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Physiology of Interregional Connectivity in the Human Brain

Primary Purpose

Healthy, Stroke, Traumatic Brain Injury

Status
Unknown status
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Single-pulse transcranial magnetic stimulation (spTMS)
Paired associative stimulation (PAS)
Repetitive transcranial magnetic stimulation (rTMS)
Sponsored by
Shirley Ryan AbilityLab
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Healthy focused on measuring Human, Brain, Connectivity, Stroke, Traumatic brain injury, Multiple sclerosis, Transcranial magnetic stimulation, Paired associative stimulation, Electroencephalography, Magnetic resonance imaging

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Inclusion Criteria for Healthy Participants:

  • Age from 18 to 85 years
  • Right-handed
  • Normal hearing and (corrected) vision
  • Able to understand and give informed consent
  • English speaker

Inclusion Criteria for Patients:

  • Age from 18 to 85 years
  • Stroke (ischemic subcortical, intermediate level, chronic phase 3 weeks or more from lesion)
  • TBI (closed-skull, intermediate level, chronic phase 3 weeks or more from lesion)
  • MS (white matter subcortical lesion)
  • Clinical and radiological evidence supporting the above diagnoses
  • One or more behavioral symptoms possibly linked to the white matter lesion(s)
  • Stable medical condition
  • English speaker

Exclusion Criteria:

Exclusion Criteria for Healthy Participants:

  • Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps
  • Metal in the body (rods, plates, screws, shrapnel, dentures, IUD) or metallic particles in the eye
  • Surgical clips in the head or previous neurosurgery
  • Any magnetic particles in the body
  • Cochlear implants
  • Prosthetic heart valves
  • Epilepsy or any other type of seizure history
  • Any neurological diagnoses or medications influencing brain function
  • History of significant head trauma (i.e., extended loss of consciousness, neurological sequelae)
  • Known structural brain lesion
  • Significant other disease (heart disease, malignant tumors, mental disorders)
  • Significant claustrophobia; Ménière's disease
  • Pregnancy (ruled out by urine ß-HCG if answers to screening questions suggest that pregnancy is possible), breast feeding
  • Non prescribed drug use
  • Failure to perform the behavioral tasks or neuropsychological evaluation tests
  • Prisoners

Exclusion Criteria for Patients:

  • Same as above, excluding the requirement of no structural brain lesion, and medications influencing brain function are allowed
  • Patients with cortical lesions or CSF-filled cysts/cavities near the TMS sites
  • MS patients with acute exacerbation

Sites / Locations

  • Shirley Ryan AbilityLabRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Healthy Participants

Patients

Arm Description

Healthy participants without disorders or medications influencing brain function will be scanned with MRI and undergo single-pulse TMS and PAS during several visits, each with a different asynchrony, while EEG and MEPs are recorded.

Participants with stroke, traumatic brain injury (TBI), or multiple sclerosis (MS) will be scanned with MRI and undergo single-pulse TMS and paired associative stimulation during several visits while EEG is recorded.

Outcomes

Primary Outcome Measures

Changes in EEG effective connectivity
EEG will be recorded with a 64-channel whole-head TMS-compatible device (NeurOne, Bittium, Kuopio, Finland). Data will be collected before (Pre-PAS) and at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS. To record spTMS-evoked EEG responses the investigators will deliver 80 single TMS pulses to the two areas receiving PAS, one target after the other in separate runs. Effective connectivity will be measured by comparing the source-resolved EEG evoked response waveforms before (Pre-PAS) and at 1 (Post-PAS T1) and at 60 minutes after PAS (Post-PAS T60).
Changes in resting-state EEG coherence
Resting-state EEG will be recorded with a 64-channel whole-head device (NeurOne, Bittium, Kuopio, Finland). Data will be collected before (Pre-PAS) and at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS. Resting-state EEG coherence will be computed in the source space for the two areas receiving PAS from 1 to 100 Hz.

Secondary Outcome Measures

Motor evoked potentials (MEPs)
To assess the effects of PAS in participants where the primary motor cortex (M1) was targeted, spTMS will be administered to the M1 at 110% of resting motor threshold (rMT) while MEPs are recorded from the contralateral hand (NeurOne, Bittium, Kuopio, Finland). The MEPs will be recorded before (Pre-PAS), at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS.
MRI functional connectivity
Functional connectivity will be assessed with resting-state MRI (rs-MRI).
MRI structural connectivity
Structural connectivity will be assessed with diffusion tensor imaging (DTI).

