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Reprogramming the Cerebral CortexPlasticity following central and peripheral lesions$

Stephen Lomber and Jos Eggermont

Print publication date: 2006

Print ISBN-13: 9780198528999

Published to Oxford Scholarship Online: September 2009

DOI: 10.1093/acprof:oso/9780198528999.001.0001

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Adaptive functional changes in the cerebral cortex during multiple sclerosis

Adaptive functional changes in the cerebral cortex during multiple sclerosis

(p.325) Chapter 18 Adaptive functional changes in the cerebral cortex during multiple sclerosis
Reprogramming the Cerebral Cortex

Hasini Reddy

Oxford University Press

Abstract and Keywords

This chapter examines reorganization following damage due to the progression of multiple sclerosis in humans studied using functional magnetic resonance imaging (fMRI) and other imaging techniques. It also discusses difficulties in assessing such reorganization and the methods used to bypass these difficulties.

Keywords:   fMRI, multiple sclerosis, reorganization, brain injury

Exploring patterns of injury and functional recovery in multiple sclerosis

Multiple sclerosis is characterized pathologically by recurrent focal demyelination at multiple sites in the central nervous system. Clinically, most patients show good recovery from attacks in the early stages of the illness, but eventually develop progressive functional deterioration. In recent years, there has been a shift from considering functional impairment as resulting from changes in the electrical conduction properties of axons after demyelination, towards an appreciation of the importance of axonal injury and loss (Matthews et al. 1998). Evidence of axonal injury can be found in lesions and also remote from the foci of demyelination in the so-called normal appearing white matter (NAWM)(Fu et al. 1998; Evangelou et al. 2000).

With acute demyelination, remyelination of lesions may be extensive. Axonal injury also may be partially reversible (De Stefano et al. 1995). These mechanisms contribute to, but probably are not wholly responsible for, clinical recovery. As has been shown with brain injury from stroke (Cramer et al. 1997) or tumours (Seitz et al. 1995) cerebral functional reorganization also may be expected to occur in MS. Cortical reorganization that occurs with injury may be adaptive and contribute to recovery even with persistent central nervous system damage.

The extent of subcortical injury as well as patterns of cortical activation in multiple sclerosis can be examined using magnetic resonance techniques. Lesion load on T2-weighted MRI, though not a reliable indicator of extent of disability, can indicate the burden of disease and be used to follow disease evolution (Filippi et al. 1998; Rovaris and Filippi 2000). The extent of axonal injury can be assessed with magnetic resonance spectroscopy (MRS) by measuring the concentration of N-acetylaspartate (NAA), a compound found only in neurons (including dendrites and axons) in the mature brain (Moffett et al. 1991). NAA concentration is reduced in both acute and chronic lesions of MS, as well as in NAWM (Arnold et al. 1998).

Patterns of cortical reorganization can be described by functional magnetic resonance imaging (fMRI). fMRI depends on the blood oxygenation level-dependent (BOLD) effect to show areas of cortex that have greater local blood flow and volume, reflecting greater neural activity during task performance compared to a baseline state. The functional image can be registered to a higher resolution image to define the underlying brain structure. Many fMRI experimental paradigms for patient evaluation use motor tasks because they are easily taught and evaluated and motor pathways are relatively well-defined for identification on MRI scans. Also, responses are well-characterized in normal controls (Wexler et al. 1997).

Measurements of clinical impairment such as motor task performance or measurements of disability such as the Expanded Disability Status Scale (EDSS) can be correlated with MR parameters of injury and reorganization.

(p.326) Evidence of cortical functional changes in MS

A limited number of studies have identified changes in cortical function associated with multiple sclerosis. Positron emission tomography (PET) which can provide measures of resting cerebral blood flow and metabolism has shown decreases of cortical metabolism associated with clinical progression in MS (Blinkenberg et al. 1999) and Sun et al. (1998) showed a correlation between decreased oxidative metabolism and increasing disability. Roelcke et al. (Roelcke et al. 1997) demonstrated that changes in brain glucose metabolism are correlated with symptoms of fatigue in MS, suggesting that functional imaging may provide a means of evaluating otherwise subjective symptoms. However, determination of local changes in brain activation is a more direct approach to understanding changes in cortical functional capacity associated with task performance.

