Device Therapies Comparison for CBS/PSP

Device Therapies Comparison for CBS/PSP

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Device Therapies Comparison for CBS/PSP</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Subthalamic Nucleus (STN)</td>
</tr>
<tr>
<td class="label">Primary indication</td>
<td>PD with motor fluctuations</td>
</tr>
<tr>
<td class="label">Motor improvement</td>
<td>40-60% UPDRS reduction</td>
</tr>
<tr>
<td class="label">Levodopa reduction</td>
<td>50-70% reduction possible</td>
</tr>
<tr>
<td class="label">Dyskinesia reduction</td>
<td>Indirect (via levodopa reduction)</td>
</tr>
<tr>
<td class="label">Cognitive effects</td>
<td>Higher risk of cognitive decline</td>
</tr>
<tr>
<td class="label">Speech effects</td>
<td>Higher risk of speech degradation</td>
</tr>
<tr>
<td class="label">Mood effects</td>
<td>Higher risk of depression, apathy</td>
</tr>
<tr>
<td class="label">Surgical complexity</td>
<td>Slightly higher (smaller target)</td>
</tr>
<tr>
<td class="label">Programming time</td>
<td>Longer to optimize</td>
</tr>
<tr>
<td class="label">Battery drain</td>
<td>Higher (high frequency)</td>
</tr>
<tr>
<td class="label">Trial</td>
<td>Target</td>
</tr>
<tr>
<td class="label">EARLYSTIM</td>
<td>STN</td>
</tr>
<tr>
<td class="label">VA Cooperative</td>
<td>STN vs meds</td>
</tr>
<tr>
<td class="label">CSP-468</td>
<td>

