Investigation of metaplasticity associated with transcranial focused ultrasound neuromodulation in humans

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.