Theta–gamma coupling as a cortical biomarker of brain–computer interface-mediated motor recovery in chronic stroke

Chronic stroke patients with upper-limb motor disabilities are now beginning to see treatment options that were not previously available. To date, the two options recently approved by the United States Food and Drug Administration include vagus nerve stimulation and brain–computer interface therapy. While the mechanisms for vagus nerve stimulation have been well defined, the mechanisms underlying brain–computer interface-driven motor rehabilitation are largely unknown. Given that cross-frequency coupling has been associated with a wide variety of higher-order functions involved in learning and memory, we hypothesized this rhythm-specific mechanism would correlate with the functional improvements effected by a brain–computer interface. This study investigated whether the motor improvements in chronic stroke patients induced with a brain–computer interface therapy are associated with alterations in phase–amplitude coupling, a type of cross-frequency coupling. Seventeen chronic hemiparetic stroke patients used a robotic hand orthosis controlled with contralesional motor cortical signals measured with EEG. Patients regularly performed a therapeutic brain–computer interface task for 12 weeks. Resting-state EEG recordings and motor function data were acquired before initiating brain–computer interface therapy and once every 4 weeks after the therapy. Changes in phase–amplitude coupling values were assessed and correlated with motor function improvements. To establish whether coupling between two different frequency bands was more functionally important than either of those rhythms alone, we calculated power spectra as well. We found that theta–gamma coupling was enhanced bilaterally at the motor areas and showed significant correlations across brain–computer interface therapy sessions. Importantly, an increase in theta–gamma coupling positively correlated with motor recovery over the course of rehabilitation. The sources of theta–gamma coupling increase following brain–computer interface therapy were mostly located in the hand regions of the primary motor cortex on the left and right cerebral hemispheres. Beta–gamma coupling decreased bilaterally at the frontal areas following the therapy, but these effects did not correlate with motor recovery. Alpha–gamma coupling was not altered by brain–computer interface therapy. Power spectra did not change significantly over the course of the brain–computer interface therapy. The significant functional improvement in chronic stroke patients induced by brain–computer interface therapy was strongly correlated with increased theta–gamma coupling in bihemispheric motor regions. These findings support the notion that specific cross-frequency coupling dynamics in the brain likely play a mechanistic role in mediating motor recovery in the chronic phase of stroke recovery.