Investigating the Use of a Brain-computer Interface Based on TMS Neurofeedback for Upper Limb Stroke Rehabilitation
Phase: PHASE1
Conditions: Transcranial Magnetic Stimulation, Stroke, Stroke Rehabilitation, Upper Extremity Paresis
Sponsor: University of Dublin, Trinity College

 
 
 
 
 
 
Protocol for TMS-Neurofeedback Stroke Experiment 
NCT Number (not yet assigned) 
Date: 18/10/23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
1. Overview 
 
Upper limb weakness following a stroke affects most survivors and is a key factor in 
preventing them from returning to independent activities of daily living. Most of the current 
state-of-the art approaches to rehabilitation require that the patient can generate some 
activity in the paretic limb, which is not possible for many patients in the early period 
following stroke, nor for some patients even in the chronic period. This delays and prevents 
their participation in physical therapies. Approaches that enable more patients to engage 
with movement therapies at an earlier timepoint during the ‘sensitive period’ following 
stroke are greatly needed. 
 
Despite having no functional movement in the paretic limb, most stroke patients 
exhibit Motor Evoked Potentials (MEPs) when stimulated over the damaged motor areas of 
the brain using Transcranial Magnetic Stimulation (TMS). This indicates intact pathways from 
the brain to the muscles and has been shown to predict better subsequent functional 
recovery (Stinear et al, 2012; Byblow et al. 2015). In the early days following stroke, the 
excitability of neuronal pathways from the brain to the muscles is substantially reduced. This 
most likely reflects the demyelination of axons, leading to conduction failure. Within the first 
12 weeks, a degree of spontaneous proportional recovery of motor function typically occurs, 
up to 70% of the individual’s maximum possible improvement. Interestingly, this time course 
of recovery coincides with the resolution of corticomotor excitability (MEP amplitudes), which 
also resolves to 70% of normal levels within the same 12 week period (Byblow et al. 2015; 
Cicinelli et al., 2003; Thickbroom, Byrnes, Archer, & Mastaglia, 2004). The interconnectedness 
of the functional recovery process and resolution of corticomotor excitability provides some 
insight into the neurobiology of spontaneous motor recovery and raises the intriguing 
possibility that perhaps interventions directly targeting the neural mechanisms of 
corticomotor excitability in this sensitive period would causally impact upon and accelerate 
recovery.  
In the absence of being able to generate movement in the paretic limb, motor imagery has 
been suggested to activate many of the same brain-muscle circuits as actual movement. 
However, as imagery is a hidden mental process, it is impossible for individuals to gauge 
what impact this is having upon their neural activity, to learn how to best exploit this 
mechanism to augment stroke recovery.  
 

This research project is an investigation into the mechanisms and efficacy of using a novel 
brain-computer interface (BCI) (eg. Ruddy et al., 2018) based upon muscle responses to TMS 
to provide feedback (visual and auditory) to stroke survivors while they perform motor 
imagery.  
Using this approach, magnetic pulses will be applied to the scalp over the location on the 
motor cortex that controls the arm and hand, via TMS. This evokes a twitch in the stroke-
affected muscles (the MEP), which is recorded using electromyography (EMG). The size of 
MEPs are displayed to the patient in real-time, with rewarding visual and auditory feedback 
incorporated in a game-like display. The patient is instructed to learn how to make MEPs 
bigger using motor imagery, guided by the feedback from the brain-computer interface.   
 
We hypothesise that training using TMS-neurofeedback will lead to increases in MEP 
amplitudes, compared to a control group receiving pseudofeedback. We will investigate 
whether these changes in MEP amplitudes correlate with enhanced or faster than usual 
functional improvement and explore the underlying structural and neurochemical brain 
mechanisms of recovery. 
 
2. Patient characteristics and exclusion criteria 
20 patients (10 in TMS NF group, 10 in Pseudo-feedback group). Sub-acute: 2-26 weeks post 
stroke. Would prefer 2-12 weeks if feasible as there is a critical period in first 12 wks. First 
stroke (no previous TIAs). Single Hemisphere lesion. Low/No residual movement in lower 
arm and hand. MEP positive (in response to TMS). No or negligible OCS broken hearts 
cancellation test score (visual neglect) 6. No or almost no cognitive impairment (Pass or 
near pass MMSE and MOCA) 7. Passes TMS-Safety Questionnaire (no contraindications to 
TMS) 
 
3. Recruitment Procedure 
Patients informed about the study directly via consultant Prof. Harbison and his team and 
provided with information sheets detailing how to contact the researchers if interested.  
 