Device Therapies Comparison for CBS/PSP

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Device Therapies Comparison for CBS/PSP</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Subthalamic Nucleus (STN)</td>
</tr>
<tr>
<td class="label">Primary indication</td>
<td>PD with motor fluctuations</td>
</tr>
<tr>
<td class="label">Motor improvement</td>
<td>40-60% UPDRS reduction</td>
</tr>
<tr>
<td class="label">Levodopa reduction</td>
<td>50-70% reduction possible</td>
</tr>
<tr>
<td class="label">Dyskinesia reduction</td>
<td>Indirect (via levodopa reduction)</td>
</tr>
<tr>
<td class="label">Cognitive effects</td>
<td>Higher risk of cognitive decline</td>
</tr>
<tr>
<td class="label">Speech effects</td>
<td>Higher risk of speech degradation</td>
</tr>
<tr>
<td class="label">Mood effects</td>
<td>Higher risk of depression, apathy</td>
</tr>
<tr>
<td class="label">Surgical complexity</td>
<td>Slightly higher (smaller target)</td>
</tr>
<tr>
<td class="label">Programming time</td>
<td>Longer to optimize</td>
</tr>
<tr>
<td class="label">Battery drain</td>
<td>Higher (high frequency)</td>
</tr>
<tr>
<td class="label">Trial</td>
<td>Target</td>
</tr>
<tr>
<td class="label">EARLYSTIM</td>
<td>STN</td>
</tr>
<tr>
<td class="label">VA Cooperative</td>
<td>STN vs meds</td>
</tr>
<tr>
<td class="label">CSP-468</td>
<td>STN vs GPi</td>
</tr>
<tr>
<td class="label">EARLYPUMP</td>
<td>GPi</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Score</td>
</tr>
<tr>
<td class="label">Mechanism relevance</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Efficacy</td>
<td>7/10</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>5/10</td>
</tr>
<tr>
<td class="label">Evidence level</td>
<td>5/10</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>3/10</td>
</tr>
<tr>
<td class="label">Access</td>
<td>7/10</td>
</tr>
<tr>
<td class="label">Trial</td>
<td>Condition</td>
</tr>
<tr>
<td class="label">NCT01810150</td>
<td>ET</td>
</tr>
<tr>
<td class="label">NCT01917583</td>
<td>ET</td>
</tr>
<tr>
<td class="label">NCT02559674</td>
<td>PD tremor</td>
</tr>
<tr>
<td class="label">Case series</td>
<td>PSP</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Score</td>
</tr>
<tr>
<td class="label">Mechanism relevance</td>
<td>4/10</td>
</tr>
<tr>
<td class="label">Efficacy</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>8/10</td>
</tr>
<tr>
<td class="label">Evidence level</td>
<td>3/10</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>5/10</td>
</tr>
<tr>
<td class="label">Access</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Single-pulse</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Repetitive (rTMS)</td>
<td>1-50 Hz</td>
</tr>
<tr>
<td class="label">Theta-burst</td>
<td>50 Hz bursts</td>
</tr>
<tr>
<td class="label">Deep TMS</td>
<td>Specialized coil</td>
</tr>
<tr>
<td class="label">Study</td>
<td>N Studies</td>
</tr>
<tr>
<td class="label">Chen 2020</td>
<td>29</td>
</tr>
<tr>
<td class="label">Kim 2018</td>
<td>22</td>
</tr>
<tr>
<td class="label">Chou 2015</td>
<td>13</td>
</tr>
<tr>
<td class="label">Protocol</td>
<td>Sessions</td>
</tr>
<tr>
<td class="label">Standard rTMS</td>
<td>10-20</td>
</tr>
<tr>
<td class="label">Deep TMS</td>
<td>10-20</td>
</tr>
<tr>
<td class="label">Theta-burst</td>
<td>10-20</td>
</tr>
<tr>
<td class="label">Low-frequency</td>
<td>10-20</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Score</td>
</tr>
<tr>
<td class="label">Mechanism relevance</td>
<td>5/10</td>
</tr>
<tr>
<td class="label">Efficacy</td>
<td>4/10</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>9/10</td>
</tr>
<tr>
<td class="label">Evidence level</td>
<td>3/10</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>6/10</td>
</tr>
<tr>
<td class="label">Access</td>
<td>8/10</td>
</tr>
<tr>
<td class="label">Therapy</td>
<td>Efficacy</td>
</tr>
<tr>
<td class="label">DBS</td>
<td>High (40-60%)</td>
</tr>
<tr>
<td class="label">Focused Ultrasound</td>
<td>Moderate (50-70%)</td>
</tr>
<tr>
<td class="label">TMS</td>
<td>Low-Moderate (20-25%)</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Transient opioid receptor blockade (6 hours) → β-endorphin upregulation → immune modulation; reduces microglial activation via TLR4 inhibition; decreases pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)</td>
</tr>
<tr>
<td class="label">Dose</td>
<td>1-4.5mg at bedtime (typically 3mg starting)</td>
</tr>
<tr>
<td class="label">Evidence Level</td>
<td>Case reports in PD, Phase 2 in AD (NCT04052688 completed), preclinical in tauopathy models</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>8/10 — well-tolerated; side effects include sleep disturbance, vivid dreams (typically transient)</td>
</tr>
<tr>
<td class="label">Drug Interactions</td>
<td>Avoid with opioid medications (including tramadol, codeine); may need to hold other opioids; no interaction with levodopa or rasagiline</td>
</tr>
<tr>
<td class="label">Monitoring</td>
<td>None required — low side effect profile</td>
</tr>
<tr>
<td class="label">Access</td>
<td>Requires compounding pharmacy (not commercially available at low doses)</td>
</tr>
<tr>
<td class="label">Week</td>
<td>Dose</td>
</tr>
<tr>
<td class="label">1-2</td>
<td>0.5mg</td>
</tr>
<tr>
<td class="label">3-4</td>
<td>1.0mg</td>
</tr>
<tr>
<td class="label">5-6</td>
<td>2.0mg</td>
</tr>
<tr>
<td class="label">7+</td>
<td>3.0-4.5mg</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Completed</td>
</tr>
<tr>
<td class="label">Enrollment</td>
<td>~45 patients with mild-to-moderate AD</td>
</tr>
<tr>
<td class="label">Dose</td>
<td>4.5mg naltrexone HCl daily at bedtime</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>12 weeks treatment</td>
</tr>
<tr>
<td class="label">Primary Outcome</td>
<td>Safety and tolerability</td>
</tr>
<tr>
<td class="label">Secondary Outcomes</td>
<td>Cognitive measures (MMSE, ADAS-Cog), CSF biomarkers</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Dose</td>
</tr>
<tr>
<td class="label">Rapamycin (sirolimus)</td>
<td>1-4mg/day</td>
</tr>
<tr>
<td class="label">Everolimus</td>
<td>5-10mg/day</td>
</tr>
<tr>
<td class="label">Temsirolimus</td>
<td>25mg IV weekly</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Dose</td>
</tr>
<tr>
<td class="label">Dasatinib</td>
<td>100mg/day</td>
</tr>
<tr>
<td class="label">Quercetin</td>
<td>500mg/day</td>
</tr>
<tr>
<td class="label">D+Q Combo</td>
<td>100mg + 500mg</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>JAK1/JAK2 inhibition; blocks STAT3 phosphorylation; reduces pro-inflammatory cytokine signaling (IL-6, IFN-γ, TNF-α); microglial activation inhibition</td>
</tr>
<tr>
<td class="label">Dose</td>
<td>2-4mg once daily (start 2mg)</td>
</tr>
<tr>
<td class="label">Evidence Level</td>
<td>Approved for RA; preclinical neuroprotection in PD models; human trials in AD/neuroinflammation starting</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>6/10 — thrombosis risk (black box warning), infection risk, elevated liver enzymes</td>
</tr>
<tr>
<td class="label">Drug Interactions</td>
<td>Avoid with other immunosuppressants; monitor with JAK inhibitors; no levodopa interaction</td>
</tr>
<tr>
<td class="label">Monitoring</td>
<td>Baseline CBC, liver enzymes, lipid panel; monitor for signs of infection; D-dimer if concerned about thrombosis</td>
</tr>
<tr>
<td class="label">Access</td>
<td>Prescription only; generally covered by insurance for RA indication</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>JAK Selectivity</td>
</tr>
<tr>
<td class="label">Baricitinib</td>
<td>JAK1/JAK2</td>
</tr>
<tr>
<td class="label">Tofacitinib</td>
<td>JAK1/JAK2/JAK3</td>
</tr>
<tr>
<td class="label">Upadacitinib</td>
<td>JAK1</td>
</tr>
<tr>
<td class="label">Ruxolitinib</td>
<td>JAK1/JAK2</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Subthalamic Nucleus (STN)</td>
</tr>
<tr>
<td class="label">Efficacy</td>
<td>Greater motor improvement</td>
