Functional connectivity alterations in the motor and fronto-parietal network relate to behavioral heterogeneity in Parkinson's disease

• Striatal hypo-connectivity relates to worse motor impairment in PIGD.
• PPN hyper-connections contribute to PIGD pathophysiology.
• IPL-related hyper-connectivity indicates compensatory mechanisms in TD.
• Neural network resting-state FC alterations underscore behavioral heterogeneity in PD.

BackgroundInsight into the neural mechanisms of postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes in Parkinson's disease (PD) is indispensable for generating pathophysiology hypotheses underlying this phenotyping. This cross-sectional study aimed to gain insight in specific and brain-wide functional connectivity (FC) and its correlation with motor deterioration and preservation in PD subtypes.Methods68 PD patients classified as PIGD (n = 41), TD (n = 19) or indeterminate (n = 8) and 19 age-matched controls underwent resting-state fMRI while ‘off’ medication to assess FC between regions of interest (ROIs) in the motor and fronto-parietal network and on a whole-brain level using a parcellated template. FC alterations were correlated with quantitative behavioral measures.ResultsROI-analyses showed decreased FC between the caudate and putamen in PIGD compared to TD. This hypo-connectivity was correlated with behavioral impairment. In contrast, TD-specific hyper-connectivity between motor cortical areas and the inferior parietal lobule correlated with less behavioral impairment, suggesting compensatory mechanisms. Both subgroups showed hyper-connectivity between the left supplementary motor area and pedunculopontine nucleus, whereas PIGD-specific right lateralized hyper-connectivity was shown between this nucleus and the premotor cortex. Whole-brain analyses revealed 65% hypo-connectivity and 35% hyper-connectivity in PIGD compared to TD. TD also revealed primarily hypo-connectivity compared to controls, but had more pronounced hyper-connectivity involving temporo-occipital areas.ConclusionThis multilevel analysis showed differential connectivity alterations in large scale neural networks and between motor and cognitive control areas that related to behavioral heterogeneity in PD, underscoring the classic TD-PIGD phenotypical classification.