Modulating Plasticity in the Motor Cortex Using Repetitive Transcranial Magnetic Stimulation to Improve Motor Function in Autism Spectrum Disorder
Phase: NA
Conditions: Autism Spectrum Disorder, Motor Activity
Sponsor: Centre for Addiction and Mental Health

 
 
 
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Modulating plasticity in the motor c
ortex using 
repetitive transcranial magnetic stimulation to 
improve motor function in autism spectrum 
disorder  
 
Protocol Identifying Number: 
180/2023 
Principal Investigator:
 Dr. Pushpal Desarkar  
Version Number:  1.0 
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Principal Investigator:
 
 
 
 
Co-Investigators:  
 
 
 
 
 
 
Dr. Pushpal Desarkar 
1025 Queen Street West, Toronto, ON M6J 1H1 
416-535-8501 ext. 32726 
 
Stephanie Ameis, MD, MSc, FRCPC 
Daniel M. Blumberger, MD, MSc, FRCPC 
Meng-Chuan Lai, MD, PhD 
Hsiang-Yuan Lin, MD 
Yona Lunsky, PhD 
Stewart Mostofsky, MD 
Tarek Rajji, MD, FRCPC 
Marcos Sanches, MSc 
Christoph Zrenner, MD 
 
Funder:  
Canadian Institutes of Health Research (CIHR) 
 
Research Analyst : 
Ashna Imran 
 
 
 

 
 
 
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Table of Contents
 
 
STATEMENT OF COMPLIANCE ................................................................................................................. 6 
LIST OF ABBREVIATION S.......................................................................................................................... 7 
1.0 INTRODUCTION .................................................................................................................................. 9 
1.1 
BACKGROUND ................................................................................................................................ 9 
1.1.1 
THE RATIONALE FOR TARGETING MOTOR FUNCTION DIFFICULTIES IN AUTISTIC ADULTS ..................... 10 
1.1.2 
WHAT IS KNOWN ABOUT THE NEUROBIOLOGY OF MOTOR FUNCTION DIFFICULTIES IN ASD ................ 10 
1.1.3 
OUR PUBLISHED DATA SHOWING HYPERPLASTICITY (EXCESSIVE LT) IN M1 IN AUTISTIC ADULTS  ....... 11 
1.1.4 
MEASUREMENT OF LTP ................................................................................................................ 11 
1.2 
STUDY INTERVENTION .................................................................................................................. 12 
1.2.1 
THE RATIONALE FOR USING RTMS TO MODULATE HYPERPLASTICITY IN M1 AND IMPROVE MOTOR 
FUNCTION DIFFICULTIES IN ASD ................................................................................................................. 12 
1.2.1.1 OUR PILOT DATA SHOW PROMISING EVIDENCE THAT RTMS CAN REDUCE AN EXCESSIVE LTP IN M1 IN 
AUTISTIC ADULTS46 .................................................................................................................................... 12 
1.2.1.2 WHY STUDY PRIMARY MOTOR CORTEX (M1)? ................................................................................ 13 
1.2.1.3 WHY NOT OTHER THERAPIES? ...................................................................................................... 13 
1.2.1.4 HOW WOULD HYPERPLASTICITY IN THE M1 AFFECT MOTOR FUNCTION? ........................................... 13 
1.3 
PRECLINICAL DATA TO DATE ......................................................................................................... 14 
1.4 
RISKS/ BENEFITS ......................................................................................................................... 15 
1.4.1 
RISK ............................................................................................................................................ 15 
1.4.1.1 ASSESSMENTS ............................................................................................................................. 15 
1.4.1.2 TMS AND TMS-EEG ................................................................................................................... 15 
1.4.2 
BENEFIT ...................................................................................................................................... 15 
2.0 CLINICAL TRIAL OBJEC TIVES ....................................................................................................... 16 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 16 
2.2 
SECONDARY OBJECTIVE ............................................................................................................... 16 
2.3 
TERTIARY OBJECTIVE ................................................................................................................... 16 
2.4 
EXPLORATORY OBJECTIVE ........................................................................................................... 17 
3.0 CLINICAL TRIAL DESIG N ................................................................................................................ 17 
3.1 
OVERALL DESIGN ......................................................................................................................... 17 
3.1.1 
PROJECT TIMELINE ...................................................................................................................... 17 
3.1.2 
CLINICAL ASSESSMENTS .............................................................................................................. 18 
3.1.3 
ASSESSMENT OF MOTOR FUNCTION IN ASD AND NT CONTROLS ..................................................... 18 
3.2 
PRIMARY ENDPOINTS ................................................................................................................... 18 
3.2.1 
ASSESSMENT OF PLASTICITY IN M1 USING INTERMITTENT THETA-BURST STIMULATION (ITBS) ......... 18 
3.2.1.1 PRIMARY MEASURE OF PLASTICITY ................................................................................................ 18 
3.2.1.2 SECONDARY MEASURE OF PLASTICITY USING EEG ........................................................................ 19 
3.2.2 
PRIMARY ENDPOINT OF RTMS INTERVENTION ................................................................................ 20 
3.3 
SECONDARY ENDPOINTS .............................................................................................................. 20 
4.0 PARTICIPANT SELECTIO N AND WITHDRAWAL  .......................................................................... 20 
4.1 
TARGET POPULATION ................................................................................................................... 20 
4.2 
PARTICIPANT RECRUITMENT AND SCREENING................................................................................ 20 
4.3 
EQUITY, DIVERSITY AND INCLUSION CONSIDERATIONS ................................................................... 21 
4.4 
ELIGIBILITY CRITERIA ................................................................................................................... 21 
4.4.1 
Inclusion Criteria .................................................................................................................... 21 
4.4.2 
Exclusion Criteria................................................................................................................... 22 
4.5 
LIFESTYLE CONSIDERATIONS ........................................................................................................ 23 
4.6 
SCREEN FAILURES ....................................................................................................................... 23 
4.7 
PARTICIPANT WITHDRAWAL CRITERIA ........................................................................................... 23 

 
 
 
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4.7.1 
When and How to Withdraw Participants .............................................................................. 23 
4.7.2 
Follow-up for Withdrawn Participants .................................................................................... 23 
4.7.3 
Early Termination Visit .......................................................................................................... 23 
4.7.4 
Participants who are Lost to Follow-up ................................................................................. 24 
 
 
5.0 STUDY INTERVENTION ................................................................................................................... 24 
5.1 
DESCRIPTION ............................................................................................................................... 24 
5.1.1 
REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (RTMS) TRIAL............................................... 24 
5.1.1.1 TRIAL DESIGN .............................................................................................................................. 24 
5.1.1.2 DURATION OF RTMS EFFECT – WILL THE EFFECT BE TRANSIENT? ................................................... 24 
5.1.1.3 CONTROLLING CONFOUNDING EFFECTS OF RTMS – THE RATIONALE BEHIND CHOOSING ‘SHAM – 
STIMULATION’ ............................................................................................................................................ 25 
5.2 
TREATMENT REGIMEN .................................................................................................................. 25 
5.3 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ................................................. 26 
5.4 
ADMINISTRATION OF STUDY INTERVENTION ................................................................................... 26 
5.5 
PARTICIPANT COMPLIANCE MONITORING ....................................................................................... 26 
5.6 
CONCOMITANT THERAPY .............................................................................................................. 26 
5.7 
PACKAGING ................................................................................................................................. 26 
5.8 
BLINDING OF STUDY INTERVENTION .............................................................................................. 26 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 26 
5.9.1 
Receipt of Study Intervention Supplies ................................................................................. 26 
5.9.2 
Storage .................................................................................................................................. 26 
5.9.3 
Dispensing of Study Intervention........................................................................................... 26 
5.9.4 
Return or Destruction of Study Intervention .......................................................................... 26 
6.0 RESEARCH PROCEDURES ............................................................................................................. 27 
6.1 
RESEARCH VISITS ........................................................................................................................ 27 
6.2 
SCHEDULE OF EVENTS ................................................................................................................. 29 
7.0 STATISTICAL PLAN  ......................................................................................................................... 30 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 30 
7.2 
STATISTICAL METHODS ................................................................................................................ 30 
7.2.1 
SEX AND GENDER CONSIDERATION ................................................................................................ 30 
7.2.2 
TESTING HYPOTHESIS 1A ............................................................................................................. 30 
7.2.3 
TESTING HYPOTHESIS 1B ............................................................................................................. 31 
7.2.4 
TESTING HYPOTHESIS 2A AND 2B .................................................................................................. 31 
7.2.5 
TESTING HYPOTHESIS 3 ............................................................................................................... 31 
8.0 SAFETY AND ADVERSE E VENTS ................................................................................................... 31 
8.1 
DEFINITIONS ................................................................................................................................ 31 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 32 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................. 32 
8.3.1 
Investigator Reporting: Notifying the Sponsor ....................................................................... 31 
8.3.2 
Investigator Reporting: Notifying the REB ............................................................................. 31 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada .................................................... 31 
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites .................................................................... 31 
8.4 
REPORTING OF DEVICE DEFICIENCIES ........................................................................................... 32 
8.5 
SAFETY MANAGEMENT PLAN ........................................................................................................ 33 
8.6 
UNBLINDING PROCEDURES ........................................................................................................... 33 
8.7 
DATA AND SAFETY MONITORING BOARD ....................................................................................... 33 
9.0 CLINICAL TRIAL DISCO NTINUATION AND CLOSU RE ................................................................. 33 
9.1 
CLINICAL TRIAL DISCONTINUATION ................................................................................................ 33 

