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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 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]
In the citing paper
“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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“20 Preclinical studies in animal models of AD have demonstrated that administration of low-intensity FUS results in safe, focal, and reversible BBB opening, 11–13 with reduction of β -amyloid plaque, increased neurogenesis, and memory improvement.”
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“Focused ultrasound is being explored as a way to mechanically actuate the nervous system by focusing energy deep in the brain with a noninvasive transducer.(36) A disadvantage of focused ultrasound is the need for a large external transducer, which would be awkward to use outside a controlled environment.”
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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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“3 There were two major outcomes: (1) memory improvements up to 3 months post-stimulation, and (2) neurophysiological”
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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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“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].”
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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].”
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“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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“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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“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…”
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Controlling action potentials with magnetoelectric nanoparticles
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“…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].”
BackgroundDavidson, B., Mithani, K., Huang, Y., Jones, R. M., Goubran, M., Meng, Y., Snell, J., Hynynen, K., Hamani, C., & Lipsman, N. (2020) · Journal of neurosurgery · doi:10.3171/2020.6.jns201302 · Cited by 25
New Targets and New Technologies in the Treatment of Parkinson’s Disease: A Narrative Review
Montemurro, N., Aliaga, N., Graff, P., Escribano, A., & Lizana, J. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19148799 · Cited by 25
Shin, D. H., Son, S., & Kim, E. Y. (2023) · Brain Sciences · doi:10.3390/brainsci13101433 · Cited by 25
“However, irreversible tissue ablation using high-energy FUS has some procedure-related complications or side effects on neighboring structures [22,44,50].”
BackgroundCaballero‐Insaurriaga, J., Rodríguez‐Rojas, R., Martínez‐Fernández, R., Del‐Alamo, M., Díaz‐Jiménez, L., Ávila, M., Martínez‐Rodrigo, M., García‐Polo, P., & Pineda‐Pardo, J. A. (2019) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.26746 · Cited by 24
Fan, W., Chen, Y., Wang, Y., Wang, Y.-Q., Hu, J., Tang, W., Feng, Y., Cheng, Q., & Xue, L. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01186-2 · Cited by 23
Todd, N., McDannold, N. J., & Borsook, D. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.06.007 · Cited by 22
“Focused ultrasound treatments in the brain have now entered the clinic (Krishna et al., 2018).”
Carradori, D., Chen, H., Werner, B., Shah, A., Leonardi, C., Usuelli, M., Mezzenga, R., Platt, F., & Leroux, J. (2020) · Small · doi:10.1002/smll.202004735 · Cited by 19
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Mitigating the Consequences of Subconcussive Head Injuries
Nauman, E. A., Talavage, T. M., & Auerbach, P. S. (2020) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-091219-053447 · Cited by 23
“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.”
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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 22
“For example, FUS cannot be performed in patients with unfavorable cranial thickness or contraindications to magnetic resonance imaging.(83,84)”
BackgroundLibrizzi, L., Uva, L., Raspagliesi, L., Gionso, M., Regondi, M. C., Durando, G., DiMeco, F., de Curtis, M., & Prada, F. U. (2022) · Scientific Reports · doi:10.1038/s41598-022-06791-7 · Cited by 22
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
“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 19
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 21
“Technological developments in ultrasound applications for treatment of neurological diseases are rapidly growing and need to be separated from diagnostic implementations 36 .”
Shi, Y., Cai, G., & Wu, W. (2025) · Journal of NeuroEngineering and Rehabilitation · doi:10.1186/s12984-025-01753-2 · Cited by 24
“In the past decade, low-intensity tFUS has emerged as a novel neuromodulation tool [14].”
Maragkos, G. Α., Kosyakovsky, J., Zhao, P., Kearns, K. N., Rush-Evans, S., Moosa, S., & Elias, W. J. (2023) · Neurosurgery · doi:10.1227/neu.0000000000002518 · Cited by 18
Neurosurgical neuromodulation therapy for psychiatric disorders
Ranjan, M., Mahoney, J. J., & Rezai, A. R. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00366 · Cited by 21
“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].”
BackgroundSelf-citationChesney, K. M., Keating, G. F., Patel, N. P., Kilburn, L. B., Fonseca, A., Wu, C., Nazarian, J., Packer, R. J., Donoho, D. A., Oluigbo, C. O., et al. (2024) · Child s Nervous System · doi:10.1007/s00381-024-06413-9 · Cited by 18
Sammartino, F., Snell, J., Eames, M. D. C., & Krishna, V. (2021) · Neurosurgery · doi:10.1093/neuros/nyab238 · Cited by 16
Self-citationCranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery)
Bene, M. D., Raspagliesi, L., Carone, G., Gaviani, P., Silvani, A., Solbiati, L., Prada, F. U., & DiMeco, F. (2022) · Journal of Neuro-Oncology · doi:10.1007/s11060-021-03929-x · Cited by 19
Recent developments in imaging of epilepsy
Wiest, R., & Beisteiner, R. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000704 · Cited by 18
Moshayedi, A. J., Mokhtari, T., & Andani, M. E. (2024) · Brain Sciences · doi:10.3390/brainsci15010020 · Cited by 17
“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
Lafond, M., Payne, A., & Lafon, C. (2024) · International Journal of Hyperthermia · doi:10.1080/02656736.2024.2389288 · Cited by 17
Metadata
- 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 › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- 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
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