The results of this study provide evidence for an inverse association between cardiorespiratory fitness and brain tissue damage in individuals with multiple sclerosis. These results are exciting in that they suggest the possibility of preserved GM volume and intact tract integrity in the presence of a demyelinating disease. Given that higher levels of fitness in MS participants were also associated with higher scores on the composite measure of information processing speed (ZIPS), and better processing speed was in turn related to preserved structural measures (both GM volumes and WM tract integrity) suggests a clear triple association between fitness, cognitive functioning and GM and WM structures.
Consistent with previous research with MS participants (Chard et al., 2002
, Dalton et al., 2004
, Roosendaal et al., 2009
, Dineen et al., 2008
), we found that relative to healthy controls, MS participants demonstrated a decline in global GM volume and FA reductions in global mean skeleton. In addition, in line with a previous study employing VBM to assess regional differences in GM in persons with RRMS (Prinster et al., 2006
), we found that MS participants demonstrated a reduction in the GM volume of the midline cortical structures and frontal and temporal regions. The midline cortical structures were also positively associated with fitness, suggesting that higher-fit MS participants demonstrated preserved GM volume in structures known to deteriorate as a result of the neurodegenerative process (Charil et al., 2007
, Bendfeldt et al., 2009
). Specifically, in MS there is a greater deterioration in the GM volumes of structures that are heavily interconnected with other regions (Charil et al., 2007
, Bendfeldt et al., 2009
), such as the ACC and the medial frontal gyrus. One possible reason for greater atrophy in structures with extensive cortico-cortical connections with other regions could be due to the indirect influence of distal lesions in the WM through processes of anterograde or Wallerian degeneration (Waller, 1850
, Simon et al., 2000
, Ciccarelli et al., 2003
). The finding of preserved GM volume in these interconnected structures with increasing fitness suggests that aerobic fitness may play a key role in slowing the neurodegeneration caused by MS. Future intervention studies directly addressing this question will provide vital information on the causal relation between exercise and functioning in MS participants.
In addition to GM atrophy, increased levels of fitness were also inversely correlated with FA reductions in the white matter tracts. Using a relatively new approach to analysis of diffusion imaging data (TBSS, Smith et al., 2006
), we were able to confirm previous reports of global and regional differences in the integrity of the white matter tracts in MS. MS participants showed a reduction in the integrity of the tracts involved in the NAWM, and though there was some degree of overlap with the lesion probability map, there was also a significant partial dissociation from the LPM providing further evidence that NAWM plays an important role in the pathological processes of MS (Zivadinov et al., 2001
, Rovaris et al., 2002b
, Dineen et al., 2008
). Lifestyle factors that might be associated with sparing of the NAWM, thus need to be better understood in order to reduce the burden associated with the disease. Specifically, we found that higher levels of fitness were associated with higher FA values in the posterior thalamic radiation (including the optic radiation) and anterior corona radiata, including the genu of the corpus callosum. Both these tracts have been investigated in the MS literature and studies consistently report a reduction in the FA values of these tracts in MS participants relative to healthy controls (Roosendaal et al., 2009
, Dineen et al., 2008
). Posterior thalamic radiation, including the optic radiation involves projection from the lateral geniculate nucleus of the thalamus to the visual cortex (Mori et al., 2005
). Disruptions in the integrity of these tracts may be causally related to problems of vision seen extensively in persons with MS (Roosendaal et al., 2009
, Plant et al., 2008
). Corpus callosum (CC) has been well studied in MS, with studies reporting reduced FA in CC (Ge et al., 2004
, Coombs et al., 2004
, Hasan et al., 2005
), which in turn shows modest correlations with disease duration and neurological disability, suggesting that the reductions in the integrity of the white matter play an important role in the clinical progression of MS. Higher levels of fitness were associated with preserved integrity of both these tracts, as reflected by increase in FA values with increasing fitness, suggesting that fitness indeed might be an important variable playing a neuroprotective effect in the pathology of MS.