 
 
 
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10.0 DATA HANDLING AND RE CORD KEEPING ................................................................................... 34 
10.1 
SOURCE DOCUMENTS & CASE REPORT FORMS ............................................................................. 34 
10.2 
PROTOCOL DEVIATIONS ............................................................................................................... 34 
10.3 
RECORD RETENTION .................................................................................................................... 34 
10.4 
CLINICAL TRIAL REGISTRATION ..................................................................................................... 34 
11.0 STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 34 
11.1 
STUDY MONITORING PLAN ............................................................................................................ 34 
11.2 
AUDITING AND INSPECTING ........................................................................................................... 35 
12.0 ETHICAL CONSIDERATIO NS .......................................................................................................... 35 
12.1 
RESEARCH ETHICS BOARD (REB) APPROVAL ............................................................................... 35 
12.2 
INFORMED CONSENT PROCESS & DOCUMENTATION ...................................................................... 36 
13.0 PRIVACY AND CONFIDENTIALITY ................................................................................................. 37 
14.0 CLINICAL TRIAL FINAN CES ............................................................................................................ 37 
14.1 
FUNDING SOURCE ........................................................................................................................ 37 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 37 
15.0 PUBLICATION POLICY/D ATA SHARING  ........................................................................................ 37 
15.1 
FUTURE SECONDARY USE OF DATA .............................................................................................. 37 
16.0 REFERENCES ................................................................................................................................... 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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STATEMENT OF COMPLIANCE 
 
A statement confirming the clinical trial will be conducted in compliance with the protocol, 
ICH GCP, applicable regulatory bodies and institutional requirements must be included 
here.  
 
For multi-site clinical trials: A statement of compliance should also be included for each 
site, with the site Principal Investigator’s (PI) signature.   
 
This clinical trial will be carried out in accordance with the following:  
• International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
• Tri-Council Policy Statement 2018 (TCPS 2) 
• ISO 14155:2020 for Medical Device Clinical Trials 
• Personal Health Information Protection Act (PHIPA), 2004; Chapter 3 Schedule A 
(PHIPA) and applicable regulations 
• Food and Drugs Act  
o Part C, Division 5 of the Food and Drug Regulations 
o Part 3, Medical Device Regulations 
o Part 4, Natural Health Products Regulations 
• U.S. Federal Policy for the Protection of Human Subjects (Common Rule) 
• U.S. FDA Regulations 
• Institutional and REB policies and procedures 
 
 
 
 
 
________________________________  
_____31st 
October, 
2023 
________________________ 
Signature of PI 
 
 
 
 
Date 
or 
 
 
 
 
 
 
Signature of site PI (multi-centre clinical trials)  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS  
AE 
 
Adverse Event 
ASD  
Autism Spectrum Disorder 
CRF   
Case report form(s) 
DSMB  
Data Safety & Monitoring Board 
GCP   
Good Clinical Practice 
iTBS  
Intermittent Theta Burst Stimulation 
ICF  
 
Informed consent form 
LTP 
 
Long Term Potentiation 
MEP  
Motor Evoked Potentials 
NT 
 
Neurotypical 
PHI 
 
Personal Health Information 
PHIPA 
Personal Health Information Protection Act 
PI 
 
Principal Investigator 
QI 
 
Qualified Investigator 
RMT  
Resting Motor Threshold 
SAE  
Serious Adverse Event 
SUSAR  
Suspected unexpected serious adverse reaction 
TBS  
Theta Burst Stimulation 
TCPS 2 
Tri-Council Policy Statement  
rTMS  
Repetitive Transcranial Magnetic Stimulation  
 
 
 
 

 
 
 
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1.0 INTRODUCTION 
 
1.1 
Background  
 
Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental 
disorders, affecting ~ 1 in 66 children and youth in Canada5. ASD is a persistent 
disabling condition accounting for 111 disability-adjusted life-years per 100,000 
population6. Motor function difficulties involving  fine and gross motor skills such as 
coordination, strength, balance and mobility in ASD are very common7-13 and they 
emerge early14-17 and persist into adulthood13,18-21. These motor function difficulties 
significantly contribute to core challenges in social and communication skills19,22-25 
and negatively impact quality of life26-27 and daily living skills28 throughout the 
lifespan28. Interventions improving daily functioning in autistic adults have been 
identified as one of the top research priorities29 in the autism  community. Thus, the 
motor system represents a key therapeutic target for biological interventions. 
However, despite the centrality of motor functions in daily functioning, there is 
paucity of research in autistic adults. At this point, there is no quality evidence 
supporting the clinical use of any motor skill intervention in ASD30. Although 
alterations of functional connectivity and white matter pathways involving motor 
networks, including primary motor cortex (M1), have been found to underlie motor 
function difficulties in ASD31-42, the findings are inconsistent and the brain 
mechanisms informing biological  interventions remain elusive. Converging evidence 
indicates that the neurobiology of ASD is characterized by atypical plasticity. In 
particular, an excessive plasticity (i.e. hyperplasticity) in the form of excessive long-
term potentiation (LTP), operationally indexed by a significantly longer lasting 
facilitation of motor evoked potentials (MEPs), was observed in M1 of human 
participants with ASD, when compared to neurotypical (NT) controls, based on the 
theta-burst stimulation (TBS)43-46. We recently replicated the finding of M1 
hyperplasticity in autistic adults46. Our finding of hyperplasticity (i.e. excessive LTP) 
in autistic adults is a direct human translation of the consistent finding of excessive 
LTP found in valproic acid animal models of ASD47-48. One key insight from animal 
models of ASD is that hyperplasticity adversely affects behavior
47,49. Besides 
replicating the finding of M1 hyperplasticity, as a foundation for intervention, we also 
collected pilot data using a repetitive transcranial magnetic stimulation (rTMS) 
protocol designed to strengthen inhibitory mechanisms, which reduced 
hyperplasticity in autistic adults46. Here we propose a new line of translational 
inquiry: i) Testing whether M1 hyperplasticity underlies motor function difficulties in 
ASD, and ii) Using ‘mechanism-driven’ rTMS with autistic adults to examine whether 
resulting reduced M1 hyperplasticity is associated with clinical improvements in 
motor function. If successful, our project will identify a brain mechanism, i.e. 
hyperplasticity, underlying motor function difficulties in ASD and will also identify a 
‘mechanism-driven’ neurostimulation treatment to reduce hyperplasticity and 
improve motor function difficulties in ASD. 
 

 
 
 
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1.1.1 The rationale for targeting motor function difficulties in 
autistic 
adults   
Although motor function difficulties are seen in a range of neurodevelopmental 
disorders such as attention-deficit/hyperactivity disorder, such deficits in ASD are 
significantly more common50, more severe50, and are linked with the core behavioral 
characteristics of ASD19,22-25,51-52. Two meta-analyses confirm consistent and robust 
motor function difficulties in individuals with ASD, involving a large effect size12-13. 
Such motor function difficulties involve a broad range of skills necessary to fine and 
gross motor coordination, arm movement, walking speed, and balance. These 
difficulties appear early14-17 and even precede social-communication deficits in 
ASD53. They tend to be present across the lifetime13, e.g., they persist into 
adolescence54-58 and young adulthood18-20, are present in older adults21 and may 
even get worse with aging59-60. Further, motor function difficulties in ASD negatively 
affect quality of life26-27, autonomy, independence, community participation61 and 
daily adaptive living skills in autistic adults28. A recent systematic review identified 
that interventions improving daily functioning in autistic adults have been identified 
as one of the top research priorities29 in the autism community. Thus, given the 
centrality of motor function in daily functioning, motor systems represent an 
important therapeutic target for biological interventions to improve outcomes in 
autistic adults. To highlight the paucity of research in this area, at present there is 
no ongoing trial to improve motor function in autistic adults registered on 
Clinicatrials.gov. Stakeholder input : We have engaged with a panel of advisors 
comprising of autistic adults at the Centre for Addiction and Mental Health (CAMH) 
during grant development. The feedback has consistently been that this is one of 
the high priority areas of significant unmet need for autistic adults that has been 
much neglected. The group welcomed the effort to identify brain mechanism 
underlying motor function difficulties and felt improving motor skills could 
‘significantly boost their confidence, improve their appearance, increase community 
participation, and overall, improve their daily living skills’. The other feedback was to 
use ‘motor function difficulties’ instead of ‘motor deficits’ and add an exploratory 
objective to test any potential association between changes in the adaptive daily living 
skills and changes in the motor function following rTMS. The feedback on the rTMS 
course for this project (5-session) and duration of visits (described later) was 
positive. 
 
