Cardiorespiratory fitness: A predictor of cortical plasticity in multiple sclerosis
Introduction
Multiple sclerosis (MS) is the most common neurological disease among young and middle-aged adults, affecting an estimated 1,000,000 individuals worldwide (Kantarci and Wingerchuk, 2006). This autoimmune disease involves demyelination and axonal damage in the central nervous system. The demyelination and axonal damage interfere with neuronal conduction and are associated with MS-related symptoms of which cognitive impairment is a prominent symptom that is reported in 45–65% of people with MS (Rao et al., 1991, Bobholz and Rao, 2003). Deficits are frequently seen in working memory (processing of information in temporary storage), executive control functions (planning, scheduling, and task coordination), attention and concentration, and speed of information processing. The deficits in cognitive function coincide with declines in brain structure (reductions in white and grey matter volume) and function (Bobholz and Rao, 2003). The decrements in cognitive function influence the quality of an individual’s life, leading to disease-related unemployment, reductions in activities of daily living, and compromised social relationships. Consequently, development of strategies to maintain or enhance cognitive function in MS is an important public health goal.
In addition to the necessity of developing training programs that target amelioration of cognitive deficits in the MS population, recent neuroimaging studies have provided evidence for the existence of cortical plasticity in those with MS (Staffen et al., 2002, Penner et al., 2003, Filippi et al., 2004, Audoin et al., 2005). These studies, using a wide variety of cognitive tasks, have examined and found altered patterns of brain activation in MS. Most of these studies have reported similar brain areas to be activated by healthy controls and MS patients, but also report that MS patients show a greater extent of overall activation, thereby arguing for a compensatory mechanism of the recruited brain areas. Despite the cortical adaptability evidenced by MS patients research on the management of cognitive impairment in this population has been limited (Bobholz and Rao, 2003, Heesen et al., 2006). Current symptomatic treatments are cognitive rehabilitation (e.g., cognitive exercises/drills) and pharmacological management (e.g., disease-modifying agents). To date, there is limited scientific evidence that those treatments are effective, the treatments are often costly and time intensive, and pharmacological management, in particular, is associated with unwanted side effects. Hence, identifying alternative methods for mitigating MS-related cognitive impairment through interventions such as cardiorespiratory fitness training would be beneficial for the MS population.
The initial foundation for examining the relationship between fitness and cognitive impairment in MS is based on the aging, neurocognition, and cardiorespiratory fitness literature. Among older adults, cardiorespiratory fitness has demonstrated a protective effect against age-related declines in cognitive function. Indeed, a meta-analysis of 18 intervention studies conducted between 1966 and 2001 examined aerobic fitness training effects on cognitive function among older adults (Colcombe and Kramer, 2003). The analysis indicated a moderate benefit of fitness training across a broad set of cognitive processes for older adults.
The literature on aging, fitness and neurocognitive function has further examined aerobic exercise and cardiorespiratory fitness effects on human brain structure and function. For example, in a cross-sectional study of humans ranging in age from 55 to 79 years, the trajectory of age-related declines in cortical tissue density was significantly reduced as a function of cardiorespiratory fitness level, with the greatest effects observed in the frontal, prefrontal, and parietal cortices (Colcombe et al., 2003). Subsequent research demonstrated that highly fit or aerobically trained older adults exhibited greater task-related activity, reflected in changes in fMRI activation, in the regions of the prefrontal and parietal cortices that were involved in spatial selection and inhibitory functioning respectively, compared with low-fit or untrained older adults (Colcombe et al., 2004). In a recently completed randomized controlled trial, our research group compared the effects of participation in an aerobic exercise program designed to enhance cardiorespiratory fitness with a stretching/toning control condition, on brain structure and function. Participants in the aerobic conditioning group demonstrated increases in regional grey matter volume and, more importantly, these changes took place in the frontal regions of the cortex, regions that are associated with a broad array of higher order attentional control and memory processes (Colcombe et al., 2006). Further, our intervention resulted in increased white matter volume for the aerobic fitness training condition in the region of the anterior white matter tracts. These white matter tracts facilitate communication between the left and right hemispheres of the brain and deterioration of these tracts are associated with age-related cognitive decline. The results of human studies are consistent with a rapidly expanding animal literature, which has begun to explicate the influence of fitness training on brain structure, function and neurochemistry (Cotman and Berchtold, 2002).
Overall, the extant literature on cognitive function and cardiorespiratory fitness suggests that aerobic exercise and cardiorespiratory fitness can have a beneficial effect on cognition and brain function. There is emerging emphasis to conduct research that examines exercise and physical activity effects on neurocognition among people with MS (for a review see Heesen et al., 2006). Herein, we examined the relationship between cardiorespiratory fitness, brain function and cognition in a group of 24 relapsing–remitting multiple sclerosis patients (RRMS). Participants were scanned in a MRI system while they performed the Paced Visual Serial Addition Test, the visual version of the Paced Auditory Serial Addition Test (PASAT), which is used as a core measure of the multiple sclerosis functional composite (MSFC). PVSAT, a task of working memory, has been extensively studied with both the MS population (Staffen et al., 2002, Chiaravalloti et al., 2005) and healthy controls (Fos et al., 2000, Lazeron et al., 2003) with a number of studies consistently implicating activation of the left frontal and parietal lobes during task performance in healthy controls. In addition to the regions of the left hemisphere, MS patients recruit the right frontal and parietal regions (Audoin et al., 2005, Chiaravalloti et al., 2005) presumably to assist in task performance. In our study, we hypothesized that higher levels of cardiorespiratory fitness would be associated with better task performance in terms of faster reaction time and reduced errors on the PVSAT. In addition we predicted that increases in cardiorespiratory fitness would be coupled with greater recruitment of regions of the right hemisphere that are recruited by MS patients during performance of the PVSAT, thereby suggestive of a compensatory mechanism to counter the effects of the neural disease.
