Electrical Stimulation of the Nucleus Accumbens for Severe, Refractory Self-Injurious Behaviour in Children (EASE-SIB): protocol for a randomised double-blinded crossover trial

Abstract

Introduction

Self-injurious behaviour (SIB) consists of persistent, repetitive movements that can result in serious injury without suicidal intent. These behaviours are prevalent among children with neurodevelopmental disorders, including profound autism. Although many individuals benefit from currently available therapies, some exhibit treatment-refractory SIB that necessitates ongoing use of personal protective equipment and restraint, presumably due to stronger neurobiological drivers. We recently completed a phase I, open-label clinical trial demonstrating the safety, feasibility and preliminary efficacy of bilateral deep brain stimulation targeting the nucleus accumbens (NAc-DBS) in children with profound autism and severe, refractory SIB. The objective of the proposed study is to characterise the effectiveness of NAc-DBS in treating severe, refractory SIB in this unique and vulnerable population.

Methods and analysis

A single-centre, randomised double-blinded, crossover trial is proposed. Informed by the results of our pilot study, 25 subjects with autism spectrum disorder and severe, refractory SIB will undergo bilateral NAc-DBS. Following a 4-week recovery period, participants will be randomised to either group A (stimulation ON then OFF) or group B (stimulation OFF then ON). Each block will last 12 weeks, separated by a 2-week washout period. Following completion of the second block, all participants will enter a 6-month open-label phase with stimulation ON. The primary outcome is the difference in the Repetitive Behaviour Scale–Revised total score, between DBS-ON and DBS-OFF conditions. Secondary outcomes include measures of quality of life, caregiver burden, daily logs of SIB events and direct observation of SIB under structured analogues.

Ethics and dissemination

The proposed trial has been approved by the institutional Research Ethics Board (1000081171). Trial results will be disseminated through peer-reviewed publications and conference presentations.

Trial registration number

NCT06529380

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Randomised, double-blinded clinical trial.

• Within-subject crossover design reduces inter-individual variability and ensures all participants receive the active intervention.

• Use of multiple validated and complementary outcome measures (caregiver-reported scales, daily behaviour diaries, structured functional analyses) enhances reliability.

• Lack of an objective, norm-referenced measure of self-injurious behaviour necessitates reliance on caregiver-reported outcomes, partly mitigated by supplementary behaviour diaries and blinded functional analyses.

• Crossover design carries the risk of carryover effects; a 2-week washout was included as a pragmatic balance between methodological rigour and ethical feasibility.

Introduction

Background

Self-injurious behaviour (SIB) consists of persistent, repetitive movements that cause harm to oneself, without suicidal intent.¹ SIB is prevalent among individuals with neurodevelopmental disorders, including profound autism,^{2 3} and in severe cases can result in serious injury, permanent disability and death.⁴ Children who do not benefit from behavioural or pharmacological interventions have few other treatment options, often necessitating routine use of personal protective equipment or restraint.^{5 6} There is a critical and unmet need to develop effective therapies for children with severe, refractory SIB.

Self-injury is thought to arise from interactions between biological variables related to neurodevelopmental disabilities and experiences that occasion and reinforce SIB. Some forms of SIBs are modulated by socially mediated events and reinforcers, termed ‘socially maintained’ (subtype 1) SIB.⁷,⁹ Mechanistically based behavioural interventions that target the contingencies that occasion and reinforce socially maintained SIB are often effective and supported by a large body of empirical evidence.¹⁰,¹² Conversely, SIB that persists independent of social reinforcements is termed ‘automatically maintained’ SIB, which has been further classified into subtypes 2 and 3 (which co-occurs with self-restraint behaviour). These individuals present with more frequent and severe injuries compared with other types and require ongoing use of personal protective equipment.^{7 9 13 14} It is thought that the reduced efficacy of intervention for automatically maintained SIB stems from stronger contributions from underlying neurobiological drivers relative to the other types of SIB.^{13 15}

The neurobiological substrates of automatically maintained SIB are incompletely understood. SIB is thought to involve impairments in inhibitory, sensory and reward-feedback systems, mediated by frontal corticostriatal circuitry (see Zhang et al¹⁶ for a review). Preclinical studies have linked cellular, electrophysiological and biochemical changes at striatal synapses and corticostriatal circuits with repetitive behaviours that lead to physical injury in rodents.¹⁷ Corticostriatal circuitry has also been strongly implicated in repetitive/compulsive behaviours,¹⁸,²⁰ which are prevalent and comorbid with SIB.²¹ Furthermore, children with autism exhibit accelerated striatal growth compared with matched neurotypical controls, the rate of which is correlated with the severity of repetitive behaviours and insistence on sameness.²²

