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Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Abstract Background The Albert J. Solnit Integrated Training Program (AJSP) is an educational initiative designed to prepare physician-scientists for independent careers in the investigation and treatment of childhood psychiatric disorders. Methods We compared fifteen cohorts (each representing a consecutive year of matriculation) of AJSP trainees and graduates (n = 30) to peers who were comparably ranked in our original match lists but ultimately pursued residency programs elsewhere (n = 60). Outcomes of interest between the two groups included professional affiliation, as measured by: (1) membership in the American Academy of Child and Adolescent Psychiatry (AACAP); and (2) certification by the American Board of Psychiatry and Neurology (ABPN), as well as three domains of research productivity: (1) Competitive awards received from AACAP; (2) Publication-related metrics derived from the National Library of Medicine (NLM); and (3) Federal grant funding from the National Institutes of Health (NIH). Results AJSP participants were more commonly affiliated with AACAP and board certified in CAP. AJSP graduates and trainees outperformed their control group peers in several research outcomes: (1) Receipt of AACAP awards and number of awards per recipient were higher, and time to first award shorter in the AJSP than in the control group; (2) AJSP participants had more publications in PubMed, more first-authored publications, a higher h-index, and a shorter time to first publication than participants in the control group; and (3) NIH K- or R-series funding success rate was higher among AJSP participants (p

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.

abstract: Children's environments - especially relationships with caregivers - sculpt not only developing brains but also multiple bio-behavioral systems that influence long-term cognitive and socioemotional outcomes, including the ability to empathize with others and interact in prosocial and peaceful ways. This speaks to the importance of investing resources in effective and timely programs that work to enhance early childhood development (ECD) and, by extension, reach communities at-scale. Given the limited resources currently devoted to ECD services, and the devastating impact of COVID-19 on children and communities, there is a clear need to spur government leaders and policymakers to further invest in ECD and related issues including gender and racial equity. This essay offers concrete examples of scholarly paradigms and leadership efforts that focus on child development to build a peaceful, equitable, just, and sustainable world. As scholars and practitioners, we need to continue to design, implement, assess, and revise high-quality child development programs that generate much-needed evidence for policy and programmatic changes. We must also invest in global partnerships to foster the next generation of scholars, practitioners, and advocates dedicated to advance our understanding of the bio-behavioral systems that underlie love, sociality, and peace across generations. Especially where supported by structural interventions, ECD programs can help create more peaceful, just, and socially equitable societies.

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS.Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS.Results: A significant relationship between OCS and the right thalamus SPC (p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS.Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes.

Background: The Albert J. Solnit Integrated Training Program (AJSP) is a novel educational initiative designed to prepare physician-scientists for independent careers in the investigation and treatment of childhood psychiatric disorders.Methods: We conducted a qualitative study to explore the impact and active components of the AJSP through hour-long individual interviews of its enrollees and graduates. We were specifically interested in identifying individual or programmatic traits for success that could be replicated elsewhere. As components of our theoretical framework, we used sources on Strength, Weakness, Opportunity, and Threat (SWOT) Analysis as applied to healthcare, and on mentorship and career development as pertaining to child and adolescent psychiatry (CAP).Results: Thirty-four individuals matriculated into the AJSP between 2004 and 2020, 33 (97%) of whom participated. Through iterative thematic analysis, we developed a model consisting of quadrants resulting from the intersection of a developmental perspective (spanning professional or personal spheres) and a reflective direction (with outward- or inward-facing vantage points). The model can be of practical utility through putative questions that trainees/program leaders could ask themselves by using the four domains as points of departure: (I) Individual: “Is becoming a clinician-scientist right for me?”/“What traits are we looking for in prospective applicants?”; (II) Program: “Is this the right program for me?”/“What is the right balance between structure and freedom for trainees to thrive in?”; (III) Mentorship: “What is the right number and constellation of mentors for me?”/“How can we optimize our experience and backgrounds toward the benefit of our trainees?”; and (IV) Charting Course: “Who do I want to become?”/“How can we help our charges embrace, find, or reconnect with their true vocation?”Conclusion: Our analytic approach can help identify, refine, and replicate programs that are urgently needed to increase the workforce of clinician-scientists dedicated to improving the well-being and mental health of children and families. The model we describe can be fruitfully applied to the self-reflection by individuals or program leaders. Although based on a single program with very specific goals, the model could also be applied to other training initiatives within psychiatry—and beyond.

