Comparing Outcomes of Theta Burst Stimulation in Depression Using Advanced PET Imaging

Measuring Neuroplasticity Outcomes of Theta Burst Stimulation in Depression Using Advanced PET Imaging

The proposed project will investigate the neurobiological mechanisms of accelerated intermittent Theta Burst Stimulation (iTBS) in major depressive disorder (MDD) using an advanced multimodal imaging approach. This single-arm, within-subject study will deliver one week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity. We will combine [¹⁸F]SynVesT-1 PET with functional, neurochemical and anatomical MRI, such as resting-state fMRI, magnetic resonance spectroscopy (MRS) and neurite orientation dispersion and density imaging (NODDI), to capture treatment-related plasticity. This integrated design will link molecular and network-level mechanisms to clinical improvement, providing an unprecedented mechanistic map of how accelerated iTBS restores brain function in depression.

Study Overview

• Status: Not yet recruiting
• Conditions: Depression; Major Depressive Disorder (MDD); Depressive Episode; Depression - Major Depressive Disorder
• Intervention / Treatment: Device: repetitive Transcranial Magnetic Stimulation

Detailed Description

Major depressive disorder (MDD) is one of the most prevalent and disabling disorders worldwide, affecting approximately one in 20 Canadians at any given time and ranking among the leading causes of lost productivity, poor quality of life, and suicide. Despite major advances in pharmacological and psychotherapeutic interventions, only 40-60% of patients respond to first-line treatments. Theta Burst Stimulation (TBS) represents the next generation of rTMS technology: by delivering patterned bursts of magnetic pulses that mimic intrinsic theta-gamma coupling, TBS is thought to more efficiently engage synaptic plasticity mechanisms that underlie mood regulation. Clinically, iTBS achieves antidepressant efficacy comparable to conventional 10 Hz rTMS in one-tenth of the stimulation time, enabling faster, more accessible treatments. Yet, despite its growing clinical use and regulatory approval in multiple countries, the fundamental mechanisms by which iTBS modulates limbic-cortical networks to alleviate depressive symptoms remain poorly understood. Addressing this knowledge gap is essential to optimizing treatment protocols and advancing precision neuromodulation strategies.

Understanding how iTBS drives recovery thus requires moving beyond traditional symptom-based approaches toward multi-level indices of brain plasticity that capture functional, neurochemical, and microstructural change. Current evidence remains largely descriptive, with limited direct insight into the underlying synaptic or cellular mechanisms of iTBS-induced modulation. Integrating PET with high-resolution MRI techniques provides a unique window on these processes. We now have full capacity for in-house synthesis and imaging with [F18]SynVesT-1. Thus, this tracer quantifies synaptic density in vivo, providing a direct molecular measure of plasticity. The ability to pair [F18]SynVesT-1 PET simultaneously with MRI represents a transformative advance for mechanistic neuromodulation research.

Clinical trials show that accelerated TBS, individually targeted to the DLPFC region most anti-correlated to sgACC, can produce rapid symptom relief within days rather than weeks. However, the neurobiological mechanisms underlying these effects remain unknown. It is hypothesized that repeated stimulation sessions promote cumulative synaptic potentiation and large-scale network reorganization. Elucidating these processes is crucial to optimize dosing parameters, understand inter-individual variability in response, and guide the next generation of biologically informed treatment strategies.

The proposed project will investigate the neurobiological mechanisms of accelerated TBS in MDD using an advanced multimodal imaging approach. In this single-arm, within-subject study, participants will undergo one week of accelerated iTBS treatment while completing pre- and post-treatment positron emission tomography (PET) and magnetic resonance imaging (MRI). PET imaging with the synaptic vesicle tracer [¹⁸F]SynVesT-1 will quantify changes in synaptic density, while MRI sequences such as resting-state functional MRI, magnetic resonance spectroscopy, and neurite orientation dispersion and density imaging (NODDI) will assess functional connectivity and microstructural plasticity. By integrating molecular, functional, and structural measures of brain plasticity, the study will provide new insight into how accelerated iTBS alters brain circuits implicated in depression and how these changes relate to clinical improvement.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stacey Shim; Phone Number: 6356 613-722-6521; Email: rtms@theroyal.ca
• Study Contact Backup: Name: Emma Cummings; Phone Number: 6586 613-722-6521