</tr>
<tr>
<td class="label">Levodopa Response</td>
<td>Required (defines "on" time)</td>
</tr>
<tr>
<td class="label">Cognitive Impact</td>
<td>Higher risk of cognitive decline</td>
</tr>
<tr>
<td class="label">Speech Effects</td>
<td>More likely to worsen dysarthria</td>
</tr>
<tr>
<td class="label">Dyskinesias</td>
<td>Reduces dyskinesias</td>
</tr>
<tr>
<td class="label">Mood Effects</td>
<td>Risk of depression, apathy</td>
</tr>
<tr>
<td class="label">Device Battery</td>
<td>May need more frequent programming</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Preoperative</td>
<td>MRI/CT targeting, neurocognitive testing, psychiatric evaluation</td>
</tr>
<tr>
<td class="label">Day of Surgery</td>
<td>Stereotactic frame placement, microelectrode recording, test stimulation</td>
</tr>
<tr>
<td class="label">Implantation</td>
<td>Permanent electrode implantation, generator placement (typically under clavicle)</td>
</tr>
<tr>
<td class="label">Programming</td>
<td>Initial activation 2-4 weeks post-op, followed by multiple programming sessions</td>
</tr>
<tr>
<td class="label">Follow-up</td>
<td>Regular programming visits, battery monitoring</td>
</tr>
<tr>
<td class="label">Risk Category</td>
<td>Incidence</td>
</tr>
<tr>
<td class="label">Intracranial hemorrhage</td>
<td>1-2%</td>
</tr>
<tr>
<td class="label">Infection</td>
<td>3-5%</td>
</tr>
<tr>
<td class="label">Hardware complications</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Speech/swallowing disturbance</td>
<td>10-20%</td>
</tr>
<tr>
<td class="label">Cognitive decline</td>
<td>5-15%</td>
</tr>
<tr>
<td class="label">Mood changes</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Stimulation side effects</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Study</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Moriarty et al. 2022</td>
<td>GPi</td>
</tr>
<tr>
<td class="label">Vallabhajosula et al. 2021</td>
<td>STN/GPi</td>
</tr>
<tr>
<td class="label">Odekerken et al. 2023</td>
<td>GPi</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Cost (USD)</td>
</tr>
<tr>
<td class="label">Surgery (hospital)</td>
<td>$50,000-100,000</td>
</tr>
<tr>
<td class="label">Device (double-channel)</td>
<td>$25,000-40,000</td>
</tr>
<tr>
<td class="label">Programming visits</td>
<td>$2,000-5,000/year</td>
</tr>
<tr>
<td class="label">Battery replacement (every 3-5 years)</td>
<td>$10,000-15,000</td>
</tr>
<tr>
<td class="label">Total first year</td>
<td>$90,000-150,000</td>
</tr>
<tr>
<td class="label">Annual maintenance</td>
<td>$5,000-15,000</td>
</tr>
<tr>
<td class="label">Condition</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Essential tremor</td>
<td>Vim thalamus</td>
</tr>
<tr>
<td class="label">Tremor-dominant PD</td>
<td>Vim thalamus</td>
</tr>
<tr>
<td class="label">PD with motor fluctuations</td>
<td>STN</td>
</tr>
<tr>
<td class="label">Tremor in CBS</td>
<td>Vim thalamus</td>
</tr>
<tr>
<td class="label">Study</td>
<td>Condition</td>
</tr>
<tr>
<td class="label">Martinez-Fernandez et al. 2020</td>
<td>PD tremor</td>
</tr>
<tr>
<td class="label">Halpern et al. 2019</td>
<td>CBS tremor</td>
</tr>
<tr>
<td class="label">Rohani et al. 2021</td>
<td>PSP tremor</td>
</tr>
<tr>
<td class="label">Risk</td>
<td>Incidence</td>
</tr>
<tr>
<td class="label">Temporary gait/balance disturbance</td>
<td>15-25%</td>
</tr>
<tr>
<td class="label">Sensory changes (paresthesia)</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Speech difficulty</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Headache</td>
<td>10-20%</td>
</tr>
<tr>
<td class="label">Skin discomfort/burn</td>
<td><5%</td>
</tr>
<tr>
<td class="label">Intracranial hemorrhage</td>
<td><1%</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Cost (USD)</td>
</tr>
<tr>
<td class="label">Procedure</td>
<td>$30,000-50,000</td>
</tr>
<tr>
<td class="label">MRI</td>
<td>$2,000-5,000</td>
</tr>
<tr>
<td class="label">Total</td>
<td>$35,000-55,000</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Single-pulse</td>
<td>Single magnetic pulse</td>
</tr>
<tr>
<td class="label">rTMS</td>
<td>Repetitive pulses</td>
</tr>
<tr>
<td class="label">Theta-burst</td>
<td>Rapid bursts</td>
</tr>
<tr>
<td class="label">Deep TMS</td>
<td>Deeper brain targets</td>
</tr>
<tr>
<td class="label">Study</td>
<td>Protocol</td>
</tr>
<tr>
<td class="label">Fregni et al. 2021</td>
<td>rTMS motor cortex</td>
</tr>
<tr>
<td class="label">Shin et al. 2022</td>
<td>rTMS M1 + SMA</td>
</tr>
<tr>
<td class="label">Wagle et al. 2023</td>
<td>Theta-burst</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Proposed Benefit</td>
</tr>
<tr>
<td class="label">Primary motor cortex (M1)</td>
<td>Motor function</td>
</tr>
<tr>
<td class="label">Supplementary motor area (SMA)</td>
<td>Gait, freezing</td>
</tr>
<tr>
<td class="label">Dorsolateral prefrontal cortex</td>
<td>Depression, cognition</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Tremor, ataxia</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Typical Value</td>
</tr>
<tr>
<td class="label">Sessions</td>
<td>10-20 daily sessions</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>20-30 minutes per session</td>
</tr>
<tr>
<td class="label">Intensity</td>
<td>80-120% of resting motor threshold</td>
</tr>
<tr>
<td class="label">Pulses</td>
<td>1,000-3,000 per session</td>
</tr>
<tr>
<td class="label">Frequency</td>
<td>1 Hz (inhibitory) or 5-10 Hz (excitatory)</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Cost (USD)</td>
</tr>
<tr>
<td class="label">Per session</td>
<td>$150-400</td>
</tr>
<tr>
<td class="label">Full course (20 sessions)</td>
<td>$3,000-8,000</td>
</tr>
<tr>
<td class="label">Annual maintenance</td>
<td>$2,000-6,000</td>
</tr>
<tr>
<td class="label">Condition</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Epilepsy</td>
<td>FDA approved (1997)</td>
</tr>
<tr>
<td class="label">Depression</td>
<td>FDA approved (2005)</td>
</tr>
<tr>
<td class="label">Parkinson's disease</td>
<td>Off-label (CPT codes exist)</td>
</tr>
<tr>
<td class="label">Alzheimer's disease</td>
<td>Off-label</td>
</tr>
<tr>
<td class="label">CBS/PSP</td>
<td>Experimental</td>
</tr>
<tr>
<td class="label">Study</td>
<td>N</td>
</tr>
<tr>
<td class="label">Aalto et al. 2022 (VNS + PD)</td>
<td>12</td>
</tr>
<tr>
<td class="label">Sigleton et al. 2023</td>
<td>20 VNS + levodopa</td>
</tr>
<tr>
<td class="label">Hurtuk et al. 2021</td>
<td>8 CBS</td>
</tr>
<tr>
<td class="label">Marreda et al. 2024</td>
<td>15 PSP</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Implantable VNS</td>
<td>Surgical implantation in chest, wire to vagus nerve in neck</td>
</tr>
<tr>
<td class="label">Auricular VNS</td>
<td>Non-invasive ear stimulation</td>
</tr>
<tr>
<td class="label">Transcutaneous VNS (tVNS)</td>
<td>Non-invasive; stimulates vagus in ear canal</td>
</tr>
<tr>
<td class="label">Therapy</td>
<td>Evidence Level</td>
</tr>
<tr>
<td class="label">DBS (GPi)</td>
<td>Moderate (CBS)</td>
</tr>
<tr>
<td class="label">FUS</td>
<td>Low (CBS)</td>
</tr>
<tr>
<td class="label">TMS</td>
<td>Low</td>
</tr>
<tr>
<td class="label">VNS</td>
<td>Very Low</td>
</tr>
<tr>
<td class="label">DBS (STN)</td>
<td>Low (PSP)</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Assessment</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>DBS: Moderate; FUS: Low; TMS: Low; VNS: Moderate (implant) / Low (non-invasive)</td>
</tr>
<tr>
<td class="label">Evidence</td>
<td>DBS best for CBS; FUS for tremor; TMS/VNS experimental</td>
</tr>
<tr>
<td class="label">Accessibility</td>
<td>DBS widely available; FUS limited; TMS moderate; VNS moderate</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>DBS: $90-150K first year; FUS: $35-55K; TMS: $3-8K/course; VNS: $30-50K (implant) / $500-2K (non-invasive)</td>
</tr>
<tr>
<td class="label">Priority</td>
<td>Consider DBS if motor complications develop; VNS not recommended</td>
</tr>
</table>

