ReviewPlasticity of the motor system in multiple sclerosis
Introduction
A core feature of neuronal function is the capacity of single neurons – and eventually of the whole nervous system – to adapt dynamically in response to external stimuli, environmental changes, or lesions. Altogether, these phenomena are commonly referred to as neural plasticity (Sharma et al., 2013). Under physiological conditions, neural plasticity is believed to be the key mechanism underlying brain development (Johnston et al., 2009), learning (Draganski et al., 2006, Dayan and Cohen, 2011), and memory (Martin and Morris, 2002). However, in the context of neurological disorders, neural plasticity may substantially contribute to functional recovery of acute or chronic brain injuries, although in some circumstances it may be maladaptive. Depending on the spatial and temporal scales considered, the neural ability to adapt can take many forms, from changes in the strength of single synapses to alterations in cortical anatomy, and from rapid-onset plasticity to chronic reorganization (Fig. 1).
Changing the balance of excitation and inhibition can be a very quick way of adaptation (Jacobs and Donoghue, 1991). As the anatomical connectivity of neurons is usually much larger than their territory of functional influence, removal of tonic inhibition may rapidly increase their region of influence, in other words “unmask” part of their latent connections (Jacobs and Donoghue, 1991). As a second mechanism of adaptation, changes in neuronal membrane excitability mediated by voltage-gated ion channels have been described (Cantrell and Catterall, 2001). Given the role of Na+ channels in setting the threshold for action potential generation, these channels may be capable of mediating cellular plasticity (Cantrell and Catterall, 2001). Another rapidly available adaptive process is the modulation of synaptic efficacy. Depending on the arriving stimuli, existing synapses can be strengthened or weakened, resulting in processes which are referred to as long-term potentiation (LTP) or long-term depression (LTD) (Hess et al., 1996, Hess and Donoghue, 1996). The direction and magnitude of such changes depend on the order and precise temporal interval between presynaptic and postsynaptic spikes, thus referred to as spike-timing-dependent plasticity, which is considered an important factor for activity-dependent neural plasticity (reviewed in Feldman, 2012). These processes are particularly attractive for clinical research as they can be assessed in vivo by non-invasive brain stimulation protocols (e.g., Stefan et al., 2000, Wolters et al., 2003, Huang et al., 2005). Additionally, metaplastic mechanisms might contribute to functional compensation following brain damage by setting the stage for efficient recovery (Hulme et al., 2013). Finally, and requiring a longer period of time, anatomical changes can appear as a consequence of chronic cortical reorganization, which can be induced by either macroscopic lesions or diffuse damage (Toni et al., 1999, Martino, 2004). While the exact mechanisms sustaining such reorganization are still unknown, sprouting of axons to form compensatory pathways and the formation of new synapses have been shown to occur, possibly sustained by the recapitulation of ontogenetic developmental programmes (Martino, 2004). The knowledge of which of the mechanisms outlined above and summarized in Fig. 1 applies to which adaptive phenomenon remains incomplete. Insight into adaptive plasticity is complicated by the fact that its mechanisms operate in different time periods and are not mutually exclusive, but seem to appear partly in parallel, partly successively with one building on the other (Hallett, 2001).
In this review, we have concentrated on the plasticity of the motor system in patients with multiple sclerosis (MS). First, we provide a brief overview of what challenges the CNS in the course of MS. Second, we describe what is known about central motor plasticity in MS as evidenced by functional magnetic resonance imaging (fMRI), transcranial magnetic stimulation (TMS), and motor training studies. Finally, we discuss possible clinical implications of the current knowledge and important questions to be assessed by future research.
Section snippets
Why to suppose neural plasticity in MS
MS pathology is characterized by inflammation and neurodegeneration within the CNS. Focal inflammation results in asymmetrically located lesions distributed throughout the white and, to a lesser extent, gray matter of the CNS (Hauser and Oksenberg, 2006, Lassmann, 2013). In addition, extensive demyelination is seen in gray matter areas such as the cerebral and cerebellar cortex, the deep gray matter nuclei and the gray matter of the spinal cord (Lassmann, 2013). Moreover, diffuse inflammation
Central motor plasticity – evidence from functional imaging
The majority of studies assessing neural plasticity in MS are based on fMRI, which can provide a large-scale average of neural activity during a defined task or at resting-state. fMRI measures the blood oxygenation level-dependent (BOLD) signal, which is affected by changes in the local balance between neuronal excitation and inhibition (Tomassini et al., 2012b). Increased neural activity results in an increased cerebral blood flow and an increased metabolic rate of oxygen. As the fractional
Central motor plasticity – evidence from TMS
There are different approaches to assess mechanisms and consequences of central plasticity by means of TMS. Stimulation-induced plasticity may be investigated by interventional protocols of repetitive TMS, with assessment of motor excitability and/or behavioral tasks before and after intervention. Single-pulse TMS at the hand area and a number of adjoining sites can be used to establish cortical motor maps of a respective target muscle. The induction of “virtual lesions” by single-pulse TMS or
Central motor plasticity – evidence from motor training
Motor training is probably the most “natural” way to stimulate motor plasticity. Given that an improvement in a distinct motor task is associated with a reorganization of the output organization of the motor cortex (Karni et al., 1995, Classen et al., 1998), repeated performance of a motor task may directly challenge rapid-onset mechanisms of central motor plasticity. In the study of LTP-like rapid-onset motor plasticity described above, we also tested motor learning in the course of repeated
Clinical implications and future studies
Put in a nutshell, the mechanisms underlying short-term motor plasticity are preserved in MS patients over a rather long period after disease onset. Concurrently, chronic reorganization of the brain occurs early and is functionally important for the compensation of MS-related CNS injury. Therefore, available evidence argues against the notion that – within the range covered by the studies described above – increasing pathology is accompanied by an early failure of adaptive plasticity, although
Summary
For a long time, research has focused on the destructive aspects of MS, rather than the compensatory effects of repair and brain plasticity (Enzinger and Fazekas, 2005). However, expanding the view in favor of compensatory mechanisms may contribute substantially to the understanding of the variability in the disease course and likely to the development of therapies to promote the adaptive functional capacity of the brain, which could limit clinical pathology in MS (Tomassini et al., 2012b).
Conflict of interest
The authors declare no competing financial interests.
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