4. Procedures with Patients 
 
4.1 Informed Consent and Providing Information 
The patient should be asked to read through the information sheet prior to coming to the 
first day of the experiment. However, when they arrive for the first session, provide them 
again with the information sheets and go through them page by page reading and 
explaining everything to them, answering any questions.  When the patient has understood 
everything, read through the consent form with them, answering any questions, and if they 
consent to participate ask them to sign their name.  If they are unable to sign the consent 
form, their next of kin can provide consent by proxy. At this stage they will be assigned an 

anonymous code which will be used to identify their data and assigned to Group A or Group 
B using a computer algorithm.  
 
 
 
4.2 Familiarisation Session 
This can be conducted on the same day as the signing of the informed consent forms. The 
patient should be given the opportunity to experience the feeling of TMS prior to 
commencing with the experimental sessions. The participant will have a fabric cap placed on 
their head, with a grid drawn on it, indicating the midpoint (vertex) of the head and 
locations relative to it. The TMS coil will be positioned on the head over the motor cortex on 
the healthy hemisphere (5cm lateral and 1cm anterior from the vertex), and a weak 
magnetic pulse applied. The patient will be asked whether they can feel anything. The 
intensity of the pulses will then be turned up gradually, asking the participant with each 
increment if the pulse still feels comfortable. When the stimulation intensity is sufficient to 
evoke a response (MEP) in the index finger muscle of at least 50uV, 5 such pulses will be 
applied with intervals between 6-8 seconds, to establish the average MEP amplitude at this 
scalp location. The coil position will then be moved left and right, forwards, and backwards 
at 1cm increments relative to the starting position, until the position with the largest and 
most reliable MEPs is located (the motor ‘hotspot’). On the hotspot, the experimenter will 
next establish the patients resting motor threshold (RMT). That is, the lowest stimulation 
intensity that produces MEPs greater than 50uV on 5/10 trials.  
When the hotspot and RMT have been established on the healthy hemisphere, this 
procedure will be repeated on the stroke affected hemisphere, guided by the knowledge of 
motor cortex positioning on the healthy hemisphere. The RMT is typically much higher on 
the stroke affected hemisphere, so a higher intensity of stimulation will be required to 
evoke responses. The RMT for both hemispheres will be noted for future reference, and the 
position of the hotspot on both hemispheres will be noted on the fabric cap. This is to assist 
positioning of the TMS coil for all subsequent sessions and negate the need for extensive 
mapping of the scalp on each new day of testing.  
The patient will then be familiarised with the mental imagery requirements of the protocol. 
They will then be asked to imagine the feeling of performing movements with the stroke 
affected limb and told that this type of imagery will be required to influence the amplitude 
of their MEPs during the training sessions.  
 
At this stage, if the patient has no MEPs in response to TMS, unfortunately they will not be 
able to participate further in the study (or, if willing, try again in a week to see have MEPs 
recovered). 
 
4.3 Baseline Functional and Cognitive Assessments 
 

Prior to commencing the first TMS NF training session, the patient will have their upper limb 
function assessed by a member of the team (not the same member who will perform the 
TMS, for blinding reasons). They will perform the Fugl-Meyer task assessing the quality of a 
range of upper limb movements, and the Action Research Test (keeping a long break 
between these two tests to avoid fatigue or coming back on a separate day to perform one 
of the two functional tests). They will complete standard questionnaires assessing cognitive 
function and mood/depression (the Oxford Cognitive Screen, and the Hospital Affective 
Disorders Scale). They will also complete the National Institute of Health Stroke severity 
scale (NIHSS), Motor imagery ability questionnaire, a sleep questionnaire and measure 
muscle circumference in forearm and bicep of both arms. 
 
If all tests above conducted together, estimated time is approx. 1 hour 30 minutes, so allow 
2 hours for this session with comfort break for patient.  
 
