Deep Brain Stimulation in Children With Autism

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and possible effectiveness of deep brain stimulation (DBS) of the nucleus accumbens in children with autism spectrum disorder and treatment-refractory, repetitive self-injurious behavior. Six (6) patients will be recruited and enrolled in this pilot study and study duration for each patient will be one (1) year. All will undergo surgical implantation of the Medtronic DBS system and will receive stimulation of the nucleus accumbens (2 electrodes per patient).This will be an open, non-blinded, non-randomized, pilot, phase I trial.Expected study duration is 36 months.

Detailed Description
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This is a phase I, non-blinded, non-randomized, pilot trial for safety and efficacy of deep brain stimulation for medically-refractory, repetitive self-injurious behaviours in children with ASD (i.e. secondary stereotypies). The trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s). Patients who meet inclusion and exclusion criteria will be identified and recruited the Neurosurgical Clinic at The Hospital for Sick Children. The study will proceed according to the schedule laid out below, and both patients and treating team will be aware of all treatment parameters at all times. Six (6) subjects will be enrolled in this study and study duration for each patient will be one (1) year. Previous phase I trials of DBS in psychiatric and Alzheimer's Disease populations have utilized 6 subjects per surgical target. Such a number is sufficient to demonstrate initial safety, as well as feasibility and clinical effectiveness.

Official Title
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Deep Brain Stimulation for the Treatment of Refractory Repetitive Self-Injurious Behaviour in Children With Autism Spectrum Disorder: A Pilot Project

Conditions
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Autism Spectrum Disorder, Self-Injurious Behavior

