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

## TL;DR

Combining robotic therapy with non-invasive brain stimulation in mice improves stroke recovery by restoring brain rhythms and neuron activity.

## Contribution

A novel noninvasive treatment combining robotic rehabilitation and gamma neuromodulation to restore poststroke motor function in mice.

## Key findings

- Stroke disrupts gamma band activity and parvalbumin interneuron function in the brain.
- Combining robotic rehabilitation with gamma neuromodulation improves motor recovery in mice.
- Noninvasive 40 Hz stimulation restores gamma oscillations and interneuron connectivity.

## 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. More importantly, by pairing robotic rehabilitation with a clinical-like noninvasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements 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.

Stroke-induced motor deficits are accompanied by alteration of gamma modulation and PV-IN network; all of these parameters are restored by noninvasive gamma stimulation and robotic therapy.

How can motor function be restored after stroke? This study shows in mice that combining robotic rehabilitation with non-invasive gamma band neuromodulation improves motor recovery by restoring movement-related oscillations and parvalbumin interneuron dynamics.