The Immediate Effects of Intermittent Theta Burst Stimulation on Intracortical Excitability of the Primary Motor Cortex in Patients With Chronic Stroke

Study Overview
=================
Brief Summary
-----------------
This study is to investigate the immediate effects of intermittent theta burst stimulation (iTBS) on intracortical excitatory and inhibitory circuits, neural connectivity, and network properties in patients with chronic stroke, using transcranial magnetic stimulation and electroencephalogram (TMS-EEG) and TMS-electromyography (EMG) and approaches.

Detailed Description
-----------------
The neurophysiological effect of intermittent theta burst stimulation (iTBS) has been examined with TMS-electromyography (EMG)-based outcomes in healthy people; however, its effects in intracortical excitability and inhibition are largely unknown in patients with stroke. Concurrent transcranial magnetic stimulation and electroencephalogram (TMS-EEG) recording can be used to investigate both intracortical excitatory and inhibitory circuits of the primary motor cortex (M1) and the property of brain networks. This study is to investigate the immediate effects of iTBS on intracortical excitatory and inhibitory circuits, neural connectivity, and network properties in patients with chronic stroke, using TMS-EEG and TMS-EMG approaches. In this randomized, sham-controlled, crossover study, 21 patients with chronic stroke receive two separate stimulation conditions: a single-session iTBS or sham stimulation applied to the ipsilesional M1, in two separate visits, with a washout period of five to seven days between the two visits after crossover. A battery of TMS-EMG and TMS-EEG measurements are taken before and immediately after stimulation during the visit.

Official Title
-----------------
The Immediate Effects of Intermittent Theta Burst Stimulation on Intracortical Excitability of the Primary Motor Cortex in Patients With Chronic Stroke: A Concurrent TMS-EEG Sham-controlled Crossover Study