Full Information

First Posted
October 22, 2018
Last Updated
October 26, 2018
Sponsor
Shirley Ryan AbilityLab
Collaborators
Northwestern University
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1. Study Identification

Unique Protocol Identification Number
NCT03723434
Brief Title
Physiology of Interregional Connectivity in the Human Brain
Official Title
Physiology of Interregional Connectivity in the Human Brain
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Unknown status
Study Start Date
May 31, 2017 (Actual)
Primary Completion Date
November 2020 (Anticipated)
Study Completion Date
November 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Shirley Ryan AbilityLab
Collaborators
Northwestern University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to understand the physiology of connectivity between cortical regions in the human brain in healthy participants and in patients with white matter lesions. Specifically, the investigators will examine the effects of paired associative stimulation (PAS) which consists in delivering brief (< 1 ms) current pulses separated by a short millisecond-level time interval ("asynchrony") to two cortical areas. The used techniques are all non-invasive and considered safe in humans: transcranial magnetic stimulation (TMS), electroencephalography (EEG), magnetic resonance imaging (MRI), and functional MRI (fMRI). Based on prior literature in animals and human studies, it is hypothesized that PAS may increase or decrease effective connectivity between the stimulated areas depending on the asynchrony value. The main outcome measure is source-resolved EEG responses evoked by single-pulse TMS; this is a more direct measure of neuronal changes occurring at the targeted cortical area than motor evoked potentials (MEPs) or sensor-level EEG responses used in previous studies.
Detailed Description
This study consists of two experiments. In Experiment A, healthy participants without disorders or medications influencing brain function (N=24) will be recruited. A range of negative and positive asynchronies (from minus 50 to + 50 ms) will be tested. To allow comparison with prior studies that used MEPs as outcome measures, in 12 participants the primary motor cortex in the left and right hemisphere will be targeted. In another 12 participants, two cortical areas within the same hemisphere will be stimulated. In Experiment B, participants with stroke, traumatic brain injury (TBI), or multiple sclerosis (MS) (total maximum N across all such participants is 52) will be recruited. These participants are required to have one or more subcortical white matter lesions, which would be expected to result in cortico-cortical disconnections. Here, the investigators will only test PAS with positive asynchronies, with the goal of testing if the findings observed in healthy participants are similar in participants with white matter lesions. It will also be examined if the PAS-induced connectivity changes persist beyond the stimulation sessions if PAS is given repeatedly over several days. PAS will be applied to two cortical targets that have been disconnected from each other. The rationale for including more than one disorder in Experiment B is that the disconnections are in all cases caused by white matter lesions and the results may therefore be similar. To detect possible differences between disorders, the data from the three groups will also be analyzed separately.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Healthy, Stroke, Traumatic Brain Injury, Multiple Sclerosis
Keywords
Human, Brain, Connectivity, Stroke, Traumatic brain injury, Multiple sclerosis, Transcranial magnetic stimulation, Paired associative stimulation, Electroencephalography, Magnetic resonance imaging