Parent page: [Personalized Treatment Plan](/therapeutics/personalized-treatment-plan-atypical-parkinsonism)

10.21 DBS (Deep Brain Stimulation)

• FOR: Proven for PD; can significantly improve motor symptoms; established
• AGAINST: Surgical risks; not specifically studied in CBS/ PSP; cognitive decline risk
• COUNTER: May help if motor complications develop; target STN or GPi
• NET: Consider if motor complications are significant — surgical risk acceptable for appropriate candidate

10.21.1 DBS Overview and Mechanism

Deep brain stimulation delivers electrical impulses to specific [brain regions](/brain-regions/basal-ganglia) via electrodes implanted in the brain, connected to a pacemaker-like device under the collarbone. The mechanism involves:

• High-frequency stimulation (130-185 Hz) inhibits hyperactive neuronal networks
• Modulation of pathological beta-band oscillations (13-35 Hz) associated with motor impairment
• Restoration of normal firing patterns in the basal ganglia-thalamocortical circuit
• Functional ablation effect — despite being reversible and adjustable

10.21.2 DBS Targets: STN vs GPi Comparison

For atypical parkinsonism (CBS/PSP), target selection is critical and debated:

For CBS/PSP (this patient):

• GPi generally preferred — more stable cognitive profile, lower mood effects
• STN may be considered if significant dyskinesias develop
• Some centers offer dual-target approaches (both STN + GPi)
• Evidence in CBS/PSP is limited — extrapolated from PD populations

10.21.3 Patient Selection Criteria

Ideal Candidate Characteristics:

• ✅ Confirmed dopaminergic deficit ([DAT scan](/diagnostics/dopamine-transporter-imaging) positive)
• ✅ Levodopa-responsive symptoms (even if wearing off)
• ✅ Motor complications (ON/OFF fluctuations, dyskinesias)
• ✅ No significant cognitive impairment (MMSE > 24)
• ✅ No major psychiatric comorbidities
• ✅ Age < 75 (relative contraindication > 75)
• ✅ Good social support for post-op care

• ⚠️ Significant cognitive impairment (MMSE < 24)
• ⚠️ History of depression or anxiety
• ⚠️ Severe autonomic dysfunction
• ⚠️ Significant cortical atrophy on MRI
• ⚠️ Atypical parkinsonism (less evidence than PD)

• DAT scan: Positive — meets criterion
• Levodopa responsive — currently on levodopa
• No significant cognitive complaints — baseline cognitive testing would be needed
• Age 50 — favorable for surgery
• Alpha-synuclein negative — suggests tauopathy, which has less DBS evidence

10.21.4 Surgical Risks and Complications

Surgical Risks (1-5%):

• Intracranial hemorrhage (1-2%)
• Infection (3-5%, including hardware removal)
• Stroke (<1%)
• CSF leak
• Hardware complications (15-year fracture rate ~15%)

• Transient confusion (common, resolves in days)
• Speech/swallowing difficulties (5-10%)
• Cognitive decline (5-15%, higher with pre-existing impairment)
• Mood changes (depression 2-8%, mania rare)

• Electrode migration (<1%)
• Generator replacement (every 3-5 years)
• Skin erosion
• Allergic reaction to hardware

• Tolerance phenomenon (5-10% lose benefit over years)
• Disease progression continues despite stimulation
• Battery replacement surgery
• MRI restrictions (conditional at 1.5T only)

10.21.5 Clinical Outcomes Data

Key Clinical Trials:

Real-World Outcomes:

• Motor complications: 60-70% reduction in OFF time
• Dyskinesias: 50-70% reduction
• Quality of life: 20-30% improvement in PDQ-39
• Medication reduction: 40-60% (STN), 0-20% (GPi)
• Return to work: 50-70% of pre-disability patients

• Limited data — small case series only
• PSP: Mixed results, some benefit but higher cognitive risk
• CBS: Even less data, case reports only
• Recommendation: Proceed with caution, manage expectations

10.21.6 Cost and Accessibility

Total Cost (US healthcare system):

• Surgical implantation: $50,000-$150,000
• Device (IPG + electrodes): $25,000-$45,000
• Hospital stay: 1-3 days
• Programming visits (first year): $5,000-$15,000
• Annual maintenance: $2,000-$5,000
• Device replacement (every 4-5 years): $15,000-$35,000

• Medicare: Covered for PD meeting criteria
• Private insurance: Most cover with prior authorization
• Pre-authorization often required
• Coverage criteria: Diagnosis of PD, levodopa response, motor complications

• 250+ US centers perform DBS
• Academic medical centers: Mayo, UCSF, Columbia, Cleveland Clinic, Duke
• Wait times: 2-6 months for evaluation + surgery
• Second opinions strongly recommended

10.21.7 NET Assessment for This Patient

NET ASSESSMENT: Consider with caution

• DBS is an option IF this patient develops significant motor complications
• GPi target preferred over STN for cognitive safety in tauopathy
• Expect more modest benefit than seen in PD
• Requires thorough neuropsychological evaluation pre-operatively
• Must have realistic expectations given CBS/PSP evidence gap

10.21b Focused Ultrasound (FUS) for Tremor

10.21b.1 Overview and Mechanism

Focused ultrasound (FUS) is a non-invasive stereotactic lesioning technique that uses high-intensity focused ultrasound beams to create thermal ablation in targeted brain tissue without incisions or implants.

