Focused Ultrasound Ablation for Neurological Disorders.

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Published before final editing as: Biol Psychiatry. 2026 May 8:S0006-3223(26)01228-X. doi: 10.1016/j.biopsych.2026.04.027 Focused Ultrasound Ablation for Neurological Disorders Haiden S Berton a , Haden D Ray a , Nicole Silva a , Varina L Boerwinkle b , Paul Dayton c , Daniel Roque b , Vibhor Krishna a, * Author information Copyright and License information a Department of Neurosurgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA b Department of Neurology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA c Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA * Corresponding author. vibhor_krishna@med.unc.edu PMC Copyright notice PMCID: PMC13222645  NIHMSID: NIHMS2175203  PMID: 42107848 The publisher's version of this article is available at Biol Psychiatry Abstract Focused ultrasound (FUS) was explored for neurological indications more than half a century ago, but only recent technological advances have enabled its practical transcranial use for movement and neuropsychiatric disorders. FUS can produce stereotactic thermal lesions via focused ultrasound ablation (FUSA), while non-thermal lesioning (e.g., FUS histotripsy) and non-ablative approaches such as neuromodulation and blood-brain barrier opening are under active clinical investigation. FUSA is FDA-approved for essential tremor and Parkinson’s disease, and is now being evaluated for additional syndromes, including epilepsy, dystonia, and treatment-resistant psychiatric disorders. Neuroimaging, particularly magnetic resonance (MR) imaging and MR thermometry, is central to feasibility, targeting, intraprocedural monitoring, and post-treatment assessment. Clinical studies demonstrate substantial and durable motor symptom reduction in essential tremor and Parkinson’s disease, with growing evidence for emerging indications. The goal of this review is to integrate mechanistic concepts with the current clinical evidence for FUSA, and to define priorities that can improve patient selection, optimize targeting, and guide expansion across neurological and neuropsychiatric disorders. Introduction Focused Ultrasound (FUS) has been pursued for neurological disorders for more than 70 years, but only over the past two decades has it become a practical transcranial therapy. Key advancements (such as phased-array transducers, improved skull aberration correction, and aberration correction for real-time monitoring) have enabled reproducible focal energy delivery for deep brain targets without craniotomy ( 1 ). These developments coincide with a renewed interest in functional neurosurgery on network-level interventions for both movement and psychiatric disorders, creating a timely context for reassessing lesion-based strategies and their clinical translation. In current clinical practice, the most established application is MR-guided FUS ablation (FUSA), which produces a stereotactic thermal lesion under imaging guidance. FUSA is FDA-approved for staged-bilateral thalamotomy in essential tremor (ET), tremor-dominant Parkinson’s disease (PD), PD-fluctuations and dyskinesia, with ongoing investigation into additional Parkinsonian phenotypes and, more recently, staged bilateral approaches ( 2 ). Beyond ablation, low intensity focused ultrasound neuromodulation (FUSN) and FUS-mediated blood-brain-barrier opening (FUS-BBBO) are emerging modalities that may support reversible network modulation ( 3 , 4 ) and targeted drug delivery ( 5 , 6 ). This review centers on FUSA as the most clinically used intervention, while briefly situating FUSN and FUS-BBBO as adjunct approaches relevant to neuropsychiatric conditions. For the readership of Biological Psychiatry , FUS is relevant because it enables precise manipulation of brain networks implicated in psychiatric disorders. While technological advances have provided precise lesioning with FUSA, precision does not eliminate the need for explicit safeguards, outcomes testing, and mechanistic investigations. Accordingly, we summarize the mechanisms and current clinical applications of FUSA, with emphasis on evidence, outcomes, and future directions for expanding its use into neuropsychiatric indications. Focused Ultrasound Ablation Workflow, Monitoring, and Constraints Procedural Workflow FUSA candidates undergo multidisciplinary assessment to confirm symptom phenotype and laterality, medication refractoriness and functional impairment, and suitability for an MRI-guided procedure ( 7 ). Structural MRI supports target localization and exclusion of contraindications ( 8 ). A preoperative CT is obtained for skull modeling, phase correction, and to inform treatment feasibility ( 9 , 10 ) (see Patient Selection and Skull Constraints section). When relevant, diffusion MRI acquisitions (e.g., diffusion tensor imaging) can be useful to derive white matter tractography, which helps define targets with respect to symptom-relevant connections and any neighboring tracts associated with side effects (e.g., cerebellothalamic pathways for tremor ablation and corticospinal tracts to avoid side effects) ( 11 , 12 ). FUSA is performed in an MRI suite using a hemispheric phased-array transducer (e.g. Insightec’s Exablate Neuro and Exablate Prime systems, see figure 1A ) ( 1 ). After headframe immobilization and acoustic coupling, real-time MRI confirms alignment and identifies treatment coordinates, including sonication energy, monitoring planes, and safety margins ( 13 ). Figure 1. Commercially Available Focused Ultrasound Devices for Neurological Disorders. Open in a new tab Overview of current FUS devices for neurological applications. This includes Inscitec’s Exablate Prime phased-array system for thermal lesioning (A), Brainsonix’s system for neuromodulation and BBB opening (B), and CarThera’s implantable single-element device (C). System-specific parameters and capabilities are described in the context of therapeutic applications like ET, PD, and other investigational indications. A defining feature of FUSA is iterative escalation in prescribed energy based on clinical feedback. Low-power, sub-ablative sonications are commonly used to verify targeting and physiologic mapping to detect any clinical adverse effects prior to delivering ablative energy. In tremor disorders, bedside testing to detect tremor changes or early sensory/motor/ataxia side effects can inform parameter adjustments ( 13 ). For other targets, sub-ablative testing serves primarily for target confirmation and safety probing rather than efficacy assessment. Once the ablation