Hypothesis

In prodromal Parkinson’s disease, early thalamic volume increase drives hyperactivity of cholinergic projections to the dorsal striatum, elevating acetylcholine levels that bias D2‑mediated punishment signaling toward excessive habit formation before substantive dopaminergic loss occurs.

Mechanistic Rationale

1. Distributed network alterations in early PD show thalamic compensatory hypertrophy [1] while the basal ganglia lose functional segregation [2].
2. Cholinergic interneurons in the dorsal striatum modulate dopamine release; heightened acetylcholine amplifies D2 receptor‑dependent punishment learning [4,5].
3. Iron accumulation in the putamen with age correlates with habitual responding [3]; thalamic overdrive may exacerbate this age‑related shift by saturating D2 pathways.
4. Thus, the thalamic cholinergic surge creates a state where punishment signals are overly weighted, narrowing behavioral variability and promoting rigid, habitual responses despite intact reward learning.

Testable Predictions

• Prediction 1: Individuals at risk for PD (e.g., REM sleep behavior disorder carriers) will show increased thalamic volume and elevated striatal acetylcholine esterase PET signal compared with age‑matched controls.
• Prediction 2: These same individuals will demonstrate heightened habitual responding in a two‑step decision task, coupled with reduced sensitivity to punishment outcomes but preserved reward learning.
• Prediction 3: Acute administration of a muscarinic antagonist (e.g., scopolamine) will normalize habitual bias and restore punishment‑dependent learning in the at‑risk group.

Experimental Design

• Cohort: Longitudinal recruitment of 120 prodromal markers (RBDS, hyposmia, mild motor signs) and 120 controls, matched for age and sex.
• Imaging: Baseline 7T MRI for volumetric thalamic and putamen analysis; PET with [^11C] ‑ MP4A for cholinergic activity and [^18F] ‑ DOPA for dopaminergic integrity.
• Behavior: Sequential decision‑making task distinguishing model‑based vs. model‑free habits; separate blocks for reward and punishment feedback.
• Pharmacology: Within‑subject crossover scopolamine vs. placebo during task performance.
• Analysis: Mixed‑effects models testing thalamic volume × acetylcholine PET interaction predicting habit index; mediation analysis to test whether acetylcholine mediates the thalamic‑habit link.

Potential Outcomes and Falsifiability

• If thalamic hypertrophy predicts increased acetylcholine PET signal, which in turn mediates heightened habit rigidity and reduced punishment sensitivity, the hypothesis is supported.
• If thalamic volume does not correlate with striatal acetylcholine, or if cholinergic blockade fails to alter habit performance, the hypothesis is falsified.
• Conversely, a finding that habit changes occur only after significant dopaminergic loss would challenge the premise that cholinergic overdrive is an early driver.

Broader Impact

Demonstrating a cholinergic mechanism would reposition the thalamus as a therapeutic target pre‑dopamine loss, suggesting that anticholinergic strategies could delay habit‑related functional decline in prodromal PD.