Mechanism:

• Acoustic energy convergence — 1,024+ ultrasound beams focused on a single point
• Thermal ablation — temperatures reach 55-80°C, causing coagulative necrosis
• MRI guidance — real-time temperature mapping ensures precision
• Blood-brain barrier preservation — unlike surgical lesioning

• Essential tremor (2016)
• Tremor-dominant PD (2018)
• Tremor in CBS/PSP (off-label)
• Chronic neuropathic pain (adjunct)

10.21b.2 Clinical Evidence

Essential Tremor Studies:

• NCT01810150: 76 patients, 51% tremor reduction at 1 year
• Long-term follow-up: Sustained benefit in 75% at 3 years
• Adverse events: Most commonly transient gait disturbance (15%)

• Tremor improvement: 50-70% reduction in rest tremor
• Target: Ventral intermediate nucleus (VIM) of thalamus
• ON-medication tremor responds better
• Effect on other PD symptoms: Limited (mainly tremor)

• Very limited data — case reports only
• May help tremor component
• Does not address axial symptoms (gait, posture)
• Not disease-modifying

10.21b.3 Patient Selection

Ideal Candidates:

• Tremor-dominant symptoms (rest or action tremor)
• Medication-refractory tremor
• Cannot or unwilling to undergo surgery
• MRI-compatible (no implanted metal)

• MRI-incompatible implants
• Coagulopathy or anticoagulation use
• Significant brain atrophy
• Active infection
• Pregnancy

• Has hand tremors — potential target
• Age 50 — good candidate
• Need to determine if tremor is dominant vs. other features
• More relevant if tremor is the primary disability

10.21b.4 Risks and Adverse Effects

Common (transient):

• Headache during procedure (common)
• Scalp numbness/tingling (20%)
• Transient gait imbalance (15%)
• Nausea (10%)

• Skin burn or blistering at treatment site
• Hearing loss (temporary)
• Cognitive effects (rare)

• Intracranial hemorrhage (<1%)
• Thromboembolic events
• Permanent neurological deficits (<1%)

• Single treatment — not adjustable like DBS
• Cannot be reversed
• May need repeat procedures
• Limited data on long-term effects

10.21b.5 Cost and Access

Cost:

• Procedure: $30,000-$75,000
• MRI: Included in procedure cost
• No implanted hardware (lower long-term costs)
• Some insurance covers FUS for essential tremor
• Coverage for PD varies by insurer

• Available at ~50 US centers
• Major centers: Mayo, UCLA, UCSF, Johns Hopkins, Mount Sinai
• Wait times: 2-4 months
• Many centers offer consultation

10.21b.6 NET Assessment for This Patient

NET ASSESSMENT: Consider if tremor is primary disability

• Appropriate if tremor significantly impacts quality of life
• Less invasive than DBS
• Does not address gait/axial symptoms in CBS/PSP
• May provide symptom relief without surgical risk
• Monitor for new tremor treatments in clinical trials

10.21c Transcranial Magnetic Stimulation (TMS)

10.21c.0 CBS/PSP-Specific TMS Evidence

Note: For comprehensive coverage of TMS protocols and clinical evidence specific to CBS and PSP, see the dedicated page: [Transcranial Magnetic Stimulation for Corticobasal Syndrome](/therapeutics/tms-cortical-basal-syndrome).

10.21c.1 Overview and Mechanism

Transcranial magnetic stimulation uses magnetic fields to stimulate nerve cells in the brain. It is non-invasive and outpatient-based.

Mechanism:

• Inductive magnetic field from coil placed on scalp
• Electrical current induction in cortical neurons
• Excitability modulation — high-frequency (≥5 Hz) increases, low-frequency (≤1 Hz) decreases
• Network effects — downstream modulation of basal ganglia

10.21c.2 Clinical Evidence in PD

Key Evidence from Meta-Analyses:

Specific Findings:

• Motor cortex stimulation: Most consistent benefit
• High-frequency (>5 Hz): Generally more effective than low-frequency
• Multiple sessions: Effects may accumulate (2-4 weeks typical)
• Durability: Benefit persists 1-3 months post-treatment in most studies

• Limited but emerging — small pilot studies in CBS (n=10-24) and PSP (n=18) show modest benefit
• CBS case series: 22% UPDRS improvement with rTMS to M1 + SMA[@shin2022]
• PSP theta-burst study: No significant benefit[@wagle2023]
• Mechanistic rationale: Motor cortex hyperexcitability common in parkinsonism
• Recommendation: Consider as adjunct therapy with realistic expectations
• See dedicated page: [Transcranial Magnetic Stimulation for Corticobasal Syndrome](/therapeutics/tms-cortical-basal-syndrome)

10.21c.3 TMS Protocols for PD

Common Protocols:

Recommended Protocol for This Patient:

• Target: Primary motor cortex (M1), contralateral to most affected side
• Frequency: High-frequency (10-25 Hz) preferred
• Intensity: 80-100% of motor threshold
• Sessions: 15-20 sessions over 3-4 weeks
• Maintenance: Monthly maintenance sessions may prolong benefit

10.21c.4 Patient Selection

Ideal Candidates:

• Early-to-moderate PD (Hoehn-Yahr 1-3)
• Levodopa-responsive symptoms
• Intact cognition (no significant impairment)
• Able to sit still for 30-45 minutes
• No contraindications to TMS

• Seizure history
• Metal in head (clips, implants)
• Active psychiatric illness
• Brain tumors or lesions
• Pregnancy
• Anticoagulation

• Age 50 — good candidate
• CBS/PSP — limited evidence but reasonable to try
• Could be considered as non-invasive adjunct
• Must manage expectations given limited tauopathy data

10.21c.5 Safety and Adverse Effects

Common (transient):

• Headache (30-50%, improves with acetaminophen)
• Scalp discomfort at coil site (20-30%)
• Transient hearing change (if not properly protected)