Yousry et al. (1998), using fMRI, have shown that patients with motor weakness show increased activation of ipsilateral and accessory motor areas, whereas normal controls show a more lateralized contralateral motor cortex activation for a simple motor task. Werring et al. (2000) found activation outside the primary visual cortex in MS patients recovering from optic neuritis. However, it remains unclear whether the extensive abnormal activation demonstrated in these patients is adaptive or simply a marker of injury. Interestingly, in accordance with PET results, fMRI has shown decreased activation of motor areas that correlate with extent of fatigue reported by MS patients (Filippi et al. 2002a).

Correlating fMRI activation with injury: is reorganization adaptive?

A few groups have correlated measures of brain injury with extent of reorganization. Pantano et al. measured T1 and T2 lesion load in the corticospinal tract of MS patients with a first MS attack resulting in hemiparesis (Pantano et al. 2002). Patients had fully recovered at the time of the fMRI study. They found that T2 lesion load positively correlated with bilateral motor cortex activation. Relative ipsilateral hemispheric activation of sensorimotor areas can be expressed as a lateralization index. Lee et al. found brain T2 lesion load to correlate not only with decreasing lateralization index (i.e. more bilateral activation) but also with a posterior shift in the geometric centre of activation of the contralateral sensorimotor area (Figure 18.1) (Lee et al. 2000).

Abnormal activations in MS patients performing a simple motor task may be found not only in traditional motor areas but also in the insula and temporal, parietal, and occipital areas, which

                      Adaptive functional changes in the cerebral cortex during multiple sclerosis

Figure 18.1 Geometric centres of the contralateral motor cortex activation in control subjects (yellow) and MS patients (red) performing a dominant (right) hand tapping task (Lee et al. 2000). Talairach co ordinates for controls are 39, 21, 51 and for patients are 38, 30, 58. Please see the colour plate section for a colour version of this figure.

(p.327) are thought to be important in multimodal integration. Decreased activation may also be observed in the ipsilateral cerebellum, which has a role in facilitating motor circuits (Rocca et al. 2002; Filippi et al. 2002b). Extent of overall activation was correlated with injury in the brain as measured by lesion load and in the cervical cord as assessed by magnetization transfer. This suggests that one response to injury may be recruitment of accessory networks that would not normally be activated for the task being performed. However, local expansion of cortical areas normally activated for the task is also important. Many mechanisms could contribute to these changes such as unmasking of existing pathways, axonal sprouting, or new synapse formation (Seil 1997). As patients in the Pantano study did not have a motor deficit, it may be postulated that these responses are adaptive.

Combined MRS and fMRI studies have been used to assess injury in the context of normal or improved performance and explore the contribution of functional reorganization to recovery. There is a strong correlation between disability as measured by the EDSS and reversible decreases of NAA in acute lesions of multiple sclerosis (De Stefano et al. 1998). In later stages of the illness, with progressive axonal loss there are concomitant irreversible decreases in NAA. As cortical reorganization accompanies subcortical damage and correlates with disease burden as measured by T2-weighted lesion load (Lee et al. 2000), it should also correlate with decreases in NAA. Furthermore, if aspects of reorganization are adaptive and able to functionally compensate for axonal injury, then this reorganization may occur after the injury even in the absence of behavioral impairment or disability. Finally, the pattern of task-associated cortical activation should evolve with the progression of recovery of axonal injury in the relevant functional tract.

In a study by Reddy et al. (2000b), a patient with a new large demyelinating lesion in the corticospinal tract was followed after the new onset of hemiparesis from MS with serial MRS and fMRI. Clinical recovery preceded normalization of NAA, but was accompanied by relative increases in ipsilateral pre-motor area and supplementary motor area activation (Figure 18.2). This suggested that these altered patterns of recruitment of elements of the cortical motor network helped to maintain normal levels of function (e.g. via activation of additional descending motor pathways) despite injury to the corticospinal tract. The covariation of MRS and fMRI responses suggests that dynamic reorganization of the motor cortex occurred in response to axonal injury associated with relapse in MS.

Changes in cortical activation have been shown to occur even very early in MS and in patients without symptoms in the affected functional system. For example patients with optic neuritis as their only presentation of MS show functional changes in motor areas compared with controls (Pantano et al. 2002). In another study, MS patients with no motor or sensory impairment of the upper limbs were investigated with fMRI and MRS (Reddy et al. 2000a). The lateralization index of activation was found to be abnormally low in the patients and to decrease progressively with decreases in the relative brain NAA concentrations (Figure 18.3). Since these results were obtained from patients who had normal hand function, the potential confound that arises from performance differences was absent. Thus, these results emphasize that damage in MS occurs much earlier than is detectable simply by clinical evidence and may be masked by cortical functional adaptations.

