well-characterized children, adolescents, and adults diagnosed with OCD (N = 1366) participated in the study. All completed the Dimensional Yale-Brown Obsessive-Compulsive Scale, which contains an expanded checklist of 87 distinct OCD symptoms. Exploratory and confirmatory factor analysis were used to outline empirically supported symptom dimensions, and interconnections among the resulting dimensions were established using network analysis. Associations between dimensions and sociodemographic and clinical variables were explored using structural equation modeling (SEM). RESULTS: Thirteen first-order symptom dimensions emerged that could be parsimoniously reduced to eight broad dimensions, which were valid across the lifespan: Disturbing Thoughts, Incompleteness, Contamination, Hoarding, Transformation, Body Focus, Superstition, and Loss/Separation. A general OCD factor could be included in the final factor model without a significant decline in model fit according to most fit indices. Network analysis showed that Incompleteness and Disturbing Thoughts were most central (i.e. had most unique interconnections with other dimensions). SEM showed that the eight broad dimensions were differentially related to sociodemographic and clinical variables. CONCLUSIONS: Future research will need to establish if this expanded hierarchical and multidimensional model can help improve our understanding of the etiology, neurobiology and treatment of OCD.

Prevalence of mental disorders in school children and adolescents in China: diagnostic data from detailed clinical assessments of 17,524 individuals.

BACKGROUND: To date, no national-scale psychiatric epidemiological survey for children and adolescents has been conducted in China. In order to inform government officials and policymakers and to develop a comprehensive plan for service providers, there was a clear need to conduct an up-to-date systematic nationwide psychiatric epidemiological survey. METHODS: We conducted a two-stage large-scale psychiatric point prevalence survey. Multistage cluster stratified random sampling was used as the sampling strategy. Five provinces were selected by comprehensively considering geographical partition, economic development, and rural/urban factors. In Stage 1, the Child Behavior Checklist was used as the screening tool. In Stage 2, Mini-International Neuropsychiatric Interview for Children and Adolescents and a diagnostic process based on the Diagnostic and Statistical Manual were used to make the diagnoses. Sampling weights and poststratification weights were employed to match the population distributions. Exploratory analyses were also performed using socio-demographic factors. Prevalence in socio-demographic factor subgroups and overall were estimated. Rao-Scott adjusted chi-square tests were utilized to determine if between-group differences were present. Factor interactions were checked by logistic regression analyses. RESULTS: A total of 73,992 participants aged 6-16 years of age were selected in Stage 1. In Stage 2, 17,524 individuals were screened and diagnosed. The weighted prevalence of any disorder was 17.5% (95% CI: 17.2-18.0). Statistically significant differences in prevalence of any psychiatric disorder were observed between sexes [χ2 (1, N = 71,929) = 223.0, p < .001], age groups [χ2 (1, N = 71,929) = 18.6, p < .001] and developed vs. developing areas [χ2 (1, N = 71,929) = 2,129.6, p < .001], while no difference was found between rural and urban areas [χ2 (1, N = 71,929) = 1.4, p = .239]. Male, younger individuals, children, and adolescents from developed areas had higher prevalence of any psychiatric disorder. The prevalence of any psychiatric disorder was found to decrease with the age in the male group, while the female group increased with the age. Individuals diagnosed with attention-deficit hyperactivity disorder, oppositional defiant disorder, a tic disorder, conduct disorder, and major depression disorder had the highest rates of comorbidity. CONCLUSIONS: The prevalence of any psychiatric disorder we found is the highest ever reported in China. These results urgently need to be addressed by public mental health service providers and policymakers in order to provide access to the necessary treatments and to reduce the long-term negative impact of these conditions on families and the society as a whole.

What are we optimizing for in autism screening? Examination of algorithmic changes in the M-CHAT.

The present study objectives were to examine the performance of the new M-CHAT-R algorithm to the original M-CHAT algorithm. The main purpose was to examine if the algorithmic changes increase identification of children later diagnosed with ASD, and to examine if there is a trade-off when changing algorithms. We included 54,463 screened cases from the Norwegian Mother and Child Cohort Study. Children were screened using the 23 items of the M-CHAT at 18 months. Further, the performance of the M-CHAT-R algorithm was compared to the M-CHAT algorithm on the 23-items. In total, 337 individuals were later diagnosed with ASD. Using M-CHAT-R algorithm decreased the number of correctly identified ASD children by 12 compared to M-CHAT, with no children with ASD screening negative on the M-CHAT criteria subsequently screening positive utilizing the M-CHAT-R algorithm. A nonparametric McNemar's test determined a statistically significant difference in identifying ASD utilizing the M-CHAT-R algorithm. The present study examined the application of 20-item MCHAT-R scoring criterion to the 23-item MCHAT. We found that this resulted in decreased sensitivity and increased specificity for identifying children with ASD, which is a trade-off that needs further investigation in terms of cost-effectiveness. However, further research is needed to optimize screening for ASD in the early developmental period to increase identification of false negatives.