Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.
Keywords: AFNI, analysis of functional neuroimages; ALS, amyotrophic lateral sclerosis; ALSFRS-R, amyotrophic lateral sclerosis rating scale; ANCOVA, analysis of covariance; BOLD, blood oxygen-level dependent; Cerebellum; Connectivity; DTI, diffusion tensor imaging; Epi, echo planar imaging; FA, fractional anisotropy; FSL, FMRIB Software Library; FWE, family-wise error; MNI, Montreal Neurological Institute; Motor neuron disease; PLS, primary lateral sclerosis; Primary lateral sclerosis; ROI, region of interest; Resting state functional MRI; TBSS, tract based spatial statistics; TFCE, threshold-free cluster enhancement; TORTOISE, tolerably obsessive registration and tensor optimization indolent software ensemble; fMRI, functional magnetic resonance imaging.