1.1.2 What is known about the neurobiology of motor function 
difficulties in ASD?
 
Even though neurobiology of ASD is characterized by atypical plasticity, to our 
knowledge, no study yet looked into the relationship between atypical plasticity in M1 
and motor function difficulties in ASD. Existing studies on the neurobiology of motor 
function in autism used neuroimaging research and the findings are inconsistent, 
i.e. the findings include both reduced31-35 and increased36-37 functional connectivity 
of motor networks. Further, reduced asymmetry of functional connectivity38, altered 
organization of the motor network39 and increased white matter volume in M140, and 

 
 
 
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atypical functional connectivity of cerebellar network involving motor function were 
also reported41-42. Overall, these findings are inconsistent and the brain mechanisms 
informing new biological interventions remains elusive. 
 
1.1.3 Our published data showing hyperplasticity (excessive LTP) in 
M1 in autistic adults  
 
Figure 1: This figure depicts baseline-corrected MEP amplitude following iTBS and cTBS in the 
ASD and NT groups at 11 time points up to 120 min post-TBS. LTP following iTBS (ASD: 
106.93±30.37minutes; NT: 86.33±38.23minutes; p=0.023; partial η2=0.092, i.e. medium effect 
size) was clearly excessive in the ASD group, indicating hyperplasticity46. We also found 
excessive long-term depression (LTD) following continuous TBS or cTBS. Error bars indicate 
standard error of means. 
 
Using a randomized, cross-over design, we (PI: Desarkar) assessed plasticity using TBS 
in the left M1 in 31 right-handed autistic adults and 30 handedness, sex, intelligence 
quotient (IQ), and age-matched controls46. During TBS, the TMS stimulation pattern 
involves the delivery of a biphasic burst of 3 pulses at 50Hz at intervals of 200ms (i.e. 5 
Hz) (total 600 pulses)62. In the iTBS paradigm, a 2-second train of TBS is repeated 
intermittently (hence intermittent TBS or iTBS), i.e. every 10-second for a total of 190 
seconds62. We calculated LTP by measuring the duration of enhancement (after iTBS) of 
TMS-evoked MEPs (Figure 1) that reflect cortico-spinal excitability, which is indexed by 
the size of the peak-to-peak amplitude of MEPs evoked by single pulse TMS delivered at 
a rate of 0.1Hz and at the intensity of 120% of each participant’s resting motor threshold 
(RMT). 
 
1.1.4 Measurement of LTP  
The duration of facilitation of MEP amplitude, is indexed by the time for the MEP 
amplitude to return to baseline values following iTBS. The selection of the time point 
at which MEP values were judged to have returned to baseline following iTBS was 

 
 
 
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based on published criteria44,46: a) the time point when the  mean MEP value reaches 
‘within the 95% confidence interval of the baseline amplitude’, and b) does not go 
‘outside that interval on subsequent time point measures’. MEP values for each 
participant was standardized by baseline correction. Standardized values represent 
a ratio of post-/average baseline MEP amplitude. Thus, for iTBS, values >1 represent 
facilitation. For the ASD and NT control groups, we used one sample t test (against 
1) to test if facilitation was significant46. After controlling for sex, age, IQ, and TBS 
order, we found that LTP was significantly increased in the ASD group, indicating 
hyperplasticity (Figure 1). 
 
1.2 
Study  Intervention  
1.2.1 The rationale for using rTMS to modulate hyperplasticity in M1 
and improve motor function diffic
ulties in ASD  
1.2.1.1 Our pilot data show promising evidence that rTMS can reduce 
an excessive LTP in M1 in autistic adults
46 
 
 
Figure 2:  Our pilot data show the attenuation of LTP (assessed by iTBS) in the ASD 
group following active vs. sham rTMS.  
 
We (PI: Desarkar) recently published pilot data46 showing preliminary evidence that rTMS, 
which was previously shown to maximally potentiate brain inhibitory mechanisms in M1, 
reduced excessive LTP in M1 in autistic adults. In our study, 29 autistic adults were 
randomized (1:1) to receive a single session of active (n=14) or sham (n=15) (6,000 
pulses at 20Hz) over left M1 and plasticity was reassessed on the next day following 
rTMS. The mean reduction of LTP (‘meanpre – meanpost rTMS’) assessed using iTBS in 
the active rTMS group was 15.00 minutes and -2.14 minutes in the sham group (Figure 
2), indicating a large effect size (partial η2=0.167) of active rTMS on LTP. The inhibitory 
effect of such rTMS was previously documented by our group81-82. Compared to 1Hz or 
10Hz rTMS, 20Hz rTMS with an extended delivery of pulses had more pronounced 
‘inhibitory’ effect81, and such ‘inhibitory’ effect was maximal when 20 Hz rTMS was 
delivered for 6,000 total pulses82. In the altered excitation/inhibition model of ASD77, 

 
 
 
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hyperplasticity in M1 is likely linked with the increased excitation/inhibition ratio and the 
reduction of hyperplasticity in the ASD group in our published work (PI Desarkar)  by the 
rTMS could be due to facilitation of inhibition46. We had previously published the rationale 
behind such approach83. 
1.2.1.2 Why study primary motor cortex (M1)?
 
The human motor cortex is comprised  of three areas: the primary motor cortex (M1), pre-
motor area and supplementary motor area. Human motor control network involves 
communication between motor cortex and other areas including basal ganglia system, 
frontal lobe, cerebellum, sensory cortex, thalamus, and medulla. Within motor cortex, M1 
receives inputs from pre-motor areas, supplementary motor areas and plays a critical role 
in encoding force, direction, extent and speed of a movement84-86. The well-defined links 
between M1 and motor control provides strong biological validity for our approach, as 
does published data revealing M1 hyperplasticity in autistic adults and preliminary data 
suggesting that rTMS may rectify hyperplasticity in M1. Further, stimulation of M1 is an 
established method to improve motor function in neurological conditions such as 
Parkinson’s disease87 and stroke88. 
1.2.1.3 Why not other therapies?
 
Common motor skills intervention in ASD involved teaching and strengthening locomotor 
and various object control skills such as balance, throwing, running, etc. and training fine 
motor skills. Other studies used robot-assisted training and training using video games30. 
A recent review30 of motor skills interventions for children and adolescents with ASD 
found preliminary suggestion of possible beneficial effects of these interventions; 
however, only two studies were randomized controlled trials (RCTs)89-90. While one did 
not report significant improvement after motor skills intervention90, the other RCT did not 
compare the two active intervention programs89. Further, the training sessions in these 
intervention studies required more time commitment, i.e., up to 5 days a week for 6-12 
weeks, than what is proposed in this project (i.e., 2 hours/day for 5 days)30. At this point, 
there is no quality evidence supporting the clinical use of any motor skill intervention in 
ASD. 
1.2.1.4 How would hyperplasticity in the M1 affect motor function?
 
Hyperplasticity can be a compensatory mechanism91 or part of physiological 
development92. The relationship between plasticity and behavior/cognition is ‘inverted 
U’49. While deficient plasticity prevents brain to adequately adjust itself to changing 
conditions, one key insight from animal experiments is that hyperplasticity may 
compromise behavior47,49. A model of plasticity pathology continuum posits that, at the 
circuit level, persistent and excessive LTP could lead to excitotoxicity, which leads to 
neuronal loss and reduced synaptic density, compromising behavior93. In the context of 
M1 hyperplasticity, a meta-analysis of post-mortem studies did reveal reduced dendritic 
spines in M1 in ASD94. 

 
 
 
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Figure  3: Illustrating the incomplete  inverted U relationship in relation to hypothesis 1b. 
 
1.3 
Preclinical Data  to Date  
 
The role of atypical plasticity in the neurobiology of ASD is supported by a growing 
number of genes associated with ASD that are involved in synaptic plasticity63-69. 
Among animal models of ASD, while deficient plasticity was found in some70-72, e.g. 
FMR1, SHANK3, etc, hyperplasticity was observed in valproic acid models47-48. By 
contrast, a more direct evidence of hyperplasticity was consistently observed in 
human M1 using TMS43-46 with one exception73. Our finding replicating M1 
hyperplasticity in  autistic adults using TBS is consistent with what was observed in 
3 studies (Cohen’s d 1.21-2.47)43-45. The only TMS study73 that found reduced LTP 
in M1 using paired associative stimulation, another way to assess plasticity, had a 
small sample (n=9) with a mixed population of children and adults, and the effects 
of sex and intellectual ability were not controlled for. The generation of LTP in the 
classical post-synaptic model is mediated via N-methyl-D-aspartate (NMDA) 
receptors74. Consistent with this model, it was shown that the LTP-like after-effects 
of patterned high-frequency stimulation such as TBS was NMDA-dependent75. At the 
synaptic level, post-synaptic NMDA74 and both gamma aminobutyric acid (GABA) A 
and B receptors play a critical role in the LTP generation76. One explanation of 
observed hyperplasticity is the excitation/inhibition imbalance created by over-
expression of NMDA77-78 and/or reduced expression of GABAA or GABAB receptors 
observed in the ASD brain78-79. A systematic review  of TMS studies found evidence 
of increased excitation/inhibition ratio in M1 in ASD80. 
 
