A Review of the Current Therapies, Challenges, and Future Directions of Transcranial Focused Ultrasound Technology: Advances in Diagnosis and Treatment
Abstract
Importance: Magnetic resonance imaging-guided focused ultrasound ablation has been approved for the treatment of refractory essential tremor and is being studied for other neurological indications, including dyskinesias and tremor in Parkinson disease, dystonia, neuropathic pain, obsessive-compulsive disorder, epilepsy, and brain tumors. Objective: To review the scientific foundations of FUS technology, existing neurological applications, and future advances. Evidence Review: PubMed was searched for the past 10 years using the terms "transcranial ultrasound," "focused ultrasound," and "neurological applications." Relevant references were selected from the author's reference collection. From the 2855 unique records, 243 publications were screened. After excluding abstracts detailing in vitro studies or non-neurological applications, 86 full texts were retrieved for qualitative review. Findings: Advances in the transducer design and electronic phase correction have allowed efficient focusing of ultrasounds for transcranial treatment. The mid-frequency (650 kHz) transducer can make small (4-6 mm in diameter) and precise (accuracy of <2 mm) brain lesions. The treatment monitoring is achieved via "live" anatomical thermography imaging and clinical feedback. The initial results from its clinical application in movement disorders are encouraging. Emerging applications in epilepsy and neurobehavioral and cognitive disorders are being explored. The low-frequency (220 kHz) transducer coupled with microbubbles can potentially enable targeted drug delivery for novel applications, such as Alzheimer disease and brain tumors. Finally, neuromodulation with subthreshold sonications may allow the interrogation of brain areas previously not accessible for electrical stimulation. Conclusions and Relevance: Transcranial focused ultrasound for both ablative and nonablative applications is noninvasive, making it suitable for selected patients who are not candidates for conventional surgical options. Future advancements in imaging and sonication algorithms will improve the safety and efficacy of this technology.
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Animal studies have demonstrated safe and reversible blood-brain barrier opening with focused ultrasound.
“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [4]
Animal studies have demonstrated reduction of amyloid-beta plaque, neurogenesis, and improvement of memory with focused ultrasound.
“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [4]
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“on MR-guided high-intensity focused ultrasound see for example (Krishna et al., 2018; Schlesinger et al., 2017) .”
Enhanced microbubble contrast agent oscillation following 250 kHz insonation
Ilovitsh, T., Ilovitsh, A., Foiret, J. L., Caskey, C. F., Kusunose, J., Fite, B. Z., Zhang, H., Mahakian, L. M., Tam, S. M., Pauly, K. B., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-34494-5 · Cited by 82 · see citing works
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“No more than 140 seconds of continuous PLIFUS was emitted to one brain target per session reported in most previous single-element piezoelectric transducer PLIFUS human studies (Izadifar et al. 2017; Krishna et al. 2017; Monti et al. 2016; Yoo 2018) and acoustic intensity was estimated to reach ISPTA = 4.”
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Emerging clinical applications of high-intensity focused ultrasound
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“3 There were two major outcomes: (1) memory improvements up to 3 months post-stimulation, and (2) neurophysiological”
BackgroundNoninvasive Focused Ultrasound for Neuromodulation
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Low intensity focused ultrasound: a new prospect for the treatment of Parkinson’s disease
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Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review
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Self-citationPredictors of Outcomes After Focused Ultrasound Thalamotomy.
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Self-citationNeurodegenerative disorders management: state-of-art and prospects of nano-biotechnology
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Perspectives on Recent Progress in Focused Ultrasound Immunotherapy
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“Transcranial FUS has been explored as an intervention for a variety of neurological pathologies including neurodegenerative diseases, primary and metastatic brain tumors, neuropathic pain, and psychiatric disorders [27].”
BackgroundUltrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery
Arsiwala, T. A., Sprowls, S. A., Blethen, K. E., Adkins, C. E., Saralkar, P. A., Fladeland, R. A., Pentz, W. H., Gabriele, A., Kielkowski, B. N., Mehta, R. I., et al. (2021) · Neoplasia · doi:10.1016/j.neo.2021.04.005 · Cited by 59 · see citing works
Self-citationSensors and Devices Guided by Artificial Intelligence for Personalized Pain Medicine
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“As a noninvasive approach with low risk, US therapy allows for the customization of treatment parameters based on the specific conditions and responses of patients, making it suitable for a wide range of pain conditions [112].”