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive–compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.

Objective: The goal of this article is to review the past decade's literature and provide a critical commentary on the involvement of immunological mechanisms in normal brain development, as well as its role in the pathophysiology of Tourette syndrome, other Chronic tic disorders (CTD), and related neuropsychiatric disorders including Obsessive-compulsive disorder (OCD) and Attention deficit hyperactivity disorder (ADHD).Methods: We conducted a literature search using the Medline/PubMed and EMBASE electronic databases to locate relevant articles and abstracts published between 2009 and 2020, using a comprehensive list of search terms related to immune mechanisms and the diseases of interest, including both clinical and animal model studies.Results: The cellular and molecular processes that constitute our “immune system” are crucial to normal brain development and the formation and maintenance of neural circuits. It is also increasingly evident that innate and adaptive systemic immune pathways, as well as neuroinflammatory mechanisms, play an important role in the pathobiology of at least a subset of individuals with Tourette syndrome and related neuropsychiatric disorders In the conceptual framework of the holobiont theory, emerging evidence points also to the importance of the “microbiota-gut-brain axis” in the pathobiology of these neurodevelopmental disorders.Conclusions: Neural development is an enormously complex and dynamic process. Immunological pathways are implicated in several early neurodevelopmental processes including the formation and refinement of neural circuits. Hyper-reactivity of systemic immune pathways and neuroinflammation may contribute to the natural fluctuations of the core behavioral features of CTD, OCD, and ADHD. There is still limited knowledge of the efficacy of direct and indirect (i.e., through environmental modifications) immune-modulatory interventions in the treatment of these disorders. Future research also needs to focus on the key molecular pathways through which dysbiosis of different tissue microbiota influence neuroimmune interactions in these disorders, and how microbiota modification could modify their natural history. It is also possible that valid biomarkers will emerge that will guide a more personalized approach to the treatment of these disorders.

Background: Tourette disorder (TD) and other chronic tic disorders are neurodevelopmental/neuropsychiatric disorders characterized by motor and/or vocal tics. Family studies indicate that TD strongly aggregates within families and that other chronic tic disorders are biologically related such that studies typically combine them into any chronic tic disorder (CTD). Because of stigma, bullying, and comorbidity with other neuropsychiatric disorders, CTDs can severely impact the quality of life of individuals with these disorders.Objectives: The genetic architecture of CTDs is complex and heterogeneous, involving a myriad of genetic variants. Thus, providing familial recurrence risks is based on empirical recurrence risk estimates rather than genetic testing. Because empiric recurrence risks for CTDs have not been published, the purpose of this study is to calculate and report these recurrence risks estimates.Methods: Based on population prevalence and increased risk to different relatives from a large population-based family study, we calculated the empiric recurrent risk estimate for each relative type (full sibling, parents, offspring, all first-degree, and all second-degree).Results: The recurrence risk estimate for CTDs in first-degree relatives is 29.9% [95% confidence interval (CI) = 23.2–38.5%]. The risk is higher in males, 33.7% (95% CI = 26.2–43.3%), than females, 24.3% (95% CI = 18.9–31.3%).Conclusions: Given the complex, heterogeneous genetic architecture of CTDs, individuals concerned about recurrence risk should be referred to genetic counseling. Such counseling should include discussion of the derivation and limitations of these empiric recurrence risk estimates, including the upper and lower limits of the range of risk.

