Neuroplasticity and functional recovery in multiple sclerosis

Abstract

The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions.

Figure 1

Non-pharmacological modulation of brain plasticity in MS^,. Patients with MS and healthy volunteers performed a visuomotor task in which they tracked a continuously moving bar on a computer screen by altering pressure applied to a handle held in the right hand. The task was performed in blocks of 38 sec. Participants practised the task in short-term (10 blocks for a total of ~25 min) and in the longer-term (daily for 15 days consecutively) settings. Performance was measured as the mean tracking error across each block (short-term) or day (longer-term) of practice. During the first and last session, participants underwent fMRI scanning. As depicted in the graphs, short-term (a) and longer-term (b) task practice significantly improved visuomotor performance in both healthy controls and patients with MS, across levels of disability according to EDSS scores. As shown in the fMRI scans, these performance improvements were associated with a reduction in blood oxygenation level-dependent signal in brain regions involved in visuomotor integration. Abbreviations: EDSS, Expanded Disability Status Scale; fMRI, functional MRI; MS, multiple sclerosis; R, right hemisphere. Permission obtained from SAGE Publications © Tomassini, V. et al. Mult. Scler. 17, 103–115 (2011), and Tomassini, V. et al. Neurorehabil. Neural Repair 26, 581–593 (2012).

Figure 1

Non-pharmacological modulation of brain plasticity in MS^,. Patients with MS and healthy volunteers performed a visuomotor task in which they tracked a continuously moving bar on a computer screen by altering pressure applied to a handle held in the right hand. The task was performed in blocks of 38 sec. Participants practised the task in short-term (10 blocks for a total of ~25 min) and in the longer-term (daily for 15 days consecutively) settings. Performance was measured as the mean tracking error across each block (short-term) or day (longer-term) of practice. During the first and last session, participants underwent fMRI scanning. As depicted in the graphs, short-term (a) and longer-term (b) task practice significantly improved visuomotor performance in both healthy controls and patients with MS, across levels of disability according to EDSS scores. As shown in the fMRI scans, these performance improvements were associated with a reduction in blood oxygenation level-dependent signal in brain regions involved in visuomotor integration. Abbreviations: EDSS, Expanded Disability Status Scale; fMRI, functional MRI; MS, multiple sclerosis; R, right hemisphere. Permission obtained from SAGE Publications © Tomassini, V. et al. Mult. Scler. 17, 103–115 (2011), and Tomassini, V. et al. Neurorehabil. Neural Repair 26, 581–593 (2012).

Figure 2

Pharmacological modulation of brain plasticity in MS. Patients with MS and healthy volunteers underwent a counting Stroop task during fMRI scanning. Patients had comparable cognitive performance to controls, but a significantly greater BOLD signal change in the left prefrontal cortex - a difference that reflects functional reorganization. BOLD signal changes in these regions correlated with cognitive performance and brain volume. A functional score, the activation ratio (AR), representing the ratio between the magnitude of prefrontal cortex activation on the left (found in MS patients) relative to right hemisphere, was calculated to test the effect of pharmacological modulation of brain adaptive plasticity with rivastigmine, a cholinesterase inhibitor. Before rivastigmine administration or following administration of placebo, mean AR in patients was greater than in controls. After rivastigmine administration, mean AR in patients was reduced to within the range of controls. Abbreviations: BOLD, blood oxygenation level-dependent; fMRI, functional MRI; MS, multiple sclerosis; R, right hemisphere. Permission obtained from Oxford University Press © Parry, A. M. et al. Brain 126,2750–2760 (2003).

Figure 3

Effects of disease and pharmacological interventions on generation of BOLD fMRI signal. The graphs illustrate normal (N), elevated (+) or reduced (−) levels in processes that generate the measured BOLD signal. These processes include neural and vascular factors such as signalling to the vasculature and vascular responsiveness. (a) A schematic fMRI activation map in a control group or under placebo administration. (b) Changes in neural activity induced by disease or drugs are correctly reflected in the final statistical map when the confounding effects of signalling and vascular responses are taken into account. (c) Changes in neural activity induced by disease or drugs are incorrectly reflected in the final statistical map because of the intervening confounds of altered neurovascular signalling or vascular responsiveness. Abbreviations: BOLD, blood oxygenation level-dependent; fMRI, functional MRI. Permission obtained from Elsevier Ltd © Iannetti, G. D. & Wise, R. G. Magn. Reson. Imaging 25, 978–988 (2007).