BackgroundEvolution of concepts in epilepsy surgery*
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Medical and Surgical Treatments for Dystonia
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Treatment of Dystonia: Medications, Neurotoxins, Neuromodulation, and Rehabilitation
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“[49,52] Additionally, contrast‑enhanced ultrasonography technology has also recently been developed.”
BackgroundPassive Aβ Immunotherapy: Current Achievements and Future Perspectives
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“Focused ltrasound (FUS) just rec ntly provided very promising results to increase the penetration of drugs through the blood–brain barrier (BBB) [67,68].”
BackgroundInfluentialFocused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease
LeWitt, P. A., Lipsman, N., & Kordower, J. H. (2019) · Movement Disorders · doi:10.1002/mds.27722 · Cited by 45 · see citing works
“ultrasound (FUS), involves pulses of sonication directed at tiny gas-filled microbubbles circulating with blood in the capillary vasculature.(6) FUS has the unique benefit of offering precisely controlled localization of drug delivery in an awake patient.”
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Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry
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Stem cell therapeutics and gene therapy for neurologic disorders
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Full-Matrix Phase Shift Migration Method for Transcranial Ultrasonic Imaging
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Ultrasound Ablation in Neurosurgery: Current Clinical Applications and Future Perspectives
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The patchy tremor landscape: recent advances in pathophysiology
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Nanomedicine and nanobiotechnology applications of magnetoelectric nanoparticles
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“Moreover, the safety of ultrasound waves in biomedical applications has been widely demonstrated, and it is extensively utilized in the clinic for biomedical imaging, rehabilitation physiotherapy, thrombolysis and tumor ablation (Krishna et al., 2017).”
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“Some of the downfalls of these drugs can be attributed to the failure to breach the BBB. Focused ultrasound opens the BBB, enhancing effective drug delivery [269].”
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New horizons in Parkinson’s disease in older populations
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Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises
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Focused Ultrasound Neuromodulation: Exploring a Novel Treatment for Severe Opioid Use Disorder
Rezai, A. R., Thompson-Lake, D. G. Y., D’Haese, P.-F., Meyer, N. H., Ranjan, M., Farmer, D. L., Finomore, V. S., Marton, J. L., Hodder, S., Carpenter, J., et al. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.01.001 · Cited by 36 · see citing works
“High-intensity FUS ablative procedures are routinely used worldwide to treat essential tremor and Parkinson ’ s disease (19 – 21).”
Self-citationFocused Ultrasound and Other Lesioning Therapies in Movement Disorders
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Recent Trends in the Use of Electrical Neuromodulation in Parkinson’s Disease
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Essential Tremor – Deep Brain Stimulation vs. Focused Ultrasound
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Treatment of Epilepsy Associated with Periventricular Nodular Heterotopia
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Ray Theory-Based Transcranial Phase Correction for Intracranial Imaging: A Phantom Study
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“In recent years, focused ultrasound (FUS) has emerged as a noninvasive therapeutic approach that enables the treatment of the brain at low frequencies (below 650 kHz) that can penetrate an intact human skull.(3,4) FUS-mediated thermal ablation has been used to treat over 500 patients for brain indications including br…”
BackgroundPérez‐Neri, I., González-Aguilar, A., Sandoval, H., Pineda, C., & Rı́os, C. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200720175253 · Cited by 26 · see citing works
Controlling action potentials with magnetoelectric nanoparticles
Zhang, E., Shotbolt, M., Chang, C.-Y., Scott‐Vandeusen, A., Chen, S., Liang, P., Radu, D. R., & Khizroev, S. (2024) · Brain stimulation · doi:10.1016/j.brs.2024.08.008 · Cited by 25 · see citing works
“…deep regions in the brain across multiple studies [15,17,18], but signal attenuation through the skull creates large variations in delivered power [19], and treatment modalities are more focused on higher risk, ablative approaches that are currently less successful than DBS treatments [20].”
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New Targets and New Technologies in the Treatment of Parkinson’s Disease: A Narrative Review
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“However, irreversible tissue ablation using high-energy FUS has some procedure-related complications or side effects on neighboring structures [22,44,50].”
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“Focused ultrasound treatments in the brain have now entered the clinic (Krishna et al., 2018).”
