MRI Guided Closed-loop TMS-EEG

Spatiotemporally Precise Neuromodulation by Transcranial Magnetic Stimulation Guided by Multimodal Neuroimaging

The goal of this interventional study is to develop an individualized approach using transcranial magnetic stimulation (TMS) in a high-precision manner. This approach will use TMS to modulate brain activity at multiple locations simultaneously. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) will record the responses and guide the stimulation. Specifically, the placement and orientation of TMS coils will be tailored to stimulate the targeted functional brain areas informed by fMRI. To maximize the interventional effect, stimulation pulses will be delivered based on EEG oscillations.

Study Overview

• Status: Recruiting
• Conditions: Normal Physiology; Amnestic Mild Cognitive Impairment
• Intervention / Treatment: Device: TMS

Detailed Description

Background:

Transcranial magnetic stimulation (TMS) is a non-invasive technique that uses a transient electromagnetic field over a small area of the scalp to alter neuronal activity. It has been approved by Health Canada for the treatment of major depressive disorder and obsessive-compulsive disorder. Despite its clinical prevalence, TMS has a response rate of less than 50% and high intra- and inter-subject variability. Even among healthy subjects, the probability of inducing neuro-modulatory effects can be as low as 50%.

Design:

Depending on the study's aims, participants will have to visit Sunnybrook Health Sciences Centre two or three times on separate days. Participants will be screened with a medical record review before their first visit.

In the first visit, participants will have a magnetic resonance imaging (MRI) session. During the MRI session, participants will be brought inside an MRI scanner to collect images, including structural and functional MRI scans. During structural scans, participants will be asked to stay inside the MRI while images are taken. During functional MRI scans, participants will be asked to take rests with eyes open, watching and/or listening to audiovisual stimuli, and respond to stimuli by button pressing. Before starting MRI scans, a short training on the task will be taken. An additional assessment and, if necessary, training sessions will be conducted to ensure that participants undergo imaging while being able to keep their heads sufficiently for acceptable fMRI data quality. Before entering the MRI room, participants will be asked to remove any metal or magnetic sensitive objects (e.g., jewelry, keys, credit cards) to ensure safety. Earplugs or earphones will be provided to participants to reduce the loud noise produced by the MRI scanner. During the MRI scans, participants will perform the same task as notified in the training session. Short breaks will be arranged between tasks. The entire MRI procedure will take approximately one hour. If electroencephalograph (EEG) is to be recorded during MRI scans, an additional one hour is needed for EEG preparation before the MRI scans. After MRI scans, participants may be asked to rate their feelings toward the audiovisual stimuli, cognitive states, and emotional states on a computer.

Participants will be asked to attend TMS-MRI experiments twice on separate days for aim 1. In the TMS-MRI session, participants will take TMS and MRI separately. For TMS, participants will be led to a treatment room and seated in a comfortable chair in a slightly reclined position. A research staff will place an electromagnetic coil softly against each participant's head. A TMS coil will painlessly deliver magnetic pulses stimulating nerve cells at predetermined intervals. Electrodes may be mounted on the participants' wrists and around the eyes to monitor muscle activities. The treatment protocol for each participant will be based on his/her MRI scans, EEG signals, or motor responses. This step may be helped by using a camera. During TMS, participants will hear clicking sounds generated by the TMS coil and may have touching or twitching senses over their faces. After TMS, participants will be brought to an MRI room for MRI scans as described above. A rating of the participant's feelings and task performance may be taken after MRI scans.

For aims 2 and 3, participants will be asked to attend a TMS-EEG-MRI experiment once. In the TMS-EEG-MRI session, participants will first undergo TMS and EEG together. Then, participants will undergo an MRI. For TMS-EEG, participants will be led to a treatment room and seated in a comfortable chair in a slightly reclined position. Each participant will be asked to wear an EEG cap. A device is then used to measure the EEG electrode locations over the cap. Then, conductive gel will be applied to EEG electrodes over the cap. Participants may feel skin scratching when the research staffs apply the conductive gel. Additional electrodes will be attached around the participants' eyes and wrists to monitor muscle movement. During TMS, a research staff will place an electromagnetic coil softly against the participant's head. A TMS coil will painlessly deliver magnetic pulses that stimulate nerve cells. The investigators will determine the treatment protocol based on each participant's MRI scans, EEG signals, or motor responses. This step may be helped by using a camera. During TMS, participants will hear clicking sounds generated by the TMS coil and may have touching or twitching senses over their faces. After TMS, participants will be brought to an MRI room for MRI scans as described above. A rating of the participants' feelings and task performance may be taken after MRI scans.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fa-Hsuan Lin, PhD; Phone Number: 65709 416-480-6100; Email: fhlin@sri.utoronto.ca
• Study Contact Backup: Name: Hsin-Ju Lee, PhD; Phone Number: 63285 416-480-6100; Email: hsinju.lee@utoronto.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Fa-Hsuan Lin, PhD; Phone Number: 65709 416-480-6100; Email: fhlin@sri.utoronto.ca
      • Contact: Hsin-Ju Lee, PhD; Phone Number: 63285 416-480-6100; Email: hsinju.lee@utoronto.ca