Situated within the ventral striatum, the nucleus accumbens (NAc) presents a particularly compelling neuromodulation target for automatically maintained SIB. The NAc is a central component of the mesolimbic reward pathway, serving an important role in mediating response inhibition and integrating dopaminergic reinforcement signals.²³,²⁵ In adults, deep brain stimulation (DBS) of the NAc is the most common target for obsessive compulsive disorder,²⁶ a disease characterised by impaired frontostriatal dynamics²⁷ and impaired inhibitory control.²⁸ In preclinical models, activation of frontostriatal pathways involving the NAc has been shown to reduce repetitive and reward-seeking behaviours,²⁹,³³ whereas lesioning the NAc increases their frequency.³⁴,³⁷ Together, these convergent findings support the role of the NAc in governing repetitive behaviours and highlight its potential as a target for neuromodulatory interventions in refractory variants of SIB.

We recently completed a phase I clinical trial³⁸ investigating the safety and feasibility of bilateral DBS of the NAc for the treatment of refractory SIB in the context of neurodevelopmental disorders.³⁹ Six children and adolescents (ages 7–14) with profound autism and severe, treatment-refractory SIB underwent NAc-DBS and completed 1-year follow-up. All participants tolerated the treatment, and no serious adverse events were observed. Preliminary data on treatment efficacy revealed significant reductions in SIB and SIB-associated behaviours across multiple standardised scales, concurrent with clinically meaningful improvements in quality of life. At the end of the study period, participants no longer required personal protective equipment or physical restraint to mitigate harm from SIB. Ambulatory actigraphy completed for 2 weeks at baseline and 1-year follow-up revealed significant reductions in high-amplitude movements post-treatment, and [¹⁸F]Fluorodeoxyglucose positron emission tomography demonstrated significant reductions in resting-state glucose metabolism within cortical-striatal-thalamic circuits with NAc-DBS. Together, these findings provide evidence that NAc-DBS may be safe, feasible and potentially efficacious for severe, refractory SIB in paediatric populations with profound autism.

Objective

Building on the results of our pilot trial, the proposed study aims to characterise the effectiveness of NAc-DBS in treating severe, refractory SIB in children with profound autism.

Trial design

The proposed study is a single-centre, randomised double-blinded, crossover trial (figure 1). Following standard pretreatment evaluation and collection of baseline metrics, all participants will undergo surgical implantation of bilateral DBS electrodes targeting the NAc. After a 4-week recovery period, participants will be randomised to either group A (DBS-ON then DBS-OFF) or group B (DBS-OFF then DBS-ON). This randomisation phase consists of two blocks, each lasting 12 weeks, separated by a 2-week washout period. During the first block, group A will undergo active stimulation, while group B will not. Stimulation will then be deactivated for everyone during a 2-week washout period, following which participants will cross over to the opposite condition for 12 weeks. At the conclusion of the second block, all participants will enter a 6-month open-label phase of active stimulation. Outcome data will be collected at baseline, at the start and end of each block, and at the conclusion of the study (i.e., baseline, 4 weeks, 16 weeks, 18 weeks, 30 weeks and 54 weeks postsurgery). An accessible, child-friendly version of the timeline has been prepared for participant use (figure 2).

Figure 1. Overview of proposed randomised crossover trial. Following collection of baseline measures, all participants will undergo surgical implantation of DBS targeting the bilateral NAc. After a 4-week recovery period and monopolar review, participants will be randomised to either group A (DBS ON then OFF) or group B (DBS OFF then ON). Randomisation blocks last 12 weeks each, with a 2-week washout period in between. This is followed by a 6-month open-label phase where stimulation is active for everyone. DBS, deep brain stimulation; NAc, nucleus accumbens.

Figure 2. Accessible, child-friendly version of timeline for proposed study. DBS, deep brain stimulation; SIB, self-injurious behaviour.

Methods

Study setting

The proposed study is a single-centre trial that will be conducted at the Hospital for Sick Children in Toronto, Canada. Our institution is uniquely positioned to conduct this trial given our extensive experience with paediatric DBS,⁴⁰ access to specialised resources and personnel trained to work with this unique and vulnerable population, and a large referral volume as the only paediatric comprehensive surgical neuromodulation clinic in Canada. The Hospital for Sick Children also serves as an international hub for a multi-centred registry on paediatric DBS outcomes.^{41 42}

Eligibility criteria

Inclusion and exclusion criteria for participants in the proposed trial are outlined in table 1. Implantation of DBS devices will be performed by a surgical team led by a single paediatric functional neurosurgeon (GMI).

