Brain-computer interfaces (BCI) are used in stroke rehabilitation to translate brain signals into intended movements of the paralyzed limb. However, the efficacy and mechanisms of BCI-based therapies remain unclear. Here we show that BCI coupled to functional electrical stimulation (FES) elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors more effectively than sham FES. Such recovery is associated to quantitative signatures of functional neuroplasticity. BCI patients exhibit a significant functional recovery after the intervention, which remains 6–12 months after the end of therapy. Electroencephalography analysis pinpoints significant differences in favor of the BCI group, mainly consisting in an increase in functional connectivity between motor areas in the affected hemisphere. This increase is significantly correlated with functional improvement. Results illustrate how a BCI–FES therapy can drive significant functional recovery and purposeful plasticity thanks to contingent activation of body natural efferent and afferent pathways.
Despite considerable efforts over the last decades, the quest for novel treatments for arm functional recovery after stroke remains a priority1. Synergistic efforts in neural engineering and restoration medicine are demonstrating how neuroprosthetic approaches can control devices and ultimately restore body function2,3,4,5,6,7. In particular, non-invasive brain-computer interfaces (BCI) are reaching their technological maturity8,9 and translate neural activity into meaningful outputs that might drive activity-dependent neuroplasticity and functional motor recovery10,11,12. BCI implies learning to modify the neuronal activity through progressive practice with contingent feedback and reward —sharing its neurobiological basis with rehabilitation13.
Most attempts to use non-invasive BCI systems for upper limb rehabilitation after stroke have coupled them with other interventions, although not all trials reported clinical benefits. The majority of these studies are case reports of patients who operated a BCI to control either rehabilitation robots14,15,16,17,18,19 or functional electrical stimulation (FES)20,21,22,23. A few works have described changes in functional magnetic resonance imaging (fMRI) that correlate with motor improvements17,18,22.
Recent controlled trials have shown the potential benefit of BCI-based therapies24,25,26,27. Pichiorri et al.26recruited 28 subacute patients and studied the efficacy of motor imagery with or without BCI support via visual feedback, reporting a significant and clinically relevant functional recovery for the BCI group. As a step forward in the design of multimodal interventions, BCI-aided robotic therapies yielded significantly greater motor gains than robotic therapies alone24,25,27. In the first study, involving 30 chronic patients24, only the BCI group exhibited a functional improvement. In the second study, involving 14 subacute and chronic patients, both groups improved, probably reflecting the larger variance in subacute patients’ recovery and a milder disability25. The last study27 showed that in a mixed population of 74 subacute and chronic patients, the percentage of patients who achieved minimally clinical important difference in upper limb functionality was higher in the BCI group. The effect in favor of the BCI group was only evident in the sub-population of chronic patients. Moreover, the conclusions of this study are limited due to differences between experimental and control groups prior to the intervention, such as number of patients and FMA-UE scores, which were always in favor of the BCI group.
In spite of promising results achieved so far, BCI-based stroke rehabilitation is still a young field where different works report variable clinical outcomes. Furthermore, the efficacy and mechanisms of BCI-based therapies remain largely unclear. We hypothesize that, for BCI to boost beneficial functional activity-dependent plasticity able to attain clinically important outcomes, the basic premise is contingency between suitable motor-related cortical activity and rich afferent feedback. Our approach is designed to deliver associated contingent feedback that is not only functionally meaningful (e.g., via virtual reality or passive movement of the paretic limb by a robot), but also tailored to reorganize the targeted neural circuits by providing rich sensory inputs via the natural afferent pathways28, so as to activate all spare components of the central nervous system involved in motor control. FES fulfills these two properties of feedback contingent on appropriate patterns of neural activity; it elicits functional movements and conveys proprioceptive and somatosensory information, in particular via massive recruitment of Golgi tendon organs and muscle spindle feedback circuits. Moreover, several studies suggest that FES has an impact on cortical excitability29,30.
To test our hypothesis, this study assessed whether BCI-actuated FES therapy targeting the extension of the affected hand (BCI–FES) could yield stronger and clinically relevant functional recovery than sham-FES therapy for chronic stroke patients with a moderate-to-severe disability, and whether signatures of functional neuroplasticity would be associated with motor improvement. Whenever the BCI decoded a hand-extension attempt, it activated FES of the extensor digitorum communis muscle that elicited a full extension of the wrist and fingers. Patients in the sham-FES group wore identical hardware and received identical instructions as BCI–FES patients, but FES was delivered randomly and not driven by neural activity.
As hypothesized, our results confirm that only the BCI group exhibit a significant functional recovery after the intervention, which is retained 6–12 months after the end of therapy. Besides the main clinical findings, we have also attempted to shed light on possible mechanisms underlying the proposed intervention. Specifically, electroencephalography (EEG) imaging pinpoint significant differences in favor of the BCI group, mainly an increase in functional connectivity between motor areas in the affected hemisphere. This increase is significantly correlated with functional improvement. Furthermore, analysis of the therapeutic sessions substantiates that contingency between motor-related brain activity and FES occurs only in the BCI group and contingency-based metrics correlate with the functional improvement and increase in functional connectivity, suggesting that our BCI intervention might have promoted activity-dependent plasticity.[…]