Interhemispheric disconnection of the motor system in early relapsing remitting multiple sclerosis (RRMS)

Abstract

Aims: RRMS starts as a focal inflammatory disease but typically progresses to diffuse demyelination and axonal loss. The Corpus Callosum (CC) is often affected in the earliest stages of the disease. Here we employed measures of effective interhemispheric connectivity and microstructural integrity to investigate the role of the motor CC as an early focus of pre-macrostructural disease activity. We then related these measures to the expanded disability status scale (EDSS), disease duration and T2-weighted MRI lesion load. Methods: 33 right-handed early RRMS patients (mean age: 35±8 years; 23 female; median EDSS: 1.5; median disease duration: 18 months; median number of T2 weighted lesions: 8) were compared to 12 right-handed healthy controls (mean age: 31±9 years). All patients had a lesion free motor CC in T1-weighted and T2-weighted MRI. Interhemispheric inhibition (IHI), a measure of effective connectivity between the two primary motor cortices, was determined by paired coil transcranial magnetic stimulation (TMS) (1). In a subgroup of patients (n=16), DTI tractography was applied to identify the callosal motor fibers (CMFs) connecting the hand areas of the primary motor cortices (M1) of the two hemispheres. Fractional anisotropy of CMFs within the CC (FA-CC) assessed their microstructural integrity. Results: IHI and FA-CC were significantly reduced in patients with RRMS compared to controls. Regression analysis showed a significant positive correlation between FA and the degree of IHI in healthy controls. Within the RRMS group, there were no significant correlations between IHI and FA-CC, EDSS, disease duration and the number of T2-weighted lesions. Conclusions: The reduced IHI in early RRMS is independent of microstructural changes (FA), EDSS, disease duration and number of T2-weighted lesions, strongly suggesting a biological marker of neural network dysfunction in the earliest phase of RRMS when macrostructural lesion is still absent.