Movement, behavioral, and neuropsychiatric disorders in children have been linked to infections and a group of anti-neuronal autoantibodies, implying dopamine receptor-mediated encephalitis within the basal ganglia. The purpose of this study was to determine if anti-neuronal biomarkers, when used as a group, confirmed the acute disease in Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). IgG autoantibodies against four neuronal autoantigens (tubulin, lysoganglioside GM1, and dopamine receptors D1 and D2) were detected in SC sera (N=8), sera and/or cerebrospinal fluid (CSF) from two groups of PANDAS cases (N=25 first group and N=35 second group), sera from Tourette's syndrome (N=18), obsessive-compulsive disorder (N=25), attention deficit hyperactivity disorder (N=18), and healthy controls (N=28) by direct enzyme-linked immunosorbent assay (ELISA). IgG specific for neuronal autoantigens was significantly elevated during the acute symptomatic phase, and the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) pathway was significantly elevated in human neuronal cells. Five assays confirmed the disease in SC and in two groups of children with PANDAS. In 35 acute onset PANDAS patients, 32 sera (91.4%) were positive for one or more of the anti-neuronal autoantibodies compared with 9 of 28 healthy controls (32.1%, p

Background: Obsessive-compulsive disorder (OCD) is often a life-long disorder with high psychosocial impairment. Serotonin reuptake inhibitors (SRIs) are the only FDA approved drugs, and approximately 50% of patients are non-responders when using a criterion of 25% to 35% improvement with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). About 30% are non-responders to combined first-line therapies (SRIs and exposure and response prevention). Previous research (one open, one randomized clinical trial) has demonstrated that Kundalini Yoga (KY) meditation can lead to an improvement in symptoms of obsessive-compulsive severity. We expand here with a larger trial.Design: This trial compared two parallel run groups [KY vs. Relaxation Response meditation (RR)]. Patients were randomly allocated based on gender and Y-BOCS scores. They were told two different (unnamed) types of meditation would be compared, and informed if one showed greater benefits, the groups would merge for 12 months using the more effective intervention. Raters were blind in Phase One (0–4.5 months) to patient assignments, but not in Phase Two.Main Outcome Measures: Primary outcome variable, clinician-administered Y-BOCS. Secondary scales: Dimensional Yale-Brown Obsessive Compulsive Scale (clinician-administered), Profile of Mood Scales, Beck Anxiety Inventory, Beck Depression Inventory, Clinical Global Impression, Short Form 36 Health Survey.Results: Phase One: Baseline Y-BOCS scores: KY mean = 26.46 (SD 5.124; N = 24), RR mean = 26.79 (SD = 4.578; N = 24). An intent-to-treat analysis with the last observation carried forward for dropouts showed statistically greater improvement with KY compared to RR on the Y-BOCS, and statistically greater improvement on five of six secondary measures. For completers, the Y-BOCS showed 40.4% improvement for KY (N = 16), 17.9% for RR (N = 11); 31.3% in KY were judged to be in remission compared to 9.1% in RR. KY completers showed greater improvement on five of six secondary measures. At the end of Phase Two (12 months), patients, drawn from the initial groups, who elected to receive KY continued to show improvement in their Y-BOCS scores.Conclusion: KY shows promise as an add-on option for OCD patients unresponsive to first line therapies. Future studies will establish KY’s relative efficacy compared to Exposure and Response Prevention and/or medications, and the most effective treatment schedule.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01833442.

Face perception is a highly conserved process that directs our attention from infancy and is supported by specialized neural circuitry. Oxytocin (OT) can increase accuracy and detection of emotional faces, but these effects are mediated by valence, individual differences, and context. We investigated the temporal dynamics of OT’s influence on the neural substrates of face perception using event related potentials (ERPs). In a double blind, placebo controlled within-subject design, 21 healthy male adults inhaled OT or placebo and underwent ERP imaging during two face processing tasks. Experiment 1 investigated effects of OT on neural correlates of fearful vs. neutral facial expressions, and Experiment 2 manipulated point-of-gaze to neutral faces. In Experiment 1, we found that OT reduced N170 latency to fearful faces. In Experiment 2, N170 latency was decreased when participant gaze was directed to the eyes of neutral faces; however, there were no OT-associated effects in response to different facial features. Findings suggest OT modulates early stages of social perception for socially complex information such as emotional faces relative to neutral. These results are consistent with models suggesting OT impacts the salience of socially informative cues during processing, which leads to downstream effects in behavior. Future work should examine how OT affects neural processes underlying basic components of social behavior (such as, face perception) while varying emotional expression of stimuli or comparing different characteristics of participants (e.g., gender, personality traits).

