Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis

Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy abnormalities using functional connectivity gradient (FCG) analysis and evaluated their clinical relevance in ALS.

Resting-state functional MRI images were acquired from 17 definite ALS patients and 29 healthy controls. Unimodal-to-transmodal cortical gradient values were derived from functional connectivity matrices using diffusion map embedding, a nonlinear dimensionality reduction method. Intergroup differences were examined with two-sample t tests at the voxel and network levels.

Gradients primarily in transmodal areas (including the bilateral frontal and parietal cortex and anterior cingulate gyrus) decreased, and gradients primarily in unimodal areas (including the bilateral precentral and postcentral gyrus and occipital cortex) increased in ALS patients (false discovery rate (FDR)-corrected P < 0.05). Network-level gradients in ALS were elevated in the sensorimotor (SMN) and visual networks (VN) but reduced in the frontoparietal (FPN) and limbic networks (FDR-corrected P < 0.05). Among ALS patients, the gradient values in SMN (r = 0.506; P = 0.038), VN (r = 0.534; P = 0.027) and FPN (r = -0.792; P < 0.001) correlated with disease duration, and the gradient value in FPN correlated with disease severity (r = 0.532; P = 0.028). Gradient measures demonstrated moderate accuracy for diagnosing ALS (AUC = 0.712-0.866).

Aberrant cortical hierarchy may elucidate pathophysiological mechanisms of multisystem dysfunction in ALS. FCG analysis may provide biomarkers related to hierarchical functional systems for assessing ALS progression and diagnosis.