Clinical trial NCT04586205: Task Augmentation of Transcranial Magnetic Stimulation (TMS)
Official title: A Pilot Proof of Concept, Within Subjects, Randomized Study of the Effects of Activation of the DLPFC Promotion System on TMS Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Conditions: Healthy
Keywords: TMS
fMRI
dlPFC
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2020-10-14
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A within-subjects design was used. Healthy participants between the ages of 18 and 60 who met basic eligibility criteria were invited to participate.

In the first phase, all participants completed both the Sternberg task (SST) and the International Affective Picture System (IASP) task, each containing high- and low-load trials.

In the second phase, participants completed the IASP task during two separate TMS sessions: one with active rTMS and one with sham rTMS, in a randomized crossover design. No TMS-alone condition was included. All TMS sessions were conducted in the MRI scanner, allowing investigators to collect both brain activation to single-pulse TMS probes and connectivity data.

Participants were randomized to receive either active or sham rTMS during the first session, and then crossed over to the alternate condition after a two-week break. This design allowed for within-subject comparison of cortical response during the same task across both stimulation conditions.
Primary purpose: OTHER

Brief summary: This pilot, within-subjects, randomized proof-of-concept study investigates the effects of activating the DLPFC promotion system on TMS treatment outcomes. Twenty-five healthy volunteers will participate in four sessions involving either active or sham repetitive transcranial magnetic stimulation (rTMS). Using anatomically guided TMS paired with cognitive tasks, the study tests the hypothesis that cognitive paired associative stimulation enhances cortical responses. For this pilot study, we are focusing only on the augmentation of TMS with the IASP task.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Sternberg Sorting Task (SST) at Baseline
timeFrame: Baseline (Visit 1)
measure: International Affective Picture System (IAPS)
timeFrame: Baseline
Secondary outcomes:
measure: International Affective Picture System (IAPS) at Post-intervention (Active/Sham)
timeFrame: post-intervention (Active/Sham) (Week 6 Final Visit)
measure: Comparing the Impact of Sternberg Sort Task (SST), the Working Memory Task and International Affective Picture System (IAPS) Emotional Task on TMS-Induced DLPFC Activation; Post-intervention (Active/Sham)
timeFrame: post-intervention (Active/Sham) (Week 6 Final Visit)
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Center for Neuromodulation in Depression and Stress
state: Pennsylvania
Study officials:
References: