Individualized Closed Loop TMS for Working Memory Enhancement

Individualized Closed Loop Transcranial Magnetic Stimulation (TMS) for Working Memory Enhancement

The study is investigating working memory brain states by using transcranial magnetic stimulation (TMS) in combination with functional magnetic resonance imaging (fMRI). The study uses a novel, individualized targeting approach for TMS based on each subject's individual multi-modal fMRI data. The individualized target will be stimulated in a TMS/ fMRI imaging session to investigate working memory states and optimal stimulation frequencies.

Study Overview

• Status: Completed
• Conditions: Memory
• Intervention / Treatment: Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Device: Repetitive Transcranial Magnetic Stimulation (rTMS)

Detailed Description

Prior to any study visits, all subjects will be pre-screened through a REDCap online self-report screening REDCap. The study involves 11 study visits.

The first study visit will consist of a consenting and extended screening visit. All participants will have the opportunity to ask questions before signing the electronic consent form. We will complete a semi-structured clinical interview and will demonstrate TMS to ensure the participant is comfortable with all study procedures. This visit will be completed both remote and in-person.

The second study visit will involve a 1-hour MRI scan. During the scan, the participant will complete multiple computerized tasks. The MRI scan will include both structural and functional scans, and those scans will be used to localize the stimulation target for the subsequent sessions.

The third study visit will be a 2-hour TMS/fMRI session, and the participant will engage in behavioral tasks while interleaved rTMS rounds are delivered at different excitatory frequencies (frequency range:

2Hz-20Hz). This scan will be used to determine the optimal stimulation frequency for the individual participant.

The fourth, fifth, and sixth study visits will involve neuromodulation with either the optimized frequency or the frequency least successful in moving a participants brain state, as determined from the third study visit. Each subject will receive ~3000 pulses in each session, including the pulses from the motor threshold determination. We will determine the stimulation amplitude by using the Stokes equation, which accounts for differences in cortical distance from the site relative to motor cortex (where the motor threshold is found).

The seventh study visit will involve a 1-hour TMS/fMRI session while the participant is engaging in a behavioral task. This visit is designed to examine brain and behavioral changes after the first round of neuromodulation.

The seventh and the eighth visit will be scheduled at least one week apart.

The eighth, ninth, and tenth study visits will mirror the fourth, fifth, and sixth study visits and will involve neuromodulation with either the optimized or least-optimized individual frequency. The order of optimized and least-optimized frequencies will be counterbalanced across participants between Visit 4-6 and Visit 8-10 (i.e., half of the participants will receive stimulations of the two frequencies in one order, and the other half will receive stimulations of the two frequencies in the reverse order). The eleventh visit will mirror the seventh visit and will examine brain and behavioral changes after the second round of neuromodulation.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1)18-60 years old 2) Right handed 3) No psychiatric history as diagnosed by the SCID-V 4) Normal cognition 5) Capacity to give informed consent and follow study procedures 6) Sufficient command of English language to understand and respond to written as well as verbal instructions

Exclusion Criteria:

