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To date, the two options recently approved by the United States Food and Drug Administration include vagus nerve stimulation and brain\u2013computer interface therapy. While the mechanisms for vagus nerve stimulation have been well defined, the mechanisms underlying brain\u2013computer 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\u2013computer interface. This study investigated whether the motor improvements in chronic stroke patients induced with a brain\u2013computer interface therapy are associated with alterations in phase\u2013amplitude 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\u2013computer interface task for 12 weeks. Resting-state EEG recordings and motor function data were acquired before initiating brain\u2013computer interface therapy and once every 4 weeks after the therapy. Changes in phase\u2013amplitude 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\u2013gamma coupling was enhanced bilaterally at the motor areas and showed significant correlations across brain\u2013computer interface therapy sessions. Importantly, an increase in theta\u2013gamma coupling positively correlated with motor recovery over the course of rehabilitation. The sources of theta\u2013gamma coupling increase following brain\u2013computer interface therapy were mostly located in the hand regions of the primary motor cortex on the left and right cerebral hemispheres. Beta\u2013gamma coupling decreased bilaterally at the frontal areas following the therapy, but these effects did not correlate with motor recovery. Alpha\u2013gamma coupling was not altered by brain\u2013computer interface therapy. Power spectra did not change significantly over the course of the brain\u2013computer interface therapy. The significant functional improvement in chronic stroke patients induced by brain\u2013computer interface therapy was strongly correlated with increased theta\u2013gamma 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.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac136","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T05:57:05Z","timestamp":1653544625000},"source":"Crossref","is-referenced-by-count":35,"title":["Theta\u2013gamma coupling as a cortical biomarker of brain\u2013computer interface-mediated motor recovery in chronic stroke"],"prefix":"10.1093","volume":"4","author":[{"given":"Nabi","family":"Rustamov","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery, Washington University School of Medicine , St Louis, MO , USA"},{"name":"Center for Innovation in Neuroscience and Technology, Washington University School of Medicine , St Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Humphries","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Washington University in St Louis , St Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University in St Louis , St Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Leuthardt","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Washington University School of Medicine , St Louis, MO , USA"},{"name":"Center for Innovation in Neuroscience and Technology, Washington University School of Medicine , St Louis, MO , USA"},{"name":"Department of Biomedical Engineering, Washington University in St Louis , St Louis, MO , USA"},{"name":"Department of Neuroscience, Washington University School of Medicine , St Louis, MO , USA"},{"name":"Department of Mechanical Engineering and Materials Science, Washington University in St Louis , St Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"2022061114455773100_fcac136-B1","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1161\/01.STR.32.6.1279","article-title":"Estimates of the prevalence of acute stroke impairments and disability in a multiethnic population","volume":"32","author":"Lawrence","year":"2001","journal-title":"Stroke"},{"key":"2022061114455773100_fcac136-B2","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1136\/jnnp.52.11.1267","article-title":"Arm function after stroke. 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