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

Official title

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

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• Change in Synaptic Density Following iTBS Measured by [¹⁸F]SynVesT-1 PET [Time frame: Administered at baseline (prior to first iTBS treatment), and after the iTBS treatment course (i.e. one week later).]

Secondary outcome measures (4)

• Change in Resting-State Functional Connectivity Following accelerated iTBS [Time frame: Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).]
• Change in Cortical Neurochemistry Following iTBS [Time frame: 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 [Time frame: 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 [Time frame: Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).]

Eligibility criteria

Inclusion criteria

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

• 18 to 55 years old.
• Competent to provide voluntary informed consent.
• 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
• Referred by their treating physician.
• Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode.
• Symptoms of MDD have not improved after ≥ 1 adequate antidepressant medication trial in the current depressive episode29.
• Baseline score of ≥18 on the 17-item Hamilton Rating Scale for Depression (HRSD-17).
• 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:

• 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
• Current or past (< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria.
• Positive urine test for illegal substances, cannabis, or cotinine.
• Significant unstable medical or neurologic illness confirmed by medical history (e.g. uncontrolled diabetes, or renal dysfunction).
• Breastfeeding or pregnant (confirmed via urine test).
• BMI > 30 or BMI < 18.
• Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker).
• Contraindication for MRI (e.g. metallic implant, claustrophobia).
• Have received a cumulative radioactivity dose > 15.2mSv during the last 12 months.
• Have active malignancies (due to high chance of undergoing radiation therapy).
• Suicide attempt in the past three months and/or active suicidal intent.
• Failed (non-response) course of ECT or rTMS treatment in the current depressive episode.
• 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)
• Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• The Royal's Institute of Mental Health Research — Ottawa

Publications

• 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. PMID 30670304
• 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. PMID 25744500
• 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. PMID 21731066
• 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. PMID 32512125
• 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. PMID 32245086
• 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. PMID 29726344

Identifiers

NCT: NCT07620288 · 0383

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