Title: Brain Reserve in Multiple Sclerosis
Description: Multiple sclerosis (MS) is a prevalent and progressive autoimmune inflammatory disease affecting both white and gray matter and resulting in lesions and atrophy within the central nervous system (CNS) (Bermel & Bakshi, 2006; Confavreux & Vukusic, 2006; Cree, 2012; Friese, Schattling, & Fugger, 2014). Fine motor impairment, including manual motor speed and fine motor dexterity deficits, is common in MS patients (e.g., Benedict et al., 2011; Chipchase, Lincoln, & Radford, 2003). However, impairment does not progress uniformly across patients (Confavreux, Vukusic, Moreau, & Adeleine, 2000; Filippi & Rocca, 2011; Scalfari, Neuhaus, Daumer, DeLuca, & Muraro, 2013) and the association between disease burden and physical disability is moderate at best (Bermel & Bakshi, 2006; Filippi et al., 2013). Though the brain reserve hypothesis has helped to explain the clinico-pathologic dissociation between cognitive functioning and disease burden in MS patients (Sumowski et al., 2013; Sumowski et al., 2014a), there is no published literature on brain reserve and motor functioning in MS.

Instead, only preliminary data have been presented on brain reserve and general physical disability (Sumowski et al., 2014b). As such, the purpose of this dissertation was to examine the protective effect of brain reserve, estimated via intracranial volume (ICV), on fine motor functioning in relapse-onset MS patients. A sample of 178 relapse-onset, right-handed MS patients underwent neuropsychological testing along with neurological examination, including magnetic resonance imaging (MRI). As part of the evaluation, patients were administered the Nine Hole Peg Test (NHPT; a measure of fine motor speed and dexterity) and the Finger Tapping Test (FTT; a measure of manual motor speed), which served as this study’s outcomes (i.e., dependent variables). Predictors (i.e., independent variables) included demographic variables (age, sex), disease variables (disease duration and disease phenotype, including relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS)), MRI estimates of disease burden (T2 lesion volume [T2LV], normalized brain volumes as measures of cerebral atrophy), and MRI-derived measures of ICV as an estimate of brain reserve.

Results revealed that phenotype (r = .56, p < .001) significantly predicted performance on the NHPT, such that patients with SPMS did worse than patients with RRMS. Regarding disease burden, T2LV (r = .24, p = .001) and normalized gray matter volume (r = -.18, p = .019) predicted NHPT, with less disease burden associated with better performance. Greater ICV (r = -.21, p =.006) was also significantly associated with better performance on the NHPT. Next, phenotype (r = -.45, p < .001) predicted FTT with SPMS patients again performing worse than RRMS patients. Sex (r = .40, p < .001) was a significant predictor of FTT with men outperforming women, on average. For FTT, normalized gray matter volume (r = .36, p < .001) was the only measure of disease burden that predicted performance, with greater volume (i.e., less atrophy) associated with better performance. Similarly, greater ICV (r = .31, p < .001) significantly predicted better performance on the FTT. For both NHPT and FTT, interactions between measures of disease burden and ICV were not significant.

As such, some evidence from this study was not consistent with the reserve hypothesis; however, this finding may be due to differences in the way brain reserve impacts motor outcomes (relative to cognitive outcomes). Nonetheless, as ICV was associated with better performance for both outcome measures, these findings provide partial support for the brain reserve hypothesis in fine motor functioning in MS. Therefore, findings from this study have real-life applications with regard to improved understanding of fine motor disability in MS and identification of patients at risk for upper extremity dysfunction, leading to the possibility of early intervention. Findings also have implications for informing clinical research in MS. Future research should examine the protective effect of brain reserve on fine motor functioning within larger cross-sectional samples (i.e., RRMS vs. SPMS), within primary-progressive MS (PPMS) patients, and when using additional measures of upper extremity disability (e.g., Grip Strength Test).

Longitudinal research would also help to determine whether there is a moderating effect of brain reserve on fine motor disability progression as well as allow patients to serve as their own baseline, which would control for individual differences in motor functioning. Next, examining reserve in patients experiencing lesions and atrophy in specific brain regions underlying motor function (e.g., cerebellum and precentral gyrus) may help explain why interactions between disease burden and ICV were not significant within the present study. Finally, by testing the brain reserve hypothesis as it relates to fine motor functioning in non-clinical, healthy controls, it would be possible to determine whether the protective effect of reserve is present premorbidly.