FUS: Focused ultrasound in epilepsy

Focused ultrasound has gained attention as a non-invasive neuromodulatory approach for epilepsy.

Why focused ultrasound has attracted interest in epilepsy

Epilepsy remains a major neurological disorder worldwide, with approximately one third of patients continuing to experience seizures despite adequate trials of antiseizure medications. For these individuals, drug-resistant epilepsy represents not only a clinical challenge but also a major determinant of impaired quality of life, cognitive burden, and psychosocial disability. While resective epilepsy surgery and established neuromodulation techniques such as vagus nerve stimulation or deep brain stimulation have expanded therapeutic options for selected patients, a substantial proportion of individuals are not eligible for invasive procedures because of seizure localization, comorbidities, or personal preference. This persistent unmet need has driven growing interest in non-invasive therapeutic strategies.

Focused ultrasound (FUS) has emerged within this context as a potential non-invasive approach capable of targeting specific brain regions with high spatial precision. Delivered under magnetic resonance guidance, focused ultrasound allows acoustic energy to be concentrated on a predefined intracranial target while sparing surrounding tissue. Depending on the intensity and parameters used, FUS can induce either focal thermal ablation or reversible neuromodulation without permanent structural damage. In epilepsy, current research efforts have predominantly focused on low-intensity focused ultrasound as a neuromodulatory technique rather than on ablative approaches, reflecting a cautious attempt to influence epileptogenic networks while minimizing the risks associated with irreversible lesions.

The biological rationale for ultrasound-based neuromodulation is supported by a growing body of experimental evidence. Preclinical studies have shown that low-intensity focused ultrasound can modulate neuronal excitability, alter synaptic transmission, and suppress epileptiform activity in animal models of focal epilepsy. These effects appear to be mediated by mechanical interactions with neuronal membranes and ion channels, rather than by thermal injury. Importantly, such studies provide a plausible mechanistic foundation for the exploration of focused ultrasound in epilepsy, although they do not in themselves establish clinical efficacy. As highlighted in conceptual frameworks, focused ultrasound should therefore be understood as a platform technology with multiple potential applications, rather than as a single, well-defined therapeutic intervention.

What clinical studies show — and what they do not

Despite a solid experimental rationale, the clinical evidence supporting the use of focused ultrasound in epilepsy remains limited and heterogeneous. As summarized in recent narrative and systematic reviews, most published human studies consist of small pilot trials, feasibility studies, or early-phase investigations with open-label designs. These studies vary widely in terms of stimulation parameters, anatomical targets, patient selection criteria, and outcome measures, making direct comparison difficult. While some reports describe reductions in seizure frequency or changes in electroencephalographic patterns following ultrasound-based interventions, these findings are inconsistent and cannot be generalized.

A recent systematic review and meta-analysis integrating both preclinical and clinical data confirmed that focused ultrasound consistently suppresses epileptiform activity in animal models. In contrast, the available human evidence was found to be sparse and insufficient to support routine clinical use. The authors emphasized substantial methodological heterogeneity across studies, including differences in ultrasound intensity, duration, targeting strategies, and follow-up. These limitations underscore the current gap between experimental promise and clinical readiness, and they highlight the need for standardized protocols and outcome measures in future research.

FUS, still an investigational modality

Focused ultrasound has nevertheless begun to enter early-stage clinical evaluation. A notable example is a phase 1 open-label trial assessing MR-guided unilateral anterior thalamotomy in patients with focal onset epilepsy. This study primarily aimed to evaluate safety and technical feasibility rather than efficacy. The results demonstrated that deep epileptogenic networks can be targeted using focused ultrasound without major acute adverse events, providing proof of concept for the approach. Preliminary signals of seizure reduction were observed in some participants; however, the small sample size, absence of a control group, and limited follow-up preclude any definitive conclusions regarding clinical benefit or durability of effect.

At present, focused ultrasound should therefore be regarded as an investigational modality within the broader landscape of epilepsy treatment. Key uncertainties remain regarding optimal patient selection, target identification, stimulation parameters, and long-term outcomes. It is also unclear whether focused ultrasound will ultimately function as a stand-alone therapy, an adjunct to existing neuromodulation strategies, or a bridge to more definitive interventions. Addressing these questions will require well-designed prospective trials with adequate sample sizes, standardized endpoints, and extended follow-up.

From a broader clinical perspective, the development of focused ultrasound reflects a wider shift in epilepsy care toward non-invasive and network-oriented approaches. Rather than focusing exclusively on seizure freedom as a binary outcome, contemporary management increasingly considers seizure burden, cognitive effects, and quality of life as meaningful therapeutic targets. In this evolving framework, focused ultrasound may eventually offer incremental benefits for carefully selected patients. For now, however, its role remains exploratory, and cautious interpretation of emerging data is warranted.

References
  1. Succop BS Jr, Seas A, Woo J, Bode Padron KJ, Bartlett AM, Shah B, Agashe S, Harward Ii S. Focused Ultrasound in the Treatment of Epilepsy: Current Applications and Future Directions. Stereotact Funct Neurosurg. 2025;103(3):166-188. doi: 10.1159/000545716. Epub 2025 Apr 23. PMID: 40267897.
  2. Soltani Khaboushan A, Zafari R, Sabahi M, Khorasanizadeh M, Dabbagh Ohadi MA, Flouty O, Ranjan M, Slavin KV. Focused ultrasound for treatment of epilepsy: a systematic review and meta-analysis of preclinical and clinical studies. Neurosurg Rev. 2024 Nov 10;47(1):839. doi: 10.1007/s10143-024-03078-5. PMID: 39521750.
  3. Bubrick EJ, McDannold NJ, White PJ. Low Intensity Focused Ultrasound for Epilepsy- A New Approach to Neuromodulation. Epilepsy Curr. 2022 Mar 29;22(3):156-160. doi: 10.1177/15357597221086111. PMID: 36474831; PMCID: PMC9684587.
  4. Krishna V, Mindel J, Sammartino F, Block C, Dwivedi AK, Van Gompel JJ, Fountain N, Fisher R. A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy. Epilepsia. 2023 Apr;64(4):831-842. doi: 10.1111/epi.17535. Epub 2023 Mar 1. PMID: 36745000.