Table 1. Inclusion and exclusion criteria for NAc-DBS in children with severe SIB.

Inclusion criteria

Age 5–17 at the time of enrolment Diagnostic and Statistical Manual of Mental Disorders, Fitfth Edition (DSM-5) diagnosis of autism spectrum disorder History of repetitive SIB, as reported by parents and documented on clinical assessment, either at the time of enrolment into the study or in prior medical records. The definition of self-injury is contextual, but requires ongoing, intermittent or continuous manifestation of self-mediated physical injury to the child. Foreseeable risk of serious future self-harm. Screening by study team for presence automatically reinforced SIB subtype 2 or subtype 3 based on caregiver history. Failure or non-eligibility of medical therapy with ongoing repetitive SIBs, at 6 months or more after initiation of therapy. Parents or legal guardians, including caregivers, informed and able to provide written consent. Able to comply with all testing, follow-up visits 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 scanning. Presence of cardiac arrhythmias, or other cardiac, respiratory, renal or endocrine conditions that may incur significant risk from a surgical procedure. Pregnancy.

NAc-DBS, deep brain stimulation targeting the nucleus accumbens; SIB, self-injurious behaviour.

Eligibility for enrolment is determined through a multivisit, multidisciplinary assessment process within the SickKids Multi-Disciplinary Deep Brain Stimulation Clinic. This process typically spans several weeks to months and incorporates longitudinal review of clinical history, structured functional analyses and input from caregivers and multiple specialists. As such, enrolment is based on persistent, treatment-refractory SIB rather than an isolated episode of symptom exacerbation.

Baseline assessments

Following informed consent and prior to surgical implantation, baseline outcome data are collected longitudinally. Caregiver-reported SIB diaries are maintained for a minimum of twelve weeks prior to surgery, allowing aggregation of daily SIB counts and characterisation of natural day-to-day variability. Baseline severity is therefore derived from aggregate measurements over multiple weeks rather than a single timepoint. This design was selected in part to mitigate potential regression-to-the-mean effects that could arise if enrolment coincided with a transient period of unusually severe behaviour.

Intervention

All children enrolled into this study will undergo neurosurgical implantation of DBS electrodes targeting the bilateral NAc, along with subclavicular, subfascial implantation of an implantable pulse generator. The bilateral NAc will be targeted with a combination of direct and indirect targeting using preoperative, high-resolution structural MRI including Fast Grey Matter Acquisition T1 Inversion Recovery sequences.⁴³ The procedure will be performed under general anaesthesia using frame-based stereotaxy and intraoperative fluoroscopy. Children will be admitted per institutional protocols pertaining to postoperative recovery from DBS. An adaptive care plan will be developed in conjunction with a multidisciplinary team to allow participants to safely tolerate the hospital admission. Prophylactic intravenous antimicrobial therapy will be administered for 72 hours (cefazolin 30 mg/kg every 8 hours) followed by oral antibiotics (cefalexin 50 mg/kg every 6 hours) for a total of 2 weeks. During the first week of admission, a monopolar review will be performed of the device, whereby contacts are sequentially stimulated to monitor for potential stimulation-related adverse events. on discharge, the device will remain OFF during a 4-week recovery period. Thereafter, children will then be randomly allocated into one of the following groups:

Group A: DBS will be switched ON for 3 months. The DBS device will then be switched OFF for 2 weeks (washout period) and will remain OFF for the following 3 months.

Group B: DBS will remain OFF for 3 months, as well as the 2 week washout period. It will then be switched ON for the following 3 months.

Randomisation and device programming during the cross-over phase will be performed by the single unblinded paediatric neurologist with expertise in DBS programming, who will have no role in outcome assessment (CG) and will use a randomisation schedule prepared by an unblinded statistician.

Electrical stimulation will be activated based on random group allocation, as described above. In the DBS-ON condition, all participants will receive double monopolar stimulation of the ventral electrode contacts at 4.5mA, 60µsec and 150 Hz or below the threshold of side effects (if any) on monopolar review during the first week post-operatively. Stimulation parameters were selected based on pilot data from the phase I clinical trial and are consistent with previous studies showing optimal effects when delivering DBS at high frequency (>100 Hz),⁴⁴,⁴⁹ medium current density^{44 46 47} and medium pulse width (60µsec).⁴⁵,⁴⁹ Importantly, these settings were well-tolerated by all participants in the phase I study.

