Combining gamma neuromodulation and robotic rehabilitation after a stroke restores parvalbumin interneuron dynamics and improves motor recovery in mice

Nothing here resembles a protocol, so totally useless information that can get survivors recovered!

Combining gamma neuromodulation and robotic rehabilitation after a stroke restores parvalbumin interneuron dynamics and improves motor recovery in mice

Livia Vignozzi 1, Francesca Macchi 2, Elena Montagni 2 3, Maria Pasquini 4, Alessandra Martello 2 5, Antea Minetti 2, Éléa Coulomb 2 6, Anna Letizia Allegra Mascaro 2 3, Silvestro Micera 4 7, Matteo Caleo 1 2, Cristina Spalletti 2

Affiliations 

• PMID: 41086129
 
• PMCID: PMC12520394
 
• DOI: 10.1371/journal.pbio.3002806

Abstract

Stroke is a leading cause of long-term disability, frequently associated with persistent motor deficits. Gamma band oscillations, generated by synchronous discharge of parvalbumin-positive interneurons (PV-INs), are critically affected after stroke in humans and animals. Both gamma band and PV-INs play a key role in motor function, thus representing a promising target for poststroke neurorehabilitation. Noninvasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. Here, we present a novel, clinically relevant, noninvasive, and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. During the sub-acute poststroke phase, we scored profound deficits in motor-related gamma band activity in the perilesional cortex. These deficits were accompanied by reduced PV-IN firing rates and increased functional connectivity, both at the perilesional and at the whole-cortex levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-IN-driven gamma band stimulation in a subacute poststroke 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(Where is the protocol to accomplish recovery? Since you didn't do that, all this is fucking useless!). More importantly, by pairing robotic rehabilitation with a clinical-like noninvasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements(Same question as above!) mediated by the effective restoring of movement-related gamma band power, improvement of PV-IN maladaptive network dynamics, and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in poststroke 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.

Copyright: © 2025 Vignozzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.