Section snippets
Participants
We recruited 24 right-handed females (mean age = 44.71, range = 29–53, SD = 7.07) diagnosed with definite relapsing–remitting MS with a mean Expanded Disability Status Score (EDSS (Kurtzke, 1983)), of 2.61 (SD = 1.76). Refer to Table 1 for participant demographics. Participants were excluded from the study if they met any one of the following criteria: a score below 51 on the Modified Mini-Mental State Examination (mMMSE, highest score = 57; Stern et al., 1987), lack of consent from their primary
Neuropsychological results
The results from the partial correlation analysis between VO2peak and each of the neuropsychological variables are presented in Table 2. We found that only the scores on the PASAT were significantly correlated with VO2peak (pr = 0.42, p < 0.03). Cardiorespiratory fitness was not significantly related to MMSE or K-BIT (verbal) performance, suggesting that fitness does not have an influence on these measures of general cognitive functioning and crystallized intelligence.
Behavioral results
Mean RT for our sample of MS
Discussion
This study is, to our knowledge, the first to establish a relationship between cardiorespiratory fitness, cerebrovascular functioning and cognition in MS patients. Higher cardiorespiratory fitness was found to be associated not only with improved task performance but greater recruitment of the right IFG/MFG, a region of the cerebral cortex, known to be recruited by MS patients during performance of PVSAT, presumably to compensate for the decline in information processing speed owing to
Acknowledgments
This study was funded by research grants R37 AG25667 and R01 AG25032 from the National Institute on Aging, support from the Institute for the Study of Aging, and the Riken Brain Science Institute. The authors would like to thank the undergraduate assistants Avni Danak, Edward Malkowski, Aaron Knauer, Jennifer Scott, Jessica Gosney, and Rachael Gliottoni along with MR technicians Nancy Dodge and Holly Tracey for their help in data collection.
References (35)
- et al.
General multi-level linear modeling for group analysis in fMRI
NeuroImage
(2003) - et al.
Exercise: a behavioral intervention to enhance brain health and plasticity
Trends Neurosci.
(2002) - et al.
A functional MRI study of cortical activations associated with object manipulation in patients with MS
NeuroImage
(2004) - et al.
A Paced Visual Serial Addition Test of fMRI
J. Neurol. Sci.
(2003) - et al.
Cardiovascular fitness and neurocognitive function in older adults: a brief review
Brain Behav. Immun.
(2004) - et al.
Paced Visual Serial Addition Test in multiple sclerosis
NeuroImage
(2005) - et al.
Differences in cerebral activation patterns in idiopathic inflammatory demyelination using paced visual serial addition task: an fMRI study
J. Neurol. Sci.
(2006) - et al.
Accurate, robust and automated longitudinal and cross-sectional brain change analysis
NeuroImage
(2002) - et al.
Multi-level linear modelling for fMRI group analysis using Bayesian inference
NeuroImage
(2004) - et al.
Functional MRI study of PASAT in normal subjects
Magma
(2005)
Cognitive dysfunction in multiple sclerosis: a review of recent developments
Curr. Opin. Neurol.
The counting Stroop: an interference task specialized for functional neuroimaging: validation study with functional MRI
Hum. Brain Mapp.
Hemispheric asymmetry reduction in old adults: the HAROLD model
Psychol. Aging
Cerebral activation patterns during working memory performance in multiple sclerosis using fMRI
J. Clin. Exp. Neuropsychol.
Fitness effects on the cognitive function of older adults: a meta-analytic study
Psychol. Sci.
Aerobic fitness reduces brain tissue loss in aging humans
J. Gerentol.
Cardiovascular fitness, cortical plasticity, and aging
Proc. Natl. Acad. Sci.
Cited by (117)
Dosage and Effectiveness of Aerobic Training on Cardiorespiratory Fitness, Functional Capacity, Balance, and Fatigue in People With Multiple Sclerosis: A Systematic Review and Meta-Analysis
2021, Archives of Physical Medicine and RehabilitationExercise training and cognition in multiple sclerosis: The GET Smart trial protocol
2021, Contemporary Clinical TrialsCitation Excerpt :Worsening performance on the SDMT predicts loss of employment over a three-year period [65]. In addition, faster processing speed on measures such as the PASAT-3″ are correlated with higher levels of cardiorespiratory fitness in persons with MS. [66] Aerobic conditioning improves performance on the SDMT in older adults with mild cognitive impairment [30]. We chose to use a composite primary outcome variable that combines these two measures for several reasons.