Participants will be permitted to continue any ongoing pharmacological or behavioural treatments present at the time of enrolment. However, no escalation in medication type, dosage or the intensity/frequency of behavioural therapies will be permitted for the duration of the study.

Outcomes

The primary outcome of this study is the severity and frequency of SIB, as indexed by the Repetitive Behaviours Scale–Revised (RBS-R)⁵⁰—A 44-item parent/caregiver questionnaire that quantifies Stereotyped Behaviour, SIB, Compulsive Behaviour, Routine Behaviour, Sameness Behaviour and Restricted Behaviour in participants. Caregivers are asked to quantify how often the participant exhibits a particular behaviour on a scale of 0–3, as well as a summary measure of how often the repetitive behaviours occur overall on a scale of 1–100.

Although several standardised scales have been used to capture SIB severity and/or frequency, feedback from caregivers in our pilot study pointed to RBS–R as the most relevant as it provides a quantitative, continuous measure of the full spectrum of repetitive behaviours, of which SIB is the most extreme. The RBS-R was developed based on a theoretical framework involving latent processes and has been extensively studied in children as young as 3 years of age, as well as across many cultures, through confirmatory factor analysis for internal validity.⁵¹,⁵⁴ It has been validated across ages and sexes with no systematic differences in the total score or any subscores.⁵⁵ It has also been externally validated⁵¹ against several variables related to SIB including varying developmental abilities,⁵⁶ adaptive behaviour,^{57 58} autism symptoms⁵⁹ and other unusual behaviours.⁶⁰

Additional, secondary outcomes of this trial include:

1. Caregiver-reported diaries of the daily frequency of SIB events: Caregivers will report daily SIB counts using a standardised recording instrument.

2. Functional analysis⁶¹: Will be performed by board-certified behavioural analysts preoperatively and at the end of each randomisation block to assess potential treatment-related changes in (a) the function of SIB (including Subtype of automatically maintained SIB), (b) the frequency of SIB and (c) the occurrence of self-restraint.

3. Autism Diagnostic Observation Schedule⁶²: A series of structured and semistructured tasks, administered by a trained psychologist at baseline and after each randomisation block, designed to observe social interaction, communication and play, as well as restricted and repetitive behaviours. Behaviours are scored based on predefined, standardised criteria, with scores ranging from 0 (no abnormality) to 3 (moderate to severe abnormality).

4. Paediatric Quality of Life Inventory (PedsQL)⁶³: A 23-item parent/caregiver questionnaire designed to evaluate health-related quality of life in children with acute and chronic health conditions. The inventory includes measures of physical, emotional, social and school functioning with summary scores tabulated as total score, physical health summary score and psychosocial health summary score. A>4.5-point change in total PedsQL score is defined as the threshold for a minimal clinically important difference.⁶³

5. The Burden Scale for Family Caregivers–Short Version⁶⁴: This 10-item scale quantifies caregiver burden, has been validated against measures of caregiver depression and is associated with risk of institutionalisation of the individual being cared for.

Sample size and recruitment

The required sample size for the proposed trial was estimated from our pilot data, as this constitutes the only available evidence of the effects of NAc-DBS in this population. In the Phase I study, the treatment effect on total RBS-R score at 3-month postsurgery was Cohen’s d=0.85 (95% CI 0.42 to 2.08). Targeting a type-I error rate of 0.05 and a power of 0.80, this yields an estimated sample size of 13 participants. Given that the phase I trial was not meant to test efficacy, we elected to use a more conservative Cohen’s d estimate of 0.60 (1 SE below the group average), which leads to a pragmatic sample size of 25 participants to account for potential overestimation of treatment effects and possible attrition.

Prospective participants will be identified through referrals to the SickKids Multi-Disciplinary Deep Brain Stimulation Clinic, a unique world-first collaborative for the assessment of children for DBS. This clinic, led by the proposed trial’s principal investigators, serves as a national referral centre for children across Canada. Furthermore, the Clinic has established partnerships and referral streams with several specialised SIB clinics and residential care institutions across Canada.

Assignment of interventions

Subjects will undergo random allocation into Group A (DBS-ON then DBS-OFF) or Group B (DBS-OFF then DBS-ON) using the Clinical Trial Randomisation Tool developed by the United States National Cancer Institute (National Institutes of Health, Bethesda, Maryland, USA).⁶⁵ This algorithm is based on maximum tolerated imbalance (MTI) using the asymptotic maximal procedure to determine probabilities of arm assignments throughout the randomised sequence.⁶⁶ The MTI is a value representing the MTI between the trial arms at any point during the randomisation process (set to 3) and will restrict how imbalanced the arms may become as they are assigned. Under-assigned arms are favoured by a balance-forcing probability that depends solely on the current magnitude of arm imbalance.

