Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity

Study Overview
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Brief Summary
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The aim of this project is to increase our understanding of how two different protocols of repetitive transcranial magnetic stimulation (rTMS), inhibitory (1 Hz) and excitatory (5 Hz), applied over the primary motor cortex of the presumed dominant hemisphere, affect functional connectivity and neurochemistry in the brain.

Detailed Description
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Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method which is effective for treating both psychiatric and non-psychiatric disorders, such as posttraumatic stress disorder, obsessive compulsive disorder, pain syndromes and for improving motor function in neurodegenerative diseases or following stroke. rTMS uses series of brief pulses of magnetic field applied to the surface of the head for a period of time (e.g. 20 minutes). The effects of rTMS are transient, and critically dependent upon the location, frequency and intensity of stimulation. Several studies have provided evidence that rTMS can influence the excitability and function of neurons (neuromodulation) for up to one hour, both near to, and distant from, the site of stimulation. However it is still unclear how these transient local and distant changes in function induced by specific rTMS protocols are mediated. In this project we will combine expertise in Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS) and rTMS neuromodulation to develop and test protocols for examining the changes produced by non-invasive brain stimulation on healthy subjects. rTMS will be applied outside the scanner using standard TMS coils and MRI/S at 7 Tesla will be acquired before and immediately after rTMS. Our aim is to increase the understanding of how the two different rTMS protocols, inhibitory (1 Hz) and excitatory (5 Hz), applied over the primary motor cortex of the presumed dominant hemisphere, affect functional connectivity and neurochemistry in the brain.

Official Title
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Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity

Conditions
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Non-invasive Neuromodulation in Healthy Subjects

Intervention / Treatment
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* Device: Inhibitory rTMS (1 Hz)
* Device: Excitatory rTMS (5 Hz)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Those volunteers who are evaluated as normal and not met exclusion criteria will be potential candidates for this study. Exclusion Criteria: The following participants will be excluded from this study, including but not limited to: Females Left handed males Participants who never underwent MRI at 7 Tesla Participants with: any type of bio-implant activated by mechanical, electronic, or magnetic means (e.g. cochlear implants, pacemakers, neurostimulators, bio stimulators, electronic infusion pumps.) any type of ferromagnetic bio-implant that could potentially be displaced or damaged, such as aneurysm clips, metallic skull plates, etc. non-removable piercing or permanent eyeliner retained metal in their body, either from a medical procedure or an injury Participants who: have been diagnosed by a physician as having a psychiatric disorder, substance abuse, neurological and/or cardiovascular disease have cardiac or known circulatory impairment, and/or the inability to perspire (poor thermoregulatory function) have hyper- or hypotension or arrhythmias have known conditions which can lead to emergency medical care had a head injury that caused them to lose consciousness for more than 30 minutes or have amnesia for more than 24 hours had a brain tumor or stroke had one or more seizures, or been given a diagnosis of epilepsy have a history of sleep apnea or head trauma that may have caused Traumatic Brain Injury (TBI) have a history of anxiety, syncope, panic attacks and/or claustrophobia cannot adhere to the experimental protocol for any reason started taking chemotherapy or immunomodulatory agents, or had any radiation treatment that could affect the brain are currently on any medication

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhibitory rTMS (1 Hz)<br>Subjects are exposed to a 20-min inhibitory rTMS intervention that transiently suppresses the excitability of cortical structures beneath the site of stimulation. Subjects undergo MRI and MRS both before and right after the rTMS intervention. | Device: Inhibitory rTMS (1 Hz)<br>* Participants receive rTMS at a rate of 1 Hz, applied with a 70-mm figure-eight TMS coil connected to a stimulator, over the motor cortex hotspot contralateral to the dominant arm for 20 minutes at an intensity of 90% resting motor threshold (RMT) for a total of 600 TMS pulses. The total number of stimuli applied is well within the published safety guidelines for use of rTMS. rTMS is applied outside the scanner, whereas functional connectivity and neurochemistry are measured with MRI and MRS, respectively, at 7 Tesla. The MRI/MRS data are collected right before and immediately after the inhibitory rTMS intervention.<br>|
| Experimental: Excitatory rTMS (5 Hz)<br>Subjects are exposed to a 20-min excitatory rTMS intervention that transiently increases the net excitability of cortical structures beneath the site of stimulation. Subjects undergo MRI and MRS both before and right after the rTMS intervention. | Device: Excitatory rTMS (5 Hz)<br>* Participants receive rTMS at a rate of 5 Hz, applied with a 70-mm figure-eight TMS coil connected to a stimulator, over the motor cortex hotspot contralateral to the dominant arm for 20 minutes at an intensity of 90% RMT for a total of 600 TMS pulses. The total number of stimuli applied is well within the published safety guidelines for use of rTMS. rTMS is applied outside the scanner, whereas functional connectivity and neurochemistry are measured with MRI and MRS, respectively, at 7 Tesla. The MRI/MRS data are collected right before and immediately after the excitatory rTMS intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change of GABA Concentration in a Voxel Encompassing the Left Motor Cortex, Measured at 30 Min After rTMS | GABA concentration is quantified with MRS at 7 Tesla. Percent change of GABA concentration is calculated from baseline (i.e., pre-rTMS). | Baseline/Pre-rTMS and 30 min after rTMS | 
| Percent Change of GABA Concentration in a Voxel Encompassing the Right Motor Cortex, Measured at 60 Min After rTMS | GABA concentration is quantified with MRS at 7 Tesla. Percent change of GABA concentration is calculated from baseline (i.e., pre-rTMS). | Baseline/Pre-rTMS and 60 min after rTMS | 
| Percent Change of Functional Connectivity in Left Motor Cortex, Where Functional Connectivity is Measured as a Dimensionless Fractional Amplitude of Low-frequency Fluctuations (fALFF), at 80 Min After rTMS | Functional connectivity is measured with MRI at 7 Tesla as a dimensionless fractional amplitude of low-frequency fluctuations (fALFF). This is an index which reflects the intensity of spontaneous regional brain activity. It is calculated as the ratio of power spectra of low frequency (0.01-0.08 Hz) to that of the entire frequency range. Percent change of functional connectivity is calculated from baseline (i.e., pre-rTMS). | Baseline/Pre-rTMS and 80 min after rTMS | 
| Percent Change of Functional Connectivity in Right Motor Cortex, Where Functional Connectivity is Measured as a Dimensionless Fractional Amplitude of Low-frequency Fluctuations (fALFF), at 80 Min After rTMS | Functional connectivity is measured with MRI at 7 Tesla as a dimensionless fractional amplitude of low-frequency fluctuations (fALFF). This is an index which reflects the intensity of spontaneous regional brain activity. It is calculated as the ratio of power spectra of low frequency (0.01-0.08 Hz) to that of the entire frequency range. Percent change of functional connectivity is calculated from baseline (i.e., pre-rTMS). | Baseline/Pre-rTMS and 80 min after rTMS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, MRS, rTMS