Individualized Closed Loop TMS for Working Memory Enhancement

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Memory

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation (rTMS)


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Task and resting fMRI will be used to determine an individualized brain target for each participant. In a subsequent session, participants will complete a task fMRI with repetitive TMS neuromodulation; during this session, various stimulation protocols will be interleaved with working memory task blocks to result in online brain readouts of the degree in which modulation affected the brain state in regards to working memory performance. Based on this testing, an optimal and sub-optimal TMS stimulation frequency will be determined for each individual participant. Each frequency will be administered separately across three stimulation days using a crossover design, with the order of frequencies being randomized and counterbalanced. Therefore, each subject will receive six days of TMS stimulation: three using the optimal frequency, and three using the sub-optimal frequency. The initial TMS/ task fMRI testing session will be completed at the midpoint and end of the study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optimized TMS frequency, Then Sub-Optimal TMS Frequency<br>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. | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* The investigators will create individualized TMS targets using deep learning methods on task and resting fMRI data to target working memory augmentation. The individualized target will be stimulated in a subsequent fMRI scan involving working memory task performance interleaved with repetitive TMS (rTMS) delivered at a variety of stimulation frequencies. Based on activation readouts in response to rTMS, an optimal and sub-optimal brain state frequency to impact working memory performance will be selected for each participant. Participants will receive rTMS at each frequency separately for three days (six days total), with the order of frequency randomly assigned and counterbalanced. Following each three day protocol, another fMRI working memory readout will be conducted to support the targeting and frequency selection algorithms.<br>|
| Experimental: Sub-Optimal TMS Frequency, Then Optimized TMS frequency<br>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. | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* The investigators will create individualized TMS targets using deep learning methods on task and resting fMRI data to target working memory augmentation. The individualized target will be stimulated in a subsequent fMRI scan involving working memory task performance interleaved with repetitive TMS (rTMS) delivered at a variety of stimulation frequencies. Based on activation readouts in response to rTMS, an optimal and sub-optimal brain state frequency to impact working memory performance will be selected for each participant. Participants will receive rTMS at each frequency separately for three days (six days total), with the order of frequency randomly assigned and counterbalanced. Following each three day protocol, another fMRI working memory readout will be conducted to support the targeting and frequency selection algorithms.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of different TMS frequencies on N-back performance | During the TMS/fMRI scan, subjects complete working memory task (N-back). To assess the effect of different repetitive TMS frequencies (5-20hz) on N-back performance, each rTMS train is followed by a block of the N-back task. Performance will be measured using percent accuracy for each Nback block. Higher percent accuracy indicates better task performance. | Single visit ( 2 hours) | 
| Effect 'Optimal' vs 'Least-Optimal' rTMS frequency on the Delayed Match to Sample Task | Each subject completes two 3-day neuromodulation sessions, one using their 'optimal' rTMS frequency, and the other using their 'least-optimal' rTMS frequency, as determined by ther TMS/fMRI Visit. After each neuromodulation session, subjects complete a working memory task (Delayed Match to Sample). To assess the effect of each rTMS frequency on the Delayed Match to Sample task performance, percent accuracy will be measured. Higher percent accuracy indicates better task performance. | Up to 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS, memory, healthy, MRI