The allocation sequence will be generated by the sole unblinded investigator (CG), a paediatric neuromodulation neurologist who is also responsible for activating or deactivating DBS devices. All other study personnel, caregivers and participants will be blinded to allocation. If unblinding is deemed necessary (see Section on Monitoring below for criteria for unblinding), the sole unblinded investigator (CG) will reveal the participant’s allocation assignments to relevant parties.

Data acquisition

All data will be captured and organised through an electronic database created using Research Electronic Data Capture (REDCap) tools.⁶⁷ Caregiver-reported/participant-reported questionnaires will be collected using electronic forms distributed by REDCap through secure, personalised links. A trained, blinded, research coordinator familiar with all outcome measures will be available to assist with completion of these questionnaires and to address technical difficulties. The same research coordinator will also audit questionnaires at each timepoint for each participant to ensure completeness and consistency. To prevent inter-rater variability in the completion of outcome measures, a pre-specified caregiver will be assigned to complete all questionnaires for the duration of the study when feasible.

SIB diaries will be collected using standardised, structured forms. These logs will be audited weekly by a designated research coordinator to ensure completeness and monitor for adverse behavioural effects. As SIB counts exhibit significant day-to-day variability,⁶⁸ the mean per diem SIB count during each randomisation block will be examined as a secondary outcome.

Functional analyses will be performed by a team of Board Certified Behaviour Analysts (BCBAs) to observe how systematically manipulating environmental variables affects the manifestation of SIB.^{8 14 69} Environmental variables are manipulated through four standardised conditions: No Interaction, Attention, Escape and Play (control), and structured, objective and replicable criteria are used to determine the function of and the subtype of automatically maintained SIB in each individual.^{70 71} Each functional analysis will be conducted in two phases. The first phase will consist of pairwise comparisons between several 300 s sessions in the No Interaction and Play (control) conditions. After enough sessions of each condition have been completed (minimum three of each), the next phase will consist of a multielement comparison between Attention, Escape and Play (control) conditions. The second phase of the functional analysis will be considered complete when the behaviour analyst determines a social function has been ruled out (or in). In addition to a determination of the function of SIB, the type and number of self-injury events during each condition will be examined for treatment effects. Notably, if the presurgical functional analysis determines that substantial elements of the participant’s SIB are socially maintained, caregivers may be counselled to attempt specialised behavioural treatments instead of, or prior to, proceeding with surgical intervention. Any such instances will be explicitly documented and included in final reporting of the results from the proposed trial.

Data analysis plan

The primary comparison in the proposed trial will be the within-subject difference in the primary outcome (RBS–R) and secondary outcomes between the DBS-ON and DBS-OFF condition using a paired t-test. We will also report differences in secondary outcomes between DBS-ON and DBS-OFF conditions in a similar manner. A secondary comparison will evaluate within-subject change in primary and secondary outcome measures at the end of the open-label period relative to the presurgical baseline. These analyses assume a normal distribution, which will be investigated through normal QQ plots. If there are concerns about the normality assumption, a Wilcoxon signed-rank test will be used to perform the planned comparisons. To test for potential carryover effects, the primary outcome measure (RBS-R) will be collected at the end of the washout period. Mixed-effects modelling will be used to examine whether treatment order (ie, DBS-ON then DBS-OFF vs DBS-OFF then DBS-ON) affects the change in the primary outcome (RBS-R).

Missing data and protocol non-adherence

To minimise the risk of missing data, outcome measures at each timepoint will be monitored for completeness by a designated research coordinator. At the conclusion of the trial, patterns of missing data will be examined, and Little’s test will be used to assess whether the missingness is consistent with Missing Completely at Random (MCAR).⁷² If data are consistent with MCAR, available case or complete case analysis may be used, as appropriate. If MCAR is not supported, more robust approaches (eg, model-based methods or inverse probability weighting) will be considered. In all cases, sensitivity analyses will be performed to assess the robustness of results under different missing data assumptions.

In the event of protocol non-adherence, a per-protocol analysis will be used for the primary analysis, including only participants who adhered to the study protocol (ie, received both DBS-ON and DBS-OFF conditions in the assigned order). To assess the impact of deviations, additional sensitivity analyses using intention-to-treat and as-treated approaches will be performed.

