Correlation of thalamic functional organization disturbances and genetic architecture in motor subtypes of Parkinson’s disease

The thalamus is a critical relay center in motor circuit and plays a key role in the pathophysiology of Parkinson's disease (PD). Hierarchical organization is a fundamental principle underlying human brain networks. However, how thalamic functional gradient relates to PD motor symptoms and their genetic modulation remains unclear. Here, we employed dimensional reduction techniques on thalamocortical functional connectome in two independent cohorts and derived lateral-medial and anterior-posterior thalamic functional axes. Dataset 1 included 46 healthy controls (HC), 72 postural instability and gait difficulty (PIGD) patients, and 71 tremor-dominant (TD) patients. Dataset 2 comprised 118 HC, 99 PIGD patients, and 101 TD patients. We observed expansions in TD subtype and contractions in PIGD subtype along lateral/medial principal axis, as well as contractions along anterior/posterior secondary axis in both two subtypes, reflecting potentially altered thalamocortical interactions across unimodal and transmodal networks. Thalamic network gradient analysis revealed widespread network-level gradient alterations in both PIGD and TD subtypes. Notably, ventral attention network gradients within the first two gradients were negatively correlated with motor impairment in both subtypes. Transcription-neuroimaging association analyses using Allen Human Brain Atlas data identified subtype-specific genes associated with thalamic gradient alterations, which were enriched in distinct biological processes and overexpressed in developmental periods as early as "early fetal" stage. These findings characterize alterations in thalamocortical functional organization in PD motor subtypes and provide a multiscale description linking thalamic functional gradients with gene expression patterns.