target is established, sonication parameters are escalated to achieve therapeutic temperatures within the intended target. MR thermometry provides real-time estimates of temperature change within the target region and adjacent structures, enabling energy delivery to the planned target, while limiting off-target heating ( 14 ). Between sonications, patients are evaluated for neurologic changes (e.g., speech, strength, sensation, ataxia, where feasible), and treatment parameters are adjusted accordingly (e.g., power modulation, focal steering, repositioning, or termination). Immediate post-ablation T2-weighted MRI confirms target engagement; lesions appear as a hypointense core with a hyperintense ring, diffusion restriction, and surrounding edema, though evolution over subsequent days may alter the clinical profile ( 15 ) ( Figure 5 ). Longitudinal studies suggest a correlation between lesion volume and clinical outcomes, underscoring the importance of imaging for assessing long-term efficacy and safety ( 13 ). Figure 5. MRI appearance of FUSA lesions on MRI imaging. Open in a new tab Multimodal MRI across pre- and postoperative timepoints for staged bilateral FUSA of the ventral intermediate nucleus (VIM). Each row shows, left-to-right, T1 white matter-nulled (WMn), T2-weighted FLASH, and diffusion-weighted ADC images. (A) Pre-operative baseline. (B) Immediate post-operative after right-sided VIM FUSA: a clear hypointense core with a hyperintense ring, indicative of lesion site postoperative edema and swelling, but no signal on the T2 or DWI. (C) Three months post-op (right-sided lesion): T1 appears very similar to baseline; T2 shows a hyperintense core with a hypointense ring at lesion site; DWI/ADC shows a hypointense area at the lesion site. (D) Three months after second-side (left) ablation (i.e., ~1 year after the initial right-sided ablation): T1 shows reduced, but persistent, signal bilaterally; T2 demonstrates a clear hyperintense core with a hypointense ring bilaterally; DWI/ADC shows slight hypointense signal at both lesion sites. Follow-up is essential because clinical benefit and adverse effects may evolve over days to weeks as edema resolves and network-level adaptation occurs. Standardized symptom scales and functional measures should be prespecified. When indications carry cognitive or behavioral risks, structured neuropsychological and psychiatric outcomes should be embedded in the follow-up protocol. Patient Selection and Skull Constraints Skull composition and geometry influence ultrasound transmission efficiency, focal distortion, and near-field heating. A primary screening factor in candidate selection is the skull density ratio (SDR), a CT-based metric representing the proportion of cortical to cancellous bone in the skull ( 10 ). While SDR thresholds (typically ≥ 0.4) were initially used as strict eligibility criteria, emerging clinical data have challenged the use of cut-offs. D’Souza et al. ( 9 ) reported effective FUSA in patients with SDR < 0.40, though achieving therapeutic temperatures was less consistent. Lower SDR and related skull properties generally increase required energy and reduce heating efficiency, affecting procedural planning and outcomes. In borderline cases, planning should anticipate tradeoffs and incorporate mitigation strategies such as conservative parameter escalation and close intraoperative thermometry review. Mechanisms of Action Focused ultrasound effects depend on acoustic parameters and tissue interaction. For brain applications, mechanisms are commonly grouped into thermal ablation (FUSA) and non-ablative effects that modulate neural activity or transiently increase BBB permeability. Thermal Ablation (FUSA) Clinical lesioning uses high-intensity sonications to raise temperature within a precise target volume. When sufficient heating is achieved (approximately 55-60°C) ( 16 ), irreversible thermal ablation ( Figure 2 ) occurs through protein denaturation, coagulative necrosis, and cell death ( 8 , 14 , 17 ). In practice, ablation is achieved through iterative sonications with progressive dose escalation while monitoring temperature in near-real time with MR thermometry. Figure 2. Thermal Mechanisms of Focused Ultrasound Ablation. Open in a new tab Schematic illustration of FUS-induced thermal ablation. Continuous sonication raises tissue temperatures to 3 50 °C, leading to protein denaturization, coagulative necrosis, and cell death. Thermal FUSA of the VIM is an FDA-approved incisionless treatment for ET. The principal advantages of FUSA are spatial precision and immediate lesion confirmation. The principal limitation is irreversibility, with limited ability to mitigate delayed adverse effects related to edema, lesion evolution, or network adaptation. Non-Thermal Lesioning FUS histotripsy (FUSH) is a non-thermal mechanical tissue fractionation approach that uses FUS to generate controlled microbubble activity ( 18 ). Two main approaches (cavitation cloud histotripsy and boiling histotripsy) both achieve tissue disintegration through controlled microbubble activity ( Figure 3 ). Cavitation, previously an unwanted FUSA side effect, now forms the basis of FUSH in preclinical models ( 19 , 20 ). Boiling histotripsy involves shorter (millisecond) bursts of acoustic energy to generate endogenous vapor bubbles that mechanically fragment tissue with cell-scale precision ( 19 ). FUSH has reached human clinical use outside the brain, including FDA authorization for a liver tumor histotripsy system (HistoSonics Edison ). Intracranial FUSH remains investigational. Because histotripsy does not rely on heat, it may offer increased precision and reduced risk of thermal damage to adjacent structures ( 21 ). Key barriers include skull-induced distortion of the acoustic field, target-adjacent safety margins in densely functional tissue, and real-time monitoring requirements. Ex vivo proof-of-concept work in human brain tissue has been reported, but in vivo intracranial safety remains experimental. Figure 3. Focused Ultrasound Histotripsy: A Non-Thermal Lesioning Modality. Open in a new tab Rendering of Histotripsy, a non-thermal FUS technique that uses high-amplitude, shortduration acoustic pulses to generate controlled cavitation. The collapse of endogenous vapor bubbles within the targeted tissue results in mechanical tissue fractionation at sub-cellular precision. Ongoing investigations are exploring its application in neuropathic pain targets, such as the Cingulate Gyrus. Non-Ablative Modalities Low-intensity pulsed FUS neuromodulation (FUSN) can alter neural excitability