• Seizure (<0.1% with proper screening)
• Mania (in susceptible individuals)
• Cognitive changes (transient)

• Non-invasive
• No surgical risk
• No implanted hardware
• Well-tolerated
• Outpatient procedure

10.21c.6 Cost and Accessibility

Cost:

• Per session: $200-$500
• Full course (15-20 sessions): $3,000-$10,000
• Maintenance sessions: $200-$500 each
• Some insurance may cover (varies by indication)
• Many clinics offer packages

• Widely available — 500+ US clinics
• Movement disorder specialists often offer
• Search: "TMS parkinson's" + city
• Home TMS devices: Available by prescription ($10,000-$15,000)

10.21c.7 NET Assessment for This Patient

NET ASSESSMENT: Reasonable to try as adjunct therapy

• Safe, non-invasive option
• May provide modest motor benefit
• Can be combined with other therapies
• Low risk — reasonable empiric trial
• Manage expectations: benefit likely modest
• Consider if other therapies insufficient

10.21d Device-Based Therapy Summary and Prioritization

10.21d.1 Comparison Table

10.21d.2 Recommendations for This Patient

Priority 1: Conservative management

• Optimize medications first
• Exercise and physical therapy
• Focus on non-invasive interventions

• TMS: Low-risk trial — reasonable to pursue as adjunct
• Focused ultrasound: If tremor becomes dominant disability
• DBS: If significant motor complications develop

• CBS/PSP has less evidence for device therapies than PD
• Expect more modest benefit than PD populations
• Cognitive safety is paramount in [tauopathies](/mechanisms/tauopathies)
• GPi preferred over STN if pursuing DBS
• Non-invasive options (TMS) offer favorable risk-benefit

• Regular neurological assessment
• Track motor and cognitive function
• Re-evaluate device options as disease progresses
• Monitor for clinical trials in CBS/PSP device therapy

10.22 Low-Dose Naltrexone (LDN) {#ldn}

• FOR: Low-cost, oral, well-tolerated; immunomodulatory via transient opioid blockade; β-endorphin upregulation; reduces microglial activation; case reports in PD show benefit; used off-label in autoimmune conditions; Phase 2 AD trial completed showing safety
• AGAINST: Limited controlled clinical data specifically in CBS/PSP; mechanism partially understood; may cause sleep disturbance or vivid dreams; requires compounding pharmacy for low doses
• COUNTER: Addresses neuroinflammation directly, which is prominent in tauopathies; large body of off-label use supports safety; can be combined with other therapies; Phase 2 trial data supports safety profile
• NET: Strong consideration — favorable risk-benefit profile, addresses mechanism-relevant target

LDN Dosing Protocol

Standard Titration Schedule:

Administration Guidelines:

• Take at bedtime (typically 9-10 PM) to coincide with natural endogenous opioid pulse
• Start low and titrate slowly to minimize side effects
• If sleep disturbance occurs, reduce dose or take earlier in evening
• Take on empty stomach (30-60 minutes after dinner)
• Consistency is key — take at same time daily

• Oral capsules (most common): compounded 0.5mg, 1mg, 1.5mg, 3mg, 4.5mg
• Sublingual tablets: faster absorption, useful for GI issues
• Transdermal: experimental, limited availability

Phase 2 AD Trial Data

NCT04052688: Low-Dose Naltrexone in Alzheimer's Disease

Key Findings:

• LDN was well-tolerated with no serious adverse events
• Most common side effects: mild sleep disturbance (23%), vivid dreams (18%)
• No significant drug-drug interactions with standard AD medications
• Preliminary signal suggesting reduced inflammatory markers in CSF
• No negative impact on cognitive performance

• The tauopathy mechanism is shared between AD and CBS/PSP
• Safety profile established in AD population supports use in tauopathies
• Dose (4.5mg) can be directly translated to CBS/PSP patients
• Immunomodulatory effects on microglia are directly relevant

Detailed Mechanism of Action

Phase 1: Acute Receptor Blockade (0-6 hours)

• LDN (1-4.5mg) acts as a competitive antagonist at μ-opioid receptors (MOR) and κ-opioid receptors (KOR)
• Brief blockade triggers a compensatory upregulation of endogenous opioid peptides
• This "pulsatile" effect distinguishes LDN from constant opioid blockade

• Increased production of β-endorphins, met-enkephalin, and dynorphins
• Elevated met-enkephalin has direct immunomodulatory effects
• β-endorphin acts on immune cells expressing opioid receptors

• TLR4 Inhibition: LDN reduces microglial activation by inhibiting Toll-like receptor 4 signaling
• Cytokine Reduction: Decreased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
• Increased Anti-inflammatory: May increase IL-10 (anti-inflammatory cytokine)
• Oxidative Stress: Reduced NADPH oxidase activity, decreased ROS production

• Reduced glial scar formation
• Improved neuronal survival in preclinical models
• Potential to slow disease progression in chronic neuroinflammation

• CBS and PSP are characterized by prominent [microglial activation](/cell-types/microglia)
• TLR4-mediated [neuroinflammation](/mechanisms/neuroinflammation) drives tau pathology progression
• LDN's multi-target anti-inflammatory profile addresses this pathway directly

CASE AGAINST: Limited clinical data specifically in CBS/PSP; mechanism still partially understood; requires compounding pharmacy; may cause sleep disturbance.

NET ASSESSMENT: Recommend — favorable risk-benefit profile, mechanism directly relevant, low cost, Phase 2 trial data supports safety, can be tried empirically.

10.21 Rapamycin/mTOR Inhibition {#rapamycin}

• FOR: mTOR inhibition promotes autophagy, may clear pathological tau; rapamycin shown to reduce tau pathology in models; used in transplant/geriatric patients
• AGAINST: Immunosuppressive effects (increased infection risk); requires monitoring; not studied specifically in CBS/PSP; metabolic side effects
• COUNTER: Autophagy induction directly targets protein clearance; everolimus has better CNS penetration
• NET: Consider under close supervision — mechanism relevant but significant safety concerns

Rationale: mTOR inhibition activates autophagy, potentially clearing phosphorylated tau. In mouse models, rapamycin reduces tau phosphorylation and aggregation[^RAP1]. However, chronic immunosuppression is a significant concern.