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Z 7K4
      • The Royal's Institute of Mental Health Research
      • Contact: Sara Tremblay, PhD; Phone Number: 6227 613-722-6521; Email: Sara.Tremblay@theroyal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

For inclusion in the study, participants must fulfill all the following criteria:

1. 18 to 55 years old.
2. Competent to provide voluntary informed consent.
3. English comprehension and verbal communication (participants must be able to both understand and speak English sufficiently to follow study procedures and be understood by study personnel
4. Referred by their treating physician.
5. Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode.
6. Symptoms of MDD have not improved after ≥ 1 adequate antidepressant medication trial in the current depressive episode29.
7. Baseline score of ≥18 on the 17-item Hamilton Rating Scale for Depression (HRSD-17).
8. Maintained a stable treatment regimen for at least four weeks prior to entering the study, defined as being on a stable antidepressant regimen, a stable psychotherapy regimen, both, or neither (i.e., no treatment), with no changes during this period.

Exclusion Criteria

Participants fulfilling any of the following criteria will be excluded from the study:

1. Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, and/or bipolar I or II disorder) with the exception of anxiety/panic disorders, posttraumatic stress disorder and ADHD
2. Current or past (< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria.
3. Positive urine test for illegal substances, cannabis, or cotinine.
4. Significant unstable medical or neurologic illness confirmed by medical history (e.g. uncontrolled diabetes, or renal dysfunction).
5. Breastfeeding or pregnant (confirmed via urine test).
6. BMI > 30 or BMI < 18.
7. Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker).
8. Contraindication for MRI (e.g. metallic implant, claustrophobia).
9. Have received a cumulative radioactivity dose > 15.2mSv during the last 12 months.
10. Have active malignancies (due to high chance of undergoing radiation therapy).
11. Suicide attempt in the past three months and/or active suicidal intent.
12. Failed (non-response) course of ECT or rTMS treatment in the current depressive episode.
13. Benzodiazepine or lithium use. Other psychotropic medications (e.g. ADHD medications) are permitted, if stable in the 4 weeks prior to and during the treatment course)
14. Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Accelerated iTBS; One week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity.

Device: repetitive Transcranial Magnetic Stimulation; Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical treatments involve 30 to 45 minutes daily sessions delivered over 4 to 6 weeks. Recent technical advances allowed the development of theta burst stimulation (TBS), a novel rTMS paradigm that reduces daily sessions to 3 to 4 minutes while maintaining the same clinical efficacy. This study will specifically be administering intermittent TBS (iTBS), which is a novel refinement of conventional rTMS and consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz).; Other Names: TMS; rTMS; TBS; iTBS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Synaptic Density Following iTBS Measured by [¹⁸F]SynVesT-1 PET	We will quantify changes in synaptic density (expressed as non-displaceable binding potential (BPND)) within (a) the sgACC (primary ROI) and (b) the stimulated DLPFC (secondary ROI), with exploratory analyses in frontal, parietal and cerebellar regions identified in the seed dataset.	Administered at baseline (prior to first iTBS treatment), and after the iTBS treatment course (i.e. one week later).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Resting-State Functional Connectivity Following accelerated iTBS	Resting-state functional MRI (rs-fMRI) will be used to assess changes in functional connectivity (Fisher z-transformed correlation coefficients) within fronto-limbic networks following accelerated iTBS.	Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).
Correlation Between Changes in [18F]SynVesT-1 Binding and Depressive Symptom Improvement Following iTBS	This outcome will assess the correlation between pre-post changes in synaptic density, measured using [18F]SynVesT-1 positron emission tomography (PET) standardized uptake value ratio (SUVR), and changes in depressive symptom severity, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17) total score, following accelerated iTBS, with the outcome metric defined as the correlation coefficient between changes in [18F]SynVesT-1 PET SUVR values and HRSD-17 total scores.	Administered at screening, before the first iTBS, mid-treatment course (i.e. treatment day 3, following treatment #15), after the iTBS treatment course (i.e. treatment day 5, following treatment #30), and 1-month post treatment course.
Change in Cortical Neurochemistry Following iTBS	Magnetic resonance spectroscopy (MRS) will be used to assess changes in cortical neurochemical metabolite concentrations or metabolite ratios (e.g., Glx, GABA+/Cr) following accelerated iTBS.	Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).
Change in Cerebral Perfusion Following iTBS	Arterial spin labelling (ASL) MRI will be used to assess changes in regional cerebral blood flow levels following accelerated iTBS.	Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).
Change in Neurite Microstructure Following iTBS	Neurite Orientation Dispersion and Density Imaging (NODDI) will be used to assess changes in neurite microstructure following accelerated iTBS, as measured by changes in neurite density index (NDI) and orientation dispersion index (ODI).	Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Adverse events will be tracked and recorded.	Daily Monday-Friday throughout treatment course (1 week).
Side Effects	Side effects will be tracked and recorded on any TMS visits, using the TMS side effects questionnaire.	Daily Monday-Friday throughout study (1 week).