without producing a radiographically apparent lesion ( Figure 1B ). Proposed mechanisms are predominantly mechanical (e.g., radiation force-related displacement), but biological transduction remains incompletely resolved. Effects can be inhibitory or excitatory depending on parameters and brain state ( 3 , 4 ), protocol standardization, sham control, and biomarkers of target engagement for clinical translation. Unlike FUSN, sub-ablative test sonications are part of an ablation workflow and should not be conflated with low-intensity FUSN, which is a distinct modality. When paired with intravenously administered microbubbles, pulsed low-intensity FUS can transiently increase BBB permeability within a targeted region. In FUS-BBBO ( Figure 4 ), microbubble oscillation transiently increases BBB permeability, with restoration over hours. Safety risks (vascular injury, hemorrhage, edema, inflammatory sequelae) scale with exposure and cavitation dynamics, motivating conservative dosing, structured monitoring (including imaging confirmation of opening), and standardized adverse event surveillance ( 5 , 6 , 22 , 23 ). Figure 4. Delivery of Therapeutics & Biologics via Focused Ultrasound-Induced Blood-Brain Barrier Disruption. Open in a new tab Depiction of FUS-mediated, microbubble-enhanced BBB disruption. Low-intensity, pulsed FUS induces transient and localized BBB permeability, enabling delivery of chemotherapeutics, biologics, and gene therapies to otherwise inaccessible brain regions. Proposed application in Epilepsy is shown. Established Therapeutic Applications in Neurological Disorders MR-guided focused ultrasound ablation (FUSA) has its most mature evidence base in lesion-based treatment of medication-refractory ET and PD, where the therapeutic goal is focal interruption of symptom-relevant circuitry without implanted hardware. Across indications ( Table 1 ), outcomes depend on phenotype-driven target selection, patient-specific procedural feasibility (including skull constraints and ability to tolerate awake MRI-guided treatment), and risk tolerance for an irreversible intervention. Outcomes depend heavily on patient selection, which significantly improves outcomes in FUSA procedures ( 24 ). A multidisciplinary approach is essential for properly evaluating treatment considerations such as symptom phenotype, imaging findings, comorbidities, procedural risks, and patient expectations. Ideal patients typically present with disabling neurologic symptoms refractory to conservative therapies and are either poor candidates for open surgery or prefer less-invasive options. Table 1. Evidence Landscape for Focused Ultrasound Ablation Across Neurological and Psychiatric Indications Indication Phenotype Author., Year FUSA target Evidence Level Study Design & Scale Cohort Details Key Efficacy Outcomes Reported Treatment Durability Adverse Events Reported Other comments Essential Tremor — Elias et al., 2016 ( 27 ) VIM (Thalamus) I Randomized, sham-controlled trial (n=76). Primary: CRST hand tremor change at 3 months. Secondary: QUEST. 76; moderate-to-severe ET refractory to medications. CRST hand tremor improved more with FUS (18.1→9.6 at 3 mo) vs sham (16.0→15.8); between-group change of 8.3 points (P<0.001). Maintained benefit at 12 months (change from baseline 7.2). Gait disturbance (36%) and paresthesias /numbness (38%); persisted at 12 mo in 9% and 14%. — Essential Tremor — Cosgrove et al., 2022 ( 29 ) VIM (Thalamus) IV Long-term follow-up to a prospective, controlled multicenter trial (n=45). Scales: CRST (A, A+B, C) and QUEST. 45 completed 4-year follow-up; 40 completed 5-year follow-up. CRST postural tremor (A) improved 73.1% at 5 years; combined hand tremor/motor improved 40.4%; QUEST remained improved. Sustained benefit at 5 years. All prior AEs mild/moderate; no new progressive/ delayed complications. Stable effect through 5 years Essential Tremor — Kaplitt et al., 2024 ( 2 ) VIM (Thalamus) IV Prospective, open-label, single-arm multicenter trial (n=51). Primary: CRST A+B at 3 months. 51; mean age 73; 86.3% male; prior unilateral FUS thalamotomy. CRST A+B improved 66% at 3 mo (P<0.001); CRST C improved 73%; head/voice responders 71%/67%. Maintained benefit at 12 months. 85% mild, 13% moderate, 2% severe (1 severe UTI). Persistent mild AEs at 12 mo: numbness/tingling (n=8), dysarthria (n=7), ataxia (n=6). Led to regulatory approval by the US FDA for staged bilateral MRgFUS ablation for ET. Parkinson’s Disease Motor fluctuations, dyskinesia Krishna et al., 2023 ( 43 ) Gpi I Randomized, sham-controlled trial; 3:1 randomization; primary endpoint at 3 months; openlabel to 12 months; N randomized=94. Exablate n=68, sham n=24; mean age ~64; female ~37–42%; PD duration ~9 years; LEDD ~1060 mg. 3-mo response (≥3-point improvement in treated-side MDS-UPDRS III OFF and/or UDysRS ON): 69% active vs 32% sham (P=0.003). Majority (30/39) maintained response at 12 months. dysarthria, gait disturbance, loss of taste, visual disturbance, facial weakness. — Parkinson’s Disease Asymmetric PD Fernández et al., 2020 ( 107 ) STN I Randomized trial (n=40; 27 active, 13 control). Primary: MDS-UPDRS III (more affected side) change to 4 months. 40 enrolled; markedly asymmetric PD. Mean MDS-UPDRS III more affected side decreased 9.8 points (active) vs 1.7 (control) (P<0.001). Some deficits present in 6 patients at 12 months. Dyskinesia, speech disturbance, weakness, gait disturbance (some persisted at 4 months). — Parkinson’s Disease Tremor, rigidity, bradykinesia, dyskinesia Gallay et al., 2020 ( 108 ) PTT IV Consecutive case series. Outcomes: UPDRS (post-op off-med vs baseline on-med). 51 interventions in 47 patients; 15 bilateral PTT. Treated-side reductions: tremor 84%, rigidity 70%, 88% mean tremor relief. Most (11/20) sustained benefit at 12-month follow-up. Axial items not significantly improved; no significant cognitive change. — Parkinson’s Disease Tremor-dominant Bond et al., 2017 ( 39 ) VIM (Thalamus) I Randomized, double-blind trial (n=27; 20 FUS, 7 sham). Primary: CRST treated-hand tremor subscore at 3 months (on-med). 27 randomized; 96% male; median age 67.8; medication-refractory TDPD. Median tremor scores improved 62% (FUS) vs 22% (sham) at 3 months (P=0.04). Variable n at 12 months, not all patients reached visit at time of analysis Early heating: 2 mild hemiparesis improved. Persistent: orofacial paresthesia (20%), finger paresthesia (5%), ataxia (5%). — Dystonia Focal hand dystonia Horiaswa et al., 2021 ( 109 ) Vo (Thalamus) IV Prospective pilot (n=10). Scales: WCRS, TMDS, ADDS. 10 with FHD. WCRS 6.3→1.6 (P=0.011); TMDS 1.4→5.0 (P=0.0001) at 12 months. Benefit maintained at 12 months. One prolonged dysarthria at 12 months. — Dystonic Tremor — Andreasi et al., 2024 ( 110 ) VIM (Thalamus) III Prospective pilot cohort with comparison (DT vs ET), consecutively treated (n=45 total). 