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Implementation and Preliminary Validation of a Novel Noninvasive Neuromodulation Technique to Restore Hand Movement and Promote Recovery after Stroke

Periodic Reporting for period 1 - CortIMod (Implementation and Preliminary Validation of a Novel Noninvasive Neuromodulation Technique to Restore Hand Movement and Promote Recovery after Stroke)

Reporting period: 2016-11-01 to 2018-10-31

Most stroke patients show incomplete motor recovery despite intensive rehabilitation. There is a need for novel and improved rehabilitation interventions. Noninvasive brain stimulation provides the possibility to harness neuroplasticity for motor rehabilitation. However, results so far with these techniques are variable, modest and not well-understood.

Understanding and influencing the neural processes that allow humans to start and control movements and to learn new motor abilities is of great relevance to improve the recovery of patients who have suffered a brain lesion. This project has been aimed to propose new strategies to stimulate with higher efficacy the areas of the brain involved in the generation of voluntary actions. CortIMod merges innovative electrophysiological techniques with advanced brain signal processing methods to address two main questions: i) can brain stimulation specificity be improved using advanced models of motor cortical activation patterns and by exploiting the learning mechanisms of the brain? and ii) can a more selective brain stimulation lead to a finer control of the induced functional changes in plasticity studies?

Under the framework of this project we have carried out a set of experiments involving over 200 sessions with healthy subjects and patients. First, experiments have allowed us to obtain results showing how brain stimulation protocols can increase specificity of the induced changes in the brain by using directional brain stimulation and by targeting narrow windows of time immediately preceding voluntary movements. Experiments have also been conducted to understand the features of the brain states during movement preparation. Our findings in this regard are relevant for the brain stimulation community because they provide new evidences about the brain processes involved in movement preparation. These results will have a significant impact in future experiments conducted by researchers aiming to understand certain movement disorders (like bradykinesia or tics). Finally, over the second year of the grant we have been able to demonstrate that muscle signals provide highly reliable information about ongoing rhythmic activities in the brain. This finding implies that it is possible to design future closed-loop platforms that can target highly specific brain states by using muscle signals recorded with surface electrodes on the skin.
During the whole duration of this project we have worked on three research lines.

First, we have studied, in over 50 healthy subjects, how the brain changes in preparation for movements by applying transcranial magnetic stimuli at different times relative to the future movements to be performed. This research shows that brain responses to external stimuli during movement preparation are suppressed. It also suggests that this change in brain responses is present in all types of planned movements regardless of what triggers them. We think that this indicates that brain responses to external stimuli may reflect the dynamics of the neural populations that are evolving towards generating the desired movements at the desired time. This interpretation contradicts previous views, which proposed that the brain responses to stimuli reflected proactive inhibitory mechanisms of the motor cortex. Additionally, by carrying out this research we have found a very interesting link between self-initiated and cue-driven movements: they seem to share similar triggering mechanisms, which also means that self-initiated movements depend on triggers that can be external or internal. Overall, this research has been presented in 3 international conferences and it is expected to result in 2 articles in high impact journals. Results of this research are also expected to have impact on researchers trying to identify the neurophysiological mechanisms that lead to certain types of movements disorders (like bradykinesia in Parkinson’s Disease or tics in Tourette’s syndrome).

Second, in over 100 experiments with healthy participants, we have studied new protocols that allow us to induce brain plastic changes by delivering electrical nerve stimuli or magnetic brain stimuli that interact with the brain neural activity. The main characteristic of this research line is that we have worked on the concept of brain state-dependent brain stimulation to propose new alternatives to boost the selectivity and specificity of the neuroplastic changes induced with the stimulation protocols. Brain state-dependent brain stimulation and our work developed in this line during this project are meant to allow us in the future to achieve new brain stimulation strategies that can be used to boost the specificity and functional relevance of the plastic changes induced in the brain. The impact of this research is associated with the fact that the obtained new knowledge is expected to allow us to propose more effective neuromodulation treatments for neurorehabilitation. This research has been presented in 2 international conferences and we plan to publish the main findings in 2 articles submitted to journals of high impact.

Finally, we have initiated a very promising research line aimed to look at strategies to extract brain-relevant neural information from the muscles. The hypothesis that we have been able to demonstrate already is the fact that surface muscle recordings can be used to extract activity of spinal motor neurones that allow us to track ongoing brain oscillatory activity regardless of whether external stimuli are being applied to the brain. We have also proven that the neural activity extracted from the muscles has a very tight temporal association with ongoing brain rhythmic activity. The main impact here is expected to be the possibility of developing new ways of tracking and stimulating the brain during movement processing.
The following are the main findings in our research:

1- There are temporal restrictions that apply to stimuli delivered in brain plasticity induction protocols based on coupling movement-related brain states with brain stimulation.
2- Plastic changes can be induced in the motor cortex by coupling movement initiation with peripheral nerve stimulation or transcranial magnetic stimulation of the brain. The main impact of this finding is that, using this knowledge, new plasticity induction protocols can be implemented at a relatively low cost.
3- The brain changes in preparation for movements are accompanied by a reduction of the brain responsiveness to external stimuli. This means that the brain becomes less excitable during movement preparation, unlike what other have proposed in the past.
4- Cue-driven reactive movements and self-paced actions share similar triggering mechanisms. These mechanisms are not used in movements that are timed with predictable external signals and therefore show that self-paced actions are prepared in a way that has important resemblances with reactive movements.
5- Surface recordings of muscle activity can robustly inform about ongoing brain activity even in the case where brain stimulation is been used to bias brain states. This opens the door to very promising research proposing alternative ways to study the brain and modify it by characterising the neurones that activate our muscles when we move. Our findings open a new possibility that overcomes many of the limitations that previous closed-loop brain stimulation platforms have faced.
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