 

 
 
 
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1.4 
Risk s/Benefits  
1.4.1 Risk  
1.4.1.1 Assessments  
Assessments may impose some risk due to possible emotional discomfort and possible 
fatigue.  
 
1.4.1.2 TMS and TMS-EEG 
The most commonly reported side effect of TMS is headache (~5%). Participants may 
also experience some discomfort under the coil due to contraction of muscles and 
stimulation of nerves on the scalp. These reactions are generally minor and lack serious 
sequelae. If the participant is discomforted by the headache, it is usually easily managed 
with standard analgesics. Earplugs may be used during each TMS session to prevent 
discomfort from the clicking noise generated by the stimulation. No hearing loss has been 
found in humans exposed to single or paired pulse TMS.  
 
The occurrence of fainting from TMS has been reported but may not be very common. 
To minimize the risk of this, brain stimulation will be discontinued if participants feel 
significant dizziness or nausea through the study visits. 
The TMS-electroencephalography (TMS-EEG) neurophysiology sessions will be 
conducted during 2nd (all participants), 8th and 9th (ASD participants only) visits. This TMS 
protocol does not deliver repetitive pulses that can cause sustained therapeutic 
neuromodulation. The pulses delivered are thought only to be sufficient to assess brain 
functioning and it is not physiologically plausible that the TMS protocols intended to 
assess GABAergic neurotransmission would have a sustained effect on mood or 
cognition. In numerous studies, single or paired-pulse TMS has been found to pose no 
significant health risk to properly screened normal volunteers.  
 
Single and paired-pulse TMS is now in routine clinical diagnostic use in hundreds of 
neurophysiological laboratories worldwide. The FDA has concluded that stimulation at <1 
Hz carries only a remote likelihood of seizure and is therefore classified as a non-
significant risk device. All subjects will be screened for risk of seizure using the TMS adult 
safety screen84.  
Safety data: The rTMS protocol (6000 pulses, 20Hz, delivered at 90% of the resting motor 
threshold is within the safety parameters for rTMS138. In our pilot study137, 29 autistic 
adults and 30 control participants received rTMS and no participant reported any adverse 
effects.  
 
1.4.2 Benefit  
 

 
 
 
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There may not be any direct benefit to study participants. The study finding may advance 
our understanding of the brain mechanisms underlying motor function difficulties in ASD.  
 
1) Brain-behavior relationship in ASD: if successful, our project will identify a brain 
mechanism, i.e. hyperplasticity, underlying motor function difficulties in ASD;  
 
2) Novel neurostimulation intervention for ASD: if successful, our project will also identify 
a ‘mechanism-driven’ neurostimulation treatment to reduce hyperplasticity in the brain and 
improve motor function difficulties and thus, outcomes in ASD. The estimated lifetime cost 
of supporting an individual with ASD in Canada  is between $1.2 million to $4.7 million95. 
Thus, increasing daily functioning and independence will have significant cost-benefit.  
 
3) Informing future trials: This information will provide a foundation to test similar 
neurostimulation approach in the less able ASD population subgroups in the future. 
 
2.0 CLINICAL TRIAL OBJECTIVES  
2.1 
Primary Objective  
Objective 1:  To examine the strength and nature of association between plasticity in M1 
and motor function in autistic adults and neurotypical (NT) controls. Hypothesis  1a: 
Compared to NT controls, autistic adults will display greater plasticity in M1. Hypothesis  
1b: There will be a non-linear incom plete ‘inverted U’ shaped association (plasticity on the 
x axis, motor performance on the y axis) between plasticity in M1 and motor function, 
however, the association will be different for the two groups, i.e. autistic adults will mainly 
be in the right slope of the inverted U reflecting hyperplasticity associated with impaired 
motor function, while NT controls will cluster around the center (Figure 3). 
2.2 
Secondary Objective  
Objective 2 : To examine the efficacy of bilateral rTMS delivered to M1 in reducing 
hyperplasticity in M1 and improving motor function in autistic adults via a randomized, 
double-blind, sham-controlled  experiment. Hypothesis 2a : Autistic adults receiving 
active rTMS will have lower plasticity in M1 immediately, and 1 and 4 weeks after the 
course compared to autistic adults receiving sham rTMS. Hypothesis  2b: Autistic adults 
receiving active rTMS will have better motor function immediately, and 1 and 4 weeks 
after the course compared to autistic adults receiving sham rTMS. 
 
2.3 
Tertiary  Objective  
Objective  3: To examine if changes in the M1 plasticity correlate with changes in the 
motor function in autistic adults following active bilateral rTMS. Hypothesis  3: Changes 
in the M1 plasticity will correlate with changes in the motor function in autistic adults 
following active bilateral rTMS. 

 
 
 
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2.4 
Exploratory Objective
 
Exploratory  objective  1: To examine if changes in the motor function correlate with 
changes in the adaptive daily living skills in autistic adults following active bilateral rTMS. 
Exploratory  hypothesis  1: Changes in the motor function will positively correlate with 
changes in the adaptive daily living skills  in autistic adults following active bilateral rTMS. 
 
 
3.0 CLINICAL TRIAL DESIGN 
3.1 
Overall  Design  
Figure 4: The outline of the project 
 
 
We will recruit 100 autistic adults and significant motor function difficulties (based on 
standardized motor assessment – see below in section 3.2.1.) and 50 NT controls 
matched 2:1 based on age, sex and IQ. Day 1: all participants will complete clinical, 
adaptive and motor function assessments (~3hours). Day 2: Plasticity in the left or right 
M1 (depending on handedness, see below) will be assessed with iTBS in all participants 
(~2.5hours). Day 3-7: Following Day 2 procedures, 100 ASD participants will be 
randomized (sex- stratified, 1:1, double-blind) to receive active (n=50) or sham (n=50) 
rTMS delivered to M1 bilaterally, 1session/day for 5 days (total 5 sessions) 
(~1.5hours/day). On the last day of rTMS (i.e., Day 7) ASD participants will repeat motor 
and adaptive function assessments and iTBS will be used to assess plasticity. (~4.5-
5hours). Assessment of motor and adaptive function and plasticity using iTBS will be 
repeated 1-week (Day 8) (3-3.5hours) and 4-week (Day 9) (3-3.5hours) after the final day 
of rTMS (i.e., Day 7). In order to avoid any potential influence of iTBS on motor function 
assessments, we will always   carry out motor assessments before iTBS. 
 
3.1.1 Project Timeline  
We anticipate that a timeline of 5 years is necessary to complete all aspects of this project. 

 
 
 
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An initial 3 months start-up period is anticipated to hire and train the research staff. After 
this, we plan to recruit about 1-2 new ASD participants and 1 NT controls/month. This 
timeline will allow us to complete recruitment of all participants by month-53. Participants 
recruited in month-53 will complete the project in month-54, leaving us about 6 months to 
complete our analyses and report our results. 
 
3.1.2 Clinical Assessments
 
All clinical and baseline motor assessments will be done on Day 1 (~3hours) (Figure 4). 
The Wechsler Abbreviated Scale of Intelligence, Second Edition105 will be used to ensure 
participants have IQ>70. Edinburgh Handedness Inventory106 will be used to assess 
handedness. The daily living skills domain of Adaptive Behavior Assessment System-3rd 
edition107 (~15-20 minutes) will       be used to assess adaptive daily living skills. All ASD 
participants will have a DSM-596 diagnosis, confirmed by ADOS-297. This visit includes a 
screening for any contraindication to TMS108. 
 
3.1.3 Assessment of motor function in ASD and NT Controls
 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2)98 will be used to 
assess motor function of ASD and NT control participants. The BOT-2 is a standardized 
comprehensive test battery assessing fine manual control, manual and body 
coordination, strength and agility domains and takes about 45-60 minutes to complete. 
The total motor composite score will be used as the primary measure of motor function. 
Rationale for using BOT-2: BOT-2 is validated in the ASD population98,109-110, has most-
validated age-norms for adults98, 110-111, can be repeated to monitor progress98,109, and 
includes domains found to be impaired in ASD. 
 
3.2 
Primary Endpoints  
 
3.2.1 Assessment of Plasticity in M
1 using Intermittent Theta
-burst 
Stimulation iTBS 
3.2.1.1 Primary measure of plasticity
 
Plasticity using iTBS will be assessed at the right M1 in left-handed, and left M1 in right- 
and mixed- handed participants. Rationale: Given the high variability of handedness in 
ASD99, in order to be inclu sive, we will include participants with left, right or mixed 
handedness. The motor “hotspot” will be determined as the coil location over M1 that will 
consistently produce MEPs at the contralateral relaxed hand muscles at the lowest 
stimulator intensity. The coil will be positioned flat on the scalp over the motor hotspot of 
M1 (right or left) such that the main component of the induced electric field points in a 
postero-lateral to anteromedial direction, making a 45° angle with the midline112. iTBS will 
be administered using a MagPro stimulator (MagVenture Inc). The Resting Motor 
Threshold (RMT) is defined as the minimal TMS intensity that produces an MEP of >50 

 
 
 
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μV peak-to-peak amplitude in 5 of 10 trials in relaxed right first dorsal interosseous 
muscle113-114. iTBS pulses will be delivered at 80% of the RMT. The baseline measure of 
corticospinal excitability will be defined as the mean MEP amplitude across 150 single 
pulses. In order to track changes in corticospinal excitability following iTBS over time, we 
will follow current recommendation, i.e., blocks of 20 single pulses114 will be delivered at 
5, 10, 20, 30, 40, 50, 60, 75, 90, 105, and 120 min following iTBS. Mean amplitude of 20 
MEPs will represent the measure of corticospinal excitability at each time point. The LTP 
will be calculated using published method46 described earlier.  
 