10 DT; 35 ET. Tremor improved in both groups. Benefit maintained at 12 months. Less AEs with anterior lesions. — Epilepsy Drug-resistant focal epilepsy Krishna et al., 2023 ( 60 ) ANT (Thalamus) IV Phase 1, open-label, single-center (n=2). Primary: safety/feasibility; secondary: seizure frequency. 2 adults with treatment-refractory focal onset epilepsy. Seizure frequency reduced in both. Benefit maintained at 12 months, 1 being seizure-free. No serious complications reported. — Neuropathic Pain Trigeminal neuropathic pain Ishaque et al., 2023 ( 111 ) CL (Thalamus) II Prospective, double-blind RCT (n=10) with sham controls; primary: between-group NPRS pain intensity change baseline→3 months. 10 patients with trigeminal neuropathic pain. No significant improvement in pain intensity baseline→3 months in either group; between-group NPRS change not significantly different. Outcomes assessed to 3 months, no significant change in pain. No serious complications from FUS procedures. — Neuropathic Pain — Gallay et al., 2023 ( 112 ) CL (Thalamus) IV Single-center retrospective analysis (n=55). Outcomes: patient-rated relief and VAS. 63 interventions in 55 patients. Mean pain relief 42% at last follow-up; ≥50% relief in 51%; pain-attack frequency -92%. Mean follow-up 55 months; results stable over time. Contralateral numbness (n=3), diplopia (n=1; resolved), agitation (n=1), obtundation/somnolence (n=1; resolved). — Cancer Pain Head & neck cancer pain Elias et al., 2025 ( 62 ) Dorsal midbrain IV Prospective, nonrandomized early-phase pilot (n=5 treated). Eligible/consented n=12; treated n=5; all men; mean age 64.2±10.4. Immediate NPRS reduction POD1; 3/5 responders at last follow-up. Durability variable; follow-up limited by survival. No serious AEs; mild/moderate events noted. — Neuropathic Pain — Ahmed et al., 2024 ( 61 ) CL (Thalamus) IV Prospective, single-arm Phase I; N enrolled=10; successful ablation=9. Mean age 50.9 (SD 12.7); symptom duration 12.3 years (SD 9.7) At 1 year (n=8): BPI 7.6→3.8; PDI 43.0→25.8; NRS 7.2→4.0. Improvements through 1 year (n=8 at 1 year). NR — Obsessive-Compulsive Disorder — Jung et al., 2015 ( 113 ) ALIC IV Proof-of-concept case series (n=4). Outcomes: Y-BOCS, HAM-D, HAM-A. 4 medically refractory OCD patients. Y-BOCS mean improvement 33%; HAM-D −61.1%; HAM-A −69.4%. Follow-up 6 months; depression/anxiety improvements sustained. No procedure-related physical or neuropsychological side effects reported. — Obsessive-Compulsive Disorder & Major Depressive Disorder — Hamani et al., 2025 ( 76 ) ALIC IV Phase 1 open-label (n=27; OCD 15, MDD 12). Primary: safety; secondary: response thresholds. OCD n=15; MDD n=12. OCD: Y-BOCS −35% at 12 months; MDD: HDRS −25% (n.s.) at 12 months. Outcomes maintained at 12 months. No serious adverse effects; neuropsych testing without negative effects. — Obsessive-Compulsive Disorder & Major Depressive Disorder — Davidson et al., 2020 ( 70 ) ALIC IV Two Phase I trials (n=12; OCD 6, MDD 6). OCD n=6; MDD n=6. Response: OCD 4/6 (67%); MDD 2/6 (33%). Outcomes maintained at 12 months. No serious AEs; headaches and pin-site swelling (7/12). — Open in a new tab * CRST = Clinical Rating Scale for Tremor (Fahn–Tolosa–Marín; Parts A–C); QUEST = Quality of Life in Essential Tremor Questionnaire; UPDRS = Unified Parkinson’s Disease Rating Scale (often Part III = motor examination); MDS-UPDRS = Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (often Part III = motor examination); UDysRS = Unified Dyskinesia Rating Scale; WCRS = Writer’s Cramp Rating Scale; TMDS = Tubiana Musician’s Dystonia Scale (Tubiana’s MD scale); ADDS = Arm Dystonia Disability Scale (commonly reported as a percentage disability score); NPRS = Numeric Pain Rating Scale; NRS = Numeric Rating Scale (pain severity, typically 0–10); VAS = Visual Analog Scale; BPI = Brief Pain Inventory; PDI = Pain Disability Index; Y-BOCS = Yale–Brown Obsessive Compulsive Scale; HAM-D / HDRS = Hamilton Depression Rating Scale; HAM-A = Hamilton Anxiety Rating Scale. Essential Tremor ET is the most common movement disorder ( 25 ), typically characterized by action tremors seen in the upper limbs, head, or voice ( 26 ). The associated tremors can be disabling, and many patients abandon medications (such as beta-blockers) that are accompanied by unwanted side effects ( 26 ). ET is the most well-established indication for FUSA since its FDA approval for unilateral treatment in 2016 ( 27 ). The ventral intermediate nucleus (VIM) of the thalamus serves as the principal target due to its ability to impact the tremor circuit ( 28 ). In unilateral thalamotomy, clinical trials and long-term observational studies have demonstrated significant and durable reduction in tremor severity ( 29 , 30 ) with many patients maintaining improvements at two- and five-year post-procedure ( 29 , 31 , 32 ). Unilateral FUSA of the VIM has been demonstrated to be equally effective as unilateral DBS ( 31 , 33 ) while being significantly more cost-effective ( 34 ). FUSA thalamotomy is typically performed unilaterally to minimize adverse effects, though staged bilateral procedures (9 months between ablative procedures) were recently shown to be safe and effective. Emerging open-label clinical trials are challenging the notion that bilateral thalamotomies are more risk-prone than unilateral treatment. Kaplitt and colleagues reported a significant reduction in tremor with a similar frequency and severity of adverse events seen in unilateral ablation ( 2 ). Common adverse effects after VIM FUSA include paresthesia, gait imbalance/ataxia, and dysarthria. These effects are frequently transient but may persist in a subset of patients, underscoring conservative dose escalation, careful lesion placement relative to adjacent sensory and motor pathways, and explicit counseling regarding irreversible risk (evidence level and side effects are summarized in Table 1 ). In bilateral paradigms, counseling should address speech and balance risk and the need for staged outcome assessment before proceeding to the contralateral side. Parkinson’s Disease The second most common neurodegenerative disease ( 35 ), PD is characterized by motor symptoms such as bradykinesia, tremor, rigidity, and postural instability ( 36 ). First-line treatments, such as levodopa, address disabling motor symptoms; however, medications often lose efficacy (fluctuation) as the disease progresses and are associated with unwanted side-effects such as dyskinesias and hallucinations ( 36 ). PD is clinically heterogeneous, and the rationale for lesioning depends on the dominant motor syndrome ( 37 ). In current practice, VIM FUSA is used for medication-refractory Parkinsonian tremor and, in selected advanced PD cohorts, for medication-refractory motor complications via pallidal or pallidothalamic pathway targets. These interventions are symptom-targeted rather than disease-modifying and primarily improve contralateral symptoms. For tremor-dominant PD, unilateral VIM thalamotomy has shown comparable efficacy to its use in ET ( 38 ), with notable reductions in tremor and functional impairment ( 39 , 40 ) ( Table 1 ). In patients with broader motor dysfunction (particularly rigidity and bradykinesia), subthalamotomy targeting the subthalamic nucleus has been investigated as an incisionless alternative to DBS ( 37 , 41 ). Additionally, lesioning of the globus pallidus internus (GPi) was shown to effectively treat fluctuations and medication-induced dyskinesia, among other motor symptoms, and is FDA-approved ( 42 – 45 ). As of 2025, staged-bilateral pallidothalamic tractotomy has been FDA-approved for PD. The publication with detailed outcomes is expected soon. Nonmotor symptomology remains relatively stable in FUSA thalamotomy, with no changes in cognitive function, mood, or behavior 12 months post-surgery ( 46 , 47 ). Emerging Indications and Other Neurological Disorders Beyond ET and PD, FUSA is investigational and being evaluated across neurologic disorders in which focal interruption of pathological circuitry may provide symptom relief. Evidence is generally early-stage (case reports and small cohorts) with variable targets, endpoints, and follow-up. Interpretation should emphasize evidence level, target-symptom specificity, durability, and standardized adverse-effect profiles ( Table 1 ). Dystonia and Dystonic Tremor Dystonia comprises a diverse set of hyperkinetic syndromes in which abnormal network dynamics across cortico-basal ganglia-thalamo-cortical loops produce sustained or intermittent muscle contractions and abnormal postures ( 48 ). FUSA experience remains investigational and has focused primarily on thalamic targets within the ventro-oral (Vo) nucleus for focal, task-specific dystonias and pallidal targets (GPi) in more generalized or severe phenotypes where pallidal circuit intervention aligns with established lesioning and DBS approaches ( 33 ). Vo thalamotomy, performed unilaterally or staged bilaterally ( 49 ), has shown preliminary functional improvements in cervical ( 50 ) and focal hand dystonia ( 51 ), including musician’s dystonia ( 52 ), though FUSA experience remains limited ( 33 ). GPi lesioning, though still relatively rare in FUSA applications, has shown early promise in improving both focal and generalized dystonia ( 53 ). The potential for possibly permanent adverse events, such as speech disorder, has raised caution, but the opportunity to relieve severe dystonic symptoms might justify pallidotomy ( 53 ). Dystonic tremor and mixed tremor syndromes may reflect overlapping cerebellothalamic and basal ganglia network contributions. Target selection may therefore differ from ET, and early work suggests optimal lesion location can differ systematically across dystonic and essential tremor phenotypes. Available reports suggest tremor reduction is achievable in selected patients, but interpretation should consider whether dystonia severity improves in parallel, whether residual dystonia limits long-term quality of life despite tremor suppression, and whether adverse effects (particularly speech and gait) are acceptable given baseline dystonic features ( 52 , 54 , 55 ). Epilepsy Clinical epilepsy affects approximately 1% of the population ( 56 , 57 ). Approximately one-third of epilepsy patients develop drug-resistant epilepsy (DRE) despite adequate medication trials ( 58 ). In such cases, alternative interventions may be considered, including surgical resection, neuromodulation, and investigational therapies like FUSA. FUSA can be employed to disrupt hyperexcitable circuitry by manipulating neuronal excitability through specific tissue ablation or neuromodulation ( 3 ). Preclinical models using Kainic acid-induced seizures and subsequent tissue lesioning have demonstrated FUS’s efficacy in targeting and disrupting epileptogenic circuits ( 56 ). Early clinical case reports show promise. For example, Yamaguchi and colleagues describe a 26-year-old male with gelastic epilepsy from a hypothalamic hamartoma as 1-year seizure-free following FUSA of a parahypothalamic hamartoma ( 59 ). FUS for epilepsy is currently investigational and is primarily available through clinical trials. Candidates typically have DRE with clearly localized seizure foci in regions of interest (ROIs) such as the hippocampus or hypothalamus ( 3 ) and the anterior thalamic nucleus ( 60 ). In a phase 1, open-label pilot of unilateral anterior thalamic MR-guided focused ultrasound ablation for drug-resistant focal epilepsy (n=2), investigators deployed a comprehensive, serial neuropsychological battery spanning global cognition, language, memory, visuospatial skills, attention/executive function, processing/motor speed, and mood/QOL. Safety was adjudicated by the absence of meaningful decline on relevant tests (Animal Fluency, RAVLT, Trail Making Test–B) using a conservative regression-based Reliable Change Index (RCI; McSweeny model, 90% CI), and results showed no neurologic deficits/serious adverse events but verbal memory decline in one participant alongside marked seizure reduction (one seizure-free at 12 months; the other improved from ~90–100 seizures/month to ~3–6/month). Neuropathic pain For chronic, therapy-refractory neuropathic pain, lesioning strategies have targeted thalamic nodes implicated in pain perception and affective salience, most prominently FUSA of the central lateral (CL) thalamic nucleus. Single-center experiences and prospective studies suggest CL-FUSA is feasible and may reduce pain severity on validated scales in selected refractory populations, specifically trigeminal neuropathic pain syndromes ( 61 ). Extending FUSA beyond thalamic targets, a single-center early-phase trial of unilateral MR-guided FUSA mesencephalotomy for severe refractory head and neck cancer pain (n=5) demonstrated technical feasibility and variable analgesic benefit, with predominantly mild procedural morbidity and one transient episode of obtundation ( 62 ). However, cohorts remain relatively