Our results of a positive association between fitness and GM and WM structures compliments and extends the growing literature on the benefits of fitness on neuronal plasticity (Colcombe & Kramer et al., 2003
, Colcombe et al., 2003
, Kramer & Erickson 2007
, Prakash et al., 2007
). Much of this work conducted with healthy older adults provides evidence for the beneficial effect of exercise training on brain structure (Colcombe et al., 2006
) and function (Colcombe et al., 2004
) of older adults. Research with nonhumans has provided further support for the prophylactic influence of exercise training (van Praag et al., 1999
, Cotman and Berchtold, 2002
). In rodents, exercise has shown to induce a series of molecular and cellular cascade of events such as cell proliferation, synaptic plasticity (Black et al., 1990
, Kleim et al., 2002
, Swain et al., 2003
, Farmer et al., 2004
; Christie et al., 2008
) and an increase in the production of nerve-growth factors like brain derived neurotrophic factor (BDNF, Vaynman et al., 2004
), insulin-like growth factor-1 (IGF-1, Trejo et al., 2001
, Lopez-Lopez et al., 2004
) and vascular endothelial growth factor (VEGF, Fabel et al., 2003
), providing elucidation on the possible mechanisms through which exercise might promote neuroplasticity. In fact animal work with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, suggests that treatment with IGF-1 significantly reduces the number and area of demyelinating lesions in the spinal cord (Yao et al., 1995
). There is also evidence of a reduction in serum BDNF during relapses in MS individuals relative to episodes of remission (Azoulay et al., 2005
), which in turn is known to increase after a single bout of light exercise (Gold et al., 2003
) as well as with chronic exercise (Cotman & Berchtold, 2002
). Taken together these findings thus suggest that exercise might be associated with a sparing of brain tissue in individuals with MS, possibly as a result of increase in the nerve growth factors such as BDNF and IGF-1. Our results are cross-sectional in nature and thus do not go beyond implying an association between increased fitness levels and preserved GM volume and WM integrity. They do, however, lay the foundation for further exploring the causal effects of a fitness training intervention on the cognitive and brain functioning of individuals with MS.
An important limitation of our study, as acknowledged above, is the cross-sectional design, which prohibits us from making causal inferences about the effect of fitness on structural differences seen in MS individuals relative to healthy controls. Though the two groups of participants were matched for age, education and gender and all statistical analyses conducted within the MS cohort were controlled for age and intracranial volume, there might be other variables such as depression experienced by the participant; or other dietary variables etc. that might have an influence on the results. A randomized clinical trial examining the influence of fitness training on cortical atrophy would help to better characterize the role of exercise in MS without the presence of confounding variables. Further, it is important to note here that MS patients with lower disability scores are also better able to maintain their cardiorespiratory fitness and as a result of which may show improved cognitive functioning and preserved neuronal integrity. Another limitation of the study was the rather homogeneous sample of MS participants that was recruited for the current study, which in turn restricts the generalizations that can be made from the results of the study. We included only relapsing remitting MS female participants because of pragmatic concerns. It would be important to explore this relationship in a much more heterogeneous and a much larger sample with different disease types and greater severity of neurological disability to examine for some variables that might moderate the relation between fitness and preserved structural integrity.
Lastly, to avoid misclassification of T2 lesions as gray matter during VBM, we masked out the lesions independently so as to not contaminate estimation of GM changes in individuals with MS relative to healthy controls. Further we also included a GM mask in our analyses to avoid including pixels with a low probability of belonging to the GM, so that unbiased estimates of GM volumes in the two groups could be made. We also included a stringent threshold for multiple comparisons in both VBM and TBSS analyses, thereby reducing the likelihood of false positive results. However, brain segmentation techniques are complicated in patient populations that are characterized by WM hyperintensities because of a difference in tissue signal intensity and presence of microscopic lesions that might not be detected in T2 images. Given that our between group results are compatible with those found in previous studies employing voxelwise analyses (Prinster et al., 2006
, Roosendaal et al., 2009
), suggests that we were able to successfully mask out the effects of lesion volume on GM classification to investigate between group differences and association with cardiorespiratory fitness.
To summarize, the results of our study provide evidence for an association between aerobic fitness levels and sparing of regional gray matter volume and white matter tract integrity of NAWM in MS. Structural decline in MS, independent of demyelinating lesions, is now recognized as an important and defining feature of the neurodegenerative disease. The finding of spared brain tissue in the presence of the degenerative disease makes an important contribution to the MS literature and can have potentially significant implications for individuals diagnosed with MS.