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

Depression, Depression - Major Depressive Disorder, Depressive Episode, Major Depressive Disorder (MDD)

PET, iTBS, accelerated iTBS, rTMS, MRI

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.

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.

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