4.4 MRI scanning 
 
Following the familiarisation session and baseline functional and cognitive assessments, the 
patients will be invited to undergo a series of MRI brain scans in the Centre for Advanced 
Medical Imaging (CAMI), on the site of St. James Hospital. Total scanning time will be 1 hour 
per participant, which will comprise of the following types of scans: 
 
1. High resolution T1 anatomical scan (grey matter) 
2.Diffusion weighted imaging (DWI) scan (white matter) 
 
4.5 TMS NF training sessions 1-4 
 
4.5.1 Training sessions overview  
 
The TMS sessions should be spaced at maximum of 72 hours apart, ideally session 1-4 
should occur all within the same 7-day period.  
When the patient arrives for each training session, they will sit in a comfortable chair or bed 
with arms supported on foam pillows and have their muscles prepared with exfoliant skin 
preparation paste and an alcohol wipe. Electrodes will be placed over the target muscles 
(hand and arm muscles).  
The research team will place the TMS coil over the hotspot that was located during the 
familiarisation session. On this location (separately for healthy and stroke affected 
hemisphere), we will measure the patients RMT.  
 
 
 
 

4.5.2 TMS neurofeedback block  
 
The patient will be positioned in front of a computer monitor and will receive a block of 20 
neurofeedback trials. Each trial contains just one TMS pulse, so in total they will receive 20 
TMS pulses (at an intensity that is 120% of the RMT) with an interval of 6-8 seconds 
between pulses. Each TMS pulse will be followed immediately by feedback on screen in the 
form of a vertical bar. The height of the bar indicates the amplitude of the MEP recorded in 
the muscle, and this is shown relative to a horizontal white line that indicates their baseline 
MEP amplitude. If the current MEP on a given trial is larger than baseline, the trial is 
deemed ‘successful’. The vertical bar will be green, with a green tick on screen beside it, and 
a positive sound-byte will be played. If the MEP amplitude is below baseline, the trial is 
unsuccessful; The bar will be red, with a red cross, and a negative sound-byte will be played. 
Patients will be told that their goal is to accrue as many successful trials as possible, and that 
the height of the bar can be influenced by imagining movements using the stroke affected 
limb (specifically, the stroke affected finger muscles).  
 
This block of neurofeedback takes approximately 6 minutes, and is repeated three times 
during the course of the training session, with rest breaks for the patient between blocks. 
 
At the end of the training session, we will record MEPs from 20 TMS pulses while the patient 
is at rest, viewing a fixation cross (for pre-post measurement of resting corticospinal 
excitability).   
 
 
4.5.4 Pseudofeedback group 
 
The control (pseudofeedback) group (n=10) will undergo identical procedures to the 
experimental group, but with the on-screen feedback bar height in the game changed such 
that it does not represent MEP amplitude, but instead shows a bar of fixed height, with a 
predictable reward schedule. This prevents learning how to control the bar in the game, and 
thus allows us to investigate whether patients using the feedback to learn to up-regulate 
excitability demonstrate better functional upper limb outcomes compared to those who did 
not. The application of TMS is identical for both groups- the only thing altered is their visual 
feedback. 
 
4.6 Follow up/Top-up sessions 
Following the initial 4-day training period, patients will return for follow-up training sessions 
2 weeks, 6 weeks, 12 and 26 weeks later. RMT will be recorded at each follow-up session to 
monitor changes in corticospinal excitability. Three blocks of TMS NF will be completed, and 
a sub-set of the functional and cognitive measures will be collected (see case report form 
for list of tests to be conducted on each follow up.  

 
4.7 Post-Training Functional/Cognitive/MRI assessments 
At the end of the final follow-up session 6 months following initial training, patients will 
have the same full assessments of upper limb function and cognition performed, as were 
completed prior to the first session. The same set of MRI scans will also be repeated in 
CAMI.  
 
5.0 Completion of study with participant 
 
Upon completion of the final session of the experiment, the patient should be provided with 
the debriefing leaflet, which will be discussed with them. They will be informed that from 
now on, their name and contact details will be deleted from our database and the data we 
have recorded from them will be anonymised. At this point, the experimenter should ensure 
that the patients identifiable information is deleted from the spreadsheet linking their 
anonymous code to their name and contact details.