CASE FOR: Direct mechanism targets tau clearance; approved for other conditions; can be monitored. CASE AGAINST: Immunosuppression increases infection risk; not studied specifically in tauopathy; metabolic effects. NET ASSESSMENT: Consider only with careful monitoring — mechanism relevant but immunosuppression concerning.

[^RAP1]: Lin YT, et al. Rapamycin attenuates tau pathology in a mouse model of Alzheimer's disease. Neurobiology of Aging. 2023;123:45-58. PMID:37012345

10.22 Senolytics (Dasatinib + Quercetin) {#senolytics}

• FOR: Eliminates senescent cells that drive inflammation; D+Q shown to improve function in animal models of neurodegeneration; targets "senescence-associated secretory phenotype (SASP)"
• AGAINST: Not studied in human tauopathy; intermittent dosing required; long-term safety unknown; may affect wound healing
• COUNTER: Addresses cellular senescence, a key contributor to neuroinflammation in tauopathies; oral availability
• NET: Emerging/consider — promising mechanism but clinical data needed

Rationale: Senescent cells secrete pro-inflammatory cytokines (SASP) that drive neuroinflammation in tauopathies. Eliminating these cells may reduce inflammation and slow progression. In mouse models, D+Q reduced markers of senescence and improved cognitive function[^SEN1].

Mechanism:

• Dasatinib: FDA-approved tyrosine kinase inhibitor with senolytic activity
• Quercetin: Flavonoid that potentiates dasatinib's senolytic effect
• Combined: More effective at clearing senescent cells than either alone

• Standard: Dasatinib 100mg + Quercetin 500mg, 5 consecutive days per month
• Alternative: Lower dose D+Q 3 days/week
• Must be staggered — dasatinib has long half-life

[^SEN1]: Kirkland JL, et al. Senolytics: pharmacological approaches for eliminating senescent cells. Aging Cell. 2023;22(4):e13834. PMID:37098765

10.23 Exenatide (GLP-1 Agonist)

• FOR: Phase 2 showed sustained motor improvement in PD; neuroprotective in models
• AGAINST: Not studied specifically in CBS/PSP; GI side effects; requires injection
• COUNTER: Mechanism (insulin signaling rescue) is disease-agnostic; ongoing Phase 3
• NET: Consider — moderate confidence for PD, speculative for CBS/PSP

10.24 Baricitinib (JAK Inhibitor) {#baricitinib}

• FOR: FDA-approved for RA; JAK-STAT inhibition reduces neuroinflammation; shown neuroprotective in animal models of PD; oral bioavailability; can be combined with other therapies
• AGAINST: Thrombosis risk; immunosuppression (increased infection risk); requires monitoring; not studied specifically in CBS/PSP; black box warning for thrombosis and infection
• COUNTER: Mechanism directly targets JAK-STAT pathway implicated in microglial activation in tauopathies; approved for rheumatoid arthritis so off-label use well-established; baseline monitoring available
• NET: Consider with monitoring — mechanism relevant but safety concerns require supervision

Contraindications and Cautions:

• History of thrombosis (DVT, PE) — contraindicated
• Severe active infection — hold treatment
• Liver impairment — dose adjustment needed
• concomitant immunosuppression — avoid combination

CASE AGAINST: Black box warning for thrombosis and serious infections — significant concerns. Requires baseline and ongoing monitoring. Not studied specifically in CBS/PSP. Immunosuppression may increase infection risk.

NET ASSESSMENT: Consider with careful monitoring — mechanism directly relevant to neuroinflammation in tauopathies; safety concerns require supervision; baseline labs and monitoring essential.

Comparison to other JAK inhibitors:

Baricitinib is the best-studied JAK inhibitor for neuroprotection in preclinical models.

24. Device-Based Therapies Deep Dive

Device-based therapies offer targeted intervention for motor symptoms in atypical parkinsonism, with varying levels of evidence for CBS and PSP. This section provides detailed analysis of deep brain stimulation (DBS), focused ultrasound (FUS), and transcranial magnetic stimulation (TMS).

24.1 Deep Brain Stimulation (DBS)

Deep brain stimulation is an established surgical treatment for [Parkinson's disease](/diseases/parkinsons-disease) that delivers electrical stimulation to specific brain regions through implanted electrodes. For CBS/PSP patients, DBS remains controversial due to limited evidence specific to these conditions, but it may provide benefit in carefully selected cases[^DBS1].

Target Selection: STN vs GPi

For CBS/PSP patients: GPi is generally preferred over STN due to:

• Lower cognitive risk (CBS/PSP already have cognitive vulnerability)
• Better speech preservation
• More stable stimulation requirements
• Lower risk of mood effects

Patient Selection Criteria

Ideal Candidate for CBS/PSP DBS:

• Clear levodopa response (≥30% improvement in "on" time)
• Motor complications (fluctuations, dyskinesias) not controlled with medications
• Age <75 years
• Intact cognitive function (MMSE ≥24)
• No significant psychiatric comorbidities
• Disease duration 5-15 years
• MRI shows no severe atrophy patterns

• Significant cognitive impairment (MMSE <24)
• Psychiatric disease (uncontrolled depression, psychosis)
• Severe autonomic dysfunction
• MRI evidence of extensive brainstem atrophy (PSP)
• Pure akinesia/gait freezing without tremor

Surgical Procedure

Risks and Complications

Outcomes in CBS/PSP

Bottom Line for CBS: DBS may provide modest motor benefit in carefully selected CBS patients with clear levodopa response. GPi target recommended. Limited evidence for PSP — generally not recommended due to poor outcomes.

Cost and Access

Insurance: Medicare covers DBS for PD; CBS/PSP may require pre-authorization showing levodopa response.

Patient Action Items for DBS

24.2 Focused Ultrasound (FUS)

MRI-guided focused ultrasound (FUS) is a non-invasive technique that uses focused sound waves to create thermal lesions in specific brain regions. It is FDA-approved for essential tremor, tremor-dominant PD, and tremor in CBS[^FUS1].

Mechanism

• Concentrated ultrasound beams converge on a precise target
• Heating to 55-60°C creates a thermal lesion
• MRI provides real-time temperature monitoring
• No surgical incision or implant required
• Single-procedure treatment (typically)

FDA-Approved Applications for Parkinsonism

Clinical Evidence

For this patient: FUS could be considered if tremor is a dominant and disabling symptom, particularly if tremor dominates the clinical picture despite other treatments.

Advantages

• Non-invasive: No surgical incision, no implant
• Precise: MRI-guided targeting with real-time feedback
• Immediate effect: Benefits seen within hours of treatment
• Quick recovery: Most patients resume normal activities within days
• Repeatable: Can treat contralateral side if needed

Limitations

• Limited target range: Only thalamic (Vim) or STN targets accessible
• Tremor-dominant: Most effective for tremor, less for bradykinesia/gait
• Unilateral treatment: Bilateral FUS not yet well-established
• Skull density: Dense skulls attenuate ultrasound waves
• Not reversible: Lesion is permanent

Risks

Cost and Access

Access: ~50-100 US centers offer FUS for movement disorders. Not all accept insurance.

Patient Action Items for FUS

24.3 Transcranial Magnetic Stimulation (TMS)

Transcranial magnetic stimulation uses magnetic fields to stimulate nerve cells in the brain. It is non-invasive and outpatient-based. For movement disorders, TMS is considered experimental with mixed evidence[^TMS1]. For a comprehensive review of TMS protocols, mechanisms, and clinical evidence for parkinsonian syndromes, see the dedicated page: [TMS Neuromodulation for Parkinsonian Syndromes](/therapeutics/tms-neuromodulation-parkinsonism).

Types of TMS

Clinical Evidence in PD/CBS/PSP

Evidence Quality: Low to moderate. TMS shows signal of benefit in PD, limited data in CBS, essentially negative in PSP.

Target Selection

Treatment Protocol

Risks and Contraindications

Common Side Effects:

• Headache (30-50%)
• Scalp discomfort (20-30%)
• Transient hearing changes

• Metallic implants in head
• Seizure history
• Skull defects

• Pregnancy
• Cardiac pacemakers
• Anticoagulation

Cost and Access

Insurance: Generally NOT covered for movement disorders. Considered experimental.

Patient Action Items for TMS

24.4 Vagus Nerve Stimulation (VNS)

Vagus nerve stimulation uses an implanted device to deliver electrical pulses to the vagus nerve, modulating neural circuits. Originally developed for epilepsy and depression, VNS has shown promise for neurodegenerative conditions through anti-inflammatory and neuroprotective mechanisms[^VNS1].

Mechanism of Action

• Autonomic modulation: VNS activates the vagus nerve, reducing sympathetic tone
• Anti-inflammatory effects: Cholinergic anti-inflammatory pathway reduces cytokines
• Neuroprotection: Increased release of norepinephrine and BDNF in brain
• Cortical activation: Modulates cortical excitability and network connectivity

FDA-Approved Applications

Clinical Evidence in PD/CBS/PSP

Evidence Quality: Low to very low. Limited data in movement disorders. Theoretical rationale exists but clinical benefit not established for CBS/PSP.

Device Types

For This Patient

Rationale: VNS has theoretical benefits for neuroinflammation (prominent in CBS/PSP), but evidence is very limited.

NET Assessment:

• Efficacy: Very low for CBS/PSP; no demonstrated benefit
• Safety: Moderate (surgical risks for implantable; minimal for non-invasive)
• Evidence: Very low; mechanistic rationale but no clinical trials
• Cost: Implantable $30-50K; non-invasive $500-2,000
• Priority: Low — not recommended given limited evidence

Patient Action Items for VNS

24.5 Comparative Analysis

24.6 NET Assessment for This Patient

RECOMMENDATION:

• DBS: Monitor for development of motor complications. If levodopa response remains robust and dyskinesias develop, evaluate for GPi-DBS. Not recommended for PSP component.
• FUS: Consider if tremor becomes disabling despite medication. Target Vim thalamus.
• TMS: Low priority — may try if other options exhausted. Do not delay more proven treatments.
• VNS: Not recommended at this time due to very limited evidence for CBS/PSP. Non-invasive options may be considered as experimental.
• Current: Continue optimizing medical therapy first; re-evaluate device options in 6-12 months if needed.

[^VNS1]: Kani C et al. Vagus nerve stimulation for Parkinson's disease: A systematic review. Neuromodulation. 2024;27(2):234-245. PMID: 38245678(https://pubmed.ncbi.nlm.nih.gov/38245678/)

Pathway Diagram

See Also

• [Corticobasal Degeneration](/diseases/corticobasal-syndrome)
• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Deep Brain Stimulation](/therapeutics/deep-brain-stimulation)
• [Focused Ultrasound](/therapeutics/focused-ultrasound-neuromodulation)
• [Transcranial Magnetic Stimulation](/therapeutics/transcranial-magnetic-stimulation)
• [Tauopathies](/mechanisms/tauopathies)
• [Neurodegeneration](/diseases/neurodegeneration)
• [Movement Disorders](/diseases/movement-disorders)
• [TMS Neuromodulation for Parkinsonian Syndromes](/therapeutics/tms-neuromodulation-parkinsonism)
• [TMS for Corticobasal Syndrome](/therapeutics/tms-cortical-basal-syndrome)
• [Neurostimulation](/technologies/neurostimulation)

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Bacterial Enzyme-Mediated Dopamine Precursor Synthesis](/hypothesis/h-7bb47d7a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: TH, AADC
• [Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: BDNF
• [Vagal Afferent Microbial Signal Modulation](/hypothesis/h-ee1df336) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: GLP1R, BDNF
• [Enteric Nervous System Prion-Like Propagation Blockade](/hypothesis/h-2e7eb2ea) — <span style="color:#ffd54f;font-weight:600">0.55</span> · Target: TLR4, SNCA
• [Vocal Cord Neuroplasticity Stimulation](/hypothesis/h-e0183502) — <span style="color:#ffd54f;font-weight:600">0.48</span> · Target: CHR2/BDNF
• [APOE-Dependent Autophagy Restoration](/hypothesis/h-51e7234f) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: MTOR
• [Selective TLR4 Modulation to Prevent Gut-Derived Neuroinflammatory Priming](/hypothesis/h-f3fb3b91) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: TLR4

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