Monitoring

A Data Safety Monitoring Board (DSMB) has been established, including a paediatric intensivist (Chair), paediatric neurosurgeon (different from Principal Investigator), paediatric neurologist and a biostatistician. At a minimum, the committee will meet prior to study commencement, at the midpoint of the study, and at the end of the study. After the recruitment of 12 participants, the DSMB will perform an interim analysis of the dataset. Any decisions regarding suspension or early termination of the study will be at their discretion. The DSMB is independent from the trial sponsor and has no relevant competing interests based on self-declaration. Further details regarding the charter of the DSMB are available on written request to the corresponding author (GMI).

The decision to unblind a participant during the randomisation phase will be made by the DSMB based on the criteria below. In the case of an emergency, the decision to unblind will be made by the primary investigator (GMI) or a formally appointed delegate.

• A participant experiences a serious or unexpected adverse event and knowledge of the treatment assignment is necessary to guide appropriate medical management.

• A significant and adverse change in behaviour that poses danger to the child’s well-being.

• New-onset seizures, severe mood dysregulation or altered consciousness that may relate to stimulation status.

• A caregiver or participant withdraws consent for participation and requests to know their treatment allocation.

• Audit by a regulatory agency requiring unblinding of certain participants.

• Any reason for which the DSMB identifies a need for unblinding or a change in protocol.

Harms

Participant safety will be a foremost consideration at every stage of the proposed trial. Potential adverse events (AEs) and serious AEs (SAEs) will be recorded by study personnel at each timepoint and classified according to the Common Terminology Criteria for Adverse Events (CTCAE).⁷³ SAE will be defined as CTCAE grade 3 or higher, requiring medical or surgical intervention, resulting in hospitalisation or prolongation of hospitalisation, causing disability, or limiting self-care activities of daily living. Due to the reliance of children on caregivers for activities of daily living, we will consider events that result in significantly increased care burden on families as SAE.

An interdisciplinary team comprising a paediatric neurosurgeon, neurologist, anaesthesiologist, general and developmental paediatricians, a child and adolescent psychiatrist, a BCBA, a developmental service worker, a service coordinator and specialised nursing liaison was formed to complete the Phase I clinical trial and will continue involvement in the current study. Individualised adaptive care plans will be developed for optimising perioperative hospital admission experiences while mitigating potential exacerbation of SIB due to hospitalisation, investigations, medical procedures, surgery and recovery. Specialised resources have been allocated to accommodate the diverse needs of participants, including access to BCBAs, developmental support workers, child life specialists and tailored comfort measures. Furthermore, if deemed necessary, a paediatric intensivist may be involved to optimise perioperative management, including potential elective admission to the intensive care unit postsurgically.

Participants are screened prior to the first visit where they will undergo functional analysis to identify potential risks and initiate the planning process. A guiding principle is to select the least restrictive combination of protective procedures that ensure safety of participants and staff.⁷⁴ A range of protective procedures to prevent injury to participants and staff is employed. Environmental safety procedures include covering hard surfaces with fixed or portable padding. Response blocking includes interrupting the motion of behaviour that is potentially self-injurious using padded objects (eg, therapist arm with padded arm guard) between the body area targeted (eg, the participant’s head). Personal protective equipment includes equipment that is worn by the participant to protect targeted areas of the body, such as helmets to protect against head-banging or head-hitting, or padded gloves to protect against hand-biting. When necessary, arm splints that limit elbow flexion to reduce the occurrence of high-risk head-directed SIB that poses immediate medical risks are employed. The selection of protective procedures is informed by: (a) caregiver preferences, (b) the identified risk level, (c) the location and type of past and current injuries, (d) the topography of SIB and other challenging behaviour and (e) reactivity of the individual to protective procedures.

Finally, the proposed intervention is associated with surgical risks related to device implantation and management, including intraoperative neuronal injury during implantation or anaesthetic complications, as well as perioperative risks such as infection, hardware malfunction or stimulation-related adverse effects. In the paediatric DBS literature,^{75 76} including a series of 130 patients from our centre, the risk of SAEs is low (~4%) and comparable to adult populations.⁷⁷ Furthermore, ongoing brain growth sometimes raises concerns about lead migration or changes in relative target position over time, although in our experience, clinically significant displacement appears to be uncommon when leads are well secured. In the event that minor displacements were to occur, they could be accounted for through programming adjustments given DBS electrodes include multiple coaxial contacts along each lead. Importantly, lead migration related to brain growth has not been commonly reported in large series of DBS-related complications in paediatric population.^{75 76}

Ethics and dissemination

Research ethics approval

The proposed study has received institutional Research Ethics Board approval at the Hospital for Sick Children (REB Approval #1000081171).

