Differential effects of focused ultrasound neuromodulation in Parkinson’s disease mice versus healthy mice

<i>Objective.</i>Focused ultrasound (FUS) neuromodulation holds strong potential for treating neurological disorders, but most preclinical studies have been performed in healthy animal models. How disease states influence the FUS neuromodulation effects remains poorly understood, limiting clinical translation.<i>Approach.</i>We used Parkinson<b>'</b>s disease (PD) as a model to compare the calcium and behavioral responses to FUS neuromodulation in healthy and diseased mice. The PD mouse model was the unilateral dopamine depletion model, induced by injecting 6-hydroxydopamine into the left middle forebrain bundle. FUS was targeted at the left external globus pallidus (GPe) in freely moving mice using a wearable device. Calcium activity in the GPe was monitored via fiber photometry, and motor behavior was assessed using video tracking.<i>Main results.</i>In unilateral PD mice, FUS significantly inhibited GPe calcium activity, and this inhibition lasted for ∼3 min after stimulation. This inhibition was accompanied by motor improvements as shown by a reduction in ipsilateral circling that lasted for at least 50 min after stimulation. In healthy mice, FUS did not significantly change the calcium activity in the GPe and rotational behavior during or after the FUS. Histological analysis revealed no evidence of neuronal damage, astrocytic activation, or microglial proliferation following the FUS.<i>Significance.</i>These findings demonstrate that FUS neuromodulation produces disease-state-dependent effects on calcium activity and behavior, emphasizing the importance of evaluating neuromodulation strategies in relevant disease models for clinical translation.