The duration of facilitation of MEP amplitude, is indexed by the time for the MEP amplitude 
to return to baseline values following iTBS. The selection of the time point at which MEP 
values were judged to have returned to baseline following iTBS was based on published 
criteria44,46: a) the time point when the  mean MEP value reaches ‘within the 95% 
confidence interval of the baseline amplitude’, and b) does not go ‘outside that interval on 
subsequent time point measures’. MEP values for each participant was standardized by 
baseline correction. Standardized values represent a ratio of post-/average baseline MEP 
amplitude. Thus, for iTBS, values >1 represent facilitation. For the ASD and NT control 
groups, we will use one sample t test (against 1) to test if facilitation was significant46.  
 
 
3.2.1.2 Secondary measure of plasticity
 using E EG 
As a secondary assessment of plasticity in M1 using iTBS, we will also be recording EEG 
before, during iTBS, and also at all 11 time points i.e. at 5, 10, 20, 30, 40, 50, 60, 75, 90, 
105, and 120 min following iTBS when single pulse TMS will be delivered (see above).  
 
In this TMS-EEG method (i.e. use of EEG to index iTBS-induced plasticity), iTBS- induced 
LTP is defined by potentiation of cortical evoked activity (CEA), which is measured by 
EEG. Previously we reported the validity of CEA by measuring strong correlation between 
MEP and CEA measures123. CEA will be defined as the area under rectified curve for 
averaged EEG recordings in electrode over M1 between 50-275 millisecond post-
stimulus. The 50 millisecond cutoff is chosen as it represents the earliest artefact free 
data that can be recorded post-stimulus. The 275 millisecond cutoff is chosen as TMS-
induced CEA subsides almost to 0 by 275 millisecond post-TMS123. iTBS-induced LTP is 
indexed by maximum post-iTBS/pre-iTBS CEA ratio of the 11 time points i.e. at 5, 10, 20, 
30, 40, 50, 60, 75, 90, 105, and 120 min following iTBS.  
Prior to iTBS procedure, we will record the resting state EEG for 10 minutes (five minutes 
with eyes closed, and five minutes with eyes open).  
 
EEG will be acquired through a 64-channel Synamps 2 EEG system. A 64 channel EEG 
cap will be used to record the cortical signals, and 4 electrodes will be placed around the 
eyes to correct for eye movement artefacts. EEG signals will be recorded using direct 
current mode at 20 kiloHz sampling rate, which was shown to avoid saturation of 
amplifiers and minimize TMS artefact123. All EEG processing and analysis will be done 
offline using EEGLAB toolbox of Matlab.  
 

 
 
 
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3.2.2 Primary endpoint of rTMS
 intervention  
In this study, our second objective is to examine the efficacy of bilateral rTMS delivered 
to M1 in reducing hyperplasticity in M1 and improving motor function in autistic adults via 
a randomized, double-blind, sham-controlled  experiment. We anticipate that autistic 
adults receiving active rTMS will have lower plasticity in M1 immediately, and 1 and 4 
weeks after the course compared to autistic adults receiving sham rTMS. Further, we 
anticipate that autistic adults receiving active rTMS will have better motor function 
immediately, and 1 and 4 weeks after the course compared to autistic adults receiving 
sham rTMS. 
 
The assessment of plasticity immediately, 1 and 4 week after rTMS will be assessed using 
the same methods to assess plasticity described above (using changes in MEPs, i.e. 
primary, and CEA ratio, i.e. secondary).  
 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2)98 will be used to 
assess motor function as described above. The total motor composite score will be used 
as the primary measure of motor function. Rationale for using BOT-2: BOT-2 is validated 
in the ASD population98,109-110, has most-validated age-norms for adults98, 110-111, can be 
repeated to monitor progress98,109, and includes domains found to be impaired in ASD. 
 
3.3 
Secondary Endpoints  
There are no secondary endpoints for this study. 
4.0 PARTICIPANT SELECTION AND WITHDRAWAL 
4.1 
Target Population  
ASD participants and healthy NT controls will be recruited for this study.  
4.2 
Participant Recruitment and Screening
 
ASD participants will be recruited from i) CAMH Adult Neurodevelopmental Services that 
sees ~ 320 autistic adults without ID (~250 new, about 35%, i.e. ~ 112 females assigned 
at birth) every year, ii) the youth ASD clinic in the CAMH that sees ~ 300 new youth with 
ASD/year; iii) community partners serving autistic adults such as Autism Ontario, Kerry’s 
Place Autism, Redpath Centre, etc. Targeting a male: female (sex assigned at birth) ratio 
of 2:1, we aim for recruiting at least 34 female ASD participants over 5 years and believe 
this is highly feasible. Considering the increased rate of gender diversity among autistic 
adults4, we will collect gender identity information for all participants as a part of 
sociodemographic characterization. NT control participants will be recruited from CAMH 
healthy control registry, through advertising at universities, newspapers and online 
classified advertisements, and from the current and past projects of co-applicants Drs. 
Ameis, Lai and Lunsky.  Initial contact will be made via email and/or telephone. Contact 
information will be provided on all advertising materials.  
 

 
 
 
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CLEARR will be used to recruit participants for this clinical trial. All new referrals will be 
reviewed by the CLEARR coordinator and CLEARR physician for eligibility to participate 
using minimal inclusion/exclusion criteria outlined. Once a patient is identified as 
potentially suitable for the clinical trial, the attending physician will be notified via outlook 
calendar invite or email that their patient may be eligible for the clinical trial. The attending 
physician will decide whether research is appropriate for the patient and if so, they will 
ask the patient for consent to be contacted regarding the clinical trial. If the patient 
provides verbal consent to be contacted to receive more information about the clinical 
trial, the physician will connect the patient with the CLEARR coordinator or research team 
who will further explain the clinical trial. No personal health information (PHI) will be given 
to the research team prior to obtaining the patient’s consent.  
 
 
The CAMH Research Registry will be used to recruit participants for this clinical trial.  
Upon REB approval to use the Research Registry as a recruitment strategy, authorized 
research personnel will search and contact potential research participants included within 
the member database of the Research Registry for study participation. This clinical trial 
will also be posted on the Research Registry website, as well as the public CAMH 
website. Once posted, interested participants can use the “Find a CAMH study” feature 
to explore clinical trials that they are interested in.  
 
4.3 
Equity, Diversity  and Inclusion  Considerations  
Emerging evidence indicates sex differences in brain plasticity in ASD1. We will address 
the potential effect of sex by a) matching patient (i.e. ASD) and control group on sex, and 
b) recruiting a higher number of female ASD participants. A male to female (assigned at 
birth) ratio of 2.5:1 has been described in recent clinical samples2, compared to an earlier 
3:13. In this study, we will recruit a higher number of female ASD participants targeting a 
male to female ratio of 2:1. Further, in order to balance sex across active and sham rTMS 
groups, we will conduct a sex-stratified randomization. We will include sex as fixed 
independent factors in our analyses plans so that we could study the sex moderation 
effects. We will describe sex-stratification of findings using means/estimates and 95% 
confidence intervals, recognizing this is exploratory given that the design is likely 
underpowered for this. 
 
At this point, there is no known effect of gender identity on plasticity or motor function in 
ASD. Therefore, we will not control for gender identity in the analysis plan. However, 
considering the increased rate of gender diversity among autistic adults4, we will collect 
gender identity information for all participants as a part of sociodemographic 
characterization and will conduct gender identity stratified subgroup analysis for 
descriptive purpose. 
4.4 
Eligibility Criteria
 
4.4.1 
Inclusion Criteria  
 
ASD or control participants must meet all of the inclusion criteria to eligible for this study: 

 
 
 
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1. Aged between 18 and 40 years old. 40 years is chosen as the cut-off because of the 
report of high rates of Parkinsonism in autistic adults>39years60; 
2. Have IQ>70; 
3. Are able to read, write and communicate effectively in English; 
4. Are able to provide informed consent. We will recruit only intellectually-able autistic 
adults. The intellectual ability will be determined using WAIS. The ability to provide 
consent will be determined using clinical assessment.  
5. Have no prior history of seizure; 
6. Must sign and date the informed consent form; 
7. Stated willingness to comply with all study procedures; 
8. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study 
duration. 
All ASD participants: 
1. Will have DSM-596 diagnosis of ASD without intellectual disability, confirmed by 
clinical assessment and the Autism Diagnostic Observation Schedule – 2 (ADOS-
2)97; 
2. Will have significant motor function difficulties defined as a standard composite 
score <40 (i.e., >1 standard deviation below the mean) on either fine or gross motor 
composite scores of the Bruininks-Oseretsky Test of Motor Proficiency, Second 
Edition or BOT-298; 
3. Are clinically stable as determined by clinical assessment, with no medication 
changes over the past 4 weeks. Given the high variability of handedness in ASD99, 
we will include participants with left, right or mixed handedness.   
4.4.2 
Exclusion Criteria  
ASD or control participants will be excluded if they experience/have: 
1. current pregnancy; 
2. current or past history of co-morbid medical condition that may require urgent 
medical intervention; 
3. DSM-5 substance use disorder (other than tobacco) within the past 6 months; 
however, all participants will be asked to refrain from smoking or taking caffeine 
four hours prior to the iTBS session; 
4. significant hearing or visual impairment interfering with the ability to read or hear 
instructions; 
5. significantly debilitating medical or neurologic illness (e.g., encephalitis, 
aneurysms, tumors, central nervous system infections), or acute or unstable 
medical illnesses as determined by project physician (e.g., uncontrolled diabetes); 
6. metal implants or a pace-maker; 
7. prior rTMS treatment; 
8. claustrophobia; 
 

 
 
 
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In addition ASD participants will be excluded if they report taking benzodiazepines or 
anticonvulsants currently.  
 