Protocol amendments

In accordance with institutional policies, all proposed protocol amendments must be submitted in writing to the REB for review. Approved amendments will be disseminated to all members of the study team, trial participants and caregivers, regulatory agencies and the DSMB. Amendments will also be updated as soon as possible on the designated clinical trial registry (ClinicalTrials.gov).

Consent

A member of the prospective participant’s circle of care will introduce the proposed study to patients and their caregivers. For those potentially interested in participating, designated research personnel will explain the study in detail, answer questions, screen participants, and—if deemed eligible—obtain consent (see online supplemental materials for a copy of the participant consent form). To avoid therapeutic misconception, it will be explicitly stated that participation in the current study is voluntary and separate from other treatments the patient may undergo, with their decision about enrolment having no impact on routine care. Separate consent forms will be administered for enrolment in the study, highlighting the risks described above, and for surgical treatment, highlighting surgery-specific risks. The latter is a standard institutional surgical consent form that will be completed by the surgeon and family to highlight the typical risks of undergoing DBS implantation.

Severe, repetitive SIB typically occurs in the context of profound autism spectrum disorder and is usually accompanied by global developmental delay. As such, we anticipate that consent will be provided exclusively by caregivers. Whenever possible, however, assent will be obtained directly from participants as well. Designated assent forms with accessible language have been prepared and approved by the institutional REB.

Confidentiality

Participation in any clinical trial carries with it the risk of a data breach and associated violation of one’s privacy. This represents significant potential harm to the patient-practitioner relationship as well as psychosocial sequelae for the participant and/or their family. To mitigate the risk of this, strict confidential data management practices will be employed, including:

• De-identified data collection and storage using password-protected and encrypted databases.

• Logs linking de-identified participant IDs to identifiable information are being encrypted, password-protected and access-restricted to only approved study personnel.

• Use of software compliant with Ontario’s Personal Health Information Protection Act and regulated by our institution for collecting and storing data (ie, REDCap).

• Destruction of potentially identifiable data 7 years after completion of the study.

Access to data

The final trial dataset will be available only to the primary investigator (GMI) and designated delegates. The latter may include research coordinators, biostatisticians, research analysts and approved co-investigators within the institution. De-identified data may be made available to external collaborators through a formal, institutionally approved Data/Material Transfer and Use Agreement.

Ancillary and post-trial care

All participants enrolled in this study will be followed at the SickKids Multi-Disciplinary Deep Brain Stimulation Clinic until the age of 18, at which point their care will be formally transferred to an adult neurosurgeon with expertise in functional neurosurgery.

Dissemination policy

On completion, results of the proposed trial will be disseminated to the scientific community and healthcare professionals through peer-reviewed publications in academic journals and presentations at academic conferences. Authorship on publications and conference presentations will be determined based on individual contributions in accordance with the International Committee of Medical Journal Editors Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals.⁷⁸ The findings of this study will also be disseminated to the general public through institutional media releases and, if possible, through local, national and international media outlets. Furthermore, trial results will be updated on the designated clinical trial registry (ClinicalTrials.gov).

Discussion

Although many children with repetitive self-injury respond well to currently available therapies, a subset of individuals exhibits severe, treatment-refractory SIB. These cases often require ongoing use of personal protective equipment and physical restraint, with extremely limited treatment options. In our Phase I pilot study, we demonstrated that targeted modulation of the neural circuitry underlying these behaviours through NAc-DBS is safe, feasible and potentially efficacious. In the proposed randomised double-blinded crossover trial, we now aim to examine the efficacy of NAc-DBS in treating severe, refractory SIB.

