Healthy
Conditions
Keywords
TMS, fMRI, dlPFC
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.
Interventions
DEVICEactive 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.
DEVICEsham 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.
BEHAVIORALIASP 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.
BEHAVIORALSST 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.
OTHERMRI
Participants undergo MRI sessions to measure DLPFC cortical reactivity and connectivity.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sternberg Sorting Task (SST) at Baseline | Baseline (Visit 1) | 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. |
| International Affective Picture System (IAPS) | Baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| International Affective Picture System (IAPS) at Post-intervention (Active/Sham) | post-intervention (Active/Sham) (Week 6 Final Visit) | 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). |
| 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) | post-intervention (Active/Sham) (Week 6 Final Visit) | 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. |
Countries
United States
Participant flow
Recruitment details
There were a total of 17 people consented and completed the SST and emotion task during baseline (Week 1), three people withdrew, only 14 people completed the study, Each participant took part in both sham TMS and active TMS. They were randomized into which treatment they would receive first. All participants that completed the study, completed the emotional IAPS task high load and low load.
Participants by arm
| Arm | Count |
|---|---|
| Low-load Condition vs High-load Participants will be assigned to complete either a high-load or a low-load cognition task. They will assigned to for both Sternberg task and emotional task.
Sternberg Task: Participants will be randomized to high-load and low-load cognition task in different orders | 17 |
| TMS vs. Task Order Completion Participants will will then complete again (in randomized order) with rTMS:
1. rTMS alone
2. rTMS + SST (cognitive)
3. rTMS + IAPS (emotion)
Order of MRI procedures: Participants will be assigned to complete MRI+task, MRI +SST, and MRI + IAPS in random order | 0 |
| Determination of Neuromodulation Effect on DLPFC Activation - Cognitive vs. Emotional Participants will be assigned for the rest of the study to either complete their neuromodulation sessions while either completing the cognitive task, or the emotional task.
TMS/Sham TMS: Participants will be randomized to either complete their assigned task (cognitive vs. emotional) while doing sham rTMS vs. real rTMS during weeks 2 and 3 of the study. The order of sham rTMS vs. real rTMS is randomized. | 0 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline With MRI Scan, and SST and IAPS | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Low-load Condition vs High-load | TMS vs. Task Order Completion | Determination of Neuromodulation Effect on DLPFC Activation - Cognitive vs. Emotional | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 0 Participants | 0 Participants | 17 Participants |
| Age, Continuous | 34 years STANDARD_DEVIATION 11.25 | — | — | 34 years STANDARD_DEVIATION 11.25 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | — | — | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | — | — | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | — | — | 11 Participants |
| Region of Enrollment United States | 17 participants | — | — | 17 participants |
| Sex: Female, Male Female | 9 Participants | — | — | 9 Participants |
| Sex: Female, Male Male | 8 Participants | — | — | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 0 / 8 | 0 / 9 | 1 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 9 |
Outcome results
Primary
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.
Time frame: Baseline
Population: There were a total of 17 people that consented, one person that was receiving active TMS first withdrew from the study and two people that were receiving sham TMS first withdrew from the study so only 14 people completed. (seven receiving Active TMS first and seven that were receiving sham TMS first)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline Measurement Before Active TMS vs Sham TMS | International Affective Picture System (IAPS) | High-Load IAPS | 0.69 proportion of correct responses | Standard Deviation 0.21 |
| Baseline Measurement Before Active TMS vs Sham TMS | International Affective Picture System (IAPS) | Low-Load IAPS | 0.67 proportion of correct responses | Standard Deviation 0.09 |
| Baseline Measurement Before Sham TMS vs Active TMS | International Affective Picture System (IAPS) | High-Load IAPS | 0.52 proportion of correct responses | Standard Deviation 0.14 |
| Baseline Measurement Before Sham TMS vs Active TMS | International Affective Picture System (IAPS) | Low-Load IAPS | 0.59 proportion of correct responses | Standard Deviation 0.22 |
Comparison: The baseline measurement for this analysis is the International Affective Picture System (IAPS) at baseline. This is 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. We compare mean High-Load IAPS and Low-Load IAPS scores in the group that received active then sham TMS.p-value: 0.18t-test, 2 sided
Primary
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.
Time frame: Baseline (Visit 1)
Population: There were a total of 17 people that consented, one person that was receiving active TMS first withdrew from the study and two people that were receiving sham TMS first withdrew from the study so only 14 people completed. (seven receiving Active TMS first and seven that were receiving sham TMS first).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline Measurement Before Active TMS vs Sham TMS | Sternberg Sorting Task (SST) at Baseline | High-Load SST | 0.85 proportion of correct responses | Standard Deviation 0.17 |
| Baseline Measurement Before Active TMS vs Sham TMS | Sternberg Sorting Task (SST) at Baseline | Low-Load SST | 0.87 proportion of correct responses | Standard Deviation 0.065 |
| Baseline Measurement Before Sham TMS vs Active TMS | Sternberg Sorting Task (SST) at Baseline | High-Load SST | 0.64 proportion of correct responses | Standard Deviation 0.31 |
| Baseline Measurement Before Sham TMS vs Active TMS | Sternberg Sorting Task (SST) at Baseline | Low-Load SST | 0.66 proportion of correct responses | Standard Deviation 0.34 |
Comparison: The baseline measurement for this analysis is the Sternberg Sorting Task (SST) at Baseline. This 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).p-value: 0.024ANOVA
Secondary
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.
Time frame: post-intervention (Active/Sham) (Week 6 Final Visit)
Population: There were a total of 17 people that consented, one person that was receiving active TMS first withdrew from the study and two people that were receiving sham TMS first withdrew from the study so only 14 people completed. (seven receiving Active TMS first and seven that were receiving sham TMS first).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Baseline Measurement Before Active TMS vs Sham TMS | 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) | High-Load SST | 0.266 score on a scale |
| Baseline Measurement Before Active TMS vs Sham TMS | 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) | Low-Load SST | 0.156 score on a scale |
| Baseline Measurement Before Active TMS vs Sham TMS | 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) | High-Load IAPS | 0.232 score on a scale |
| Baseline Measurement Before Active TMS vs Sham TMS | 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) | Low-Load IAPS | 0.201 score on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | 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) | Low-Load IAPS | 0.129 score on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | 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) | High-Load SST | 0.183 score on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | 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) | High-Load IAPS | 0.135 score on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | 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) | Low-Load SST | 0.056 score on a scale |
p-value: 0.67t-test, 2 sided
Secondary
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).
Time frame: post-intervention (Active/Sham) (Week 6 Final Visit)
Population: There were a total of 17 people that consented, one person that was receiving active TMS first withdrew from the study and two people that were receiving sham TMS first withdrew from the study so only 14 people completed. (seven receiving Active TMS first and seven that were receiving sham TMS first)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Baseline Measurement Before Active TMS vs Sham TMS | International Affective Picture System (IAPS) at Post-intervention (Active/Sham) | High-Load IAPS | 178 units on a scale |
| Baseline Measurement Before Active TMS vs Sham TMS | International Affective Picture System (IAPS) at Post-intervention (Active/Sham) | Low-Load IAPS | 193 units on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | International Affective Picture System (IAPS) at Post-intervention (Active/Sham) | High-Load IAPS | 121 units on a scale |
| Baseline Measurement Before Sham TMS vs Active TMS | International Affective Picture System (IAPS) at Post-intervention (Active/Sham) | Low-Load IAPS | 223 units on a scale |
Comparison: The outcome measure for this analysis was the International Affective Picture System (IAPS).p-value: 0.19Chi-squared