Gamified Closed-Loop Intervention Enhances Tic Suppression in Children: A Randomized Trial.

BACKGROUND: Gamification of behavioral intervention for tic disorders (TDs) potentially enhances compliance and offers key clinical advantages. By delivering immediate positive feedback upon tic-suppression, games may counteract negative reinforcement, which presumably contribute to tic consolidation by relieving uncomfortable premonitory urges. OBJECTIVES: We developed a gamified protocol (XTics), which leverages this potential by combining gamified tic-triggering with immediate feedback, and evaluated its clinical value in enhancing tic suppression. METHODS: XTics encompasses two conditions: Immediate and Contingent Reward (ICR), where game progression is contingent upon successful tic suppression, and Delayed Reward (DR), where game events' outcomes are random. Employing a randomized crossover design, 35 participants (aged 7-15 years) underwent daily gaming sessions over a week per condition. Improvements in our primary measures, including the inter-tic interval (ITI) and tic severity assessment by blinded evaluators (Yale Global Tic Severity-Total Tic Score [YGTSS-TTS], Rush), and parents (Parent Tic Questionnaire [PTQ]), were compared between ICR and DR, and assessed across conditions for the 4-week protocol. RESULTS: No participant voluntarily left the study before completing its two-phase protocol. As expected, ITI showed significantly larger improvement (Z = 4.19, P = 2.85 × 10-5) after ICR (1442 ± 2250%) versus DR (242 ± 493%) training, increasing at a higher pace (t(67) = 3.15, P = 0.0025). Similarly, Rush tic severity scores reduced more post-ICR versus DR (t(47) = 3.47, P = 0.002). We observed a clinically significant reduction of 25.69 ± 23.39% in YGTSS-TTS following a f4-week protocol including both conditions. Parent-reported tic severity decreased by 42.99 ± 31.69% from baseline to 3 months post-treatment. CONCLUSIONS: The combination of gamified tic-triggering with immediate and contingent rewards demonstrates a promising approach for enhancing treatment efficacy in TDs, boosting traditional therapeutic methods. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study.

BACKGROUND: Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. OBJECTIVES: The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. METHODS: UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test. RESULTS: Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. CONCLUSION: There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of movie and video game elements on tic manifestation in children.

BACKGROUND AND PURPOSE: Children in developed countries spend a significant portion of their waking hours engaging with audiovisual content and video games. The impact of media consumption on children's health and well-being has been widely studied, including its effects on tic disorders. Previous studies have shown that tic frequency can both increase and decrease during activities like gaming and television watching, resulting in mixed findings. METHODS: To better understand the impact of audiovisual media on tics, we conducted a fine-grained tic manifestation analysis. We focused on the effects of the impact of a movie scene with suspensful elements and a video game designed to heighten anticipation, thought to stimulate phasic and striatal dopamine release. We closely monitored tic frequency throuhghout these experiences based on moment-to-moment tic annotation. The study included 20 participants (19 males aged 7-16) diagnosed with tic disorders (Yale Global Tic Severity Scale≥8), and we tested the replicability of our findings with an independent group of 36 children (15 females, aged 7-15) with tic disorders. RESULTS: During film viewing, we observed significant synchronization in the temporal tic patterns of various individuals despite diversity in their tic profiles. Furthermore, employing a video game developed for our study, we found that tic frequency increases during anticipation of a pending reward. This finding was replicated in a second experiment with an independent cohort. CONCLUSIONS: Our results indicate that tic frequency is affected by media elements in the short-term, and call for further investigation of the long-term impacts of exposure to such tic triggers.

Group comprehensive behavioral intervention for tics contribution to broader cognitive and emotion regulation in children.

There is increasing evidence for the effectiveness of behavioral techniques in managing tics in youth with Tourette syndrome and tics disorders (TDs). One such intervention is Comprehensive Behavioral Intervention for Tics (CBIT), which focuses on reducing tic severity by training control and regulation. In view of the regulation deficits characteristic to TDs, in the current study, we aimed to explore the contribution of CBIT beyond tic control, to a wider expression of regulation abilities-cognitive inhibition and emotion regulation. A total of 55 participants with TDs, aged 8-15, who were randomly assigned to group-CBIT or group-Educational Intervention for Tics, were compared on cognitive inhibition tests and use of emotion-regulation strategies, pre- and post-intervention. Whereas on none of the scales a significant interaction effect was found reflecting superiority of CBIT over EIT, repeated measures ANOVA revealed a significant time effect, with post hoc analyses indicating that cognitive inhibition and cognitive reappraisal significantly increased following CBIT intervention only. Within the group-CBIT, the increase in cognitive reappraisal was associated with higher intellectual ability. These findings may lead to a broader understanding of CBIT contribution to more than tic control, but rather to better cognitive and emotional regulation abilities.

Internet-based guided self-help comprehensive behavioral intervention for tics (ICBIT) for youth with tic disorders: a feasibility and effectiveness study with 6 month-follow-up.

Practice guidelines endorse comprehensive behavioral intervention for tics (CBIT) as first-line treatment for tic disorders (TD) in youth. Nevertheless, CBIT is rarely available due to various barriers. This study evaluated the feasibility and potential effectiveness of an Internet-based, self-help CBIT program (ICBIT) guided by parents with minimal therapist support delivered via telepsychotherapy. Forty-one youths, aged 7-18 years, were randomly assigned to receive either ICBIT (n = 25) or a wait-list (WL) condition (n = 16) in a crossover design. ICBIT was feasible to implement and at post-treatment, 64% of the participants have improved significantly. Results demonstrated clinically meaningful reductions in tic severity and improved youth global impairment and functioning. Gains were maintained over a 6-month follow-up period. The effect size for the primary outcome measure (Yale Global Tic Severity Scale) ranged between large effect size (Cohen"s d = 0.91) at post-intervention to very large effect size (Cohen's d = 2.25) 6 months after the end of the acute intervention. These were comparable to face-to-face delivery treatment trials for TD. Participants rated the intervention as highly acceptable and satisfactory. Youth receiving ICBIT experienced improvement in self-esteem and comorbidity. Finally, during the COVID-19 pandemic, the ICBIT program enabled the delivery of the intervention consecutively without interruption. The results observed provide preliminary evidence of the feasibility and effectiveness of this innovative modality to assist youth with TD and remove various barriers to treatment, including those during a public crisis, such as the COVID-19 pandemic. Larger studies with an active control group are warranted.Trial registration URL: http://clinicaltrials.gov, ClinicalTrials.gov Identifier: NCT04087616.

Group behavioral interventions for tics and comorbid symptoms in children with chronic tic disorders.

Exposure and Response Prevention (ERP), Habit Reversal Training (HRT) and Comprehensive Behavioral Intervention for Tics (CBIT) are effective in reducing tic severity. ERP and HRT have recently gained primary support in a group setting, while CBIT has not been examined similarly. We compared the efficacy of group-CBIT to group-Educational Intervention for Tics (group-EIT) for tics and comorbid symptoms. Children with Tourette Syndrome (TS) or Chronic Tic Disorder (CTD) were randomized to group-CBIT or group-EIT. Tics and comorbid symptoms were assessed in forty-six children pre- and postintervention, and 3-month later. Yale Global Tic Severity Scale (YGTSS) Motor tic severity decreased following both interventions, and was maintained at follow-up for group-CBIT only. The Parent Tic Questionnaire (PTQ) showed significant decrease in total and motor tic severity following group-CBIT only, a gain maintained three months later. YGTSS impairment score decreased following both interventions and was maintained at follow-up. YGTSS vocal tic severity score increased following both interventions, and then decreased significantly at follow up. Co-morbid symptoms including anxiety, behavioral problems, and aggressive behavior decreased following both interventions. Children with behavioral problems benefitted less while children with higher intellectual ability benefit more from intervention. Both group interventions showed efficacy in reducing tic impairment and comorbid symptoms. Group-CBIT was superior to group-EIT in reducing motor tic severity at 3-month follow-up, showing an advantage for tic-focused treatment. Based on the PTQ, group-CBIT was superior to group-EIT in reducing motor, vocal, and total tic scores, a gain maintained three months later. Clinical trial registry information-Group Intervention for Children with Chronic Tics Syndrome: CBIT vs Psychoeducational Intervention URL: http://clinicaltrials.gov , Identifier: NCT02407951, http://www.controlled-trials.com ).

Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.

Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.

Glut1 deficiency syndrome and erythrocyte glucose uptake assay.

OBJECTIVE: The Glut1 deficiency syndrome (Glut1 DS) phenotype has expanded dramatically since first described in 1991. Hypoglycorrhachia and decreased erythrocyte 3-OMG uptake are confirmatory laboratory biomarkers. The objective is to expand previous observations regarding the diagnostic value of the uptake assay. METHODS: One hundred and nine suspected cases of Glut-1 DS were studied. All cases had a consistent clinical picture and hypoglycorrhachia. The uptake assay was decreased in 74 cases (group 1) and normal in 35 cases (group 2). We identified disease-causing mutations in 70 group 1 patients (95%) and one group 2 patient (3%). RESULTS: The cut-off for an abnormally low uptake value was increased from 60% to 74% with a corresponding sensitivity of 99% and specificity of 100%. The correlation between the uptake values for the time-curve and the kinetic concentration curve were strongly positive (R(2) = 0.85). Significant group differences were found in CSF glucose and lactate values, tone abnormalities, and degree of microcephaly. Group 2 patients were less affected in all domains. We also noted a significant correlation between the mean erythrocyte 3-OMG uptake and clinical severity (R(2) = 0.94). INTERPRETATION: These findings validate the erythrocyte glucose uptake assay as a confirmatory functional test for Glut1 DS and as a surrogate marker for GLUT1 haploinsufficiency.

Glut1 deficiency: inheritance pattern determined by haploinsufficiency.

Two families manifesting Glut1 deficiency syndrome (DS) as an autosomal recessive trait are described. In 1 family, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother. A de novo mutation developed in the paternal allele, producing compound heterozygosity. In another family, 2 mildly affected sisters inherited mutations from their asymptomatic heterozygous consanguineous parents. Red blood cell glucose uptake residual activity, a surrogate of haploinsufficiency, correlated with the clinical severity. These cases demonstrate that Glut1 DS may present as an autosomal recessive trait. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency.

Acute and Long-Term Effects of an Internet-Based, Self-Help Comprehensive Behavioral Intervention for Children and Teens with Tic Disorders with Comorbid Attention Deficit Hyperactivity Disorder, or Obsessive Compulsive Disorder: A Reanalysis of Data from a Randomized Controlled Trial.

Attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD) and tic disorders (TD) commonly co-occur. In addition, specific inattention difficulties and poor impulse control are related to TD in the absence of comorbid ADHD. In this study we reanalyzed data from a recently completed study comparing internet-delivered, self-help comprehensive behavioral intervention for tics (ICBIT) with a waiting-list control group. The current study describes the effects of an (ICBIT) in children and adolescents with TD with and without comorbid diagnoses of ADHD or OCD at post intervention and over three- and six-month follow-up periods. Thirty-eight 7 to 18-year-olds completed the ICBIT. Of these, 16 were diagnosed with comorbid ADHD and 11 were diagnosed with OCD. A significant improvement in tic measures was found in all groups. Both the TD + ADHD and the TD - ADHD groups were similar in the magnitude of tic reduction from baseline to post-treatment, and at the three and six-month follow-up assessments. However, the TD + OCD group benefitted less from intervention than the TD-OCD group. There were meaningful reductions in parental reports of inattention, as well as hyperactive and impulsive symptoms at post intervention and over the 6-month follow-up period. Thus, ICBIT can be effectively delivered in the presence of comorbid ADHD or OCD symptomatology and may reduce symptoms of inattention and impulsivity. Larger studies of ICBIT in children and teens with TD and comorbid ADHD and OCD are needed to optimize responses to ICBIT.

The spectrum of movement disorders in Glut-1 deficiency.

To assess the spectrum of movement disorders, we reviewed video recordings and charts of 57 patients with Glut-1 deficiency. Eighty-nine percent of patients with Glut-1 deficiency syndrome had a disturbance of gait. The most frequent gait abnormalities were ataxic-spastic and ataxic. Action limb dystonia was observed in 86% of cases and mild chorea in 75%. Cerebellar action tremor was seen in 70% of patients, myoclonus in 16%, and dyspraxia in 21%. Nonepileptic paroxysmal events occurred in 28% of patients, and included episodes of ataxia, weakness, Parkinsonism and nonkinesogenic dyskinesias. The 40 patients (70%) who were on the ketogenic diet had less severe gait disturbances but more dystonia, chorea, tremor, myoclonus, dyspraxia, and paroxysmal events compared with the 17 patients on a conventional diet. Poor dietary compliance and low ketonuria appear to trigger the paroxysmal events in some patients. Gait disturbances and movement disorders are frequent in patients with Glut-1 deficiency and are signs of chronic and intermittent pyramidal, cerebellar and extrapyramidal circuit dysfunction. These clinical symptoms reflect chronic nutrient deficiency during brain development and may be mitigated by chronic ketosis.

The neurocognitive outcome of mild isolated fetal ventriculomegaly verified by prenatal magnetic resonance imaging.