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria for Healthy participants:

• Ages between 18 and 65 years;
• Healthy with no history of neurological impairment;
• Normal or correct-to-normal vision.

Inclusion Criteria for aMCI patients:

• Age 50-80 years;
• MCI clinical criteria: (a) self- or informant-reported cognitive complaint; (b) preserved independence in functional abilities; and (c) absence of dementia;
• Objective cognitive impairment supported by the following measures of general cognitive function: (a) Mini-Mental State Exam (MMSE) 24-27 (inclusive); (b) Montreal Cognitive Assessment (MoCA) 18-26 (inclusive); or (c) Clinical Dementia Rating Scale score of 0.5;
• Normal or correct-to-normal vision.

Exclusion Criteria for all participants:

• Women who are pregnant or breastfeeding;
• History of seizure (childhood febrile seizures are acceptable and these subjects may be included in the study), history of epilepsy in self or first degree relatives, stroke, brain tumor, brain surgery, head injury, known structural brain lesion;
• Have metal in the eye or skull area, brain stimulator, surgical metal, clips in the brain, cochlear implants, mental fragments in the eye, as these make TMS unsafe;
• Have non-MRI compatible metal in the body, for example metallic (forromagnetic) implants (e.g., cardiac pacemaker, aneurysm clip);
• Subjects who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 1 hour, and would feel uncomfortable in the MRI machine;
• Participation in any other study involving non-invasive brain stimulation less than two weeks ago;
• Abnormal findings on neurological examination that we will perform.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental_Aim1: Healthy Volunteers; All participants will receive all conditions and the order of all conditions will be counterbalanced across participants. Statistical comparisons will be within-subjects.	Device: TMS; The target locations of TMS will be cortical regions defined by either anatomical landmarks or functional regions derived from the individual's functional and structural MRI for Aim 1. TMS target locations for Aim 2 and 3 are determined by Aim 1's results. These TMS target regions will be guided by a navigation system. TMS will be parametrically varied with combinations of pulse strength and frequencies based on experimental conditions. TMS strength will be referred to the resting motor threshold (rMT), which will be determined independently for each participant. TMS pulses will be delivered at fixed time instants for Aim 2 and at time instants based on the phase of oscillatory neural activity for Aim 3.
Experimental: Experimental_Aim2: Amnestic Mild Cognitive Impairment; All participants will receive all conditions and the order of all conditions will be counterbalanced across participants. Statistical comparisons will be within-subjects.	Device: TMS; The target locations of TMS will be cortical regions defined by either anatomical landmarks or functional regions derived from the individual's functional and structural MRI for Aim 1. TMS target locations for Aim 2 and 3 are determined by Aim 1's results. These TMS target regions will be guided by a navigation system. TMS will be parametrically varied with combinations of pulse strength and frequencies based on experimental conditions. TMS strength will be referred to the resting motor threshold (rMT), which will be determined independently for each participant. TMS pulses will be delivered at fixed time instants for Aim 2 and at time instants based on the phase of oscillatory neural activity for Aim 3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional connectivity measured by fMRI	Functional connectivity during resting state and psychological tasks	At baseline and immediately after treatment
Response accuracy to psychological tasks	accuracy, or rate of conditioned responses	At baseline and immediately after treatment
Reaction times		At baseline and immediately after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG functional connectivity	Pearson correlation coefficients (r) between electrodes	At baseline and immediately after treatment

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Investigators: Principal Investigator: Fa-Hsuan Lin, PhD, Sunnybrook Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2023
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: September 3, 2023
• First Submitted That Met QC Criteria: September 18, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): August 13, 2024
• Last Update Submitted That Met QC Criteria: August 11, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; Memory Impairments
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: SUN-5474

Drug and device information, study documents

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