Focused ultrasound (FUS) is a non-invasive therapeutic technology that uses converging acoustic waves to deliver targeted energy to deep brain structures. In the context of [neurodegenerative diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases, FUS serves two major roles: therapeutic ablation (high-intensity focused ultrasound, HIFU) for movement disorder symptom relief, and [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- ([BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening (low-intensity pulsed ultrasound with microbubbles) to enable drug delivery to the central nervous system.
The [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- is the principal obstacle to delivering therapeutic antibodies, [gene therapies[/treatments/[gene-therapy[/treatments/[gene-therapy[/treatments/[gene-therapy--TEMP--/treatments)--FIX--, and nanoparticles to the brain. FUS combined with intravenous microbubbles provides transient, targeted, and reversible [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening, enabling focal delivery of agents that would otherwise be excluded from the CNS. This approach has entered clinical trials for [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX-- (AD), [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX-- (PD), and [amyotrophic lateral sclerosis[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX-- (ALS) (Meng et al., 2024).
HIFU uses high acoustic power to raise tissue temperature above 55°C at the focal point, producing a precise thermal lesion. MRI-guided focused ultrasound (MRgFUS) enables real-time temperature monitoring and targeting with sub-millimeter accuracy. The ExAblate Neuro system (Insightec) is the primary FDA-approved platform (Lipsman et al., 2014).
At low acoustic pressures, ultrasound interacts with intravenously injected lipid-shelled microbubbles (1-10 μm diameter). Microbubble oscillation within cerebral capillaries mechanically stretches tight junctions between endothelial cells, transiently opening the [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- for 4-6 hours without thermal damage. This allows macromolecules including antibodies (150 kDa) and viral vectors to enter the brain parenchyma (Hynynen et al., 2001).
In transgenic AD mouse models, repeated FUS-mediated [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening alone—without co-administered drugs—reduced [amyloid plaque] burden by 20-50% and improved cognitive performance. Proposed mechanisms include:
- [Enhanced [microglial[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX--https://pubmed.ncbi.nlm.nih.gov/23487788/); Leinenga & Götz, 2015)
| Trial |
Phase |
Target |
N |
Key Finding |
| Lipsman et al. (2018) |
I |
Right frontal lobe (AD) |
5 |
Safe, reversible [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening in AD patients (Lipsman et al., 2018) |
| Rezai et al. (2020) |
I |
[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- (AD) |
6 |
[BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening in [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- achievable |
| D'Haese et al. (2020) |
II |
[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- (AD) |
10 |
Repeated [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening safe; amyloid PET reduction in treated regions |
| ExAblate AD trial |
II/III |
Multiple regions |
Ongoing |
Evaluating [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening combined with [aducanumab[/treatments/[aducanumab[/treatments/[aducanumab[/treatments/[aducanumab--TEMP--/treatments)--FIX-- |
A 2025 systematic review and meta-analysis of FUS-mediated [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening in AD found the procedure to be safe and reversible, with evidence of local amyloid clearance in treated regions (Li et al., 2025).
FUS-[BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening dramatically increases brain penetration of anti-amyloid antibodies:
- [Aducanumab[/treatments/[aducanumab[/treatments/[aducanumab[/treatments/[aducanumab--TEMP--/treatments)--FIX--: 5-7 fold increase in brain concentration with FUS
- [lecanemab[/treatments/[lecanemab[/treatments/[lecanemab[/treatments/[lecanemab--TEMP--/treatments)--FIX--: Enhanced delivery under investigation
- [donanemab[/treatments/[donanemab[/treatments/[donanemab[/treatments/[donanemab--TEMP--/treatments)--FIX--: Enhanced delivery under investigation
This could potentially allow lower systemic doses, reducing the risk of [ARIA] (amyloid-related imaging abnormalities) while maintaining therapeutic efficacy.
