Task Augmentation of Transcranial Magnetic Stimulation (TMS) (TaskTMS)

A Pilot Proof of Concept, Within Subjects, Randomized Study of the Effects of Activation of the DLPFC Promotion System on TMS Treatment

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Device: active TMS; Behavioral: IASP Task; Behavioral: SST Task; Other: MRI; Device: sham TMS

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.

• Study Type: Interventional
• Enrollment (Actual): 17

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Center for Neuromodulation in Depression and Stress

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active rTMS + IASP; Participants perform the IASP emotional task Receive active rTMS	Device: active TMS; Participants receive active repetitive transcranial magnetic stimulation (rTMS) while performing the International Affective Picture System (IASP). Stimulation is delivered at 120% of resting motor threshold (RMT), in triplet 50 Hz bursts, repeated at 5 Hz (2s on, 8s off), totaling 600 pulses per session.; Behavioral: IASP Task; Participants complete the IASP (emotional image viewing) task during each TMS session (active and sham). The task includes both high- and low-load trials, designed to activate the dorsolateral prefrontal cortex (DLPFC). Task order and load levels are consistent across both stimulation sessions.; Behavioral: SST Task; In a separate MRI session prior to TMS sessions, participants complete the SST which includes both high-load and low-load trials. This cognitive task is used to examine baseline DLPFC activation and to contrast cognitive vs. emotional activation profiles.; Other: MRI; Participants undergo MRI sessions to measure DLPFC cortical reactivity and connectivity.
Sham Comparator: Sham rTMS + IASP; Participants perform the IASP emotional task Receive Sham rTMS	Behavioral: IASP Task; Participants complete the IASP (emotional image viewing) task during each TMS session (active and sham). The task includes both high- and low-load trials, designed to activate the dorsolateral prefrontal cortex (DLPFC). Task order and load levels are consistent across both stimulation sessions.; Behavioral: SST Task; In a separate MRI session prior to TMS sessions, participants complete the SST which includes both high-load and low-load trials. This cognitive task is used to examine baseline DLPFC activation and to contrast cognitive vs. emotional activation profiles.; Other: MRI; Participants undergo MRI sessions to measure DLPFC cortical reactivity and connectivity.; Device: sham TMS; Participants receive sham rTMS while performing the IASP task. Stimulation is mimicked without actual neural activation using the same schedule and coil placement as the active condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sternberg Sorting Task (SST) at Baseline	This Sternberg Sorting Task (SST) task is designed to assess how individuals store and retrieve random information from short-term memory. This task was administered to all participants before they were randomized into one of two groups (active TMS first then sham TMS or sham TMS first then active TMS). 0's were recorded for incorrect responses and 1's were recorded for correct responses. Therefore, the mean represents the accuracy percentage for each group.	Baseline (Visit 1)
International Affective Picture System (IAPS)	International Affective Picture System (IAPS): an emotional task using IAPS picture that will also compare low load and high load conditions. The number of images will vary by condition load, but for both the high-load & low-load conditions, participants will look at IAPS pictures and answer questions about the images. Further, jittered within this design will be both neutral and negative blocks of IAPS pictures: Baseline measurement before randomizing participants into Active or Sham groups. 0's were recorded for incorrect responses and 1's were recorded for correct responses. Therefore, the mean represents the accuracy percentage for each group.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
International Affective Picture System (IAPS) at Post-intervention (Active/Sham)	These measurements were taken at the final visits. For example, the "Active then Sham TMS" group received sham TMS during this outcome measure, and the opposite for "Sham then Active TMS." International Affective Picture System (IAPS): an emotional task using IAPS picture that will also compare low load and high load conditions. The number of images will vary by condition load, but for both the high-load & low-load conditions, participants will look at IAPS pictures and answer questions about the images. Further, jittered within this design will be both neutral and negative blocks of IAPS pictures. The mean represents the number of correct responses from each group. Values can range from 0-299 for the High-Load IAPS (0 meaning no answers correct, and 299 meaning all answers correct). Values can range from 0-326 for the Low-Load IAPS (0 meaning no answers correct, and 326 meaning all answers correct).	post-intervention (Active/Sham) (Week 6 Final Visit)
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)	In the final visit, we recorded these following tasks in an MRI, in both the group that received active then sham TMS and the group that received sham then active TMS. We are comparing the effects of two distinct cognitive tasks on augmenting the impact of TMS on dorsolateral prefrontal cortex (DLPFC) activity. The first task is the Sternberg task (SST), a working memory task designed to engage cognitive processes by requiring participants to retain and recall information. The second is the International Affective Picture System (IAPS) task, which presents emotionally evocative images to elicit emotional responses. Our goal is to determine which task-cognitive or emotional-more effectively enhances TMS-induced DLPFC activation. Brain activity and connectivity can be quantified on a normalized scale ranging from 0 to 1, where 0 indicates no detectable activity or connectivity, and 1 represents the highest level of activity or connectivity within the measured range.	post-intervention (Active/Sham) (Week 6 Final Visit)

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2019
• Primary Completion (Actual): March 4, 2020
• Study Completion (Actual): March 11, 2024

Study Registration Dates

• First Submitted: October 5, 2020
• First Submitted That Met QC Criteria: October 12, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 30, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: fMRI; TMS; dlPFC
• Other Study ID Numbers: 832232

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO