Multilevel functional network signature of Pisa syndrome in Parkinson's disease: a resting-state fMRI study

Pisa syndrome (PS) is a disabling postural complication of Parkinson's disease (PD), but its functional network basis remains insufficiently defined. The aim of this study is to determine whether PD with PS is associated with multilevel resting-state functional network abnormalities beyond differences in motor severity.

We studied 31 patients with PD and PS and 42 patients with PD without PS using resting-state fMRI. Analyses included seed-based functional connectivity, regional homogeneity, fractional amplitude of low-frequency fluctuations, and graph-theoretical metrics of whole-brain topology. Group comparisons adjusted for age, sex, education, Hoehn and Yahr (H&Y) stage, and levodopa equivalent daily dose (LEDD); sensitivity analyses further adjusted for the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III).

Compared with PD without PS, PD-PS showed reduced connectivity between the pedunculopontine nucleus (PPN) and the left supplementary motor area (SMA) and right cerebellar Crus I, reduced interoccipital connectivity, increased connectivity between the right anterior insula and posterior cingulate/medial prefrontal cortex, lower occipital and postcentral fALFF, lower right superior parietal ReHo, and disrupted whole-brain topology with lower small-worldness and efficiency and longer path length. PPN-SMA connectivity correlated inversely with MDS-UPDRS-III and positively with visuospatial/executive performance, but not with lateral flexion angle; global efficiency correlated with Hoehn and Yahr stage and lateral flexion angle. PPN-related findings reflect connectivity involving a PPN-centered brainstem region rather than the PPN nucleus per se. Findings remained significant after additional adjustment for MDS-UPDRS-III.

PS in PD is associated with convergent abnormalities involving brainstem-sensorimotor coupling, visual-parietal integration, salience-default mode interactions, and global network organization. These findings demonstrate group differences in functional network organization between PD patients with and without PS. They support a multilevel network model, but further studies are needed to determine whether these alterations are specifically related to PS severity or pathophysiology.