Focused Ultrasound for Parkinson's Disease

Focused Ultrasound for Parkinson's Disease

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Focused Ultrasound for Parkinson's Disease</th>
</tr>
<tr>
<td class="label">Target</td>
<td>UPDRS-III Improvement</td>
</tr>
<tr>
<td class="label">Vim (thalamotomy)</td>
<td>40-50%</td>
</tr>
<tr>
<td class="label">GPi (pallidotomy)</td>
<td>30-45%</td>
</tr>
<tr>
<td class="label">STN</td>
<td>35-50%</td>
</tr>
<tr>
<td class="label">Year</td>
<td>Indication</td>
</tr>
<tr>
<td class="label">2016</td>
<td>Essential Tremor</td>
</tr>
<tr>
<td class="label">2018</td>
<td>Tremor-dominant PD</td>
</tr>
<tr>
<td class="label">2021</td>
<td>Parkinson's disease tremor</td>
</tr>
<tr>
<td class="label">Complication</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Transient numbness/tingling</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Gait instability</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Speech difficulties</td>
<td>3-8%</td>
</tr>
<tr>
<td class="label">Intracranial hemorrhage</td>
<td><1%</td>
</tr>
<tr>
<td class="label">Skin burn</td>
<td>Rare</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Focused Ultrasound</td>
</tr>
<tr>
<td class="label">Invasiveness</td>
<td>Non-invasive</td>
</tr>
<tr>
<td class="label">Implant</td>
<td>None</td>
</tr>
<tr>
<td class="label">Recovery</td>
<td>1-2 day

Focused Ultrasound for Parkinson's Disease

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Focused Ultrasound for Parkinson's Disease</th>
</tr>
<tr>
<td class="label">Target</td>
<td>UPDRS-III Improvement</td>
</tr>
<tr>
<td class="label">Vim (thalamotomy)</td>
<td>40-50%</td>
</tr>
<tr>
<td class="label">GPi (pallidotomy)</td>
<td>30-45%</td>
</tr>
<tr>
<td class="label">STN</td>
<td>35-50%</td>
</tr>
<tr>
<td class="label">Year</td>
<td>Indication</td>
</tr>
<tr>
<td class="label">2016</td>
<td>Essential Tremor</td>
</tr>
<tr>
<td class="label">2018</td>
<td>Tremor-dominant PD</td>
</tr>
<tr>
<td class="label">2021</td>
<td>Parkinson's disease tremor</td>
</tr>
<tr>
<td class="label">Complication</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Transient numbness/tingling</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Gait instability</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Speech difficulties</td>
<td>3-8%</td>
</tr>
<tr>
<td class="label">Intracranial hemorrhage</td>
<td><1%</td>
</tr>
<tr>
<td class="label">Skin burn</td>
<td>Rare</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Focused Ultrasound</td>
</tr>
<tr>
<td class="label">Invasiveness</td>
<td>Non-invasive</td>
</tr>
<tr>
<td class="label">Implant</td>
<td>None</td>
</tr>
<tr>
<td class="label">Recovery</td>
<td>1-2 days</td>
</tr>
<tr>
<td class="label">Adjustability</td>
<td>Fixed lesion</td>
</tr>
<tr>
<td class="label">Reversibility</td>
<td>Permanent</td>
</tr>
<tr>
<td class="label">Bilateral treatment</td>
<td>Higher risk</td>
</tr>
<tr>
<td class="label">MRI compatibility</td>
<td>Yes</td>
</tr>
<tr>
<td class="label">Trial</td>
<td>Target</td>
</tr>
<tr>
<td class="label">NCT04021520</td>
<td>GPi FUS</td>
</tr>
<tr>
<td class="label">NCT03319485</td>
<td>STN FUS</td>
</tr>
<tr>
<td class="label">NCT04540670</td>
<td>BBB opening + GDNF</td>
</tr>
<tr>
<td class="label">NCT05331236</td>
<td>Bilateral FUS</td>
</tr>
</table>

