Effect of tACS on the Recovery of Motor Control of the Upper Limb and Cerebral Connectivity in Chronic Stroke Patients

This project seeks to evaluate the effect of transcranial alternating current stimulation (tACS) on the recovery of motor control of the upper limb and associated neuronal synchrony during a 14 sessions (5 week) rehabilitation program for adult patients with diagnosis of stroke at chronic stage. Specifically, the stimulation on Gamma ranges, because the evidence available so far allows us to propose that the tACS in the Gamma range (around 70 Hz) facilitates motor execution. For this purpose, the experimental approach involves active (70 Hz in Gamma rhythm and 7 Hz, Theta rhythm) and sham tACS together with an analytical and integrated motor training with a double-blind and randomized design.

Our hypothesis is that Gamma frequency tACS restores neuronal synchrony in Beta range, which enhances the upper limb motor recovery associated with a training program.

The general objective is to assess the effects of a combined program of tACS and upper limb training on motor performance and brain connectivity in chronic-stage stroke patients.

The specifics objectives to accomplish this are (1) Implement a system for simultaneous measurement of motor activity and EEG under tACS, considering possible postural alterations in stroke patients. (2) Evaluate the upper limb motor control and neuronal synchrony associated with motor performance during the execution of a combined stimulation and training program. Training will include analytical and functional tasks to optimize the performance in function and activity ICF level. tACS will be applied only during analytical task. (3) Analyze the changes in motor performance and neuronal synchrony for the experimental groups.

Using specific motor control parameters (kinetic and kinematic control), clinical scales and electroencephalography, the immediate and long-term (3 months after finished the training) behavioral and neurophysiological effect of this new neurostimulation paradigm (tACS plus training) for motor rehabilitation of stroke will be established.

By means of analysis of variance, clustering comparisons and linear regressions, it will be established the effect of tACS on neuronal synchrony and the parallel motor activity, as well as their underlying relationship.

We will use the REDCap platform to register all the clinical data given by the medical record and clinical assessments.

The recruitment will be made at the Clinical Center of Metropolitan University of Educational Sciences and in the Primary Care Centers that are near to the University. The sample size is 45 chronic stage stroke survivors. The sample size calculation used the data available in the study for the difference in Fugl-Meyer score between the bihemispheric and sham transcranial Direct Current Stimulation groups after the intervention (in the study of Alisar et al, 2020), considering an effect size of 1.4, a p-value of 0.05 and a power (1- beta) of 0.9, which yielded a sample size of 12 subjects per group. Now, also considering an attrition percentage of 20% and an equivalence in the size of the 3 study groups, the final sample size is 15 people per group (45 people in total).

To answer the study hypothesis, two variables will be examined as primary results:

• Behavioral level, it will be the score on the Fugl-Meyer scale (upper extremity section). This scale has been widely used in the field of neurorehabilitation to assess motor impairments (ICF function level).
• Neurophysiological level, the primary outcome will be the change in spectral power in the Beta band (13-30Hz) associated with motor performance in kinetic and kinematic tasks. Signal processing will follow a cluster approach using the Fieldtrip toolbox in Matlab software (R2016B).

Both variables will be subjected to a two-factor analysis of variance (experimental group factor (3 levels, tACS-70Hz, 7Hz and simulated) and time factor (4 levels referred to the measurement times)). Depending on the result, it will apply a post-hoc test (bonferroni) to study differences between levels and interactions. The association between the variables will be inspected through regression models. The level of significance will have a p-value of 0.05. The statistical analysis will be implemented in the R language and the Rstudio software. Complementary to the primary results, and in order to broaden the description of the study phenomenon, the scores of the clinical scales already described will be analyzed, as well as kinetic (absolute force, speed of force change) and kinematic variables (direction error, maximum speed) of the analytical and combined tasks. In addition, the long-scale synchrony will be described by means of connectivity variables between the electrodes already identified (phase locking value and weighted phase lag index).

Inclusion criteria

• Diagnosis of unilateral stroke at chronic stage (6 months or more)
• Upper Extremity -Fugl Meyer > 10
• Wrist extensors strength of the paretic limb of 2 or more in the Medical Research Council (MRC) scale
• Active shoulder movement (flexion or abduction) of 30º or more
• Be able to follow the instructions necessary to achieve the training protocol

Exclusion criteria

• Have a cerebellar stroke or ataxia
• Have some medical condition contraindicated for tACS (epilepsy, pacemaker, prosthesis between others)
• Have post-stroke epilepsy
• Limited passive range of motion in the elbow (less than 45º in flexo-extension plane)
• Limited passive range of motion in the wrist (less than 40º in flexo-extension plane)
• Limited passive range of motion in the shoulder (less than 70º in flexo-extension plane)
• Have another neurological condition that leads to upper extremity sequelae
• Have a normal performance in the clinical test