small, and durability, responder phenotypes, and comparative effectiveness versus other approaches are not yet defined. Results from early-phase studies suggest selective lesioning of the CL and other targets (e.g., the ventroposterolateral thalamic nucleus) can reduce pain perception with minimal side effects ( 61 , 63 – 65 ). Pain indications require careful attention to cognitive and affective side effects, given thalamic involvement in arousal and salience networks. Trials should pair pain outcomes with structured neuropsychological and mood assessments and report functional outcomes (sleep, daily activity, analgesic burden) in addition to pain intensity scores. Expansion to Neuropsychiatric Indications Psychiatric neurosurgery has progressed from frontal lobotomy-era to anatomically defined stereotactic lesioning, placing increasing emphasis on target specificity, patient selection, and standardized outcome assessment. Historical experience with lobotomy highlighted substantial risks of cognitive, affective, and behavioral adverse effects, underscoring the need for safeguards when operating on complex neural networks underlying mood and behavior ( 66 ).Today, neurosurgery for psychiatric diseases continues to increase in frequency across the globe, and there remains a need for ablative procedures, specifically in treatment-resistant cases. Stereotactic techniques have improved anatomical precision through invasive radiofrequency lesioning and adopted incisionless approach with gamma knife radiosurgery. FUSA offers an alternative approach that leverages image-guided, incisionless lesioning and intra-procedural monitoring to enhance target accuracy, control lesion parameters, and improve safety profiles (for additional comparisons of FUSA to other relevant modalities, please refer to Table 2 ). Neuropsychiatric disorders are increasingly conceptualized as disturbances of distributed cortico-striato-thalamo-cortical (CSTC) and limbic networks ( 67 – 69 ). Similar to its applications in movement disorders, FUSA can best be viewed as a platform for circuit intervention in psychiatric conditions through irreversible lesioning. Table 2. Comparison Between FUS and Various Ablative and Neuromodulatory Treatment Modalities. Feature Ablation Neuromodulation Focused Ultrasound Ablation (FUSA) Radiosurgery Radiofrequency Focused Ultrasound Neuromodulation (FUSN) Deep Brain Stimulation (DBS) Transcranial Magnetic Stimulation (TMS) Electroconvulsive therapy (ECT) Time scale for improvement Immediate Delayed (6 weeks-3 months) Immediate Immediate, intermediate (2-4 weeks) Time-locked with stimulation, intermediate, and delayed (3+ months) Intermediate and delayed (2-4 weeks of multiple sessions) Immediate, intermediate (1-6 weeks) Reversibility Irreversible lesion Irreversible lesion Irreversible lesion Reversible inhibition/excitation Stimulation reversible, Hardware can be explanted. Reversible Reversible Treatment titration Parameter titration possible at point-of-care. No parameter titration possible Parameter titration possible at point-of-care. Parameter titration possible at point-of-care. Programming enables personalized therapy which can be programmed for ongoing titration of symptom control Parameter titration possible at point-of-care. N/A Hardware None implanted None implanted None implanted None implanted Implanted leads/IPG; battery replacements None implanted None implanted Clinical delivery setting Outpatient Outpatient Inpatient Outpatient Inpatient/outpatient Outpatient Inpatient Visit burden Single or staged bilateral treatments and few follow-up visits Single or staged bilateral treatments and few follow-up visits Single or staged bilateral treatments and few follow-up visits Multiple treatmnent sessions and few follow-up after recovery Staged treatments and several visits for programming and hardware management Ongoing sessions; maintenance protocols vary Single or multiple sessions, Follow-up protocols vary Evidence maturity (neuro and psychiatry) Strongest in ET and PD; emerging in psychiatric conditions Moderate evidence in movement disorders and psychiatric conditions Established for movement disorders, psychiatric disorders, and pain Emerging in psychiatric conditions Strong across neurological and psychiatric disorders Strong in depression; variable across other indications Strong in depression; variable across other indications Key risks/limitations Off-target neurologic deficits; irreversibility Off-target neurologic deficits; irreversibility, radiation toxicity Surgical risks, infection, hemorrhage, off-target neurologic deficits; irreversibility Risk of cavitation reported, target engagement not established Surgical risks, infection, hemorrhage, hardware complications Seizure risk is low but non-zero; variable response Risk for memory decline Best use case scenario Medication-refractory symptom(s); anatomically defined therapeutic targets at millimeter scale; clinical feedback for improvement or off-target side effects can be useful Medication-refractory symptom(s); anatomically defined therapeutic targets at millimeter scale Medication-refractory symptom(s); anatomically defined therapeutic targets at millimeter scale; clinical feedback for improvement or off-target side effects can be useful; not often prescribed Medication-refractory symptom/s; anatomically defined therapeutic targets at millimeter scale; clinical feedback for improvement or off-target side effects can be useful Medication-refractory symptom(s); anatomically defined therapeutic targets at millimeter scale; progressive or bilateral symptoms needing adjustability Network-level modulation with repeatability Treatment-resistant symptoms, rapid symptom relief desired Future directions Parameter optimization, hardware and software enhancement, testing for novel indications. Wider adoption N/A Feedback for target engagement, parameter optimization, testing for novel indications. Closed-loop stimulation optimization, better understanding of mechanisms, patient selection Parameter optimization, wider adoption. Risk reduction strategies Open in a new tab Obsessive-Compulsive Disorder FUSA in obsessive-compulsive disorder (OCD) has focused predominantly on anterior capsulotomy targeting the anterior limb of the internal capsule (ALIC) to modulate CSTC circuitry implicated in severe, treatment-refractory OCD ( 70 , 71 ). Evidence consists primarily of open-label cohorts, with outcomes commonly assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and prespecified response criteria. Symptom change may evolve over weeks to months rather