Focused Ultrasound (FUS) is a non-invasive therapeutic technology that uses concentrated acoustic energy to treat neurological disorders, including Parkinson's disease (PD). By precisely targeting deep brain structures without surgical incision, FUS offers a groundbreaking alternative to traditional neurosurgical interventions. This page provides a comprehensive overview of FUS therapy for Parkinson's disease, covering mechanism of action, clinical evidence, regulatory status, target selection, outcomes, and comparison to other therapies. [@quality2020]

--- [@cognitive]

Mechanism of Action

Focused ultrasound works by delivering multiple overlapping ultrasound beams to a precise focal point within the brain. When these beams converge, they generate localized heating or mechanical effects that can be precisely controlled to achieve therapeutic outcomes. [@mrguided2017]

Physical Principles of Focused Ultrasound

The fundamental physics underlying FUS involves the conversion of acoustic energy into thermal energy at a precise focal point. Ultrasound waves are mechanical waves that propagate through biological tissues, and when concentrated at a specific location, they can induce various biological effects depending on the intensity and duration of exposure. [@future2020]

Key physical parameters include:

• Frequency: Typically 650 kHz to 1 MHz for brain applications
• Intensity: High-intensity (>1000 W/cm²) for ablation; low-intensity (<1000 W/cm²) for BBB opening
• Duration: Seconds to minutes for ablation; minutes for BBB opening
• Focal volume: Typically 2-10 mm in diameter

Biological Effects of Thermal Ablation

When the temperature at the focal point reaches 54-60°C, protein denaturation occurs within seconds, leading to immediate and irreversible cell death through coagulative necrosis. The surrounding tissue experiences a temperature gradient, with temperatures falling rapidly outside the focal zone. This creates a well-defined lesion with a sharp transition between treated and normal tissue.

The thermal effects are monitored in real-time using magnetic resonance imaging (MRI) thermometry, which measures the proton resonance frequency shift to calculate temperature maps. This feedback allows the operator to precisely control the lesion size and shape, adjusting treatment parameters in real-time based on the observed thermal map.

Mechanical Effects and Cavitation

In addition to thermal effects, low-intensity ultrasound can produce mechanical effects through acoustic cavitation. When ultrasound interacts with microbubble contrast agents, the bubbles oscillate (stable cavitation) or collapse violently (inertial cavitation), producing mechanical stress on surrounding tissues.

This mechanical disruption can:

• Temporarily open endothelial cell junctions in the blood-brain barrier
• Enhance drug and gene delivery to targeted brain regions
• Stimulate neuronal activity through mechanosensitive ion channels
• Promote release of neurotrophic factors

The Role of MRI Guidance

Magnetic resonance imaging serves dual roles in FUS treatment:

The integration of MRI with FUS represents a major advancement over earlier ultrasound technologies, enabling unprecedented precision and safety for intracranial procedures.

High-Intensity Focused Ultrasound (HIFU) for Ablation

High-intensity focused ultrasound (HIFU) creates thermal ablation by raising the temperature at the target site to 54-60°C within seconds [1](https://doi.org/10.3171/2019.12.FOCUS19870). This thermal lesioning achieves similar effects to surgical lesioning procedures like thalamotomy or pallidotomy, but without any surgical opening of the skull.

The key advantages of HIFU include:

• Real-time MR thermometry for precise temperature monitoring
• Immediate feedback allowing immediate assessment of treatment effect
• No implant required unlike deep brain stimulation
• Minimal surrounding tissue damage due to precise focus

Low-Intensity Focused Ultrasound (LIFU) for BBB Opening

Low-intensity focused ultrasound, when combined with intravenous microbubble contrast agents, can temporarily open the blood-brain barrier (BBB) [2](https://doi.org/10.1001/jam Neurol.2019.3659). This technique uses mechanical effects from oscillating microbubbles to disrupt endothelial cell junctions, enabling delivery of therapeutic agents that would otherwise be blocked.