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
PAS will be applied to two cortical targets at different asynchronies to modulate connectivity. PAS may selectively increase or decrease effective connectivity depending on the asynchrony. Negative asynchronies are expected to decrease effective connectivity, whereas positive asynchronies to increase it.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
76 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Healthy Participants
Arm Type
Active Comparator
Arm Description
Healthy participants without disorders or medications influencing brain function will be scanned with MRI and undergo single-pulse TMS and PAS during several visits, each with a different asynchrony, while EEG and MEPs are recorded.
Arm Title
Patients
Arm Type
Experimental
Arm Description
Participants with stroke, traumatic brain injury (TBI), or multiple sclerosis (MS) will be scanned with MRI and undergo single-pulse TMS and paired associative stimulation during several visits while EEG is recorded.
Intervention Type
Device
Intervention Name(s)
Single-pulse transcranial magnetic stimulation (spTMS)
Intervention Description
Single-pulse TMS (spTMS) will be delivered with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. 80 spTMS will be repeated at 0.2 Hz. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, St Augustin, Germany).
Intervention Type
Device
Intervention Name(s)
Paired associative stimulation (PAS)
Intervention Description
Paired associative stimulation (PAS) will be applied with two TMS stimulators (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and two TMS coils. The pulses from each stimulator/coil will be repeated at 0.2 Hz, duration of run 15 minutes (180 pulses for each stimulator/coil). In different sessions, we will deliver PAS with different asynchrony values to examine their effects on effective connectivity. Coils will be navigated using an MRI-based TMS navigation system (Localite, St Augustin, Germany).
Intervention Type
Device
Intervention Name(s)
Repetitive transcranial magnetic stimulation (rTMS)
Intervention Description
Repetitive TMS (rTMS) will be applied at 1 and 20 Hz with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. 300 rTMS pulses will be delivered during 1 and 20 Hz stimulation. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, St Augustin, Germany).
Primary Outcome Measure Information:
Title
Changes in EEG effective connectivity
Description
EEG will be recorded with a 64-channel whole-head TMS-compatible device (NeurOne, Bittium, Kuopio, Finland). Data will be collected before (Pre-PAS) and at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS. To record spTMS-evoked EEG responses the investigators will deliver 80 single TMS pulses to the two areas receiving PAS, one target after the other in separate runs. Effective connectivity will be measured by comparing the source-resolved EEG evoked response waveforms before (Pre-PAS) and at 1 (Post-PAS T1) and at 60 minutes after PAS (Post-PAS T60).
Time Frame
Experiment A: Within-session (before versus after PAS at 1 and 60 minutes). Experiment B: Within-session (before versus after PAS at 1 and 60 minutes). Across-sessions (persistence of changes up to 1 month after last PAS session).
Title
Changes in resting-state EEG coherence
Description
Resting-state EEG will be recorded with a 64-channel whole-head device (NeurOne, Bittium, Kuopio, Finland). Data will be collected before (Pre-PAS) and at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS. Resting-state EEG coherence will be computed in the source space for the two areas receiving PAS from 1 to 100 Hz.
Time Frame
Experiment A: Within-session (before versus after PAS at 1 and 60 minutes). Experiment B: Within-session (before versus after PAS at 1 and 60 minutes). Across-sessions (persistence of changes up to 1 month after last PAS session).
Secondary Outcome Measure Information:
Title
Motor evoked potentials (MEPs)
Description
To assess the effects of PAS in participants where the primary motor cortex (M1) was targeted, spTMS will be administered to the M1 at 110% of resting motor threshold (rMT) while MEPs are recorded from the contralateral hand (NeurOne, Bittium, Kuopio, Finland). The MEPs will be recorded before (Pre-PAS), at 1 minute (Post-PAS T1) and at 60 minutes (Post-PAS T60) after PAS.
Time Frame
Experiment A: Within-session (before versus after PAS at 1 and 60 minutes). Experiment B: Done only in patients where the M1 was targeted with PAS.
Title
MRI functional connectivity
Description
Functional connectivity will be assessed with resting-state MRI (rs-MRI).
Time Frame
Experiment A: Baseline. Experiment B: Baseline to 1 month after the last PAS session.
Title
MRI structural connectivity
Description
Structural connectivity will be assessed with diffusion tensor imaging (DTI).
Time Frame
Experiment A: Baseline. Experiment B: Baseline to 1 month after the last PAS session.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Inclusion Criteria for Healthy Participants: Age from 18 to 85 years Right-handed Normal hearing and (corrected) vision Able to understand and give informed consent English speaker Inclusion Criteria for Patients: Age from 18 to 85 years Stroke (ischemic subcortical, intermediate level, chronic phase 3 weeks or more from lesion) TBI (closed-skull, intermediate level, chronic phase 3 weeks or more from lesion) MS (white matter subcortical lesion) Clinical and radiological evidence supporting the above diagnoses One or more behavioral symptoms possibly linked to the white matter lesion(s) Stable medical condition English speaker Exclusion Criteria: Exclusion Criteria for Healthy Participants: Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps Metal in the body (rods, plates, screws, shrapnel, dentures, IUD) or metallic particles in the eye Surgical clips in the head or previous neurosurgery Any magnetic particles in the body Cochlear implants Prosthetic heart valves Epilepsy or any other type of seizure history Any neurological diagnoses or medications influencing brain function History of significant head trauma (i.e., extended loss of consciousness, neurological sequelae) Known structural brain lesion Significant other disease (heart disease, malignant tumors, mental disorders) Significant claustrophobia; Ménière's disease Pregnancy (ruled out by urine ß-HCG if answers to screening questions suggest that pregnancy is possible), breast feeding Non prescribed drug use Failure to perform the behavioral tasks or neuropsychological evaluation tests Prisoners Exclusion Criteria for Patients: Same as above, excluding the requirement of no structural brain lesion, and medications influencing brain function are allowed Patients with cortical lesions or CSF-filled cysts/cavities near the TMS sites MS patients with acute exacerbation
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tommi Raij, MD, PhD
Phone
312-238-4401
Email
tommi.raij@northwestern.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Julio C Hernandez Pavon, PhD, DSc
Phone
312-238-6820
Email
julio.hpavon@northwestern.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tommi Raij, MD, PhD
Organizational Affiliation
Shirley Ryan AbilityLab 355 East Erie St, Chicago, IL Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shirley Ryan AbilityLab
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tommi Raij, MD, PhD
Phone
312-238-4401
Email
tommi.raij@northwestern.edu

12. IPD Sharing Statement

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Physiology of Interregional Connectivity in the Human Brain

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