A crossover randomised controlled trial design is particularly appropriate for this study due to a combination of ethical, clinical and methodological considerations unique to the population being studied. Individuals with severe SIB represent a highly vulnerable group, often exhibiting complex and heterogeneous neurological and psychiatric profiles.^{2 79} This variability in underlying disease processes poses significant challenges for between-group comparisons in traditional parallel-group designs.⁸⁰ The crossover approach, in which each participant receives both active and control conditions in a randomised order, allows individuals to serve as their own control. This within-subject comparison substantially reduces inter-individual variability, thereby enhancing statistical power and increasing the sensitivity of the trial to detect treatment effects, even with a small sample size.⁸¹ Moreover, the reversible nature of DBS permits controlled ON/OFF conditions. The 2-week washout period was selected based on empirical observations from our Phase I trial, in which behavioural changes following stimulation initiation or cessation occurred within days. While longer-term neuroplastic adaptations cannot be excluded, any residual therapeutic effects persisting beyond the washout interval would be expected to attenuate differences between ON and OFF conditions, thereby biasing results toward the null rather than inflating treatment effects. Finally, the crossover design is also preferable from an ethical standpoint as participants eligible for this trial would have exhausted all other treatment options. In such cases, withholding active treatment altogether, as would occur in a parallel-group design with a placebo arm, would be ethically problematic.⁸² The crossover model ensures that all participants receive the active intervention at some point during the trial, aligning with the ethical imperative to maximise potential benefit while still maintaining the methodological rigour required to assess efficacy.

The safe and ethical conduct of this trial is a foremost priority at every point of its design and execution. The study was developed in accordance with the person-oriented framework outlined by the Autism Research Ethics Task Force,⁸³ which emphasises the principles of individualisation, acknowledgement of lived world, person and family empowerment in decision-making, respect for holistic personhood, and focus on research-participant relationship throughout the trial. Furthermore, insights from caregivers of affected children, gleaned through qualitative research methodology,⁶⁸ informed the selection of outcome measures. Finally, all trial procedures were designed in accordance with principles outlined in the Declaration of Helsinki by the World Medical Association.⁸⁴ The use of disease-specific ethical frameworks and consultation with multiple groups of stakeholders, including caregivers and domain-specific experts, has been critical in ensuring the safe and ethical use of the proposed experimental neurosurgical procedure in this exquisitely vulnerable population.

The proposed trial has potential limitations that warrant attention. First, although a crossover design is ideally suited for investigating an invasive procedure in this population, it carries the possibility of delaying potential benefit of treatment. Cessation of active stimulation could result in exacerbation of SIB, which may be difficult to manage for participants and caregivers. To mitigate this challenge, specialised resources have been made available to all participants of this study. This includes: (1) a member of the clinical team who will be available to caregivers at all hours for any urgent matters; (2) BCBAs and neuropsychologists with expertise in neurodevelopmental disorders; (3) child life specialists and (4) developmental service workers. Another potential limitation of the proposed study is the reliance on caregiver-reported outcome measures, which are inherently vulnerable to subjectivity and interrater variability. As there is currently no widely accepted objective, norm-referenced measure of SIB, the choice of primary outcome was based on our pilot data which identified the RBS-R to be most relevant. To reduce the risk of inter-rater variability, a single, prespecified caregiver will be requested to complete all outcome measures wherever possible. Furthermore, the collection of multiple secondary endpoints, including daily SIB logs and direct observations by blinded assessors during functional analyses, provides additional objective metrics for examining treatment effects. Finally, one limitation inherent to all crossover studies is the possibility of a carryover effect between conditions, particularly among those randomised to receive active stimulation first. To address this, a 2-week washout period has been incorporated between randomisation blocks. This duration was selected based on empirical observations from our Phase I trial, in which behavioural changes following adjustment of DBS stimulation parameters were observed to emerge within days of stimulation adjustment.³⁸ While a longer washout could theoretically further reduce the risk of possible carryover, it would also extend the duration of participant exposure to a non-therapeutic state, which is ethically challenging in this population. Thus, a 2-week interval represents a pragmatic compromise between mitigating carryover while also reducing unnecessary delay in potential benefit.

In conclusion, the proposed study has the potential to provide critical evidence supporting the use of NAc-DBS as a targeted treatment for severe, treatment-refractory SIB in paediatric populations with profound autism. This trial was explicitly designed to integrate ethical and safety considerations in applying neuromodulatory approaches to vulnerable populations through iterative, inclusive, multidisciplinary research practices. Ultimately, the current work seeks to address an urgent clinical need while simultaneously paving the way for compassionate, scientifically grounded treatment paradigms for children with neurodevelopmental conditions facing severe SIB.

The sponsor is responsible for providing the investigator with the necessary information to conduct the clinical trial, to ensure proper monitoring of the trial and ensuring compliance to ethical bodies and legislation. The sponsor is not involved in aspects of study design, report writing or data analysis. The sponsor can be contacted by email (ask.crs@sickkids.ca) or telephone (416-813-1500). The funding body had or has no involvement in study design; collection, management, analysis and interpretation of data; or the decision to submit for publication. The funding body will be informed of any planned publications, and documentation provided. These organisations played no role in any part of this study, including its design, conduct, analysis or writing.