The goal of the present clinical trial is to explore whether an innovative technology-based approach can help individuals who have had a stroke and can no longer move their hands with ease. Our approach consists of a combination of two technologies: Transcranial Magnetic Stimulation (TMS) and a Brain-Computer Interface (BCI). The former entails the application of magnetic fields over the head to stimulate the brain preparing it for a better ability to produce movement. The latter consists of measuring brain activity to personalize a type of computer-based training that is designed to increase communication between the brain and the muscles.
Diagnosis of a subcortical stroke at least 6 months before the initiation of the trial and confirmed with magnetic resonance imaging (MRI) or computed tomography
Present moderate to severe hemiparesis in an upper limb
Language comprehension as well as visual and auditory perception sufficient to engage in Brain Computer Interface training
Age from 20 to 80 years old
Drug abuse or recent changes in medications that may alter the central nervous system when the measurements begin or during the measurements (e.g., benzodiazepines, serotoninergic and dopaminergic agents)
History of seizure
Bone, joint and muscle diseases
Peripheral neuropathy or other neurological or psychiatric diseases (including, tinnitus, migraine, or mood disorders with the exception of minimal, mild, and moderate depression, reflected as a Beck depression scale score lower than 29).
Crossover
Active rTMS
DeviceThe Transcranial Magnetic Stimulation will consist of placing a figure-of-eight shape coil of wire over the head of the participants. Then, a brief electric current will pass through the coil, inducing a magnetic field capable of stimulating neurons located beneath the coil. For the active coil, the maximal stimulation intensity is reached beneath the center of the coil. In the present study, the intermittent theta-burst protocol will be implemented. This protocol is expected to modulate the excitability of the brain, priming it for a stronger activation of the motor-related brain areas engaged during brain-computer interface-based training. The structural MRI of each participant will be used to guide neuronavigation towards ipsilesional motor areas.
Sham rTMS
DeviceTo implement a placebo stimulation, a sham coil will be used to deliver the same stimulation protocol. The sham coil is identical in dimensions and weight to the active coil but produces a diminished magnetic field. For the sham coil, the stimulation intensity is minimal beneath the center of the coil, the same area with the highest intensity during stimulation with an active coil. The structural MRI scan of each participant will be used to guide neuronavigation towards the same area where the active stimulation was applied.
Motor-evoked potential (MEP) parameters
An MEP is the electromyography response to a single TMS pulse delivered over the motor cortex, over the representation of multiple muscles. MEP changes will be evaluated with a mixed effects model. mixed-effects model. The model will consider the Patient, Period, Treatment (stimulation type) and Session number. The Period\*Treatment interaction will be verified to detect carry-over effects. The investigators expect to observe a main effect of Treatment and Session number.
Fugl-Meyer upper extremity assessment of sensorimotor function
Quantitative evaluation of motor, balance, sensation and joint functions. The sums of values recorded before and after the stimulation periods will be fed into an unpaired sample t-test to evaluate carryover effects whereas the differences observed between recordings before and after the stimulation will be fed into an unpaired sample t-test for the evaluation of initial evidence of the effect of rTMS.
Event-related desynchronization (ERD)
Electroencephalography (EEG) will be recorded during a cued motor task. This data will be used to calculate event-related de-synchronization, defined as the difference in signal power in the miu (8-12 Hz) and beta bands (13-30 Hz) between a baseline period prior to the cue and a post-cue period. Changes in ERD will be evaluated with permutation-based statistics.
Brain-Computer Interface accuracy
Ratio of correct trials over the total number of trials, as a proxy of performance during brain-computer interface based training. BCI accuracy will be evaluated with a mixed-effects model. mixed-effects model. The model will consider the Patient, Period, Treatment (stimulation type) and Session number. The Period\*Treatment interaction will be verified to detect carry-over effects. The investigators expect to observe a main effect of Treatment and Session number.
Task-related functional Magnetic Resonance Imaging (t-fMRI)
fMRI will be acquired during a motor task. The fMRI acquired during the task will be used to evaluate blood-oxygen-level-dependent (BOLD) signal changes after the active stimulation over the motor areas: premotor cortex (PMC), motor cortex (M1), supplementary motor area (SMA), cerebellum and basal ganglia; and this change will be compared with the change after placebo stimulation. In addition, the investigators will explore whether changes in BOLD signal in areas involved in BCI training can be observed after active stimulation, reflecting a potential enhancement of BCI effects. Changes in fMRI will be evaluated with a mixed-effects model in a whole-brain analysis.
Jebsen-Taylor Hand Function Test
Clinical assessment of hand function that consists of 7 tasks: staking checkers, feeding, manipulating and lifting objects, writing, and page-turning. The sums of values recorded before and after the stimulation periods will be fed into an unpaired sample t-test to evaluate carryover effects whereas the differences observed between recordings before and after the stimulation will be fed into an unpaired sample t-test for the evaluation of initial evidence of the effect of rTMS.
Diffusion-based tractography
Evaluation of fractional anisotropy (FA) as a proxy of white matter changes. Diffusion-weighted images will be used to used to calculate FA. FA reflects the deviation of random diffusion of water molecules in a voxel. Analysis of effects in diffusion will be carried out at the whole brain level and using contrast weights in a flexible factorial design with multiple groups of subjects.
Adherence
Number of missed sessions per participant
Upper extremity motor activity log (UE-MAL)
The UE-MAL is a questionnaire that inspects how much and how well the participant uses their paretic arm during activities of daily living. Participants are asked standardized questions about how often they use their more-affected arm for different activities (Amount Scale or AS) and the perceived quality of their movements when executing such tasks (How Well Scale or HW). The evaluations are done on a scale from 0 to 5. 0 represents non-use and 5 is use equal to the non- paretic hand. The scores' explanations are printed on separate sheets of paper and are placed in front of the participant during the test administration. The sums of values recorded before and after the stimulation periods will be fed into an unpaired sample t-test to evaluate carryover effects whereas the differences observed between recordings before and after the stimulation will be fed into an unpaired sample t-test for the evaluation of initial evidence of the effect of rTMS.
Withdrawal rate
The proportion of participants that drop out.
Last item of the stroke impact scale (SIS)
The last item of the SIS will be used to ask participants to rank of their expected improvement due to the intervention from 0 to 100. This assessment will be used also after stimulation to assess the perceived improvement. The sums of values recorded before and after the stimulation periods will be fed into an unpaired sample t-test to evaluate carryover effects whereas the differences observed between recordings before and after the stimulation will be fed into an unpaired sample t-test for the evaluation of initial evidence of the effect of rTMS.
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Max Planck Institute for Human Cognitive and Brain Sciences
Lead sponsor
University of Halle Medical Faculty
Collaborator
