Aberrant hypothalamic-cortical functional connectivity in spinal cord injury: a neuroimaging-transcriptomic study for motor recovery prognostication.

Abstract

Spinal cord injury (SCI) disrupts supraspinal projections to spinal motor circuits, resulting in sensorimotor deficits. While emerging evidence implicates hypothalamic engagement in post-SCI locomotor recovery, the integrity of hypothalamic-cortical functional connectivity (FC) and its prognostic utility remain uncharacterized. Here, the authors employed voxelwise resting-state functional MRI (fMRI) and multivariate pattern analysis to map hypothalamic-cortical FC alterations in 30 incomplete SCI patients relative to 30 demographically matched healthy controls (HCs). Longitudinal assessments at 6-month follow-up integrated clinical metrics (American Spinal Injury Association [ASIA] motor/sensory scores) and transcriptomic decoding via spatial correlation with Allen Human Brain Atlas gene expression profiles. Mass univariate comparisons revealed reduced FC between the hypothalamus and key motor regions, supplementary motor area (SMA), precentral gyrus, and cerebellar crus in SCI patients versus HCs (cluster-level family-wise error-corrected p < 0.05). Baseline hypothalamic-SMA FC strength positively predicted initial motor impairment (Pearson's r = 0.76, p < 0.001). Longitudinal analysis demonstrated FC reorganization paralleling motor recovery (ΔFC vs ΔASIA motor score, r = 0.36, p = 0.04), and searchlight classification identified the precuneus with high classification accuracy for stratifying recovery trajectories. Transcriptomic mapping implicated dysregulated synaptic signaling genes in regions exhibiting FC abnormalities. The authors' investigation delineated a critical role for hypothalamic-cortical circuits in post-SCI motor recovery. The dynamic reconfiguration of hypothalamic-SMA connectivity, coupled with its prognostic value, positions this pathway as a biomarker for monitoring neuroplasticity in SCI.