Ignite Creation Date:
2024-05-06 @ 12:01 PM
Last Modification Date:
2024-10-26 @ 12:53 PM
Study NCT ID:
NCT03652012
Status:
UNKNOWN
Last Update Posted:
2021-04-30
First Post:
2018-04-27
Brief Title:
Probing Cortical Excitability and Cognitive Function With TMS
Sponsor:
University of Arizona
Organization:
University of Arizona
Study Overview
Official Title:
Probing Cortical Excitability and Cognitive Function in Mild Cognitive Impairment With Transcranial Magnetic Stimulation
Status:
UNKNOWN
Status Verified Date:
2021-04
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The overarching purpose of this study is to develop a technique that is capable of identifying neurophysiological biomarkers sensitive enough to detect preclinical dementia by integrating Transcranial Magnetic Stimulation TMS and Functional Magnetic Resonance Imaging fMRI More specifically this project has two specific aims
1 To characterize cortical excitability and its relation to cognitive function using single-pulse TMS paradigm in Mild Cognitive Impairment MCI and healthy older adults
2 To delineate cortical plasticity and its association to cognitive function using repetitive TMS paradigm and resting-state fMRI in MCI and healthy older adults
Techniques to artificially and precisely stimulate brain tissue are increasingly recognized as valuable tools both in clinical practice and in cognitive neuroscience studies among healthy individuals Transcranial magnetic stimulation TMS is a non-invasive approach to stimulate the brain Importantly unlike other invasive brain stimulation techniques eg surgical deep brain stimulation no surgery anesthesia or sedation is involved Instead TMS involves placing a magnetic coil on the surface of the head This coil then generates a magnetic field that is about the same strength as the magnetic field used by MRI machines and when this magnetic field rapidly alternates the neurons under the coil are excited
Extensive guidelines have been published by experts in the field to ensure safe use and the thousands of patients research participants who have received TMS in compliance with these guidelines demonstrate the safety of this practice Depending on the method of use TMS is very versatile -- it can be used to study research questions pertaining to the neural circuitry of the brain it can be used as a diagnostic device and it can be used therapeutically to treat various neurological conditions
In this study the investigators intend to further study the potential for diagnostic applications of TMS More specifically TMS and brain imaging techniques will be used in combination in order to more sensitively diagnose dementia - perhaps even before symptoms emerge Right now there is no reliable method for doing so and it is difficult to distinguish between the forgetfulness of healthy aging and the early signs of disease Our approach may provide a more sensitive diagnostic tool which is likely to improve clinical outcomes
1 To characterize cortical excitability and its relation to cognitive function using single-pulse TMS paradigm in Mild Cognitive Impairment MCI and healthy older adults
2 To delineate cortical plasticity and its association to cognitive function using repetitive TMS paradigm and resting-state fMRI in MCI and healthy older adults
Techniques to artificially and precisely stimulate brain tissue are increasingly recognized as valuable tools both in clinical practice and in cognitive neuroscience studies among healthy individuals Transcranial magnetic stimulation TMS is a non-invasive approach to stimulate the brain Importantly unlike other invasive brain stimulation techniques eg surgical deep brain stimulation no surgery anesthesia or sedation is involved Instead TMS involves placing a magnetic coil on the surface of the head This coil then generates a magnetic field that is about the same strength as the magnetic field used by MRI machines and when this magnetic field rapidly alternates the neurons under the coil are excited
Extensive guidelines have been published by experts in the field to ensure safe use and the thousands of patients research participants who have received TMS in compliance with these guidelines demonstrate the safety of this practice Depending on the method of use TMS is very versatile -- it can be used to study research questions pertaining to the neural circuitry of the brain it can be used as a diagnostic device and it can be used therapeutically to treat various neurological conditions
In this study the investigators intend to further study the potential for diagnostic applications of TMS More specifically TMS and brain imaging techniques will be used in combination in order to more sensitively diagnose dementia - perhaps even before symptoms emerge Right now there is no reliable method for doing so and it is difficult to distinguish between the forgetfulness of healthy aging and the early signs of disease Our approach may provide a more sensitive diagnostic tool which is likely to improve clinical outcomes
Detailed Description:
In total 60 participants will be recruited to participate in this trial The investigators aim to recruit 30 patients with MCI and 30 age-matched healthy adults The age range for inclusion will be 18-80 and the mean age of the healthy cohort will be matched with the mean age of the MCI cohort The following revised Mayo Clinic criteria for MCI will be used 1 cognitive concern expressed by a physician informant participant or nurse 2 impairment in 1 or more cognitive domains memory language visuospatial skills or executive functions 3 essentially normal functional activities and 4 absence of dementia Individuals with MCI will have Mini-Mental State Exam MMSE Appendix 19 scores between 18 and 23 inclusive and have a Clinical Dementia Rating Scale score of 05