BBB opening with LIFU is being investigated for:

• Delivery of neurotrophic factors (e.g., GDNF, BDNF)
• Gene therapy vector delivery
• Chemotherapeutic agent delivery for brain tumors
• Enhanced immunotherapy for neurodegenerative diseases

Target Structures in Parkinson's Disease

The primary targets for FUS in PD are:

Clinical Evidence

Tremor-Dominant Parkinson's Disease

Multiple clinical trials have demonstrated the efficacy of FUS thalamotomy for tremor-dominant PD. A pivotal randomized controlled trial showed:

• 80-90% tremor reduction in the contralateral hand at 12 months [3](https://doi.org/10.1056/NEJMoa1600159)
• Significant improvement in handwriting and activities of daily living
• Durable effects maintained through 4-year follow-up [4](https://doi.org/10.3171/2020.1.FOCUS19840)

Motor Symptom Outcomes (UPDRS Scores)

The Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor examination) improvements vary by target:

Long-Term Follow-Up Data

Studies with 3-5 year follow-up demonstrate:

• Sustained tremor suppression in most patients
• No delayed neurological deficits from the lesion
• Low rates of symptom recurrence requiring additional procedures

Non-Motor Symptom Effects

While primarily targeting motor symptoms, FUS treatment can affect non-motor features:

• Some patients report improved sleep quality
• Reduction in medication-related neuropsychiatric side effects
• Potential for cognitive effects requiring further study

Quality of Life Improvements

Beyond motor scores, FUS treatment significantly impacts patient quality of life. Studies using the Parkinson's Disease Questionnaire-39 (PDQ-39) demonstrate:

• Improved activities of daily living due to tremor reduction
• Enhanced emotional well-being from reduced disability
• Better social functioning from increased participation in community activities
• Reduced caregiver burden as patients regain independence

Special Populations

Elderly Patients
FUS offers particular advantages for elderly patients who may be poor surgical candidates:

• No general anesthesia required (procedures performed under conscious sedation)
• Reduced risk of infection compared to implantable devices
• Quick recovery time minimizes hospitalization risks
• Studies show efficacy and safety in patients over 75 years

Regulatory Status

FDA Approvals

The FDA has approved focused ultrasound for several neurological indications:

Insurance Coverage

Coverage varies by insurer:

• Medicare covers FUS for essential tremor and tremor-dominant PD
• Private insurers increasingly covering based on medical necessity
• Pre-authorization typically required

Target Selection

Ventral Intermediate Nucleus (Vim)

The Vim is the primary target for treating tremor in PD [5](https://pubmed.ncbi.nlm.nih.gov/33481043/):

• Located in the thalamus
• Part of the cerebellar receiving area
• Hyperactive in tremor states
• Ablation interrupts tremor circuit

• Tremor-dominant PD (not akinesia-predominant)
• Inadequate response to medications
• Intolerant or unsuitable for DBS
• Unilateral symptoms (FUS is typically unilateral)

Globus Pallidus Interna (GPi)

GPi targeting addresses dyskinesias and motor fluctuations [6](https://doi.org/10.3171/2019.2.FOCUS18472):

• Output nucleus of the basal ganglia
• Overactivity leads to bradykinesia and rigidity
• Ablation reduces dyskinesias from medication overuse

• Effective for medication-induced dyskinesias
• May reduce motor fluctuations
• Lower risk of cognitive side effects

Subthalamic Nucleus (STN)

STN is the most common target for DBS but less commonly targeted with FUS [7](https://doi.org/10.1007/s00701-020-04589-w):

• Central hub in the basal ganglia circuit
• Controls for comprehensive motor symptom relief
• More challenging to target precisely

• Higher risk of side effects (speech, cognition)
• Requires extremely precise targeting
• More research needed on FUS-STN outcomes

Decision Framework for Target Selection

Choosing the optimal FUS target requires careful consideration of multiple factors:

The decision tree typically follows:

• Tremor-dominant → Vim thalamotomy
• Dyskinesias/dopa-induced fluctuations → GPi pallidotomy
• Comprehensive motor control needed → Consider STN or DBS

