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Neural circuitry underlying DBS treatment for self-injurious behaviours in Autism Spectrum Disorder

Poster No:

3 

Submission Type:

Abstract Submission 

Authors:

Kristina Zhang1,2, Rafi Matin1,2, Mark Ebden1, Carolina Gorodetsky3, Jacob Ellegood4, Jason Lerch5,4, Flavia Venetucci Gouveia1, George Ibrahim1,6,2

Institutions:

1Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada, 2Institute of Medical Science, University of Toronto, Toronto, Canada, 3Division of Neurology, Hospital for Sick Children, Toronto, Canada, 4Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, Canada, 5Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom, 6Division of Neurosurgery, Hospital for Sick Children, Toronto, Canada

First Author:

Kristina Zhang  
Neurosciences & Mental Health, Hospital for Sick Children|Institute of Medical Science, University of Toronto
Toronto, Canada|Toronto, Canada

Co-Author(s):

Rafi Matin  
Neurosciences & Mental Health, Hospital for Sick Children|Institute of Medical Science, University of Toronto
Toronto, Canada|Toronto, Canada
Mark Ebden, PhD  
Neurosciences & Mental Health, Hospital for Sick Children
Toronto, Canada
Carolina Gorodetsky, MD  
Division of Neurology, Hospital for Sick Children
Toronto, Canada
Jacob Ellegood, PhD  
Mouse Imaging Centre (MICe), Hospital for Sick Children
Toronto, Canada
Jason Lerch, PhD  
Wellcome Centre for Integrative Neuroimaging, University of Oxford|Mouse Imaging Centre (MICe), Hospital for Sick Children
Oxford, United Kingdom|Toronto, Canada
Flavia Venetucci Gouveia, PhD  
Neurosciences & Mental Health, Hospital for Sick Children
Toronto, Canada
George Ibrahim, MD, PhD  
Neurosciences & Mental Health, Hospital for Sick Children|Division of Neurosurgery, Hospital for Sick Children|Institute of Medical Science, University of Toronto
Toronto, Canada|Toronto, Canada|Toronto, Canada

Introduction:

Children with Autism Spectrum Disorder (ASD) often manifest self-injurious behaviours (SIB) that may become severe and refractory with limited treatment options (Arron et al. 2011). These SIBs may lead to disability or death and deprive children and their families of quality of life. Deep brain stimulation (DBS) has recently been developed in a world-first phase I clinical trial at the Hospital for Sick Children as a potential treatment for affected children (NCT03982888; Yan et al. 2022). The nucleus accumbens (NAcc) is thought to be a relevant target because of its key role in the neurocircuitry regulating SIB. However, the neural underpinnings of NAcc stimulation for SIBs are poorly understood, and multi-disciplinary translational studies using both pre-clinical animal models and clinical data are necessary to explore the mechanisms of disease and treatment. Here, we evaluated the behavioural and neuroanatomical changes induced by NAcc-DBS in a mouse model of SIB and ASD to provide insights into the pathophysiology underlying the treatment being offered in the phase I clinical trial at the Hospital for Sick Children.

Methods:

BTBR T+ Itpr3tf/J (BTBR) mouse models of SIB and ASD received chronic DBS or sham stimulation to the bilateral NAcc (100 µA, 100 Hz, 60 µs). Treatment was followed with a series of behavioural tests evaluating ASD-related phenotypes (self-injurious, repetitive, anxiety-like, and social behaviours) and structural MRI. Deformation-based morphometry (Lerch, Sled, and Henkelman 2011) and MAGeTbrain (Multiple Automatically Generated Templates Brain Segmentation Algorithm; Chakravarty et al. 2013) pipelines were applied to identify distinct volumetric changes along the NAcc neurocircuitry and correlated with SIB improvement in BTBR mice.

Results:

Chronic, high-frequency NAcc-DBS reduced repetitive and SIBs, as well as improved sociability among BTBR mice. These behavioural improvements were correlated with reduced volume in several brain areas thought to be critical for the regulation of SIB, such as the frontal cortex, habenula, amygdala, and hypothalamus (Figure 1).
Supporting Image: OHBM_Figure1_with_caption_Nov2023.png
 

Conclusions:

We demonstrate that NAcc-DBS improves SIB outcomes in BTBR mice through induction of volumetric changes to diverse brain structures involved in SIB regulation. These findings will provide mechanistic insight to the world-first pilot trial of NAcc-DBS in children with severe SIB and ASD. Results from this study will advance our understanding of the neural circuitry subserving SIB, mechanisms underlying symptom improvement following treatment, and provide foundational evidence to establish NAcc-DBS as a therapy for affected children.

Brain Stimulation:

Deep Brain Stimulation 1

Disorders of the Nervous System:

Neurodevelopmental/ Early Life (eg. ADHD, autism) 2

Emotion, Motivation and Social Neuroscience:

Emotion and Motivation Other

Modeling and Analysis Methods:

Segmentation and Parcellation

Neuroanatomy, Physiology, Metabolism and Neurotransmission:

Subcortical Structures

Keywords:

ANIMAL STUDIES
Autism
Limbic Systems
Morphometrics
MRI
PEDIATRIC
Segmentation
STRUCTURAL MRI
Sub-Cortical
Treatment

1|2Indicates the priority used for review

Provide references using author date format

Arron, K. (2011), The prevalence and phenomenology of self-injurious and aggressive behaviour in genetic syndromes. Journal of Intellectual Disability Research: JIDR, vol. 55, no. 2, pp. 109–120
Chakravarty, M. (2013). Performing label-fusion-based segmentation using multiple automatically generated templates. Human Brain Mapping, vol. 34, no. 10, pp. 2635–2654
Lerch, J. P. (2011). MRI phenotyping of genetically altered mice. Methods in Molecular Biology , vol. 711, pp. 349–361
Yan, H. (2022). An open-label prospective pilot trial of nucleus accumbens deep brain stimulation for children with autism spectrum disorder and severe, refractory self-injurious behavior: study protocol. Pilot and Feasibility Studies, vol. 8, no. 1, pp. 24