NT controls will be excluded if they have: 
1. presence of psychopathology other than specific phobia, as screened by 
Personality Assessment Inventory100 and; 
2. a known diagnosis of Pervasive Developmental Disorder or ASD among any 
biologically related family members 
 
4.5 
Lifestyle Considerations
 
During this study, participants are asked to: 
 Refrain from consumption of alcohol, tobacco, marijuana or caffeine on the day of study 
visits. 
4.6 
Screen F ailures  
Screen failures are defined as participants who consent to participate in the clinical trial 
but do not meet one or more eligibility criteria required for participation. We will record 
information including demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAE). If there is a screen failure due to medication changes, we 
will invite back the participant after 4 weeks for their medication to stabilize.   
4.7 
Participant Withdrawal Criteria
 
4.7.1 
When and How to Withdraw Participants  
 
Participants are free to withdraw from participation in the clinical trial at any time.  
An investigator may discontinue or withdraw a participant from the clinical trial for the 
following reasons: 
1. Unable to tolerate the procedure 
2. develop significant adverse events (e.g., seizure);  
3. Participant missing or is unable to receive 2 consecutive scheduled rTMS 
treatment.  
4. Withdraw consent  
 
The reason for participant discontinuation or withdrawal from the study will be recorded      
within the participant’s research record. 
4.7.2 
Follow -up for Withdrawn Participants  
If a participant withdraws consent, they can also request the withdrawal of their subject 
to any research-specific restrictions. Once withdrawn from the clinical trial, no further 
research procedures or evaluations will be performed, or additional research-specific data 
collected on the participant. Reasonable effort will be made to obtain permission to 
document the reason for withdrawal.  

 
 
 
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4.7.3 
Early Termination Visit
 
If a participant withdraws from the clinical trial, every effort should be made to perform an 
Early Termination Visit. In the termination visit, we will assess AEs. 
4.7.4 
Participants who are Lost to Follow
-up 
A participant will be considered lost to follow-up if they fail to return for the 2 scheduled 
visits after the completion of the 5-day rTMS course and is unable to be contacted by the 
research team.  
 
The following actions will be taken if a participant fails to attend a required study visit: 
 The research team will attempt to contact the participant and reschedule the missed 
visit within a week, counsel the participant on the importance of maintaining the 
assigned visit schedule, and reconfirm whether the participant wishes to and/or should 
continue in the clinical trial.  
 Before a participant is deemed lost to follow-up, the research team will make every 
effort to regain contact with the participant (where possible, three telephone calls 
and/or, sending e-mails). These contact attempts should be documented in the 
participant’s research record. .   
 Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the clinical trial with a primary reason of lost to follow-up. 
 
5.0 STUDY INTERVENTION  
5.1 
Description  
5.1.1 Repetitive Transcranial Magnetic Stimulation (rTMS) t
rial  
5.1.1.1 Trial Design  
This project has an RCT (not as major component). We will use a randomized, double- 
blind, sham-controlled design comparing the efficacy of active vs. sham rTMS (6000 
pulses at 20 Hz/session) delivered to M1 using bilaterally, 1 session/day for 5 days (5 
sessions).  The pulses will be delivered first to one side (right or left), which will be then 
followed by the pulses being delivered to the opposite side. The sequence will be 
randomized per participants.  
 
5.1.1.2 Duration of rTMS effect – will the effect be transient?
 
While the effect of a single rTMS session on motor function may be transient, studies 
using rTMS for motor function in neurological condition such as Parkinson’s disease 
showed gradual development of long-lasting treatment effects of multiple sessions of 
rTMS115 that persisted when studied 4 weeks after the last session87. In depression, 
besides clinical improvement, rTMS led to even remission in a subset of patients that 
persisted when assessed 12 weeks after the last session116. In our study, outcome 
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evaluated at baseline, immediately, and then 1 and 4 weeks after the last rTMS session. 
No medication changes will be allowed from 4 weeks prior to the trial until its conclusion, 
i.e. day 9. (Figure 4). Project investigators including biostatistician, raters and TMS 
technicians will remain blind to treatment allocation until after project data has been 
analyzed. 
5.1.1.3 Controlling confounding effects of rTM
S – the rationale 
behind choosing ‘sham – stimulation’ 
The two methods to control for the confounding effects of active rTMS are (i) using a 
sham coil, which is by far the most widely used method, or (ii) using an ‘off-target’ active 
brain stimulation control117. Sham stimulation closely mimics placebo, however, some 
indirect stimulation aspects of active rTMS related to sensory, auditory and vibration are 
not always adequately matched using sham conditions. To  minimize this, we will use active 
and sham adapters for active and sham stimulation and the coil will remain the same in both 
conditions blinding both patients and technicians.  The sham adapter causes identical auditory 
and similar somatosensory (vibration) stimulation without cortical stimulation. Unlike 
sham stimulation, actively stimulating another brain region as a control site may address 
the specificity of the effect of active rTMS, however it comes with an additional risk 
associated with the added dose of active brain stimulation. A technical paper117 on the 
experimental control for brain stimulation recommended using active stimulation control as 
the last resort. The ethical decision-making to choose an appropriate control in rTMS trials 
depends on two factors: the safety of the population studied and quality and reliability of 
data117. We considered stimulating 5cm in front of M1 as a control site. However, we 
preferred to choose sham control for this project because 1) stimulating another site 
actively will add to the risk of rTMS exposure in an already vulnerable ASD population who 
have a baseline higher risk of seizures compared to general population118; 2) the 
requirement to add another sham-control for the added active rTMS control site (i.e. 2 
active and 2 sham stimulation in total) will add to the burden and complexity of the study; 
and 3) stimulating 5cm in front of M1 will likely have significant confounding effects on 
motor control119. We will use electrocardiography to monitor heart rate throughout the 
rTMS session to control for arousal related confounding effects of active rTMS. 
 
5.2 
Treatment Regimen  
Rationale: Bilateral stimulation of M1 is chosen because a meta-analysis of rTMS clinical 
trials for the treatment of motor function difficulties in neurological conditions such as 
Parkinson’s disease showed a clearly significant benefit of bilateral over unilateral M1 
stimulation87. Further, a significantly greater and longer lasting effect of rTMS on motor 
function was dependent on the use of ‘high-frequency’ pulses, >1 trial session, and the 
total ‘dose’ of pulses delivered during the trial87, i.e. it was found that studies with total 
stimulation pulses around 18,000 to 20,000 pulses had the most clinical benefit87. Thus, 
the total number of pulses delivered in the current project will be 30,000/ASD participant 
over 5 days. 

 
 
 
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5.3 
Method for Assigning 
Participants  to Treatment Groups  
We will conduct a sex-stratified randomization in which within each sex groups, i.e., male 
and female assigned at birth, ASD participants will be randomly (1:1) allocated to active 
or sham rTMS groups. Randomization will be completed using random permuted blocks 
of varying sizes with project personnel blinded to the block sizes. 
5.4 
Administration of 
Study  Intervention  
Active or sham rTMS will be delivered bilaterally to M1. The rTMS paradigm comprises of 
the delivery of 6,000 pulses (120 trains of 50 pulses with an inter-train interval of 30 
seconds) of active or sham 20Hz rTMS46. The Magstim Horizon TMS Therapy System 
with EZ Coil with true and sham adapters (Magstim, Plymouth, MN) will be used for rTMS. 
Participants will remain seated in a comfortable chair in semi-reclined position and the 
coils will be machine-held. rTMS will be delivered at 90% of the RMT in both conditions46. 
5.5 
Participant Compliance Monitoring
 
Not applicable. 
5.6 
Concomitant Therapy  
Not applicable. 
5.7 
Packaging  
Not applicable. 
 