Intervention / Treatment
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* Procedure: Deep Brain Stimulation
* Device: DBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or Male patients between age 7-18 Diagnosis of Autism Spectrum Disorder (as defined by the DSM-5). Failure or non eligibility of medical therapy with ongoing repetitive self-injurious behaviours, at 6 months or more after instigation of therapy. Failure is defined as a lack of improvement in self-injurious behaviours, as documented by objective evidence, including caregiver logs or clinician assessment, if the clinician has documented a baseline status prior to instigation of the medical therapy. Diagnosis of secondary stereotypies, based on clinical assessment of the treating physicians with evidence of self-injury, documented in the patient records. Parents or legal guardians, including caregivers, informed and able to give written consent. Able to comply with all testing, follow-ups and study appointments and protocols for 12 months following the end of the duration of the study. Exclusion Criteria: Substance dependence or abuse in the last 6 months, excluding caffeine and nicotine Any contraindication to MRI or PET scanning Likely to relocate away from the study site or move during the study's one year duration Presence of cardiac arrhythmias, or other cardiac, respiratory, renal or endocrine conditions that will result in significant risk from a surgical procedure. Pregnancy Unable to communicate adequately in English in order to complete the baseline and follow-up questionnaires.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DBS Treatment<br>Deep brain stimulation of both limbic and dysfunctional reward processing circuits for treatment of repetitive self injurious behaviours in children with ASD | Procedure: Deep Brain Stimulation<br>* Stimulation of the nucleus accumbens via 2 electrodes implanted in the brain per patient to reduce self-injurious behaviours.<br>Device: DBS<br>* Use of the Medtronic DBS device. DBS device consists of 2 parts: DBS lead, a thin wire with 2 electrical contacts implanted into pre-determined brain regions, and Implantable pulse generator, a small device containing the batter and computer source placed under the skin of the chest to generate electrical pulses<br>* Other names: Medtronic DBS Therapy (Device # 37601);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in repetitive behaviour | The Repetitive Behavior Scale-Revised (RBS-R; Bodfish, Symons, Parker & Lewis, 2000) will be used to measure changes in repetitive behaviour pre and post intervention. The following sub-scales will be used: Steretyped behaviour subscale Self-injurious behaviour subscale Compulsive behaviour subscale Ritualistic behaviour subscale Sameness behaviour subscale Restricted behaviour subscale All subscales are scored from 0-3 as follows: 0 = behaviour does not occur behaviour occurs and is a mild problem behaviour occurs and is a moderate problem behaviour occurs and is a severe problem Where a higher number indicates increased repetitive behaviour. Subscores are totaled and then an overall score is calculated. Measure will be completed at baseline (pre-surgery), weekly from weeks 2-6 post-surgery, bi-weekly from weeks 7-10 post surgery, monthly from weeks 11-51 post-surgery, and 1 year post surgery. | 1 year | 
| Changes in self-injurious behaviour | The Inventory of Statements about Self-Injury (ISAS; Klonsky & Olino, 2008) will be used to measure changes in self-injurious behaviour pre and post intervention. The scale is scored from 0-2 as follows: 0= not relevant somewhat relevant very relavant Where a higher number indicates increased self-injurious behaviour. Questions are scored and totaled. Measure will be completed at baseline (pre-surgery), weekly from weeks 2-6 post-surgery, bi-weekly from weeks 7-10 post surgery, monthly from weeks 11-51 post-surgery, and 1 year post surgery. | 1 year | 
| Changes in abberant behaviour | The Aberrant Behavior Checklist (Aman, Singh, Stewart & Field, 1985) will be used to measure changes in the extent that abberant behaviour is a problem pre and post intervention. The scale is scored from 0-3 as follows: 0= not at all a problem the behaviour is a problem but slight in degree the problem is moderately serious the problem is severe in degree Where the higher number indicates the behaviour is problematic. Questions are scored and totaled. Measure will be completed at baseline (pre-surgery), weekly from weeks 2-6 post-surgery, bi-weekly from weeks 7-10 post surgery, monthly from weeks 11-51 post-surgery, and 1 year post surgery. | 1 year | 
| Changes in obsessive-compulsive thoughts | The Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman, Price, Rasmussen,1989) will be used to measure changes in the amount of interference of unwanted ideas, images, or impulses pre and post intervention. The scale is scored from 0-4, where 0 represents minimal interference and 4 represents substantial interference. Questions are scored and totaled. Measure will be completed at baseline (pre-surgery), weekly from weeks 2-6 post-surgery, bi-weekly from weeks 7-10 post surgery, monthly from weeks 11-51 post-surgery, and 1 year post surgery. | 1 year | 
| Changes in quality of life | The Paediatric Quality of Life Inventory (PedsQL v. 4.0) will be used to measure changes in self-reported quality of life pre and post intervention. The statements are scored from 0-4 as follows: 0= it is never a problem 1 = it is almost never a problem 2= it is sometimes a problem 3 = it is often a problem 4= it is almost always a problem Where a higher score indicates the statement is a problem. All items are scored and totaled. Measure will be completed at baseline (pre-surgery), weekly from weeks 2-6 post-surgery, bi-weekly from weeks 7-10 post surgery, monthly from weeks 11-51 post-surgery, and 1 year post surgery. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in physical brain abnormalities | MR images will be analyzed pre and post intervention for the following to assess physical abnormalities of the brain, including type (focal cortical dysplasia, tumor, hippocampal sclerosis, hypothalamic hamartoma, gliosis, brain atrophy), side of abnormalities (left/right/ bilateral), and location (frontal, temporal, sylvian, parietal, occipital, multilobar). MRI data will be collected at baseline, 6 weeks post-surgery, and 1 year post-surgery. | 1 year | 
| Changes in metabolic brain abnormalities | FDG-PET scans will be analyzed to measure changes in neurometabolism pre and post intervention, specifically indications of hypermetabolism in the frontal lobes, hippocampus, and lentiform nucleus. FDG-PET data will be collected at baseline, 6 weeks post-surgery, and 1 year post-surgery. | 1 year | 
| Changes in activity | Changes in activity pre and post intervention will be measured using the Actiwatch Spectrum, Phillips Respironics, Bend, OR. Actigraphy is the continuous measurement of an individual's movement. Actigraph data will be collected at baseline, 6 weeks post-surgery, and 1 year post-surgery. Actigraph data will be analyzed using MATLAB (Mathworks, Natick, MA). Measures analyzed will be maximum and minimum value amplitudes, peak to peak, variance, entropy fast fourier transform, discrete cosine function, z-transform, bispectrum. | 1 year | 
| Type of adverse events reported in caregiver logs |  | 1 year | 
| Changes in number of complications pre and post intervention will be compared. |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep brain stimulation