Developing a New LIFU Neuromodulation Method to Suppress Tremor

Transcranial ultrasound stimulation is a non-invasive brain stimulation that uses low intensity focused ultrasound (LIFU) to modulate neural activity with high spatial precision (Zadeh et al., 2024). Several human and animal studies have demonstrated that LIFU can produce lasting neuromodulatory effects, including both excitatory and inhibitory responses in the primary motor cortex (Zadeh et al., 2024). Furthermore, evidence suggests that LIFU is capable of inducing plasticity in the human brain that resembles long term potentiation or long-term depression (Zeng et al., 2024). The ability of LIFU to induce bidirectional effects, either excitatory or inhibitory, depending on sonication parameters, offers a level of flexibility in tailoring neuromodulatory interventions to individual patient needs and specific neural circuit dysfunctions. Combined with real-time neuronavigation and acoustic modeling tools, LIFU provides a promising platform for precise, personalized, and non-invasive brain stimulation. The modulatory effect of LIFU depends on sonication parameters such as frequency, attenuation, and pulse repetition frequency (Zeng et al., 2024; Manuel et al., 2020), and evidence from both preclinical and clinical studies suggests these effects can persist beyond the stimulation period consistent with long-term potentiation or long-term depression-like plasticity mechanisms (Fomenko et al., 2020; Zadeh et al., 2024).

Unlike other neuromodulatory techniques such as transcranial magnetic stimulation and transcranial direct current stimulation, LIFU offers the unique capability to reach deep brain structures while maintaining a focal spatial resolution. This advantage of precise targeting of deep brain regions such as the thalamus without the need for surgical intervention make LIFU a highly useful modality for investigating disorders (Legon et al., 2018). Structures like the ventral intermediate nucleus (Vim) of the thalamus, commonly implicated in movement disorders such as essential tremor and Parkinson's disease, can be non-invasively stimulated using LIFU to modulate aberrant neural activity.

In a previous study, we piloted an ultrasound transducer integrated with standard optical tracking-based neuro-navigation to establish a safety and tolerability benchmark for LIFU to reduce tremor in patients with Essential Tremor or Parkinson's disease, while also optimizing stimulation parameters prior to broader clinical application. Our open label study, currently under review for publication, demonstrated high efficacy and safety of our system to transiently reduce, in the short term, tremor amplitude measured using accelerometric recordings. By integrating rigorous screening, controlled stimulation parameters, and standardized monitoring protocols, we propose here a randomized sham-controlled study to advance knowledge on efficacy and safety of this technology in a larger clinical sample of patients with these diagnoses. As LIFU continues to expand into therapeutic realms, such foundational research will be essential for supporting its evidence-based integration into neuroscience and medicine.

Objectives. AIM: To determine if we can low intensity focused ultrasound (LIFU, a neuromodulatory form of ultrasound) in the laboratory setting can transiently suppress tremor when targeting motor thalamus in patients with tremor.

HYPOTHESIS: Specific LIFU patterns applied to deep thalamic targets will transiently induce reduce tremor in patients with tremor.

IMPACT: If successful, we could use LIFU to help predict potential efficacy of permanent lesioning on tremor as well as support further investigation of LIFU as a novel non-invasive neuromodulation strategy for tremor.

• Change in power spectral density (PSD) of tremor accelerometric trace between post-sonication (Round 2) and baseline [Time frame: 5 minutes]
• Change in Clinical Rating Scale for Tremor sub-score corresponding to the sum of scale items related to the treated side between the post-sonication rating and the baseline rating (participants with ET) [Time frame: 5 minutes]
• Change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale sub-score corresponding to the sum of resting tremor items of the scale between the post-sonication rating and the baseline rating (participants with PD). [Time frame: 5 minutes]