OBJECTIVE: Neurocognitive outcome of preschool children, prenatal diagnosis of isolated mild ventriculomegaly compared with 2 control groups. STUDY DESIGN: Case-controlled study at the University Hospital of Tel Aviv between October 1999 and December 2002. Study groups consisted of 12 children with bilateral isolated mild ventriculomegaly, and 16 children with unilateral isolated mild ventriculomegaly, mean age 4.4 years, prenatally diagnosed by both ultrasound and fetal magnetic resonanace imaging. Control groups consisted of 16 children with normal prenatal magnetic resonance imaging and 16 regular kindergarten children. A neurodevelopmental examination and the Kaufman Assessment Battery for Children were performed. RESULTS: The neurodevelopmental and Kaufman scores were within normal range in the study groups. No significant differences between the study and control groups for most measures; however, Kaufman achievement score was significantly lower for the bilateral isolated mild ventriculomegaly group (P < .05) compared with the kindergarten children. CONCLUSION: Preschool children with isolated mild ventriculomegaly performed within normal range compared with the controls. Nevertheless, a significant percentage of the children demonstrated developmental difficulties, lower achievement scores, justifying early school years follow-up.

Consideration of gene therapy for paediatric neurotransmitter diseases.

The paediatric neurotransmitter diseases (PNDs) are a group of inborn errors of metabolism characterized by abnormalities of neurotransmitter synthesis or metabolism. Although some children may react favourably to neurotransmitter augmentation treatment, optimal response is not universal and other modes of treatment should be sought. The genes involved in many of the currently known monoamine PNDs have been utilized in pre-clinical and in phase I clinical trials in Parkinson disease (PD) and the basic principles could be applied to the therapy of PNDs with some modifications regarding the targeting and distribution of vectors. However, issues that go beyond neurotransmitter replacement are important considerations in PD and even more so in PNDs. Understanding the pathophysiology of PNDs including abnormal development resulting from the neurotransmitter deficiency will be critical for rational therapeutic approaches. Better animal models of PNDs are necessary to test gene therapy before clinical trials can be attempted.

Virtual reality training to enhance behavior and cognitive function among children with attention-deficit/hyperactivity disorder: brief report.

Purpose: To examine the feasibility and efficacy of a combined motor-cognitive training using virtual reality to enhance behavior, cognitive function and dual-tasking in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Methods: Fourteen non-medicated school-aged children with ADHD, received 18 training sessions during 6 weeks. Training included walking on a treadmill while negotiating virtual obstacles. Behavioral symptoms, cognition and gait were tested before and after the training and at 6-weeks follow-up. Results: Based on parental report, there was a significant improvement in children's social problems and psychosomatic behavior after the training. Executive function and memory were improved post-training while attention was unchanged. Gait regularity significantly increased during dual-task walking. Long-term training effects were maintained in memory and executive function. Conclusion: Treadmill-training augmented with virtual-reality is feasible and may be an effective treatment to enhance behavior, cognitive function and dual-tasking in children with ADHD.

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study.

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.

Facial Expression in Response to Smell and Taste Stimuli in Small and Appropriate for Gestational Age Newborns.

Small for gestational age newborns can later suffer from eating difficulties and slow growth. Nutritional preferences can be influenced by changes in sensory perception of smell and taste. To determine whether these could be detected at birth, the authors examined the different recognition pattern of smell and taste in small for gestational age newborns compared to appropriate for gestational age controls, as expressed by gusto-facial and naso-facial reflexes. The authors performed video analysis of facial expressions of 10 small for gestational age and 12 control newborns exposed to various tastes and smells. No difference in the facial recognition patterns for taste or smell was demonstrated between small for gestational age and controls, except for perception of distilled water. Newborns show recognizable patterns of facial expression in response to taste and smell stimuli. Perception of taste and smell in small for gestational age newborns is not different from controls, as measured by the method of facial recognition.

The effects of vascular intrauterine growth retardation on cortical astrocytes.

OBJECTIVE: We sought to determine the pathogenesis of neurodevelopmental impairments in survivors of intrauterine growth retardation (IUGR). METHODS: We used an experimental rabbit vascular IUGR model. We ligated 25% of uteroplacental vessels (partial ischemia) of one-half of the fetuses on day 25 at the end of the third trimester. We then determined hemispheral DNA and protein levels, and used glial fibrillary acidic protein (GFAP) staining to count the labeled astrocytes at the superficial cortical layers. RESULTS: Ischemic fetuses were significantly smaller than control fetuses and presented a disproportionately small body and a relatively larger head compared with the normal body/head ratio, confirming the study model as that of asymmetric IUGR. Hemispheral DNA was unchanged in IUGR fetuses, but they had decreased brain weight, hemispheral protein content, and a reduced number of mature (GFAP-positive) cortical astrocytes compared with control fetuses. CONCLUSION: Vascular IUGR, as demonstrated in our asymmetric IUGR model, adversely affected brain growth, cell size, and cortical astrocytes maturation. In view of the neurotrophic and neuroprotective functions of astrocytes, a reduced number of mature astrocytes during this critical period of development may be implicated in the pathogenesis of the neurodevelopmental impairments observed in IUGR.