Structurally Reorganizing Motor Cortex in Stroke Patients Through Hebbian-type Stimulation

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01569607

Enrollment

Registered

2012-04-03

Start date

2012-03-08

Completion date

2016-08-26

Last updated

2018-01-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Stroke

Keywords

Neurophysiology, Transcranial Magnetic Stimulation (TMS), Neurology, Stroke, Physical Medicine and Rehabilitation

Brief summary

Detailed description

Stroke is a leading cause of morbidity in the United States but identification of treatment strategies to improve outcome is limited by the incomplete understanding of the mechanisms of recovery. Motor cortex (M1) reorganization plays a major-role in the recovery of motor deficits post-stroke; hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. Non-invasive cortical stimulation can enhance the beneficial effects of motor training on performance and functional plasticity of motor cortex. Among the different approaches used in these studies, Hebbian-type M1 stimulation is particularly intriguing, as it seems to be more effective when compared to random M1 stimulation. There is emerging evidence that motor training or cortical stimulation related improvement of function are associated with increases in the grey matter of targeted brain areas. While there is therefore some evidence supporting structural reorganization in human M1 in response to motor learning and cortical stimulation, the mechanisms underlying these changes and their relationship to functional plasticity are not known. A better understanding of the sequences of events is critical to development of optimal therapeutic interventions to improve recovery following stroke. In Specific Aim 1, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances functional M1 reorganization in lesioned M1 of stroke patients. In Specific Aim 2, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances structural cortical reorganization in lesioned M1 of stroke patients and to explore whether these structural changes are related to the training induced functional cortical reorganization. The overall goal of this project is to determine the effect of Hebbian- type stimulation on both, functional and structural brain reorganization, thereby obtaining indirect evidence for the neuronal substrate underlying training related improvement and maintenance of motor function in stroke patients. This knowledge may have a substantial positive impact on treatment for stroke patients that may significantly improve recovery and could move the field of neuro-rehabilitation forward.

Interventions

DEVICERepetitive Transcranial Magnetic Stimulation (rTMS)

Training sessions for 5 days in a row

DEVICESham stimulation

Sham stimulation

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 85 Years

Healthy volunteers

Inclusion criteria

* Age 18-85 * Single cerebral ischemic infarction \> 6 month affecting the primary motor output system of the hand at a cortical (M1) level as defined by MRI of the brain * At the time of cerebral infarct a motor deficit of hand of MRC of \<4- of wrist and finger extension/flexion movement * Good recovery of hand function as defined by MRC of 4 or 4+ of wrist- and finger extension/flexion movements * Ability to perform wrist extension movements * No other neurological disorder * No intake of CNS active drugs * Ability to give informed consent * Ability to meet criteria of inclusion experiment * No major cognitive impairment * No contraindication to TMS or MRI

Design outcomes

Primary

Measure	Time frame	Description
Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Baseline, Post-Training 1 (1 Week), Post-Training 2 (4 Weeks)	Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), one week after the treatment (post-training 1), and 4 weeks after treatment (post-training 2).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.

