Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice

Vignozzi, L.; Macchi, F.; Montagni, E.; Pasquini, M.; Martello, A.; Minetti, A.; Coulomb, E.; Allegra Mascaro, A. L.; Micera, S.; Caleo, M.; Spalletti, C.

doi:10.1101/2024.08.15.608060

bioRxiv · 10.1101/2024.08.15.608060

Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice

Vignozzi, L.·Macchi, F.·Montagni, E.·Pasquini, M.·Martello, A.·Minetti, A.·Coulomb, E.·Allegra Mascaro, A. L.·Micera, S.·Caleo, M.·Spalletti, C.

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Abstract

Stroke is a leading cause of long-term disability, often characterized by compromised motor function. Gamma band is known to be related to Parvalbumin interneurons (PV-IN) synchronous discharge and it has been found to be affected after stroke in humans and animals. Both Gamma band and PV-IN also play a key role in motor function, thus representing a promising target for post-stroke neurorehabilitation. Non-Invasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. This study presents a novel, clinically relevant, non-invasive and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. In the sub-acute phase after stroke, we scored profound deficits in motor-related Gamma band regulation on the perilesional cortex. Accordingly, both at the perilesional and at the whole-cortex levels, the damage results in impaired PV-IN activity, with reduced firing rate and increased functional connectivity levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-driven Gamma band stimulation in a subacute post-stroke phase during motor training to reinforce the efficacy of the treatment. Frequency-specific movement-related Gamma band stimulation, when combined with physical training, significantly improved forelimb motor function. More importantly, by pairing robotic rehabilitation with a clinical-like non-invasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements mediated by the effective restoring of movement-related Gamma band power and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in post-stroke impairment and recovery. These results highlight the synergistic potential of combining perilesional Gamma band stimulation with robotic rehabilitation as a promising and realistic therapeutic approach for stroke patients. SummaryStroke-induced motor deficits are accompanied by alteration of Gamma modulation and PV-interneurons activity and restored by a combination of non-invasive Gamma stimulation and robotic therapy.

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Vignozzi, L., Macchi, F., Montagni, E., Pasquini, M., Martello, A., Minetti, A., Coulomb, E., Allegra Mascaro, A. L., Micera, S., Caleo, M., Spalletti, C.. 2024-08-19. Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice. https://doi.org/10.1101/2024.08.15.608060

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