Collaborators and Investigators

• Sponsor: The Royal Ottawa Mental Health Centre
• Investigators: Principal Investigator: Sara Tremblay, The Royal's Institute of Mental Health Research; Principal Investigator: Lauri Tuominen, The Royal's Institute of Mental Health Research

Publications and helpful links

General Publications

• Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011 Jul 6;12(8):467-77. doi: 10.1038/nrn3027.
• Baeken C, Marinazzo D, Everaert H, Wu GR, Van Hove C, Audenaert K, Goethals I, De Vos F, Peremans K, De Raedt R. The Impact of Accelerated HF-rTMS on the Subgenual Anterior Cingulate Cortex in Refractory Unipolar Major Depression: Insights From 18FDG PET Brain Imaging. Brain Stimul. 2015 Jul-Aug;8(4):808-15. doi: 10.1016/j.brs.2015.01.415. Epub 2015 Feb 7.
• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26.
• Cash RFH, Zalesky A, Thomson RH, Tian Y, Cocchi L, Fitzgerald PB. Subgenual Functional Connectivity Predicts Antidepressant Treatment Response to Transcranial Magnetic Stimulation: Independent Validation and Evaluation of Personalization. Biol Psychiatry. 2019 Jul 15;86(2):e5-e7. doi: 10.1016/j.biopsych.2018.12.002. Epub 2019 Jan 19. No abstract available.
• Tremblay S, Tuominen L, Zayed V, Pascual-Leone A, Joutsa J. The study of noninvasive brain stimulation using molecular brain imaging: A systematic review. Neuroimage. 2020 Oct 1;219:117023. doi: 10.1016/j.neuroimage.2020.117023. Epub 2020 Jun 5.
• Kang SG, Cho SE. Neuroimaging Biomarkers for Predicting Treatment Response and Recurrence of Major Depressive Disorder. Int J Mol Sci. 2020 Mar 20;21(6):2148. doi: 10.3390/ijms21062148.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 30, 2028
• Study Completion (Estimated): July 30, 2028

Study Registration Dates

• First Submitted: May 13, 2026
• First Submitted That Met QC Criteria: May 27, 2026
• First Posted (Actual): June 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: MRI; PET; rTMS; iTBS; accelerated iTBS
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: 0383

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

After participants have completed their participation, we will ask them for informed consent for the storage of their de-identified data on OpenNeuro (an open access database) for the purpose of unspecified research for unspecified future research.

If they do agree to participate, they will be given a unique study code (different from the participant ID used in the previous study) will be assigned to all of the study data instead of personal identifying information (ex. 'John Smith' replaced by the unique study code 'A283422'). This unique study code will be used in the Open Access database to ensure privacy and confidentiality (i.e. de-identified study data cannot be linked to participant in any way).

In addition to an unique study code, their de-identified study data used in the Open Access database will include: age, sex, handedness, education level, medical diagnosis, medication, summary scores from clinical interviews, and MRI scans.

• IPD Sharing Time Frame: Once data has been included in the OpenNeuro database, data cannot be removed or withdrawn as we will be unable to identify participant information to separate it from the database.
• IPD Sharing Access Criteria: The shared data will be hosted on the OpenNeuro (https://openneuro.org/) platform. The dataset becomes publicly available under the Creative Commons Zero (CC0) Public Domain Dedication which places no restrictions on who can use the data or what can be done with them. The OpenNeuro is supported by the United States National Institutes of Mental Health BRAIN Initiative. The OpenNeuro follows the FAIR principles, which states that in order for shared data to be maximally useful for the scientific community, they need to be Findable, Accessible, Interoperable, and Reusable.
• IPD Sharing Supporting Information Type: SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No