Secondary

Measure	Time frame	Description
Mean Time to Completion for Jebsen Hand Function Test (JTT)	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	The JTT provides a standardized and objective evaluation of fine and gross motor hand function using simulated activities of daily living assessing the speed of performance. Total score is the sum of time taken for each sub-test, which were normalized to standard scores (also expressed in seconds).Total scores range from +1 to -1 where -1 indicates best function.
Mean Peak Acceleration of Wrist Extension Movements	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	Mean peak acceleration was measured at baseline, one week after the treatment (post-training 1), and four weeks after the treatment (post-training 2). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.
Mean Reaction Time of Wrist Extension Movements	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	Subjects will be asked to perform 7 auditory-cued ballistic wrist extensions before and after motor training. Electromyographic (EMG) activity recorded during the ballistic wrist extensions will be used to measure reaction time. Reaction time is the length of time between the auditory cue and the onset of the movement-related EMG burst of the extensor carpi ulnaris muscle. A longer time indicated longer time to reaction.
Mean Motor Activity Log (MAL) Score: Amount Subtest	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	Individuals are asked to rate amount of movement during 30 daily functional tasks. Items are scored on a 0 to 6-point ordinal scale as follows: 0 = The weaker arm was not used at all for that activity (never) 1 = Occasionally used weaker arm, but only very rarely (very rarely) 2= Sometimes used weaker arm, but did the activity most of the time with stronger arm (rarely) 3 = Used weaker arm about half as much as before the stroke (half pre-stroke) 4 = Used weaker arm almost as much as before the stroke (3/4 pre-stroke) 5 = The ability to use the weaker arm for that activity was as good as before the stroke (normal) Total scores range from 0 to 140; 0 indicating the least movement 140 indicating the most movement. The scores were converted into percentage scores where higher percent score indicate more movement and lower percent score less movement.
Mean Motor Activity Log (MAL): How Well Subtest	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	Individuals are asked to rate quality of movement during 30 daily functional tasks. Items are scored on a 6-point ordinal scale as follows: 0=The weaker arm was not used at all for that activity (never); 1=The weaker arm was moved during that activity, but was not helpful (very poor); 2=The weaker arm was of some use during the activity, but needed help from the stronger arm or moved very slowly or with difficulty (poor); 3=The weaker arm was used for the purpose indicated, but movements were slow or were made with only some effort (fair); 4=The movements made by the weaker arm were almost normal, but were not quite as fast or accurate as normal (almost normal); 5=The ability to use the weaker arm for that activity was as good as before the stroke (normal) Total scores range from 0 to 140; 0 indicating the least movement and 140 indicating the most movement.
Mean Wolf Motor Function Test (WMFT) Total Time	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	The Wolf Motor Function Test (WMFT) is a quantitative index of upper extremity motor ability examinable through the use of timed and functional tasks. There are 15 timed tasks included with a time cap of 120 seconds. The max amount of time to completion is 1800 seconds if all tasks are failed. The time in seconds were summed across all the tasks to obtain the total duration. Values in the table represent the time taken in seconds to successfully complete all 15 tasks).
Mean Wolf Motor Function Test Functional Ability (WMFT-FS) Scale Score	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	The WMFT is a 17 item scale that quantifies upper extremity (UE) motor ability through timed and functional tasks. The items are rated on a 6-point scale.Total scores can range from 17 to 102. Lower scores indicate debilitating mobility (such as no or limited functionality), while higher score indicate greater mobility (such as slow movement and normal movement).
Mean Wolf Motor Function Test (WMFT) Grip Strength	Baseline, Post-Training (1 Week), Post-Training (4 Weeks)	Participants attempt to grip the dynamometer with greatest grip strength possible. The test should be conducted 3 times with a 1-minute rest between trials. The mean of grip strength exerted (kg) on 3 trials is then calculated.

Countries

United States

Participant flow

Recruitment details

Participants were recruited between March 2012 and August 2016.

Pre-assignment details

Participants completed the eligibility phase prior to being randomized to a study arm. Of the 48 participants that provided consent, 22 were eligible for participation and were randomized to an intervention.

Participants by arm

Arm	Count
Hebbian-type Stimulation Participants were randomized to receive motor training with Hebbian-type stimulation. Repetitive Transcranial Magnetic Stimulation (rTMS): Training sessions for 5 days in a row	11
Sham Stimulation Participants were randomized to receive sham stimulation. Sham stimulation: Sham stimulation	11
Total	22

Baseline characteristics

Characteristic	Sham Stimulation	Total	Hebbian-type Stimulation
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5 Participants	9 Participants	4 Participants
Age, Categorical Between 18 and 65 years	6 Participants	13 Participants	7 Participants
Race and Ethnicity Not Collected	—	0 Participants	—
Region of Enrollment United States	11 Participants	22 Participants	11 Participants
Sex: Female, Male Female	5 Participants	11 Participants	6 Participants
Sex: Female, Male Male	6 Participants	11 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 11	0 / 11
serious Total, serious adverse events	0 / 11	0 / 11

Outcome results

Primary

Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve

Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), one week after the treatment (post-training 1), and 4 weeks after treatment (post-training 2).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.

Time frame: Baseline, Post-Training 1 (1 Week), Post-Training 2 (4 Weeks)

Population: Analysis was conducted for participants that completed all study procedures.

Arm	Measure	Group	Value (MEAN)	Dispersion
Hebbian-type Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Baseline	4.68 millivolts	Standard Deviation 5.65
Hebbian-type Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Post-Training Week 1	5.01 millivolts	Standard Deviation 5.96
Hebbian-type Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Post-Training Week 4	2.66 millivolts	Standard Deviation 2.55
Sham Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Post-Training Week 1	8.04 millivolts	Standard Deviation 9.28
Sham Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Baseline	9.09 millivolts	Standard Deviation 11.28
Sham Stimulation	Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve	Post-Training Week 4	7.66 millivolts	Standard Deviation 10.67

Secondary

Mean Motor Activity Log (MAL): How Well Subtest

Individuals are asked to rate quality of movement during 30 daily functional tasks. Items are scored on a 6-point ordinal scale as follows: 0=The weaker arm was not used at all for that activity (never); 1=The weaker arm was moved during that activity, but was not helpful (very poor); 2=The weaker arm was of some use during the activity, but needed help from the stronger arm or moved very slowly or with difficulty (poor); 3=The weaker arm was used for the purpose indicated, but movements were slow or were made with only some effort (fair); 4=The movements made by the weaker arm were almost normal, but were not quite as fast or accurate as normal (almost normal); 5=The ability to use the weaker arm for that activity was as good as before the stroke (normal) Total scores range from 0 to 140; 0 indicating the least movement and 140 indicating the most movement.