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Mitigating the Consequences of Subconcussive Head Injuries
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“While some progress has been made in the treatment of brain plaques (such as those putatively associated with CTE) using invasive and noninvasive methods (79), neurologists and engineers agree that preventing brain injuries is a more efficient and cost-effective approach to the problem.”
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“[30], it has been posited that there are three levels of network reorganization relating to the development of lower grade glioma.”
BackgroundPineda‐Pardo, J. A., Máñez-Miró, J. U., López‐Aguirre, M., Rodríguez‐Rojas, R., Caballero‐Insaurriaga, J., Del‐Alamo, M., Martínez‐Fernández, R., & Obeso, J. A. (2019) · Neurosurgery · doi:10.1093/neuros/nyz566 · Cited by 21 · see citing works
Surgical Management of Parkinson's Disease in the Elderly
de Azevedo, P. C., Aquino, C., & Fasano, A. A. (2021) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.13161 · Cited by 21 · see citing works
“For example, FUS cannot be performed in patients with unfavorable cranial thickness or contraindications to magnetic resonance imaging.(83,84)”
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Transcranial Magnetic Resonance-Guided Focused Ultrasound in X-Linked Dystonia-Parkinsonism
Jamora, R. D. G., Chang, W., & Taira, T. (2021) · Life · doi:10.3390/life11050392 · Cited by 20 · see citing works
“One advantage of the tcMRgFUS is its noninvasive approach [19].”
BackgroundUsing focused ultrasound to modulate microglial structure and function
Grewal, S., de Andrade, E. G., Kofoed, R. H., Matthews, P. M., Aubert, I., Tremblay, M., & Morse, S. V. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1290628 · Cited by 18 · see citing works
Cationic Magnetic Nanoparticles Activate Natural Killer Cells for the Treatment of Glioblastoma
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Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations
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Non-invasive brain stimulation to modulate neural activity in Parkinson’s disease
Bange, M., Helmich, R. C. G., Shukla, A. W., Deuschl, G., & Muthuraman, M. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00908-1 · Cited by 20 · see citing works
“Technological developments in ultrasound applications for treatment of neurological diseases are rapidly growing and need to be separated from diagnostic implementations 36 .”
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“In the past decade, low-intensity tFUS has emerged as a novel neuromodulation tool [14].”
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Neurosurgical neuromodulation therapy for psychiatric disorders
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“MRgFUS is a non-invasive method, which involves real-time MRI guidance and application of transcranial focused ultrasound and patient monitoring without a surgical incision or surgical hardware [119,120].”
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Self-citationCranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery)
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Recent developments in imaging of epilepsy
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“In a review by Krishna et al. (2017), advancements and applications of MRgFUS for various neurological conditions were discussed [43].”
Maesawa, S., Nakatsubo, D., Tsugawa, T., Kato, S., Shibata, M., Takai, S., Torii, J., Ishizaki, T., Wakabayashi, T., & Saito, R. (2021) · Neurologia medico-chirurgica · doi:10.2176/nmc.ra.2021-0187 · Cited by 15 · see citing works
Lafond, M., Payne, A., & Lafon, C. (2024) · International Journal of Hyperthermia · doi:10.1080/02656736.2024.2389288 · Cited by 17 · see citing works
- Authors
- Krishna, V., Sammartino, F., & Rezai, A.
- Affiliations
- The Ohio State University (US)
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-02-01
- Volume
- 75
- Issue
- 2
- Pages
- 246
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W2771503729
- Cited by
- 289
- References
- 71
- Citations by year
- 2026: 32 · 2025: 40 · 2024: 45 · 2023: 47 · 2022: 31 · 2021: 28 · 2020: 32 · 2019: 20 · 2018: 14
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Physical Sciences › Engineering › Biomedical Engineering › Photoacoustic and Ultrasonic Imaging
- Keywords
- transcranial focused ultrasound, essential tremor, movement disorders, Parkinson's disease, dystonia, neuropathic pain, epilepsy, neuromodulation, microbubbles, targeted drug delivery, Alzheimer's disease, brain tumors, transducer design, phase correction, infrared thermography
- MeSH terms
- Brain Diseases, Humans, Magnetic Resonance Imaging, Therapy, Computer-Assisted, Ultrasonography, Doppler, Transcranial
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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