than immediately, consistent with historical lesion-based CSTC interventions ( 71 ). FUSA was deemed to be a safe and effective intervention for treatment-refractory OCD, with maintained effect and minimal adverse events ten years after surgery ( 72 ). Most notably, FUSA reduced levels of frontal lobe damage and cognitive decline compared to alternative lesioning modalities (e.g., radiosurgery ( 73 )), offering advantages to other surgical interventions that carry higher risks for adverse effects ( 74 ). Ongoing trials reflect continued efforts to define optimal targeting, safety margins, and durability, although more studies are needed in larger cohorts with sham controls to fully evaluate the surgical efficacy. Future studies should consider monitoring neuropsychological and affective changes, suicidal symptoms, evaluating long-term durability, and implementing structured adverse-event reporting. Treatment-Resistant Major Depressive Disorder Evidence for FUSA in treatment-resistant depression (TRD) remains early-stage, with small cohorts and non-uniform endpoints. Depression outcomes are also frequently reported in mixed cohorts, limiting cross-study generalization ( 70 ). The primary target remains the ALIC, with initial findings appearing to be more variable than those seen in OCD ( 70 ). Lower response rates were reported in a mixed-cohort design, while a dramatic symptom relief was demonstrated in another single case report as well ( 75 ). No serious adverse events have been reported, with no associated deficits in cognitive functioning ( 70 , 76 ). More trials are needed to optimize targeting in TRD cases, as preliminary evidence suggests optimal lesion location differs from that in OCD ( 76 ). Progress will likely require biomarker-linked hypotheses, standardized endpoints, and trial designs incorporating sham and blinded assessments where feasible. Substance Use Disorders Substance use disorders (SUD) are increasingly modeled as dysregulation of reward/salience and cognitive control networks, with particular interest in the nucleus accumbens (NAc) and ventral striatum as convergent nodes ( 77 ) While stereotactic surgery has demonstrated positive preliminary results of ablative techniques for reducing alcohol dependence ( 78 ), FUSA has not yet been explored in this context. High-frequency, sub-ablative targeting of the NAc has been safely attempted and corresponded with decreases in alcohol cravings ( 79 ), however, true ablation of this region remains difficult due to its anatomical position and complex circuit connections, increasing the risk for adverse effects ( 79 ). Non-Ablative Modalities Enabling Psychiatric Translation The possibility of employing low-frequency neuromodulation in psychiatric conditions represents a relatively new expansion of focused ultrasound technology. The reversibility and repeatability of FUSN make it attractive for psychiatry, but parameter- and state-dependence, as well as expectancy effects, necessitate sham control, blinded ratings, and objective biomarkers of target engagement, alongside harmonized reporting standards. FUSN has been explored as a treatment for SUD ( 80 , 81 ), depression ( 82 , 83 ), and anxiety ( 84 ) with promising early results. More studies are needed to add consistency to FUSN procedures, as well as optimization of sonication parameters, treatment schedule, and surgical targets. Future Directions in Focused Ultrasound Lesioning A prominent innovation involves further leveraging of advanced neuroimaging to characterize FUSA lesions. Correlating lesion characteristics (e.g., volume, location, diffusion profile) with clinical outcomes may provide insight into features that predict long-term benefit or side effects ( 85 ). Innovations such as passive cavitation monitoring are being integrated into clinical protocols to enhance procedural safety ( 63 ). Emerging strategies, including skull correction algorithms, phase array adjustments, and advanced acoustic simulations, are in development to expand eligibility and improve lesion precision in patients with challenging skull anatomy ( 86 , 87 ). The development of personalized medicine in FUSA is supported by advances in imaging ( 92 ). Techniques such as DTI and quantitative susceptibility mapping (QSM) allow for individualized delineation of targets based on patient-specific neuroanatomy and symptom profiles. Genetic stratification of patient cohorts, especially in disorders like dystonia and PD, may further optimize patient selection and predict treatment response. Longitudinal follow-up of genetically and phenotypically characterized patients will be critical in defining durable clinical benefit. Likewise, a deeper understanding of the long-term biological changes following FUSA is essential for optimizing FUS interventions. Resting-state functional MRI (rs-fMRI) provides a powerful tool for identifying seizure networks, thereby refining the localization of the seizure-onset zone (SOZ). Clinical studies demonstrate that incorporation of rs-fMRI can improve surgical outcomes by enhancing targeting accuracy in hypothalamic hamartomas and other focal epilepsy syndromes ( 93 , 94 ). Rs-fMRI can differentiate seizure-onset from propagation regions and provide network-level markers predictive of outcomes, increasingly enabled by AI-assisted analyses ( 95 , 96 ). Emerging research further supports integration of functional connectivity biomarkers into pre-surgical evaluation to guide individualized therapy ( 97 ). Notably, the complementary use of rs-fMRI and FUS can extend beyond epilepsy to movement disorders, where aberrant cortico-basal ganglia-thalamo-cortical loops are central to tremor and PD. Resting-state connectivity can be leveraged to optimize FUSA thalamotomy targeting in ET and Parkinsonian tremor, improving biomarker-based prediction of clinical response ( 98 ). There is also growing emphasis on understanding network dynamics in neurological disorders and defining what optimal network resetting looks like after FUSA ( 89 ). In ET, for instance, lesioning the VIM affects not just the thalamus but the entire CTC, with emerging evidence suggesting that network connectivity changes may mediate both therapeutic and adverse effects ( 90 ). Similarly, in PD, lesioning of the STN or GPi impacts broader basal ganglia-thalamocortical and cerebellar pathways ( 91 ). Ongoing investigations seek to address how neural tracts regenerate, how functional networks reorganize, and whether therapeutic effects arise solely from lesioning or also from broader network-level adaptations ( 99 ). An additional area