Task Augmentation of Transcranial Magnetic Stimulation (TMS)

The standard clinical use of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) has shown limited efficacy. One contributing factor may be the common use of scalp-based targeting rather than neuronavigation techniques using functional MRI (fMRI), which enable more precise, individualized targeting of functional brain networks. Image-guided TMS can account for anatomical variability and may enhance treatment outcomes.

Another promising approach is combining TMS with concurrent cognitive activation of the dorsolateral prefrontal cortex (DLPFC). This concept, known as cognitive paired associative stimulation, builds on traditional paired associative stimulation (PAS), where coordinated stimulation enhances cortical response. In this framework, delivering TMS to the DLPFC while participants engage in a DLPFC-activating cognitive task could produce greater neural activation than either stimulus alone. Prior research suggests that the brain's cognitive or emotional state during stimulation can significantly modulate TMS effects, though it's unclear whether this enhancement depends on the type of cognitive task or the magnitude of neural activation.

Study Design and Procedure This within-subjects, mechanism-focused pilot study builds on the Research Domain Criteria (RDoC) framework for cognitive control. The primary goal is to examine how pairing rTMS with specific task conditions affects DLPFC activation and connectivity.

Participants (ages 18-60, healthy volunteers) will undergo the following:

Screening Visit (2 hours): Consent and eligibility. Visit 1 - Baseline MRI (1 hour): Participants undergo structural and functional MRI to localize the "Fitzgerald target" in the DLPFC. Data will be analyzed using FSL and neuronavigated using BrainSight.

Visit 2 - Task-Only fMRI Session (2 hours): Participants complete both the SST (cognitive task) and the IASP (emotional task) in the scanner. Each task contains high- and low-load trials, and participants complete both tasks (they are not assigned to one or the other).

Visits 3 & 4 - TMS Sessions (2 hours each): In a randomized crossover design, participants complete the IASP task while receiving either:

Active rTMS Sham rTMS These sessions test whether pairing emotional cognitive activation with TMS enhances cortical response. Note: TMS was never delivered alone-participants always performed the IASP task during stimulation.

2-Week Break Visits 5 & 6 - Follow-Up TMS Sessions (2 hours each): Participants repeat the IASP task with the alternate stimulation condition (sham or active). fMRI data is again collected to assess DLPFC activation and connectivity post-stimulation.

Each TMS session uses:

Stimulation Parameters: 120% resting motor threshold (RMT), triplet 50 Hz bursts at 5 Hz, 2s on / 8s off, 600 pulses per session (~3 min 9 sec total).

Probe Scans: Single-pulse TMS (120% RMT; 77 pulses/session) inside the scanner to measure cortical reactivity.

Inclusion criteria

• Gender, inclusive
• 18 60 years of age
• Right-handed
• No history of meeting Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for any diagnosis
• Normal cognition
• Patients must be able to read and understand English
• Participants must be able to provide consent

Exclusion criteria

• Pregnancy (Female participants)
• Outside age range
• Meets DSM criteria for any diagnosis
• Unable to have an MRI scan
• Medical condition that interferes with the collection or interpretation of MRI data
• Implanted devices such as: aneurysm clip or cardiac pacemaker
• History of stroke, epilepsy, or brain scarring
• Cognitive impairment
• Recent use of psychoactive medications, as determined by investigators
• Otherwise determined by investigator to be unfit for participation