RESUMEN
Low intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for non-invasive brain stimulation (NIBS). TUS delivered in a theta (5Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30-60 minutes, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex.We delivered four interventions: 1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), 2) real cTBS150 followed by sham tbTUS (cTBS only), 3) real cTBS150 followed by real tbTUS (metaplasticity), and 4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation, and short-interval intracortical facilitation before and up to 90 minutes after plasticity intervention.Plasticity effects lasted at least 60 minutes longer when tbTUS was primed with cTBS150 compared to tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed.Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggest that metaplasticity can be harnessed in the therapeutic development of TUS.Significance statement Low intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for non-invasive brain stimulation (NIBS). Compared to current forms of NIBS, TUS can target deep regions of the brain, such as the basal ganglia and thalamus, with high focality. This is promising for therapeutic development. Neuroplasticity refers to the strengthening or weakening of neural connections based on neural activity. Neural activity can also change the brain's capacity for future plasticity via the process of metaplasticity. This study was the first to characterize the effects of metaplasticity on TUS-induced neuroplasticity, demonstrating that metaplastic processes can enhance and abolish TUS effects. The findings increase understanding of the mechanisms of TUS-induced plasticity and inform future therapeutic development of TUS.
RESUMEN
OBJECTIVE: Low-intensity transcranial focused ultrasound (TUS) is a novel method for neuromodulation. We aimed to study the feasibility of stimulating the bilateral primary motor cortices (M1) with accelerated theta-burst TUS (a-tbTUS) on neurophysiologic and clinical outcomes in Parkinson's disease (PD). METHODS: Patients were randomly assigned to receive active or sham a-tbTUS for the first visit and the alternate condition on the second visit, at least 10 days apart. a-tbTUS was administered in three consecutive sonications at 30-minute intervals. We used an accelerated protocol to produce an additive effect of stimulation. Patients were studied in the OFF-medication state. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) were used to assess motor cortical excitability before and after TUS. Clinical outcomes after a-tbTUS administration were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III. RESULTS: A total of 20 visits were conducted in 10 PD patients. Compared to the baseline, TMS-elicited MEP amplitudes significantly increased following active but not sham sonication (P = 0.0057). MEP amplitudes were also higher following a-tbTUS than sham sonication (P = 0.0064). There were no statistically significant changes in MDS-UPDRS-III scores with active or sham a-tbTUS. CONCLUSIONS: a-tbTUS increases motor cortex excitability and is a feasible non-invasive neuromodulation strategy in PD. Future studies should determine optimal dosing parameters and the durability of neurophysiologic and clinical outcomes in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.