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson’s disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with implanted DBS worldwide, have delayed regulatory agency approval (e.g. FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry.

Tourette syndrome (TS) is a common neuropsychiatric disorder in children characterized by multiple motor and vocal tics that fluctuate in severity and lasting for at least 1 year. Boys are more commonly affected than girls. Symptoms usually begin with simple motor or vocal tics which then evolve into more complex motor and vocal tics over time. Premonitory sensory urges are common in children over the age of 8 years, and these urges help distinguish tics from symptoms of other movement disorders. Common comorbidities of TS include attention deficit hyperactivity disorder, obsessive-compulsive disorder and learning difficulties. Several genes have been assessed as candidate genes for TS; environmental factors such as stress and streptococcal infections might also contribute to its etiology. The pathophysiology of TS mainly involves dysfunction of basal ganglia-related circuits and hyperactive dopaminergic innervations. A thorough history assessment and neurological examination are important for the correct diagnosis and differentiation from other movement disorders. Treatment for TS should focus on improving the patient's social functioning, minimizing the impairment from cormobid disorders, and controlling tics, if they are severe. Commonly used medications for TS include a2-adrenergic agonists and atypical neuroleptics. Habit reversal therapy is an effective option for TS, and repetitive transcranial magnetic stimulation may be a promising approach for severe cases.

Background: Deep brain stimulation (DBS) remains an experimental but promising treatment for patients with severe refractory Gilles de la Tourette syndrome (TS). Controversial issues include the selection of patients (age and clinical presentation), the choice of brain targets to obtain optimal patient‐specific outcomes, and the risk of surgery‐ and stimulation‐related serious adverse events.Methods: This report describes our open‐label experience with eight patients with severe refractory malignant TS treated with DBS. The electrodes were placed in the midline thalamic nuclei or globus pallidus, pars internus, or both. Tics were clinically assessed in all patients pre‐ and postoperatively using the Modified Rush Video Protocol and the Yale Global Tic Severity Scale (YGTSS). Results: Although three patients had marked postoperative improvement in their tics (>50% improvement on the YGTSS), the majority did not reach this level of clinical improvement. Two patients had to have their DBS leads removed (one because of postoperative infection and another because of lack of benefit).Discussion: Our clinical experience supports the urgent need for more data and refinements in interventions and outcome measurements for severe, malignant, and medication‐refractory TS. Because TS is not an etiologically homogenous clinical entity, the inclusion criteria for DBS patients and the choice of brain targets will require more refinement.

Objective: To investigate plasma concentrations of S100B (a calcium-binding protein derived primarily from the glia) and inflammatory cytokines in children with autism and the relationship between S100B and cytokine concentrations. Methods: Plasma levels of S100B, tumor necrosis factor alpha (TNF-α), interferon gamma, interleukin (IL)-1β, IL-4, IL-6, IL-10, and IL-17A were measured in 40 unmedicated children with autism and 35 normally developing healthy children. The severity of autism was assessed using the Childhood Autism Rating Scale (CARS). Results: Concentrations of both S100B and TNF-α were higher in children with autism before and after adjusting for a priori-selected confounders (age, sex, and body mass index). S100B concentrations were higher in children with severe autism compared to children with mild-moderate autism. However, this association remained as a trend after adjusting for confounders. S100B concentrations correlated positively with TNF-α concentrations. Conclusion: Our findings showing an increase in peripheral concentrations of S100B and TNF-α provide limited support to the hypothesis about the roles of altered immune function and S100B in autism spectrum disorder (ASD). Studies of larger numbers of well-characterized individuals with ASD are needed to clarify the potential role of the immune system in the pathophysiology of this disorder.