Conditions
-----------------
Stroke

Intervention / Treatment
-----------------
* Device: Intermittent theta burst stimulation (iTBS)
* Device: Sham intermittent theta burst stimulation (iTBS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: suffered from first-ever, ischemic or hemorrhagic, unilateral stroke, verified by neuroimaging examinations such as CT or MRI. detectable motor evoked potentials from the affected first dorsal interosseous muscle; provided written informed consent. Exclusion Criteria: had any contraindication to transcranial magnetic stimulation; had a known neurological disease excluding stroke, or psychiatric disease; were using a psychostimulant, sedative, antidepressant, or antiepileptic medication.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A single-session intermittent theta burst stimulation (iTBS)<br>The classical 600-pulse iTBS protocol is delivered to the motor hotspot over the ipsilesional hemisphere. | Device: Intermittent theta burst stimulation (iTBS)<br>* A single-session standard 600-pulse intermittent theta burst stimulation (iTBS) is applied to the ipsilesional primary motor cortex.<br>|
| Sham Comparator: A single-session sham intermittent theta burst stimulation (iTBS)<br>The sham stimulation is the same as that of iTBS, but the coil is placed five centimeters away from the scalp. | Device: Sham intermittent theta burst stimulation (iTBS)<br>* The sham stimulation is the same as that of iTBS, but the coil is placed five centimeters away from the scalp. Electrical field simulation shows that the setups for sham stimulation would not induce any valid cortical activation.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transcranial magnetic stimulation-evoked potential | Single pulses evoked an initial response in electroencephalogram, followed by a series of time- and phase-locked positive and negative deflections which could spread to the connected brain areas. The evoked potential is called transcranial magnetic stimulation-evoked potential. | Baseline (before iTBS stimulation) | 
| Transcranial magnetic stimulation-evoked potential | Single pulses evoked an initial response in electroencephalogram, followed by a series of time- and phase-locked positive and negative deflections which could spread to the connected brain areas. The evoked potential is called transcranial magnetic stimulation-evoked potential. | 10 minutes after a single-session iTBS stimulation | 
| Motor evoked potential (MEP) | Single TMS pulses with suprathreshold intensity (120% of resting motor threshold of the stimulated cortex) applied to the primary motor cortex (M1) can produce recordable MEPs in contralateral muscles; additionally, the peak-to-peak amplitude of MEPs can be used to represent the corticospinal excitability | Baseline (before iTBS stimulation) | 
| Motor evoked potential (MEP) | Single TMS pulses with suprathreshold intensity (120% of resting motor threshold of the stimulated cortex) applied to the primary motor cortex (M1) can produce recordable MEPs in contralateral muscles; additionally, the peak-to-peak amplitude of MEPs can be used to represent the corticospinal excitability | 10 minutes after a single-session iTBS stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortical silent period | The cortical silent period (cSP) is a protocol measuring the intracortical inhibition, in which suprathreshold test pulses (120% of resting motor threshold of the stimulated cortex) are applied to the contralateral M1, while participants sustain 30% maximum voluntary contraction. Specifically, cSP refers to the interruption of background electromyographic (EMG) activity after the TMS pulse. | Baseline (before iTBS stimulation) | 
| Cortical silent period | The cortical silent period (cSP) is a protocol measuring the intracortical inhibition, in which suprathreshold test pulses (120% of resting motor threshold of the stimulated cortex) are applied to the contralateral M1, while participants sustain 30% maximum voluntary contraction. Specifically, cSP refers to the interruption of background electromyographic (EMG) activity after the TMS pulse. | 10 minutes after a single-session iTBS stimulation | 
| Short-interval intracortical inhibition | Short-interval intracortical inhibition (SICI) is a form of paired-pulse protocol, in which a subthreshold conditioning pulse is delivered 2 ms before a suprathreshold test pulse. Theoretically, the amplitude of motor-evoked potentials (MEPs) evoked by a test pulse at a given intensity is suppressed compared with that evoked by a single pulse at the same intensity. Eight trials are recorded, with inter-trial intervals ranging from 4 s to 5 s. The intensity of test pulses is fixed at 120% of the resting motor threshold, and the intensity of the conditioning pulse is set at 80% of the resting motor threshold. The result of SICI is expressed as the ratio of a paired-pulse MEP amplitude to a single-pulse MEP amplitude. | Baseline (before iTBS stimulation) | 
| Short-interval intracortical inhibition | Short-interval intracortical inhibition (SICI) is a form of paired-pulse protocol, in which a subthreshold conditioning pulse is delivered 2 ms before a suprathreshold test pulse. Theoretically, the amplitude of motor-evoked potentials (MEPs) evoked by a test pulse at a given intensity is suppressed compared with that evoked by a single pulse at the same intensity. Eight trials are recorded, with inter-trial intervals ranging from 4 s to 5 s. The intensity of test pulses is fixed at 120% of the resting motor threshold, and the intensity of the conditioning pulse is set at 80% of the resting motor threshold. The result of SICI is expressed as the ratio of a paired-pulse MEP amplitude to a single-pulse MEP amplitude. | 10 minutes after a single-session iTBS stimulation | 
| Intracortical facilitation | The setups for the intensity of intracortical facilitation (ICF) are almost the same as those for SICI; however, the interstimulus interval is longer, 10 ms. Eight trials are recorded, with inter-trial intervals ranging from 4 s to 5 s. The intensity of test pulses is fixed at 120% of the resting motor threshold, and the intensity of the conditioning pulse is set at 80% of the resting motor threshold. The result of ICF is expressed as the ratio of a paired-pulse MEP amplitude to a single-pulse MEP amplitude. | Baseline (before iTBS stimulation) | 
| Intracortical facilitation | The setups for the intensity of intracortical facilitation (ICF) are almost the same as those for SICI; however, the interstimulus interval is longer, 10 ms. Eight trials are recorded, with inter-trial intervals ranging from 4 s to 5 s. The intensity of test pulses is fixed at 120% of the resting motor threshold, and the intensity of the conditioning pulse is set at 80% of the resting motor threshold. The result of ICF is expressed as the ratio of a paired-pulse MEP amplitude to a single-pulse MEP amplitude. | 10 minutes after a single-session iTBS stimulation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stroke, theta burst stimulation, transcranial magnetic stimulation-evoked potentials, intracortical inhibition, cortical excitability