Cortical dysfunction underlies disability in multiple sclerosis

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing-remitting MS patients (RRMS) and 66 controls. Results: Short interval intracortical inhibition (SPMS 3.0 +/- 2.1%; RRMS 12.8 +/- 1.7%, p < 0.01; controls 10.5 +/- 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 +/- 2.2%; RRMS 26.3 +/- 3.6%, p < 0.05; controls 24.7 +/- 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 +/- 1.9%; RRMS -2.0 +/- 1.4, p < 0.05; controls -0.9 +/- 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 +/- 4.5%; RRMS 56.0 +/- 1.5%, p < 0.01; controls 59.0 +/- 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 +/- 1.2 ms, p < 0.001) and RRMS (7.0 +/- 0.9 ms, p < 0.05) patients compared with controls (5.5 +/- 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.