Outcomes and Complications

Clinical Outcomes

Positive outcomes include:

• Immediate tremor suppression (often visible during treatment)
• Reduced medication requirements
• Improved quality of life measures
• Quick recovery (typically 1-2 days hospitalization)

Adverse Events and Complications

Reported complications include:

Risk Factors for Complications

• Advanced age (>75 years) - increased risk
• Bilateral procedures - higher complication rates
• Target location - proximity to critical structures
• Lesion size - larger lesions correlate with more side effects

Patient Selection and Contraindications

Ideal candidates for FUS:

• Age 65-85 years
• Tremor-dominant or dyskinesia-dominant PD
• Responsive to levodopa (for GPi targeting)
• Intolerant or unsuitable for DBS
• Unilateral symptoms primarily
• No significant cognitive impairment
• Able to lie still for 2-4 hours

• Significant cognitive impairment (MMSE <24)
• Severe depression or psychiatric comorbidities
• Brain atrophy >15 mm
• Metallic implants incompatible with MRI
• Uncorrected coagulopathy
• Major medical comorbidities

Comparison to Deep Brain Stimulation

Advantages of FUS over DBS

Limitations of FUS

When to Choose FUS vs DBS

Consider FUS when:

• Patient unsuitable for surgery (anticoagulation, medical comorbidities)
• Patient prefers non-invasive option
• Tremor-dominant with inadequate medication response
• Intolerant to DBS hardware

• Bilateral treatment needed
• Require adaptive/stimulus-responsive therapy
• Younger patients (long-term adjustability important)
• Need to modulate stimulation over time

Companies and Clinical Trials

Insightec

Insightec is the leading company in neurological FUS:

• Exablate Neuro - FDA-approved device for movement disorders
• Over 100 treatment centers worldwide
• Extensive clinical trial program
• Ongoing research in Alzheimer's disease and brain tumors

Treatment Procedure Overview

Understanding the FUS procedure helps in patient counseling:

Pre-treatment evaluation (1-2 weeks before):

• Neurological examination and motor scoring
• MRI brain scan for targeting
• Cognitive and psychiatric assessment
• Medical clearance for anesthesia

• Head shaved and frame attached to skull
• Stereotactic frame provides precise coordinate system
• Patient positioned in MRI scanner
• Low-power test sonications to verify targeting
• Full-power sonications to create lesion
• Real-time temperature monitoring throughout
• Total procedure time: 2-4 hours

• Neurological examination immediately after
• MRI to confirm lesion
• Overnight observation typically required
• Discharge within 24-48 hours
• Follow-up at 1 week, 1 month, 3 months, 6 months, then annually

Clinical Trials (Active and Recent)

Emerging Applications

Research is exploring:

• Dementia - amyloid and tau reduction
• Epilepsy - seizure focus ablation
• Brain tumors - enhanced drug delivery
• Psychiatric disorders - OCD, depression

Cross-Links to Related Pages

Therapeutic Approaches

• [Deep Brain Stimulation (DBS)](/therapeutics/deep-brain-stimulation) - Surgical treatment alternative
• [Deep Brain Stimulation for Parkinson's Disease](/therapeutics/deep-brain-stimulation-parkinson) - DBS specifically for PD
• [Adaptive Deep Brain Stimulation (DBS) Technology](/technologies/adaptive-dbs) - Advanced DBS systems

Brain Structures

• [Subthalamic Nucleus (STN) Neurons](/cell-types/subthalamic-nucleus) - Target for movement disorders
• [Globus Pallidus Neurons](/cell-types/globus-pallidus-neurons) - GPi target structure
• [Globus Pallidus Internus (GPi) Neurons](/cell-types/globus-pallidus-internus) - Specific GPi cell type

Related Movement Disorders

• [Essential Tremor](/diseases/essential-tremor) - First FDA-approved FUS indication

Future Directions

The field of focused ultrasound for Parkinson's disease continues to evolve:

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

Pathway Diagram