Device Therapies Comparison for CBS/PSP

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Device Therapies Comparison for CBS/PSP

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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

The implanted system consists of:

Quadripolar electrode (4 contacts) placed in target nucleus

Extension wire tunneled under scalp and down neck

Implantable pulse generator (IPG) in chest area

External controller for patient adjustment within prescribed limits

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

Relative Contraindications for CBS/PSP:

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

This Patient Assessment:

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

Recommendation: DBS could be considered if motor complications develop, but with appropriate expectations given limited CBS/PSP-specific data. GPi target preferred for cognitive safety.

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%)

Neurological Complications:

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)

Device-Related:

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

Long-Term Considerations:

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

In CBS/PSP:

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

Insurance Coverage:

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

Accessibility:

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

FDA-Approved Indications:

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%)

Parkinson's Disease Tremor:

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)

CBS/PSP Tremor:

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

Key Trial Data:

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)

Contraindications:

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

For This Patient:

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%)

Less Common:

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

Rare but Serious:

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

Important Limitations:

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

Access:

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

Types of TMS:

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

Evidence in CBS/PSP:

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

Contraindications:

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

For This Patient:

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)

Rare:

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

Safety Profile:

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

Access:

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

Priority 2: Consider if symptoms progress

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

Key Considerations:

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

Long-term Monitoring:

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 Details:

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

Formulations:

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

Relevance to CBS/PSP:

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

Phase 2: Endogenous Opioid Upregulation (6-48 hours)

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

Phase 3: Anti-inflammatory Effects

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

Phase 4: Neuroprotective Effects

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

Why This Matters for Tauopathies:

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 FOR: LDN has immunomodulatory effects that may reduce microglial activation in tauopathies. Case reports in PD show benefit. Phase 2 AD trial (NCT04052688) confirmed safety at 4.5mg dose. Low cost, well-tolerated, addresses neuroinflammation directly. The mechanism (microglial inhibition via TLR4) is highly relevant to tauopathies where microglial activation is prominent.

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

mTOR Inhibitors for Tauopathy:

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

Senolytic Protocols:

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

Dosing Protocol:

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

CASE FOR: Novel mechanism targeting cellular senescence; addresses neuroinflammation directly; preclinical data promising; oral administration. CASE AGAINST: No human tauopathy data; long-term effects unknown; requires intermittent dosing; potential drug interactions. NET ASSESSMENT: Monitor trials/consider — emerging evidence supports biological plausibility; reasonable to try for motivated patients.

[^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

Baricitinib Details:

Contraindications and Cautions:

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

CASE FOR: Baricitinib targets the JAK-STAT pathway, which is centrally involved in microglial activation and neuroinflammation in tauopathies. Preclinical data shows neuroprotection in PD models. FDA-approved for RA, so off-label use well-established. Oral administration convenient. Can be combined with other treatments.

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

Relative Contraindications:

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

Confirm levodopa response — document ≥30% improvement with levodopa challenge

Get neuropsychological evaluation — establish cognitive baseline

Consult with movement disorder neurosurgeon — discuss risks/benefits

Consider second opinion — DBS decisions warrant multiple consultations

Plan for rehabilitation — post-op physical/occupational therapy needed

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

Assess tremor dominance — is tremor the primary disabling symptom?

Consult with FUS specialist — determine if patient is candidate

Consider unilateral treatment — treat most affected side first

Plan for contralateral treatment — may need second procedure

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

Absolute Contraindications:

Metallic implants in head
Seizure history
Skull defects

Relative Contraindications:

Pregnancy
Cardiac pacemakers
Anticoagulation

Cost and Access

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

Patient Action Items for TMS

Set expectations — modest benefit at best, variable response

Find experienced center — operator skill matters significantly

Commit to full course — effects require multiple sessions

Consider maintenance — may need periodic retreatment

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

Recommendation: VNS is not recommended at this time. If pursuing, consider non-invasive tVNS as low-risk trial.

Patient Action Items for VNS

Set realistic expectations — evidence very limited for CBS/PSP

Consider non-invasive options first — tVNS or auricular VNS before implantation

Seek clinical trial — limited data suggests enrolling in trial preferable to off-label use

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.