1. History of neurological disorder or traumatic brain injury (other than mild)
2. Unable to have an MRI scan, or current or prior medical condition that could interfere with the collection or interpretation of MRI data
3. Unable to receive TMS
4. Implanted devices, such as an aneurysm clip or cardiac pacemaker
5. History of stroke, epilepsy, or brain scarring
6. Recent use of psychoactive medications, as determined by investigators
7. Pregnant, nursing, or trying to become pregnant (self-attestation alone)
8. Color blindness
9. Otherwise determined by investigator to be unfit for study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Optimized TMS frequency, Then Sub-Optimal TMS Frequency; In the first neuromodulation session, participants will receive rTMS using their optimal TMS frequency. After washout period of 1 week (minimum), the participants will start their second neuromodulation session using their sub-optimal TMS frequency instead.	Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Participants undergo resting-state and task-based fMRI to identify individualized transcranial magnetic stimulation (TMS) targets and determine optimal and sub-optimal stimulation frequencies. Additional fMRI scans are performed after each neuromodulation phase to assess changes following three days of stimulation at the optimal and sub-optimal frequencies.; Device: Repetitive Transcranial Magnetic Stimulation (rTMS); Participants first receive multiple rTMS frequencies during an fMRI scan to assess brain responses and determine individualized optimal and sub-optimal stimulation frequencies. They then complete two neuromodulation intervention periods, receiving rTMS at the identified optimal and sub-optimal frequencies. Each frequency is administered over three consecutive days, with the order of conditions randomized and counterbalanced.
Experimental: Sub-Optimal TMS Frequency, Then Optimized TMS frequency; In the first neuromodulation session, participants will receive rTMS using their sub-optimal TMS frequency. After washout period of 1 week (minimum), the participants will start their second neuromodulation session using their optimal TMS frequency instead.	Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Participants undergo resting-state and task-based fMRI to identify individualized transcranial magnetic stimulation (TMS) targets and determine optimal and sub-optimal stimulation frequencies. Additional fMRI scans are performed after each neuromodulation phase to assess changes following three days of stimulation at the optimal and sub-optimal frequencies.; Device: Repetitive Transcranial Magnetic Stimulation (rTMS); Participants first receive multiple rTMS frequencies during an fMRI scan to assess brain responses and determine individualized optimal and sub-optimal stimulation frequencies. They then complete two neuromodulation intervention periods, receiving rTMS at the identified optimal and sub-optimal frequencies. Each frequency is administered over three consecutive days, with the order of conditions randomized and counterbalanced.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reaction Time Changes During N-Back Task in Responses to Different TMS Frequencies	During the TMS/fMRI scan, participants perform a working memory task (N-back). To evaluate how different repetitive TMS frequencies (5, 10, and 20 Hz) impact reaction time during N-back task, each rTMS train is followed by a block of the N-back task. A decoder identifies one frequency as optimal frequency and another as suboptimal frequency. Reaction Time during optimal, suboptimal, and no stimulation condition is assessed by taking average of reaction time on accurate trials with faster reaction times indicating better performance.	Single visit (~2 hours)
Accuracy Changes During N-Back Task in Responses to Different TMS Frequencies	During the TMS/fMRI scan, participants perform a working memory task (N-back). To evaluate how different repetitive TMS frequencies (5, 10, and 20 Hz) impact accuracy during N-back task, each rTMS train is followed by a block of the N-back task. A decoder identifies one frequency as optimal frequency and another as suboptimal frequency. Accuracy during optimal, suboptimal, and no stimulation condition is assessed by taking average of all the trials with better accuracy indicating better performance.	Single visit (~2 hours)
Reaction Time Changes in the Delayed Matching to Sample Task Following Optimal vs. Suboptimal rTMS Stimulation	Each subject completes two 3-day neuromodulation sessions, one using their 'optimal' rTMS frequency, and the other using their 'suboptimal' rTMS frequency, as determined by their TMS/fMRI visit. After each neuromodulation session, subjects complete a working memory task (Delayed Match to Sample). The delay period reflects how long participants can retain the information in working memory. Common delay periods used in research, including our study, are 0 seconds, 4 seconds, and 12 seconds.The outcome measure shows the reaction time for each of these variables.	Up to 1 month
Accuracy Changes in the Delayed Matching to Sample Task Following Optimal vs. Suboptimal rTMS Stimulation	Each subject completes two 3-day neuromodulation sessions, one using their 'optimal' rTMS frequency, and the other using their 'suboptimal' rTMS frequency, as determined by their TMS/fMRI visit. After each neuromodulation session, subjects complete a working memory task (Delayed Match to Sample). The delay period reflects how long participants can retain the information in working memory. Common delay periods used in research, including our study, are 0 seconds, 4 seconds, and 12 seconds.The outcome measure shows the accuracy for each of these variables.	Up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reaction Time Changes in the Reaction Time Index Task Following Optimal vs. Suboptimal rTMS Stimulation	Each subject completes two 3-day neuromodulation sessions, one using their 'optimal' rTMS frequency, and the other using their 'suboptimal' rTMS frequency, as determined by their TMS/fMRI visit. After each neuromodulation session, subjects complete a reaction time index task that acted as a control task. The outcome measure shows the reaction time.	Up to 1 month
Movement Time Changes in the Reaction Time Index Task Following Optimal vs. Suboptimal rTMS Stimulation	Each subject completes two 3-day neuromodulation sessions, one using their 'optimal' rTMS frequency, and the other using their 'suboptimal' rTMS frequency, as determined by their TMS/fMRI visit. After each neuromodulation session, subjects complete a reaction time index task that acted as a control task. The outcome measure shows the movement time.	Up to 1 month

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Mental Health (NIMH)

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2021
• Primary Completion (Actual): June 13, 2024
• Study Completion (Actual): June 13, 2024

Study Registration Dates

• First Submitted: May 4, 2020
• First Submitted That Met QC Criteria: May 22, 2020
• First Posted (Actual): May 26, 2020

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: MRI; memory; healthy; TMS
• Other Study ID Numbers: 832891; R01MH120811-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes