Neural substrates of alerting dysfunction in females with Multiple Sclerosis.

MS is a disease characterised by demyelination of the central nervous system resulting in decreased quality of life, increased anxiety, depression, fatigue, and cognitive dysfunction. Attention is frequently impaired in MS. A previous study demonstrated impairment specifically in the attentional alerting domain. However, this study did not establish whether the impairment was in intrinsic or extrinsic alertness, and did not examine the neural substrates associated with the impairment. To examine the alerting deficit in MS and establish the associated neural substrates, 40 female patients with MS and 40 age and gender match controls completed an alertness-motor paradigm designed to test both intrinsic and extrinsic alertness during functional magnetic resonance imaging. We found the MS group had a significant deficit in extrinsic alertness, which was associated with a lack of dorsal prefrontal cortex (DPFC) activation. In addition, reduced gray matter volume in the dorsal prefrontal cortex, thalamus, and basal ganglia were observed. Both fMRI and VBM correlations were observed between fatigue severity scale (FSS) scores and the DPFC. The combined results of our functional and structural MRI data analysis demonstrate that attention deficits in females with MS are a result of the complex relationship between brain tissue loss having a significant impact on functional brain regions subserving executive control of cognitive functions. Understanding the underlying mechanisms of cognitive performance and how they relate to fatigue are crucial to developing novel treatments for the symptoms of MS.