MRgFUS thalamotomy (thermal ablation of the ventral intermediate nucleus, Vim) is FDA-approved for medication-refractory essential tremor and has been evaluated for tremor-dominant [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX--:
- Mechanism: Precise thermal lesion in Vim thalamus interrupts the cerebello-thalamo-cortical tremor circuit
- Efficacy: Randomized controlled trials demonstrate >50% tremor reduction sustained at 2-year follow-up
- Advantages: Non-invasive alternative to [deep brain stimulation[/treatments/[deep-brain-stimulation[/treatments/[deep-brain-stimulation[/treatments/[deep-brain-stimulation--TEMP--/treatments)--FIX-- (DBS); no implanted hardware; outpatient procedure
(Lancet Neurology, 2025)
¶ Subthalamotomy and Pallidotomy
FUS ablation of the subthalamic nucleus (STN) or globus pallidus internus (GPi) for PD motor symptoms is under investigation:
- MRgFUS subthalamotomy: Phase I trials show improvement in motor scores (UPDRS Part III)
- MRgFUS pallidotomy: Being explored for [levodopa[/treatments/[levodopa[/treatments/[levodopa[/treatments/[levodopa--TEMP--/treatments)--FIX---induced dyskinesias
A Phase I trial by Gasca-Salas et al. (2021) demonstrated that FUS-[BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening targeted at the parietal-occipital-temporal junction in PD dementia patients was safe, reversible, and repeatable (successful in 8/10 treatments), with some evidence of increased [dopamine[/entities/[dopamine[/entities/[dopamine[/entities/[dopamine--TEMP--/entities)--FIX-- transporter binding in treated regions (Gasca-Salas et al., 2021).
FUS-[BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening is being explored to enhance delivery of:
- [Antisense oligonucleotides[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy--TEMP--/treatments)--FIX-- (ASOs) targeting [SOD1[/proteins/[sod1-protein[/proteins/[sod1-protein[/proteins/[sod1-protein--TEMP--/proteins)--FIX-- or [C9orf72[/genes/[c9orf72[/genes/[c9orf72[/genes/[c9orf72--TEMP--/genes)--FIX--
- [Gene therapy[/treatments/[gene-therapy[/treatments/[gene-therapy[/treatments/[gene-therapy--TEMP--/treatments)--FIX-- vectors (AAV)
- Neurotrophic factors ([BDNF[/entities/[bdnf[/entities/[bdnf[/entities/[bdnf--TEMP--/entities)--FIX--, [GDNF)
Preclinical studies demonstrate FUS-enhanced delivery of:
- [Antisense oligonucleotides[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy--TEMP--/treatments)--FIX-- targeting mutant [huntingtin[/proteins/[huntingtin[/proteins/[huntingtin[/proteins/[huntingtin--TEMP--/proteins)--FIX--
- CRISPR components for gene editing
- Antibodies targeting mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX--
Beyond mechanical [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening, FUS produces immunomodulatory effects relevant to neurodegeneration:
- Microglial activation: FUS shifts [microglial[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX--/cell-types/[microglia[/[astrocytes[/[astrocytes[/[astrocytes[/[astrocytes[/[astrocytes[/astrocytes upregulate clearance-related gene expression following FUS
- Neurotrophin release: FUS stimulates local [BDNF[/entities/[bdnf[/entities/[bdnf[/entities/[bdnf--TEMP--/entities)--FIX-- and [GDNF[/entities/[gdnf[/entities/[gdnf[/entities/[gdnf--TEMP--/entities)--FIX-- expression
- Complement activation: Transient [complement] activation at the site of [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening may facilitate debris clearance
- T-cell infiltration: [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening allows peripheral immune cells to enter the brain, with potential benefits for immunosurveillance
([Wang et al., 2024)(https://onlinelibrary.wiley.com/doi/full/10.1002/agm2.12371))
- Common: headache during procedure, transient paresthesias
- Uncommon: persistent paresthesias, ataxia, hemorrhage at lesion site
- Skull density ratio affects treatment feasibility (>0.40 required)
- Generally well-tolerated; no serious adverse events in trials to date
- MRI findings: transient T2 hyperintensity, occasional microhemorrhages (resolving)
- [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- closure confirmed within 24 hours by contrast MRI
- Repeated treatments (up to 6 sessions) have shown no cumulative safety signals
Key safety monitoring includes [ARIA]-like changes on MRI, neurological examination, and cognitive testing.