This study protocol comprises a single testing visit comprised of four separate components a Resting-state fMRI b Single-pulse TMS paradigm c theta-burst rTMS paradigm and d a brief motor task performed on an iPad
These tasks will be repeated before and after the theta-burst rTMS paradigm c Therefore the testing visit is
a -- d -- b -- c -- b -- a -- d
This protocol will enable investigators to study the following both before and after the rTMS paradigm 1 connectivity patterns comprising the functional networks of the brain 2 measures of cortical excitability derived from single-pulse TMS and 3 upper extremity motor speed acuity
Transcranial Magnetic Stimulation
Magnetic stimulation will be performed with a high-power MagPro X100 MagVenture Inc DenmarkAppendix 11 When the TMS machine delivers stimuli patients may feel andor a clickingtapping sensation under the coil Participants will be given ear buds as an additional safety precaution to protect hearing during the TMS session Prior to beginning the TMS session the research team will make sure the participant is as comfortable as possible in the TMS chair
Single Pulse TMS Paradigm
First the device will need to be calibrated for each individual because everybody has a different sensitivity to the magnetic fields generated by TMS The TMS device will be calibrated to ensure the participant is receiving the lowest possible dose To do so the TMS coil will be placed on the scalp directly above the region of the brain that is responsible for finger motions which is a specific region of the motor cortex located on the pre-central gyrus The TMS coil will then deliver pulses that incrementally escalate until a level is reached that causes their hand to twitch specifically thumb and pointer finger This will be visually observed and recorded quantitatively with electromyography EMG sensors The amount of energy required to make their hand twitch is called the motor threshold and it varies for everybody This motor threshold will then be used to calibrate the machine for the TMS protocol
A figure-of-eight TMS coil will be held over the motor cortex at the optimum scalp position to elicit motor-evoked potentials MEPs in the contralateral first dorsal interosseous FDI muscle In addition to observing the finger movement visually the investigators will also attach surface electromyography EMG electrodes to the skin on the right FDI The electrodes will detect any activity in muscles which will yield a more accurate measurement for personal motor threshold The exact location that elicits a motor response in the contralateral FDI is referred to as the hot spot This location will be recorded using the real-time TMS 3D Neuronavigation System Localite TMS Navigator Germany httpwwwlocalitedeenproductstms-navigatorc572 to ensure testing consistency in the following trials Localite is a software package used in conjunction with TMS equipment It incorporates an infrared camera to record location of the TMS coil relative to the participants head This allows researchers to reliably place coil in the same precise location throughout the session
The resting motor threshold RMT is defined as the minimum stimulus intensity that produces a liminal MEP about 50 μV in 50 of 10 trials at rest The active motor threshold AMT is generally defined as the minimum stimulus intensity that produces a liminal MEP about 200 μV in 50 of 10 trials during isometric contraction of the tested muscle Both RMT and AMT will be expressed as a percentage of the magnetic stimulator maximal output The RMT and AMT data from individual participants will serve as a baseline measure of excitability to guide the intensity of our following single-pulses and repetitive TMS protocols respectively This will be performed for the left hemisphere The researchers will also use the Parameter Estimation Sequential Testing PEST algorithm to more efficiently identify the RMT and AMT
After the motor threshold and hot spot is identified for the participant the TMS coil will be placed over the hot spot that was previously recorded by the Localite Navigator software and set the stimulus intensity at 80 of the participants uniquely identified AMT For example if the active motor threshold of a specific individual is determined to be 40 of the MagPros maximal output then the device intensity will be set to 32 of maximal output for the single pulse protocol 32 equals 80 of 40 the AMT in this example At this time 8 TMS pulses are applied separated by 6 seconds as the TMS coil is fixed on the hot spot This step is repeated in increasing increments ie 10 of AMT up to an intensity equivalent to 150 of the participants AMT This protocol consists of 64 single-pulse stimuli which will be delivered repeatedly 6 seconds apart This procedure is safe and follows standard single-pulses TMS protocols that have been published previously