of integration of FUSA in personalized medicine is the emergence of theranostic strategies: the integration of therapy and diagnostics into a single procedure ( 100 ). Radiotracers used in Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) imaging may be combined with FUS treatments to monitor and quantify drug delivery, verify the spatial distribution of treatment effects, and guide real-time adjustments to sonication parameters. These hybrid approaches can offer a feedback-controlled system, improving both safety and therapeutic accuracy. For instance, PET radioligands targeting inflammatory markers could help assess neuroinflammation pre- and post-FUSA, while functional imaging may help validate network-level changes in disorders like OCD, depression, and PD. Challenges & Considerations Despite the promising clinical applications of FUSA, ethical, regulatory, and logistical challenges remain and must be addressed to ensure its broader adoption and sustained success. A key area of focus for FUSA safety is limiting off-target effects that can cause adverse effects, which are specific to neurological disorders and brain regions for lesioning. Further, the waning benefit of a single ablation as the disease progresses remains a concern in using FUSA as a long-term treatment of neurological disorders ( 101 ). Proper patient selection (identifying candidates whose symptoms, disease stage, and neuroanatomy are most likely to benefit from FUSA) and careful treatment planning to accurately target the intended brain region are essential for optimal clinical outcomes. In addition, larger, prospective studies are needed to establish consistent criteria for patient selection and FUSA parameter optimization in addressing specific symptoms across different neurological disorders ( 102 ). Within disease phenotypes, treatment response is not always uniform across patients due to factors such as targeting accuracy, skull characteristics, and sonication parameters ( 11 , 30 , 103 ). In VIM ablation for ET, gait instability, ataxia, and paresthesia are among the most reported adverse events, though they are typically transient and tend to improve over time ( 30 ). Efforts to refine targeting, primarily through pre-operative DTI and tractography, are underway to enhance target identification and avoid off-target ablation of critical fiber pathways ( 25 ). These imaging advances not only aim to improve safety and efficacy but also support the development of more standardized treatment protocols, potentially reducing inter-patient variability and improving reproducibility across clinical centers. Further research on bilateral procedures, consistent mapping of targets optimized for symptom relief, and limiting adverse events through precise ablation are key issues that, if addressed, would strengthen the efficacy of FUSA ( 105 , 106 ). While a few applications have received FDA approval, many indications remain investigational and subject to time-consuming clinical trial pathways. Delays in regulatory approvals are compounded by the need for rigorous safety monitoring, standardized outcome measures, and multi-center validation. Beyond regulatory barriers, patient access and education represent critical areas in need of development. Insurance reimbursement remains inconsistent, particularly in the United States, where coverage is typically limited to FDA-approved uses. Likewise, off-label or investigational applications may not be insurance covered. This financial barrier may discourage eligible patients from pursuing treatment or participating in clinical trials, limiting the pool of participants needed to develop robust, patient-centered outcome measures and ensure diversity in study populations. Outreach and education initiatives are essential for building awareness and promoting access in the future. Considerations for Expansion in Psychiatric Practice For FUSA to be adequately integrated into psychiatric practice, the following factors should be considered: limitations of current technology and imaging, patient-specific circumstances, and establishment of standardized procedural protocols. Transducers organized in hemispheric arrays favor targets near the geometric center of the brain, where beam paths are less oblique and skull trajectory is more uniform. Targets that are more lateral (closer to the cerebral cortex), or near skull base/sinuses, may be constrained by beam path geometry, aberration, and off-target heating risk. MR thermometry is foundational to safety and dosing, but it provides merely an estimate rather than direct temperature measurement and can be affected by susceptibility and local anatomic factors. Thermometry also samples selected planes/regions, reinforcing the need for conservative escalation, careful selection of monitoring planes, and prespecified safety thresholds. Because procedures are typically performed awake to permit serial neurologic examinations, patient tolerance and ability to cooperate can determine procedural success. Anxiety, pain tolerance, baseline cognitive impairment, severe involuntary movements limiting stillness, and inability to remain in the MRI environment can degrade thermometry quality and targeting precision. MRI contraindications and severe claustrophobia may preclude treatment in many settings. FUSA offers incisionless lesioning but remains irreversible, with limited capacity to respond to delayed adverse effects beyond supportive care and additional lesioning. Procedural conservatism, explicit stop rules, and collaborative decision-making are integral to the workflow. Outcomes depend not only on target and indication but also on procedural expertise, imaging protocols, thermometry review, sonication strategies, and outcome measurement. Standardization of these elements will be central to reducing inter-site variability and improving interpretability across emerging indications. Acknowledgements & Disclosures: VK was supported by the National Institute of Health (1-R01-NS125386-01). VLB was supported by the National Institute of Health (R-01-5126105). VK has received funding for clinical trials from Insightec and Focused Ultrasound Foundation. All other authors report no biomedical financial interests or potential conflicts of interest. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. References: 1. Hynynen K, Clement GT, McDannold N, Vykhodtseva N, King R, White PJ, et al. (2004): 500-element ultrasound phased array system for noninvasive focal surgery of the brain: A preliminary rabbit study with ex vivo human skulls. 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