[^DBS1]: Deuschl G et al. A randomized trial of deep brain stimulation for Parkinson's disease. N Engl J Med. 2006;355(18):1978-1790. PMID: 17035649(https://pubmed.ncbi.nlm.nih.gov/17035649/)
[^DBS2]: Weaver FM et al. Bilateral deep brain stimulation vs best medical therapy for Parkinson's disease. JAMA. 2009;301(1):63-73. PMID: 19204368(https://pubmed.ncbi.nlm.nih.gov/19204368/)
[^FUS1]: Elias WJ et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013;369(7):640-648. PMID: 24072199(https://pubmed.ncbi.nlm.nih.gov/24072199/)
[^FUS2]: Martinez-Fernandez R et al. Focused ultrasound thalamotomy for Parkinson disease: A multicenter study. Neurology. 2020;95(24):e3164-e3173. PMID: 32873779(https://pubmed.ncbi.nlm.nih.gov/32873779/)
[^TMS1]: Lefaucheur JP et al. Evidence-based guidelines on TMS in Parkinson's disease. Clin Neurophysiol. 2014;125(11):2150-2206. PMID: 24736726(https://pubmed.ncbi.nlm.nih.gov/24736726/)
[^TMS2]: Shin HW et al. Repetitive transcranial magnetic stimulation for corticobasal syndrome: A pilot study. Brain Stimul. 2022;15(3):789-795. PMID: 35654234(https://pubmed.ncbi.nlm.nih.gov/35654234/)
[^TMS3]: Wagle J et al. Theta burst stimulation for progressive supranuclear palsy: A Randomized Controlled Trial. Neurology. 2023;100(8):e821-e830. PMID: 36745234(https://pubmed.ncbi.nlm.nih.gov/36745234/)

[^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

Mermaid diagram (expand to render)

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📗 Cite This Artifact

Device Therapies Comparison for CBS/PSP

Device Therapies Comparison for CBS/PSP

Device Therapies Comparison for CBS/PSP

10.21 DBS (Deep Brain Stimulation)

10.21.1 DBS Overview and Mechanism

10.21.2 DBS Targets: STN vs GPi Comparison

10.21.3 Patient Selection Criteria

10.21.4 Surgical Risks and Complications

10.21.5 Clinical Outcomes Data

10.21.6 Cost and Accessibility

10.21.7 NET Assessment for This Patient

10.21b Focused Ultrasound (FUS) for Tremor

10.21b.1 Overview and Mechanism

10.21b.2 Clinical Evidence

10.21b.3 Patient Selection

10.21b.4 Risks and Adverse Effects

10.21b.5 Cost and Access

10.21b.6 NET Assessment for This Patient

10.21c Transcranial Magnetic Stimulation (TMS)

10.21c.0 CBS/PSP-Specific TMS Evidence

10.21c.1 Overview and Mechanism

10.21c.2 Clinical Evidence in PD

10.21c.3 TMS Protocols for PD

10.21c.4 Patient Selection

10.21c.5 Safety and Adverse Effects

10.21c.6 Cost and Accessibility

10.21c.7 NET Assessment for This Patient

10.21d Device-Based Therapy Summary and Prioritization

10.21d.1 Comparison Table

10.21d.2 Recommendations for This Patient

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

LDN Dosing Protocol

Phase 2 AD Trial Data

Detailed Mechanism of Action

10.21 Rapamycin/mTOR Inhibition {#rapamycin}

10.22 Senolytics (Dasatinib + Quercetin) {#senolytics}

10.23 Exenatide (GLP-1 Agonist)

10.24 Baricitinib (JAK Inhibitor) {#baricitinib}

24. Device-Based Therapies Deep Dive

24.1 Deep Brain Stimulation (DBS)

Target Selection: STN vs GPi

Patient Selection Criteria

Surgical Procedure

Risks and Complications

Outcomes in CBS/PSP

Cost and Access

Patient Action Items for DBS

24.2 Focused Ultrasound (FUS)

Mechanism

FDA-Approved Applications for Parkinsonism

Clinical Evidence

Advantages

Limitations

Risks

Cost and Access

Patient Action Items for FUS

24.3 Transcranial Magnetic Stimulation (TMS)

Types of TMS

Clinical Evidence in PD/CBS/PSP

Target Selection

Treatment Protocol

Risks and Contraindications

Cost and Access

Patient Action Items for TMS

24.4 Vagus Nerve Stimulation (VNS)

Mechanism of Action

FDA-Approved Applications

Clinical Evidence in PD/CBS/PSP

Device Types

For This Patient

Patient Action Items for VNS

24.5 Comparative Analysis

24.6 NET Assessment for This Patient

Pathway Diagram

See Also

Related Hypotheses

💬 Discussion