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

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT02677740
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 2
• Actual Duration (Months): 6.6
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Non-invasive Neuromodulation in Healthy Subjects	Device: Inhibitory rTMS (1 Hz); Device: Excitatory rTMS (5 Hz)	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Mechanisms of Non-Invasive Neuromodulation Interventions: Influence on Human Neurochemistry and Functional Connectivity
• Actual Study Start Date: Aug 29, 2016
• Actual Primary Completion Date: Mar 19, 2017
• Actual Study Completion Date: Mar 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inhibitory rTMS (1 Hz) 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); 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.
Experimental: Excitatory rTMS (5 Hz) 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); 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.

Outcome Measures

Primary Outcome Measures

1. Percent Change of GABA Concentration in a Voxel Encompassing the Left Motor Cortex, Measured at 30 Min After rTMS [Baseline/Pre-rTMS and 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).

2. Percent Change of GABA Concentration in a Voxel Encompassing the Right Motor Cortex, Measured at 60 Min After rTMS [Baseline/Pre-rTMS and 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).

3. 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 [Baseline/Pre-rTMS and 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).

4. 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 [Baseline/Pre-rTMS and 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Magnetic Resonance Research, Dept. of Radiology, University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• University of Minnesota

Investigators

• Principal Investigator: Silvia Mangia, PhD, Dept. of Radiology, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 1, 2019

More Information

Additional Information:

• Profile of Principal Investigator

Publications

• Bednařík P, Tkáč I, Giove F, DiNuzzo M, Deelchand DK, Emir UE, Eberly LE, Mangia S. Neurochemical and BOLD responses during neuronal activation measured in the human visual cortex at 7 Tesla. J Cereb Blood Flow Metab. 2015 Mar 31;35(4):601-10. doi: 10.1038/jcbfm.2014.233.
• Emara TH, Moustafa RR, ElNahas NM, ElGanzoury AM, Abdo TA, Mohamed SA, ElEtribi MA. Repetitive transcranial magnetic stimulation at 1Hz and 5Hz produces sustained improvement in motor function and disability after ischaemic stroke. Eur J Neurol. 2010 Sep;17(9):1203-1209. doi: 10.1111/j.1468-1331.2010.03000.x. Epub 2010 Apr 8.
• Machado S, Bittencourt J, Minc D, Portella CE, Velasques B, Cunha M, Budde H, Basile LF, Chadi G, Cagy M, Piedade R, Riberio P. Therapeutic applications of repetitive transcranial magnetic stimulation in clinical neurorehabilitation. Funct Neurol. 2008 Jul-Sep;23(3):113-22. Review.
• Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14. Review.
• Smith SM, Beckmann CF, Andersson J, Auerbach EJ, Bijsterbosch J, Douaud G, Duff E, Feinberg DA, Griffanti L, Harms MP, Kelly M, Laumann T, Miller KL, Moeller S, Petersen S, Power J, Salimi-Khorshidi G, Snyder AZ, Vu AT, Woolrich MW, Xu J, Yacoub E, Uğurbil K, Van Essen DC, Glasser MF; WU-Minn HCP Consortium. Resting-state fMRI in the Human Connectome Project. Neuroimage. 2013 Oct 15;80:144-68. doi: 10.1016/j.neuroimage.2013.05.039. Epub 2013 May 20.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT02677740
• Other Study ID Numbers: 1601M83405
• First Posted: Feb 9, 2016
• Last Update Posted: Nov 18, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Minnesota: MRI; MRS; rTMS

Study Results

Participant Flow

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
Period Title: Overall Study
STARTED	7	1
COMPLETED	7	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)	Total
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv	Total of all reporting groups
Overall Participants	7	1	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	1 100%	8 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28 (7)	22 (NA)	27 (7)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	7 100%	1 100%	8 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 14.3%	0 0%	1 12.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	6 85.7%	1 100%	7 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	1 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Percent Change of GABA Concentration in a Voxel Encompassing the Left Motor Cortex, Measured at 30 Min After rTMS
Description	GABA concentration is quantified with MRS at 7 Tesla. Percent change of GABA concentration is calculated from baseline (i.e., pre-rTMS).
Time Frame	Baseline/Pre-rTMS and 30 min after rTMS

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
Measure Participants	7	1
Mean (Standard Deviation) [percent change]	8 (9)	-27 (NA)

2. Primary Outcome

Title	Percent Change of GABA Concentration in a Voxel Encompassing the Right Motor Cortex, Measured at 60 Min After rTMS
Description	GABA concentration is quantified with MRS at 7 Tesla. Percent change of GABA concentration is calculated from baseline (i.e., pre-rTMS).
Time Frame	Baseline/Pre-rTMS and 60 min after rTMS

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
Measure Participants	7	1
Mean (Standard Deviation) [percent change]	-6 (6)	4 (NA)

3. Primary Outcome

Title	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
Description	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).
Time Frame	Baseline/Pre-rTMS and 80 min after rTMS

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
Measure Participants	7	1
Mean (Standard Deviation) [percent change]	-2 (11)	9 (NA)

4. Primary Outcome

Title	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
Description	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).
Time Frame	Baseline/Pre-rTMS and 80 min after rTMS

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhibitory rTMS (1 Hz)	Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
Measure Participants	7	1
Mean (Standard Deviation) [percent change]	-1 (10)	17 (NA)

Adverse Events

Time Frame	approximately 4 hours
Arm/Group Title	Inhibitory rTMS (1 Hz)		Excitatory rTMS (5 Hz)
Arm/Group Description	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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Inhibitory rTMS (1 Hz): 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		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. One week before the MRI/MRS acquisitions, neurophysiological parameters are also measured before and right after the rTMS intervention. Excitatory rTMS (5 Hz): 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 interv
All Cause Mortality
	Inhibitory rTMS (1 Hz)		Excitatory rTMS (5 Hz)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/1 (0%)
Serious Adverse Events
	Inhibitory rTMS (1 Hz)		Excitatory rTMS (5 Hz)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Inhibitory rTMS (1 Hz)		Excitatory rTMS (5 Hz)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		1/1 (100%)
General disorders
Sleepiness	3/7 (42.9%)	3	1/1 (100%)	1
Warmth	1/7 (14.3%)	1	0/1 (0%)	0
Metallic Taste	1/7 (14.3%)	1	1/1 (100%)	1
Headache	1/7 (14.3%)	1	0/1 (0%)	0
Tooth Pain	1/7 (14.3%)	1	0/1 (0%)	0
Shoulder Pain	1/7 (14.3%)	1	0/1 (0%)	0
Psychiatric disorders
Anxiety/Worry/Nervousness	2/7 (28.6%)	2	0/1 (0%)	0

Limitations/Caveats

The study was initially registered with a larger number of subjects (30) than what the pilot funds allowed (8) to allow more studies in the future. However, we decided to close the protocol after 8 studies reported here to avoid prolonged inactivity.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.