- Implantable FUS devices: Skull-mounted transducers (e.g., SonoCloud) for chronic, repeated [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- opening without MRI guidance
- Sono-immunotherapy: Combining FUS-BBB opening with [immunotherapy[/treatments/[immunotherapy[/treatments/[immunotherapy[/treatments/[immunotherapy--TEMP--/treatments)--FIX-- for enhanced CNS delivery of therapeutic antibodies
- FUS + gene therapy: Ultrasound-mediated delivery of AAV vectors for [gene therapy[/treatments/[gene-therapy[/treatments/[gene-therapy[/treatments/[gene-therapy--TEMP--/treatments)--FIX-- targeting specific brain regions
- Low-intensity therapeutic ultrasound: Non-BBB-opening neuroprotective effects including anti-inflammatory signaling and neuroplasticity enhancement
- AI-guided targeting: Machine learning algorithms for optimal treatment planning based on individual skull and brain anatomy
- Combination therapy: FUS-BBB opening with [anti-amyloid] antibodies, tau] antibodies, or ASOs
- [Aducanumab (Aduhelm)[/treatments/[aducanumab[/treatments/[aducanumab[/treatments/[aducanumab--TEMP--/treatments)--FIX--
- [Antisense Oligonucleotide (ASO) Therapy in Neurodegeneration[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy--TEMP--/treatments)--FIX--
- [Deep Brain Stimulation (DBS)[/treatments/[deep-brain-stimulation[/treatments/[deep-brain-stimulation[/treatments/[deep-brain-stimulation--TEMP--/treatments)--FIX--
- [Gene Therapy for Neurodegenerative Diseases[/treatments/[gene-therapy[/treatments/[gene-therapy[/treatments/[gene-therapy--TEMP--/treatments)--FIX--
- [Immunotherapy for Neurodegenerative Diseases[/treatments/[immunotherapy[/treatments/[immunotherapy[/treatments/[immunotherapy--TEMP--/treatments)--FIX--
The study of Focused Ultrasound Therapy For Neurodegenerative Diseases has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [Meng Y, Pople CB, Bhatt S, et al. (2024). Current clinical investigations of focused ultrasound Blood-Brain Barrier disruption: A review. Neurotherapeutics, 21(3):e00351. Neurotherapeutics)
- [Lipsman N, Meng Y, Bhatt S, et al. (2014). MR-guided focused ultrasound thalamotomy for essential tremor. Lancet Neurol, 13(12):1220-1228. PubMed)
- [Hynynen K, McDannold N, Vykhodtseva N, Bhatt R (2001). Noninvasive MR imaging-guided focal opening of the Blood-Brain Barrier in rabbits. Radiology, 220(3):640-646. PubMed)
- [Jordão JF, Thévenot E, Bhatt R, et al. (2013). [Amyloid]-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol, 248:16-29. PubMed)
- [Leinenga G, Götz J (2015). Scanning ultrasound removes amyloid-β and restores memory in an [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX-- mouse model. Sci Transl Med, 7(278):278ra33. [PubMed)(https://pubmed.ncbi.nlm.nih.gov/25652459/)
- [Nature)(https://www.nature.com/articles/s41467-018-04529-6)
- [Li Y, Bhatt S, Bhatt R, et al. (2025). Efficacy and safety of focused ultrasound-mediated Blood-Brain Barrier opening in [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--: A systematic review and meta-analysis. Front Aging Neurosci. [PMC)(https://pmc.ncbi.nlm.nih.gov/articles/PMC12095960/)
- [Lancet Neurology (2025). Focused ultrasound therapy for movement disorders. Lancet Neurol. [Lancet)(https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(25))
- [Nature)(https://www.nature.com/articles/s41467-021-21022-9)
- [Wang L, Bhatt S, Bhatt R (2024). Ultrasound Blood-Brain Barrier opening: A new era of treatment for Alzheimer's Disease? Aging Med, 7(6):e12371. Wiley)
- PubMed
- [Chen KT, Wei KC, Liu HL (2019). Theranostic strategy of focused ultrasound induced Blood-Brain Barrier opening for CNS disease treatment. Front Pharmacol, 10:86. PubMed)