This single-pulses TMS protocol will be performed twice both before and after the rTMS protocol Each single-pulses TMS protocol will last approximately 30 minutes Combined this equates to 128 stimuli during the Single Pulses TMS paradigms Throughout the single-pulse protocol participants will be asked to touch their pinky and thumb fingers to provide a subtle background voluntary contraction This will facilitate the motor pathway and lower the threshold for stimulation intensity throughout the protocol
rTMS
In the repetitive TMS rTMS protocol a patterned rTMS paradigm called intermittent theta burst stimulation iTBS will be used The iTBS consists of three biphasic TMS stimuli presented at 50 Hz repeated every 200 ms for 2 seconds at an intensity of 80 of AMT eg if AMT is determined to be 40 of maximal output TMS will be delivered at 32 for this protocol Therefore each stimulation train will last for two seconds 30 stimuli per train with an inter-train interval of 8 s This rTMS protocol is comprised of 10 iTBS trains totaling 300 stimuli from the magnetic coil
During this rTMS protocol the coil will be placed over the hotspot of the left hemisphere The rTMS protocol will only be performed once and it will last approximately 10 minutes
MRI Protocols
This will occur in the same building in a room adjacent to the TMS device For their safety participants will be asked to leave all metal objects and personal items eg wallet phone jewelry in the waiting room of the MRI center before entering the scanner room Participants will be asked to lie on their backs and remain still for the duration of the MRI scan They will be given earplugs to dampen the noise and to protect their hearing while they are in the scanner A Velcro strap may also be place over the forehead and foam pillows will be provided to minimize head movement during the scans Every effort will be made to make participants as comfortable as possible during the scan including blankets for warmth and cushions to be placed under the kneesback to reduce stress from lying on ones back
Participants will be reminded prior to the scan that their participation is voluntary and they may signal to stop the scan at any time There is an intercom system in the scanner which will enable the participants to communicate with the MRI technician and member s of the research team for the entire duration that they are in the scanner Additionally they will be able to immediately stop the exam at any time either by squeezing a signal ball placed in their hand which will alert the MRI technician in the control room or by raising their legs which will be seen by the experimenter in the control room
Importantly no contrast agent will be used in our collection of MRI data Also all MRI data will be acquired in resting-state so participants will just be asked to relax and remain still for the duration of the scan
More specifically MRI data will be collected on a Siemens 30 Tesla Skyra Magnet equipped with a 32-channel head coil Total scan time will be 30 minutes The order of sequences will be as follows localizer scan 62 seconds a Structural MPRAGE 9 minutes a resting-state fMRI scan 5 minutes and a diffusion-tensor imaging DTI scan 14 minutes The localizer will be collected using the following parameters - direction inferior to superior TR 86 ms echo time TE40 ms flip angle 20 FOV250 mm 5 slices 7 mm slice thickness High-resolution structural images will be acquired using a T1-weighted spoiled gradient recalled SPGR sequence TR 22ms TE 54ms FOV 256cm flip angle 20 in-plane matrix size 256 x 256 slice thickness 1mm number of slices 172 Whole-brain resting-state fMRI data will be collected using T2-weighted echo-planar imaging EPI TR 15s TE 30ms FOV 256cm flip angle 90 in-plane matrix size 64 x 64 slice thickness 4mm resulting in functional data from 39 axial slices with isotropic voxels of 4mm3 During the resting-state fMRI scan participants will fixate on a cross-hair with eyes open DTI images will be acquired in the axial plane using a diffusion sensitized parallel EPI sequence that measures diffusion in 86 directions b-factor 1000 smm2 TR 7s TE 825ms field of view FOV 256cm matrix 128 x 128 2mm interleaved slices parallel acceleration factor 2
The resting-state fMRI data will be preprocessed using a pipeline httpwikibiacdukeedubiacanalysisresting_pipeline and tools in the Oxford Centre for Functional MRI of the Brain Software Library FSL version 505 wwwfmriboxacukfsl The preprocessing steps include slice-time correction MCFLIRT for motion correction Brain Extraction Tool BET for brain extraction and FLIRT for normalization to the MNI 152 T1 template Montreal Neurological Institute Montreal Canada The investigators will regress out signal from white matter and cerebrospinal fluid on the basis of masks created in FSL FAST and smoothed the data with a 5 mm kernel using FSL SUSAN Temporal band-pass filtering will limit the data to frequencies in the 0001 to 008 Hz band Following the recommendation of Power et al the investigators will perform motion scrubbing using a frame-wise displacement threshold of 05 and timecourse variance threshold DVARS of 05
Behavioral Measure Motor Task
The researchers will use iPads equipped with the digital computer software Cantab Cambridge Cognition Ltd England for our behavioral measures Cantab is a cloud-based computerized cognitive assessment software that is a well-validated tool for academic research The investigators intend to use 1 Motor Screening Task 2 Paired Associates Learning Test on a tablet to measure functions of motor and memory respectively
