Acute levodopa reorganizes rather than normalizes the Parkinsonian brain: a multiscale connectomic, molecular, and transcriptomic analysis.

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

Abstract Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), yet whether it returns the brain toward health or reorganizes it into a new state is unresolved. We traced the acute levodopa response across scales in 34 patients (resting-state functional MRI, OFF and ON) versus 36 matched controls, following it from local activity (amplitude of low-frequency fluctuations and regional homogeneity), through the whole-brain connectome (network-based statistics, brain–behaviour coupling), to its molecular (ten neurotransmitter PET atlases) and transcriptomic (Allen Human Brain Atlas) context, with individual response estimated by connectome-based predictive modelling. At no scale did levodopa move the brain toward the control pattern. A right prefrontal abnormality persisted regardless of medication, whereas a distributed treated-state subnetwork of hyperconnectivity emerged only ON medication (387 edges; family-wise error p = 0.034; reproduced under stricter motion control). Its magnitude predicted improvement in the dopamine-responsive signs, most consistently bradykinesia (leave-one-out r = 0.30, including under fully nested cross-validation), but not the dopamine-resistant tremor or axial signs. Treated-state activity spatially aligned with dopaminergic and serotonergic systems, and the behaviourally coupled network co-localized with mitochondrial energy-metabolism genes. Acute levodopa therefore reorganizes rather than repairs the Parkinsonian brain in a way that tracks individual motor benefit.

Related topics