5.8 
Blinding of Study Intervention  
An independent assistant external to the project will manage the randomization of 
subjects. The clinician, investigators, participant and technician will all be blinded. To 
ensure blinding during treatment, either the active or sham adapter will be connected to 
the Magstim Horizon, the coil will remain the same. To ensure blinding of the technician 
and the participant an independent study assistant will connect the active or sham 
adapter for the Magstim Horizon. Both heads have identical external appearances, and 
stimulation of either coil generates identical auditory and somatosensory (vibration) 
stimuli. All raters obtaining outcome measures will also be blinded to treatment 
assignment. 
5.9 
Receiving, Storage, Dispensing and Return
 
5.9.1 
Receipt of Study Intervention  Supplies  
Not applicable. 
5.9.2 
Storage  
Not applicable. 
5.9.3 
Dispensing of Study Intervention  
Not applicable. 
 

 
 
 
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5.9.4 
Return or Destruction of Study 
Intervention  
Not applicable. 
 
 
6.0 RESEARCH PROCEDURES 
6.1 
Research Visits  
 
Screening Visit  (Visit 1) : 
During the screening visit, the following steps will be done: 
 
 Reviewing and signing the consent form 
 Completing the demographic questionnaire 
 Ensure that it is safe for participants to get Transcranial Magnetic Stimulation 
(TMS)  
 Completing assessments:  
o Wechsler Abbreviated Scale of Intelligence – Second Edition (all 
participants)  
o Autism Diagnostic Observation Schedule – 2 (ASD participants only)  
o Bruininks-Oseretsky Test of Motor Proficiency Second Edition (BOT-2) – 
(ASD participants only)  
o Edinburgh Handedness Inventory (all participants)  
o Adaptive Behavior Assessment System-3rd (ASD participants)  
o Personality Assessment Inventory (control participants only)   
The screening visit will take about 3 hours. 
 
 
Study Visit 2 
 
During the second visit, we will use iTBS to assess the plasticity in one side of the brain 
at the motor cortex. This visit will take about 2.5 hours. This will be done for all 
participants. We will then randomize the ASD participants into active vs sham rTMS 
groups for visits 3 to 7. There will be no more visits for control participants.  
 
Study Visits 3 to 7  
 
During visits we will administer active or sham rTMS bilaterally at the motor cortex to 
ASD participants only. These visits will be about 1.5hours each.  
 
Study Visit 8  
 
Exactly 1 week after visit 7, we will again repeat motor and adaptive function 
assessments. We will then again assess plasticity on one side of the brain using iTBS 
same as Day 2.  

 
 
 
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Study Vis it 9 
 
Exactly 3 weeks after visit 8, we will again repeat motor and adaptive function 
assessments. We will then again assess plasticity on one side of the brain using iTBS 
same as Day 2.  

 
 
 
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6.2 
Schedule of Events  
 
 
Procedures  
Screening and Baseline 
Visit 1, Day 1 
Study Visit 2,  
Day 2  
Study Visit 3, 
Day 3  
Study Visit 4, 
Day 4 
Study Visit 5, 
Day 5 
Study Visit 6, 
Day  6 
Study Visit 7, 
Day 7 
Study Visit 8, 
Day 14 
Study Visit 9, 
Day 35  
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Edinburgh Handedness Inventory 
X 
 
 
 
 
 
 
 
 
Wechsler Abbreviated Scale of Intelligence – Second Edition 
X 
 
 
 
 
 
 
 
 
Autism Diagnostic Observation Schedule – 2 (ASD only) 
X 
 
 
 
 
 
 
 
 
Bruininks-Oseretsky Test of Motor Proficiency Second Edition 
X 
 
 
 
 
 
 
 
 
Adaptive Behavior Assessment System-3rd 
X 
 
 
 
 
 
 
 
 
Personality Assessment Inventory (control only) 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
iTBS 
 
X 
 
 
 
 
 
X 
X 
rTMS 
 
 
X 
X 
X 
X 
X 
 
 
Adverse event review and evaluation 
Concomitant medication review  
Complete Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
 
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7.0 STATISTICAL PLAN 
7.1 
Sample Size Determination  
Hypothesis 1a – In a sample of 31 ASD and 30 NT participants, we found LTP to be 20.6 
points higher in the ASD group (Cohen’s d = 0.54)46. Therefore, a sample of 80 ASD and 
40 control participants will allow us to detect with 80% power differences of 17 points in 
LTP, equivalent to Cohen’s d = 0.48. Hypothesis 1b – A sample of 80 ASD and 40 NT 
participants will provide 80% power to detect a regression coefficient equivalent to a 
standardized effect Cohen’s f2 = 0.08 and 0.16 respectively in the ASD and control group, 
which are small and medium effect sizes. Hypothesis 2a and 2b – In both cases, 
considering a mixed effect model with 3 time points and an overall test for the main effect 
of group (active rTMS, sham rTMS), 40 participants per group will provide 80% power to 
detect a standardized effect size Cohen’s f = 0.26, i.e., a medium effect size, which is 
consistent with our recently published work46. Hypothesis 3 – A sample of 40 ASD 
participants expected to receive active bilateral rTMS will provide 80% power to detect a 
within subject medium effect size of 0.4. We will recruit 100 ASD and 50 NT participants, 
allowing for a 10-20% drop out rate. 
 
7.2 
Statistical Methods  
 
Following intent-to-treat principles, all randomized participants and available data will be 
considered in the analyses. All tests will use significance level 0.05. 
7.2.1 
Sex and gender consideration
 
Given the normative sex differences in plasticity1, we will address the potential effect of 
sex by matching ASD and NT controls (2:1) on sex and recruiting at least 34 female 
(assigned at birth) ASD participants, reflecting a 2:1 male:female ratio (compared to 2.5-
3:1 male:female ratio described in clinical samples2-3) to allow for sex-focused 
explorations. Further, in order to balance sex across active and sham groups, we will 
conduct a sex-stratified randomization. We will include sex as fixed independent factors in 
our analyses so that we could study sex-moderation effects. We will describe sex-
stratification of findings using means/estimates and 95% confidence intervals, 
recognizing this is exploratory given that the design is likely underpowered for this. At this 
point, there is no known effect of gender identity on plasticity or motor function in ASD, 
therefore, we will not control for gender identity. A gender identity stratified subgroup 
analysis will be completed for descriptive purpose. 
7.2.2 
Testing Hypothesis 1a  
This hypothesis will be tested with an analysis of covariance model, where study group 
(ASD, NT) is the primary predictor of interest, and plasticity will be entered as the 
dependent variable, controlling for age, sex, hemisphere of iTBS administration, baseline 
MEP values, and IQ. To ensure robustness, model diagnostic will be checked through 
analysis of residuals. Potential confounding effect of medication use and attention-
deficit/hyperactivity disorder comorbidity among ASD participants on plasticity will be 
investigated in a post-hoc sensitivity analysis. 

 
 
 
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7.2.3 
Testing  Hypothesis 1b  
A Generalized Additive Model (GAM)122  will be used with motor performance as 
dependent variable and an interaction between plasticity and study group (ASD, NT) as 
the effect of interest. GAM is flexible and works in a regression framework, without 
imposing an assumption of linearity, while still allowing testing the association between 
the predictor and the outcome by use of basis function. A cubic spline smoother with up 
to 5 knots will be adjusted for plasticity, addressing the expected non-linearity of the 
association. The model will control for sex, age, and IQ. 
7.2.4 
Testing Hypothesis 2a and 2b
 
Mixed effect         models with random intercepts will be used to compare the overall 
randomization group effect for plasticity and motor function (two separate models, one for 
each hypothesis). Initially, the main effect of group (active, sham rTMS), regardless of 
time (baseline, immediately, 1 and 4 weeks after rTMS) will be accessed. We will also 
add to the model the group-by-time interaction and access the evidence that the group 
difference depends on time. 
7.2.5 
Testing Hypothesis 3  
Using mixed models, we will examine within subject association between motor function 
and plasticity by separating between and within subject effects. The same approach will 
be used to examine our exploratory hypothesis 1. 
 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 
Definitions  
Adverse Event  
An adverse event  (AE) is any untoward medical occurrence in a research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the investigational product.   
 
Serious Adverse Event  
A serious adverse event  (SAE) is any AE that is:  
 Fatal; 
 Life-threatening; 
 Requires or prolongs hospital stay; 
 Results in persistent or significant disability or incapacity; 
 A congenital anomaly or birth defect; or 
 An important medical event (events that may not be life threatening but are of major 
clinical significance, such as a drug overdose or seizure that did not result in in-patient 
hospitalization).  
 

 
 
 
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Adverse Eve nt Collection Period  
The period during which adverse events must be collected is normally defined as the 
period from the initiation of any research procedures to the end of the study intervention 
follow-up. For this study, the study intervention follow-up is defined as up to 4 weeks after 
the last rTMS session.  
 
Preexisting Condition
 
A preexisting condition is one that is present at the start of the clinical trial.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the character 
of the condition worsens during the study period. Throughout the clinical trial, any new 
clinically significant findings/abnormalities that meet the definition of an adverse event will 
be recorded and documented as an adverse event.  
 
Post -study Adverse Event  
All unresolved adverse events will be followed by the PI until the events are 
resolved/stable; the participant is lost to follow-up; or the adverse event is otherwise 
explained.   
 