Motor Screening Task requires the participants to touch the flashing cross which is shown in different locations on the screen The outcome measures include the accuracy of pointing and reaction time
This study protocol comprises a single testing visit comprised of four separate components a Resting-state fMRI b Single-pulse TMS paradigm c theta-burst rTMS paradigm and d a brief motor task performed on an iPad
These tasks will be repeated before and after the theta-burst rTMS paradigm c Therefore the testing visit is
a -- d -- b -- c -- b -- a -- d
This protocol will enable investigators to study the following both before and after the rTMS paradigm 1 connectivity patterns comprising the functional networks of the brain 2 measures of cortical excitability derived from single-pulse TMS and 3 upper extremity motor speed acuity
Transcranial Magnetic Stimulation
Magnetic stimulation will be performed with a high-power MagPro X100 MagVenture Inc DenmarkAppendix 11 When the TMS machine delivers stimuli patients may feel andor a clickingtapping sensation under the coil Participants will be given ear buds as an additional safety precaution to protect hearing during the TMS session Prior to beginning the TMS session the research team will make sure the participant is as comfortable as possible in the TMS chair
Single Pulse TMS Paradigm
First the device will need to be calibrated for each individual because everybody has a different sensitivity to the magnetic fields generated by TMS The TMS device will be calibrated to ensure the participant is receiving the lowest possible dose To do so the TMS coil will be placed on the scalp directly above the region of the brain that is responsible for finger motions which is a specific region of the motor cortex located on the pre-central gyrus The TMS coil will then deliver pulses that incrementally escalate until a level is reached that causes their hand to twitch specifically thumb and pointer finger This will be visually observed and recorded quantitatively with electromyography EMG sensors The amount of energy required to make their hand twitch is called the motor threshold and it varies for everybody This motor threshold will then be used to calibrate the machine for the TMS protocol
A figure-of-eight TMS coil will be held over the motor cortex at the optimum scalp position to elicit motor-evoked potentials MEPs in the contralateral first dorsal interosseous FDI muscle In addition to observing the finger movement visually the investigators will also attach surface electromyography EMG electrodes to the skin on the right FDI The electrodes will detect any activity in muscles which will yield a more accurate measurement for personal motor threshold The exact location that elicits a motor response in the contralateral FDI is referred to as the hot spot This location will be recorded using the real-time TMS 3D Neuronavigation System Localite TMS Navigator Germany httpwwwlocalitedeenproductstms-navigatorc572 to ensure testing consistency in the following trials Localite is a software package used in conjunction with TMS equipment It incorporates an infrared camera to record location of the TMS coil relative to the participants head This allows researchers to reliably place coil in the same precise location throughout the session
The resting motor threshold RMT is defined as the minimum stimulus intensity that produces a liminal MEP about 50 μV in 50 of 10 trials at rest The active motor threshold AMT is generally defined as the minimum stimulus intensity that produces a liminal MEP about 200 μV in 50 of 10 trials during isometric contraction of the tested muscle Both RMT and AMT will be expressed as a percentage of the magnetic stimulator maximal output The RMT and AMT data from individual participants will serve as a baseline measure of excitability to guide the intensity of our following single-pulses and repetitive TMS protocols respectively This will be performed for the left hemisphere The researchers will also use the Parameter Estimation Sequential Testing PEST algorithm to more efficiently identify the RMT and AMT
After the motor threshold and hot spot is identified for the participant the TMS coil will be placed over the hot spot that was previously recorded by the Localite Navigator software and set the stimulus intensity at 80 of the participants uniquely identified AMT For example if the active motor threshold of a specific individual is determined to be 40 of the MagPros maximal output then the device intensity will be set to 32 of maximal output for the single pulse protocol 32 equals 80 of 40 the AMT in this example At this time 8 TMS pulses are applied separated by 6 seconds as the TMS coil is fixed on the hot spot This step is repeated in increasing increments ie 10 of AMT up to an intensity equivalent to 150 of the participants AMT This protocol consists of 64 single-pulse stimuli which will be delivered repeatedly 6 seconds apart This procedure is safe and follows standard single-pulses TMS protocols that have been published previously
This single-pulses TMS protocol will be performed twice both before and after the rTMS protocol Each single-pulses TMS protocol will last approximately 30 minutes Combined this equates to 128 stimuli during the Single Pulses TMS paradigms Throughout the single-pulse protocol participants will be asked to touch their pinky and thumb fingers to provide a subtle background voluntary contraction This will facilitate the motor pathway and lower the threshold for stimulation intensity throughout the protocol
