A Multicenter Examination and Strategic Revisions of the Yale Global Tic Severity Scale

Objective To examine the internal consistency and distribution of the Yale Global Tic Severity Scale (YGTSS) scores to inform modification of the measure. Methods This cross-sectional study included 617 participants with a tic disorder (516 children and 101 adults), who completed an age-appropriate diagnostic interview and the YGTSS to evaluate tic symptom severity. The distributions of scores on YGTSS dimensions were evaluated for normality and skewness. For dimensions that were skewed across motor and phonic tics, a modified Delphi consensus process was used to revise selected anchor points. Results Children and adults had similar clinical characteristics, including tic symptom severity. All participants were examined together. Strong internal consistency was identified for the YGTSS Motor Tic score (α = 0.80), YGTSS Phonic Tic score (α = 0.87), and YGTSS Total Tic score (α = 0.82). The YGTSS Total Tic and Impairment scores exhibited relatively normal distributions. Several subscales and individual item scales departed from a normal distribution. Higher scores were more often used on the Motor Tic Number, Frequency, and Intensity dimensions and the Phonic Tic Frequency dimension. By contrast, lower scores were more often used on Motor Tic Complexity and Interference, and Phonic Tic Number, Intensity, Complexity, and Interference. Conclusions The YGTSS exhibits good internal consistency across children and adults. The parallel findings across Motor and Phonic Frequency, Complexity, and Interference dimensions prompted minor revisions to the anchor point description to promote use of the full range of scores in each dimension. Specific minor revisions to the YGTSS Phonic Tic Symptom Checklist were also proposed

Timing of selective basal ganglia white matter loss in premanifest Huntington’s disease

OBJECTIVES: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. METHODS: We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. RESULTS: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. CONCLUSIONS: Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings

STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.Seaside Therapeutics Inc

Validating automated segmentation tools in the assessment of caudate atrophy in Huntington's disease

Background: Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials.Methods: Using a cohort of early Huntington's disease (HD) patients (n = 46) and controls (n = 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input.Results: All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (p < 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups.Conclusions: Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.Neurological Motor Disorder

Submerged in the mainstream? A case study of an immigrant learner in a New Zealand primary classroom

Immigrant children from diverse language backgrounds face not only linguistic challenges when enrolled in mainstream English-medium classrooms, but also difficulties adjusting to an unfamiliar learning community. The culture of primary school classrooms in New Zealand typically reflects conventions across three dimensions: interactional, instructional task performance and cognitive-academic development. All three dimensions are underpinned by the culturally specific discourse conventions involved in language socialisation. New learners may be helped by classmates or their teacher to understand and successfully use these conventions, but left on their own they may sink rather than swim. This is a case study of one Taiwanese 11-year old boy, 'John', who entered a New Zealand primary classroom midway through the school year. John's basic conversational ability was sound, but he did not possess the interactive classroom skills needed to operate in the new culture of learning. Selected from a wider study of the classroom, transcript data from audio-recorded excerpts of John's interactions over several months with his teacher and classmates are interpreted from perspectives derived from sociocultural and language socialisation theories. The article concludes with a brief consideration of the extent to which John constructed, or was constrained from constructing meaningful learning experiences, and suggestions for further research and reflection

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus

Mapping the terrain: A conceptual schema for a mental health medication support service in community pharmacy

Objective: Mental health–related problems pose a serious issue for primary care, and community pharmacy could make a significant contribution, but there is a dearth of information. Methods: This article reports synthesis of the literature on mental health interventions across a range of pharmacy models, and pharmacy services in contexts beyond mental health. To best inform the design of a community pharmacy medication support intervention for mental health consumers, the literature was reported as a conceptual schema and subsequent recommendations for development, implementation and evaluation of the service. A broad conceptualisation was taken in this review. In addition to mental health and community pharmacy literature, policy/initiatives, organisational culture and change management principles, and evaluative processes were reviewed. Key words were selected and literature reviews undertaken using EMBASE, PubMed, CINAHL and Web of Science. Results: Recommendations were made around: medication support intervention design, consumer recruitment, implementation in community pharmacy and evaluation. Surprisingly, there is a scarce literature relating to mental health interventions in community pharmacy. Even so, findings from other pharmacy models and broader medicines management for chronic illness can inform development of a medication support service for mental health consumers. Key learnings include the need to expand medicines management beyond adherence with respect to both intervention design and evaluation. Conclusion: The conceptual framework is grounded in the need for programmes to be embedded within pharmacies that are part of the health system as a whole

White matter predicts functional connectivity in premanifest Huntington's disease

Objectives The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD. The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD

Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior

Objective: The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior. Method: Thirty-eight children, ages 5-17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA. Results: Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ≥18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test). Conclusion: Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance