Paper 2 | A biological coordinate inside the patient state

Signed Dopaminergic Asymmetry Tracks Contralateral Motor Laterality in Parkinson's Disease

A magnitude says that two hemispheres differ. A sign reveals which putamen has lower binding, which body side carries greater motor burden, and whether two sources agree. Preserving that direction recovers reproducible anatomy while keeping future uncertainty visible.

Harsh Milind Tirhekar, Priyanshi Yadav, Chandrajit Bajaj

See how patients were selected Inspect Cases A-D

PPMI biological analysis: n = 1,367 Independent S4 replication: n = 56 Future-only PPMI analysis: n = 1,204

Anatomical orientation

The side of the brain and the side of the body are not interchangeable

Dopaminergic loss is read within the striatum, while motor burden is observed on the body. The clinically meaningful relation is contralateral: evidence on one brain side is aligned with signs on the opposite body side. The mirror configuration must remain distinguishable rather than being reduced to one unsigned magnitude.

PutamenStriatal DaT-SPECT binding coordinate

Substantia nigraDopaminergic source region

Contralateral bodyOpposite-side motor examination

Mirror stateDirection reverses; meaning is retained

Conceptual paired coronal brains and human bodies showing two mirror configurations of contralateral dopaminergic and motor laterality — Conceptual medical illustration for anatomical orientation only; it is neither a participant scan nor an inferential result. The exact left-right sign convention is defined in the measured, data-derived panel below.

Directional coordinate

A side-aware representation retains anatomical meaning

Positive imaging values are fixed to relatively lower left putamen binding; positive clinical values are fixed to greater right-body burden. The orientation is defined before analysis and is carried unchanged across PPMI, S4, and future outcomes.

Atlas-based left and right putamen coordinate linked to contralateral clinical laterality and future side-balance — Positive imaging and clinical values form a contralaterally compatible state. The same mapping is used in both cohorts without sign reversal. Anatomical outlines are reference atlas contours, not participant scans.

Outcome-blind selection audit

The illustrative histories were chosen before their futures were viewed

Thirty-two of 1,204 future-only participants met the strict same-month and multimodal completeness gate. Four baseline information states were defined in advance. One record was selected from each state using only landmark evidence, source freshness, model disagreement, interval width, and a hashed tie-breaker.

Outcome-blind flow from 1,204 participants to 32 candidates, archetype counts, and the signed DaT-motor state map — The strict pool contains six positive-sign concordant records, 15 mirror-direction concordant records, four near-symmetric imaging records, five imaging-clinical conflicts, and two records outside these thresholds. Outlined letters identify the displayed Cases A-D. Future value, future sign, forecast error, and later trajectory never entered this map. Pool counts are not population prevalence estimates.

Patient-state evidence explorer

Read each record as a sequence, not a pile of modalities

Each dossier keeps source age, bilateral anatomy, clinical side balance, observed history, the held-out forecast, and its uncertainty in one view. The four records were selected to expose different information states, not four favorable predictions.

Two de-identified outcome-blind PPMI histories showing mirror-image signed dopaminergic and motor states — Case A shows relatively lower left putamen binding with greater right-body burden; Case B shows the mirror state. Only one retained its imaging-indicated sign at 12 months. Current anatomy can therefore be resolved while an individual's future side-balance remains uncertain.

Evidence state Lower left putamen binding with greater right-body motor burden.

Why it matters Imaging and examination resolve the same contralateral direction.

Boundary A clear current state does not guarantee a precise future state.

Case A dated sources, bilateral state, observed motor laterality, and held-out uncertainty

Labels are arbitrary and one-use, time is relative to each landmark, and displayed values are rounded. The dossiers contain no identifier, calendar date, source record, or participant scan. They explain information states; cohort-level analyses carry the inference.

Biological replication

Signed anatomy reproduces across independent cohorts

Signed putamen DaT-SPECT asymmetry correlated with contralateral motor laterality in PPMI and S4 — Signed putamen asymmetry aligned with contralateral MDS-UPDRS Part III laterality in PPMI (n = 1,367; r = 0.676) and independently in S4 (n = 56; r = 0.551). The sign convention was neither reversed nor retuned for S4.

Replication supports a transferable anatomical coordinate. It does not establish a causal mechanism, clinical diagnosis, or treatment target by itself.

Future side-balance

Direction carries modest longitudinal information

Future-only PPMI laterality analysis comparing signed and non-directional imaging representations — In 1,204 PPMI landmarks, each 0.1 increase in baseline signed putamen asymmetry corresponded to a 0.0507 increase in 12-month clinical laterality (95% CI 0.0387-0.0626). Held-out R-squared improved by 0.0176 over a non-directional comparator, a measurable but modest increment.

0.676 PPMI cross-sectional correlation with contralateral clinical laterality

0.551 Independent S4 replication correlation using the same sign map

+0.0176 held-out R-squared gain over non-directional imaging in future laterality

Making disagreement visible

Imaging and clinical direction do not always agree

A useful state must preserve disagreement rather than forcing every source into one label. The analysis therefore separates records whose imaging and clinical signs agree, disagree, or contain weak directional evidence.

Directional agreement groups, stability estimates, prediction error, and molecular context screen — Greater imaging-clinical disagreement was associated with lower directional persistence (odds ratio 0.491 per IQR-standardized unit; 95% CI 0.297-0.711), but did not provide a validated uncertainty ranking. None of 11 dated molecular and cognitive context comparisons passed false-discovery control.

Claim boundary

What sign adds, and what it does not

Question	Result	Interpretation
Contralateral biological anatomy	Replicated	Signed putamen asymmetry tracks opposite-side motor burden in PPMI and S4
Future continuous side-balance	Limited information	Association persists, but predictive improvement is small
Binary side classification	No improvement	Sign does not improve every outcome representation
Axial motor prediction	No improvement	The coordinate is anatomically specific rather than a global severity score
Clinical utility or treatment benefit	Not tested	Prospective response and treatment-policy validation remain necessary

Contribution

A frozen signed DaT-SPECT coordinate
Independent cross-cohort biological replication
Future-only participant-held-out laterality testing
Outcome-blind patient histories that retain disagreement and uncertainty

Not claimed

Global Parkinson disease progression prediction
A causal or calibrated mechanism probability
Treatment response or treatment recommendation
Deployment-ready clinical utility