rTMS
In the repetitive TMS rTMS protocol a patterned rTMS paradigm called intermittent theta burst stimulation iTBS will be used The iTBS consists of three biphasic TMS stimuli presented at 50 Hz repeated every 200 ms for 2 seconds at an intensity of 80 of AMT eg if AMT is determined to be 40 of maximal output TMS will be delivered at 32 for this protocol Therefore each stimulation train will last for two seconds 30 stimuli per train with an inter-train interval of 8 s This rTMS protocol is comprised of 10 iTBS trains totaling 300 stimuli from the magnetic coil
During this rTMS protocol the coil will be placed over the hotspot of the left hemisphere The rTMS protocol will only be performed once and it will last approximately 10 minutes
MRI Protocols
This will occur in the same building in a room adjacent to the TMS device For their safety participants will be asked to leave all metal objects and personal items eg wallet phone jewelry in the waiting room of the MRI center before entering the scanner room Participants will be asked to lie on their backs and remain still for the duration of the MRI scan They will be given earplugs to dampen the noise and to protect their hearing while they are in the scanner A Velcro strap may also be place over the forehead and foam pillows will be provided to minimize head movement during the scans Every effort will be made to make participants as comfortable as possible during the scan including blankets for warmth and cushions to be placed under the kneesback to reduce stress from lying on ones back
Participants will be reminded prior to the scan that their participation is voluntary and they may signal to stop the scan at any time There is an intercom system in the scanner which will enable the participants to communicate with the MRI technician and member s of the research team for the entire duration that they are in the scanner Additionally they will be able to immediately stop the exam at any time either by squeezing a signal ball placed in their hand which will alert the MRI technician in the control room or by raising their legs which will be seen by the experimenter in the control room
Importantly no contrast agent will be used in our collection of MRI data Also all MRI data will be acquired in resting-state so participants will just be asked to relax and remain still for the duration of the scan
More specifically MRI data will be collected on a Siemens 30 Tesla Skyra Magnet equipped with a 32-channel head coil Total scan time will be 30 minutes The order of sequences will be as follows localizer scan 62 seconds a Structural MPRAGE 9 minutes a resting-state fMRI scan 5 minutes and a diffusion-tensor imaging DTI scan 14 minutes The localizer will be collected using the following parameters - direction inferior to superior TR 86 ms echo time TE40 ms flip angle 20 FOV250 mm 5 slices 7 mm slice thickness High-resolution structural images will be acquired using a T1-weighted spoiled gradient recalled SPGR sequence TR 22ms TE 54ms FOV 256cm flip angle 20 in-plane matrix size 256 x 256 slice thickness 1mm number of slices 172 Whole-brain resting-state fMRI data will be collected using T2-weighted echo-planar imaging EPI TR 15s TE 30ms FOV 256cm flip angle 90 in-plane matrix size 64 x 64 slice thickness 4mm resulting in functional data from 39 axial slices with isotropic voxels of 4mm3 During the resting-state fMRI scan participants will fixate on a cross-hair with eyes open DTI images will be acquired in the axial plane using a diffusion sensitized parallel EPI sequence that measures diffusion in 86 directions b-factor 1000 smm2 TR 7s TE 825ms field of view FOV 256cm matrix 128 x 128 2mm interleaved slices parallel acceleration factor 2
The resting-state fMRI data will be preprocessed using a pipeline httpwikibiacdukeedubiacanalysisresting_pipeline and tools in the Oxford Centre for Functional MRI of the Brain Software Library FSL version 505 wwwfmriboxacukfsl The preprocessing steps include slice-time correction MCFLIRT for motion correction Brain Extraction Tool BET for brain extraction and FLIRT for normalization to the MNI 152 T1 template Montreal Neurological Institute Montreal Canada The investigators will regress out signal from white matter and cerebrospinal fluid on the basis of masks created in FSL FAST and smoothed the data with a 5 mm kernel using FSL SUSAN Temporal band-pass filtering will limit the data to frequencies in the 0001 to 008 Hz band Following the recommendation of Power et al the investigators will perform motion scrubbing using a frame-wise displacement threshold of 05 and timecourse variance threshold DVARS of 05
Behavioral Measure Motor Task
The researchers will use iPads equipped with the digital computer software Cantab Cambridge Cognition Ltd England for our behavioral measures Cantab is a cloud-based computerized cognitive assessment software that is a well-validated tool for academic research The investigators intend to use 1 Motor Screening Task 2 Paired Associates Learning Test on a tablet to measure functions of motor and memory respectively
Motor Screening Task requires the participants to touch the flashing cross which is shown in different locations on the screen The outcome measures include the accuracy of pointing and reaction time
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None