Paired DBS and TMS Reveals Dentato-Cortical Facilitation Underlying Upper Extremity Movement in Chronic Stroke Survivors

Background Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement. However, there is a lack of understanding of physiologic influence of DTC in humans, largely due to difficulty in accessing the dentate nucleus. Objective Characterize DTC physiology using dentate nucleus deep brain stimulation (DBS) combined with transcranial magnetic stimulation (TMS) in stroke. Methods Nine chronic stroke survivors with moderate-to-severe UE impairment (Fugl-Meyer 13-38) underwent a paired DBS–TMS experiment before receiving experimental dentate nucleus DBS in our first-in-human phase I trial (Baker et al., 2023, Nature Medicine). Conditioning DBS pulses were given to dentate nucleus 1 to 10 ms prior to supra-threshold TMS pulses given to ipsilesional motor cortex. Effects were assessed on motor evoked potentials (MEPs). Size of DBS-conditioned MEPs was expressed relative to TMS MEPs, where values >1 indicate facilitation. Results Dentate nucleus DBS led to facilitation of MEPs at short-latency intervals (3.5 and 5 ms, P = .049 and .021, respectively), a phenomenon we have termed dentato-cortical facilitation (DCF). Higher DCF was observed among patients with more severe UE impairment. Diffusion tensor imaging revealed microstructure of thalamo-cortical portion of DTC was related to higher corticomotor excitability. Conclusions Our in vivo investigation reveals for the first time in humans the intrinsic excitatory properties of DTC, which can serve as a novel therapeutic target for post-stroke motor recovery.