At the last scheduled visit, the PI will instruct each participant to report any event(s) that 
the participant believes might reasonably be related to participation in this clinical trial.   
 
8.2 
Recording of Adverse Events
 
All adverse events occurring during the study period will be recorded. At each contact 
with the research participant, the research team will seek information on adverse events.   
8.3 
Reporting of Serious Adverse Events
 
8.3.1 
Investigator Reporting: Notifying the Sponsor
 
Not applicable.  
8.3.2 
Investigator Reporting: Notifying the REB
 
The process for notification to the REB for applicable serious adverse events (SAEs) will 
be completed as per REB reporting requirements.  
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada
 
Not applicable – not a regulated trial.  
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites
 
Not applicable.  
8.4 
Reporting of Device Deficiencies
 
Not applicable.  

 
 
 
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8.5 
Safety Management Plan  
TBS is well-established and safe in the ASD populations108,120. Our protocol  (6000 pulses, 
20Hz, delivered at 90% of RMT) is also within the safety parameters for rTMS108. In our 
pilot study46, 33 autistic adults and 30 NT control participants were recruited and 31 
autistic adults (11 females assigned at birth) received TBS. One ASD participant 
experienced vasovagal attack and the other was excluded as motor threshold could not 
be safely determined. No control participant reported any adverse effects. Further, 2 
participants dropped out because they were unable to commit further; therefore, 29 
autistic adults completed rTMS trial phase. None of the 29 ASD participants reported any 
adverse effects of the rTMS. The overall study dropout (4/33) rate was 12.1%. In another 
completed  RCT121 for youth with ASD (n=40), our team used bilateral 20Hz rTMS (20 
session, 5 days a week, for 4-week) and had 95% retention rate. The recruitment goal 
was met successfully on time and the rate of adverse events was no different between the 
active and sham rTMS groups. These pilot data clearly show that TBS and bilateral rTMS 
proposed in this project are safe and can be feasibly implemented in autistic adults. 
Recruitment is also highly feasible because of the high number of autistic adults without 
intellectual disability attending our primary recruitment clinics. Because of these reasons, 
we are uniquely positioned to meet our recruitment goals on time and believe our 
approach is highly feasible. 
8.6 
Unblinding Procedures
 
 
Unblinding will occur for a safety reasons for an SAE that is unexpected and 
thought to be related to the intervention device.
 
8.7 
Data and Safety Monitoring Board
 
A data and safety monitoring board is not required for this study.  
 
9.0 CLINICAL TRIAL DISCONTINUATION AND 
CLOSURE 
9.1 
Clinical Trial  Discontinuation  
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (i.e. closure based on PI decision, sponsor/funder decision, REB or 
other oversight bodies’ decision; review of serious, unexpected and related AEs; 
noncompliance; futility). Notification, which includes the reason for study suspension or 
termination, will be provided by the suspending or terminating party to research 
participants, the PI, funding agency, CAMH, and regulatory authorities.  If the clinical trial 
is prematurely terminated or suspended, the PI will promptly inform research participants, 
the REB, and the sponsor, and will provide the reason(s) for the termination or 
suspension. All communication with participants for this purpose will go through REB 
review and approval.  Research participants will then be contacted, as applicable, and be 
informed of changes to the study visit schedule. 

 
 
 
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10.0 DATA HANDLING AND RECORD KEEPING 
10.1 
Source Documents  & Case Report Forms  
Please reference this study’s Data Management Plan (DMP). 
 
Data for this clinical trial will be managed using REDCap electronic case report forms. 
This system is maintained on central CAMH servers, with data backed up daily, and is 
supported by the Research Informatics department.  
 
10.2 
Protocol Deviations  
No deviations from or changes to the protocol will be implemented without prior 
agreement from the sponsor as required, and approval from the REB, unless to eliminate 
an immediate hazard to a participant.  
10.3 
Record  Retention  
Study records and data will be kept for 10 years after the completion of study.  
10.4 
Clinical Trial Registration
 
This study will be registered on www.clinicaltrials.gov.  
11.0 STUDY MONITORING, AUDITING, AND 
INSPECTING 
11.1 
Study  Monitoring Plan  
 
Independent monitoring is not required. 
  
We are proposing a study that is investigator-initiated with a device and coil that has a 
Health Canada (HC) license. We will be using the Magstim Horizon TMS Therapy System 
for the delivery of active and sham rTMS. According to HC an ITA is not required for this 
trial. 
 
Below is the license for the Magstim system: 
License No.: 102253 
Type: System  
Device class: 3  
Device first issue date 2019-06-20  
License name: MAGSTIM HORIZON TMS THERAPY SYSTEM 
 

 
 
 
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11.2 
Auditing and Inspecting
  
Not applicable.  
12.0 ETHICAL CONSIDERATIONS 
Clinical trial materials (e.g., protocol, ICF, recruitment materials, written information 
provided to participants, etc.) must be submitted to the research ethics board (REB) for 
review and approval in accordance with REB requirements. Approval must be obtained 
prior to initiating any clinical trial-specific tasks, and maintained throughout the course of 
the clinical trial in accordance with REB requirements. Any amendments will require 
review and approval by the REB before the changes are implemented in the clinical trial, 
unless to eliminate an immediate hazard to the participant. The REB must be notified of 
any unanticipated issue or event that may increase the level of risk to participants or that 
has other ethical implications that may affect participants’ welfare.  
12.1 
Research Ethics Board (REB) Approval  
Research Ethics Board (REB) approval will be obtained prior to beginning any research-
specific procedures. Following initial ethics approval, ongoing ethical approval will be 
maintained and the clinical trial will undergo REB review at least annually, in accordance 
with regulatory and REB requirements. The clinical trial will be conducted in accordance 
with the REB-approved study documents and the determinations (including any 
limitations) of the REB, and in compliance with REB requirements.  
Whenever new information becomes available that may be relevant to participant 
consent, a consent form and/or consent for addendum will be presented to the REB for 
review and approval prior to its use. Any revised written information will receive REB 
approval prior to use. 
 
 

 
 
 
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12.2 
Informed Consent Process &
 Documentation  
 
 
Informed consent is a process that is initiated prior to the individual agreeing to take part 
in the clinical trial and continues throughout their participation. 
 
If consent is done in person: 
 
 
Informed consent will be obtained from each participant prior to their participation in the 
study. Informed consent will be obtained by appropriately trained and qualified CAMH 
research personnel who do not have an existing clinical relationship with the participant. 
The PI will not obtain participant consent.   
 
Each participant will be provided with a current copy of the REB approved ICF prior to the 
consent discussion. Research personnel will explain the clinical trial to the participant and 
answer any questions that may arise. This discussion will include an explanation of the 
clinical trial purpose, procedures, potential risks and benefits, confidentiality 
considerations and participant rights (e.g. participants will not be penalized or lose any 
benefits regardless of what they decide and they have the right to withdraw from the 
clinical trial at any time). Participants may take as much time as they need to make their 
decision, and may consult with others (e.g. family members, other health care providers, 
etc.) if they like. Following the consent discussion, and once the participant has decided 
to take part, the participant and the person conducting the consent discussion will 
personally sign and date the ICF. Each participant will be provided with a complete (fully 
signed) copy of the ICF. The original ICF(s) and the informed consent process will be 
documented in the source documents. 
 
 
Written Paper Consent:  
 
Following the consent discussion, the participant and the person conducting the consent 
discussion will each personally sign and date the ICF.  This will occur by emailing the ICF 
to the participant, the participant signing the ICF, and the participant emailing or faxing 
the original, scan or photograph of the consent back to CAMH.  The person conducting 
the consent discussion will also sign the ICF once received.  No research procedures will 
begin until after the ICF signed by the participant is received by CAMH, and the ICF is 
signed by the person conducting the consent discussion (i.e. the ICF and documentation 
has been completed).   
After informed consent has been obtained, a complete (fully signed) copy of the ICF will 
be provided to participants by email. 
 

 
 
 
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13.0 PRIVACY AND CONFIDENTIALITY 
All study related documents and data will be held in strict confidence and stored at CAMH 
or on CAMH servers, and will follow CAMH policies and procedures to ensure participant 
privacy and confidentiality.  
 
All research activities will be conducted in as private a setting as possible. The study 
monitor, other authorized representatives of the sponsor, representatives of the REB, 
regulatory agencies may inspect all documents and records required to be maintained by 
the PI, including but not limited to, medical records and pharmacy records for the 
participants in this clinical trial. The participant’s contact information will be securely 
stored at CAMH for internal use during the clinical trial. At the end of the clinical trial, all 
records will continue to be kept in a secure location in accordance to applicable 
institutional and regulatory requirements. 
 
14.0 CLINICAL TRIAL FINANCES 
14.1 
Funding Source  
 
This study is funded through a grant from the Canadian Institute of Health Research. 
14.2 
Conflict of Interest  
None of the investigators have any conflicts to share.  
 
15.0 PUBLICATION POLICY/DATA SHARING 
15.1 Future Secondary Use of Dat a 
De-identified data from this project may be used for future research by internal and/or 
external project collaborators.  
 
 

 
 
 
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