Altered patterns of cortical activation associated with normal functional ability has also been clearly demonstrated in systems other than sensori motor. Staffen et al. (2002) studied multiple sclerosis patients and normal controls performing a sustained attention task. Although performance was equivalent between the two groups, MS patients showed activation in right frontal and left parietal cortex not found in controls, suggesting compensatory activation. Werring et al. examined MS patients who had recovered from optic neuritis (Werring et al. 2000). Although they had decreased activation of the visual cortex on the affected side, there was extensive activation in the claustrum, the lateral temporal and posterior parietal areas, and the thalamus. All of these areas (p.328)

                      Adaptive functional changes in the cerebral cortex during multiple sclerosis

Figure 18.2 Images showing dynamic reorganization of fMRI and MRS data during serial study of single patient (Reddy et al. 2000b). The image on the left shows mean activation for seven controls performing a right hand tapping task. The other two images show activation of primary motor cortex (red), supplementary motor cortex (yellow), and other (blue) in an MS patient at 2 weeks (centre) and 26 weeks (centre) post relapse. Please see the colour plate section for a colour version of this figure.

                      Adaptive functional changes in the cerebral cortex during multiple sclerosis

Figure 18.3 Graph of Lateralization Index during a dominant hand tapping task vs. NAA in MS patients with no clinical disability (Reddy et al. 2000a). LI: C–I/C + I. C: contralateral, I: ipsilateral, motor cortex activation. Control values are 2.2 and 0.9 for NAA and LI respectively.

previously have been shown to be involved in higher order visual processing or object recognition. These results suggest that parallel pathways in these areas may have been recruited to compensate for the deficits in the primary visual pathway. Such work raises the question of whether the transition from relapsing-remitting to secondary progressive disease could be accounted for in part by a progressive failure of cortical adaptation with an increasing burden of subcortical injury.

Cortical re-organization in MS: implications

There are some difficult issues in assessing reorganization, specifically as assessed by fMRI. Increased task complexity is associated with increased activation of accessory motor areas (Rao et al. 1993; Shibasaki et al. 1993). Patients with injury also may use different strategies to accomplish a similar task to controls, providing an explanation distinct from an adaptive response. (p.329) Some studies try to control for relative task difficulty for patients compared with controls by setting rate or force as a percentage of maximum or, as we have seen, studying unimpaired patients. For motor tasks, another way to avoid the confound of increased effort by patients is to use a passive task, as passive tasks activate similar motor areas to active tasks (Weiller et al. 1996; Reddy et al. 2001).

Intriguingly, primate studies have shown that use-dependent changes occur in the motor cortex, even without injury to the nervous system. A recent combined fMRI and MRS study used active and passive tasks to explore whether the effects of injury and disability could be distinguished from each other (Reddy et al. 2002). Patients with increasing brain injury but no functional impairment performing a motor task activated greater ipsilateral premotor and bilateral supplementary motor areas. A separate contrast looking at the effects of greater disability with equivalent axonal injury as measured by MRS showed greater activation in bilateral primary and secondary somatosensory cortex. This suggests that distinct cortical functional changes occur with disability and brain injury and that disability-related shifts in activation may reflect altered patterns of use in MS patients. As these activation shifts were found even with passive tasks, they likely reflect true reorganization and not a response to increased effort due to disability.

A significant question in considering cortical reorganization as a response to injury is whether it truly is of benefit in mitigating the effects of disease on neural pathways. The technique of transcranial magnetic stimulation (TMS) has also afforded new insight into the role that cortical reorganization plays in recovery. Previous work has shown that similar patterns of reorganization of motor networks occur with subcortical injury in stroke and MS, specifically increased ipsilateral motor cortex activation (Reddy et al. 2000a). Johansen-Berg et al. used TMS in stroke patients to transiently interfere with processing in ipsilateral motor areas during performance of a hand movement task (Johansen-Berg et al. 2002). Slowing of reaction time following TMS correlated inversely with relative hemispheric lateralization as shown by fMRI. This suggests that the ipsilateral activation that occurs with injury, seen in stroke and MS patients, represents a functionally relevant, adaptive response.

An important concept that emerges from studies of MS and cortical reorganization is that the clinical picture may be a gross misrepresentation of the true burden of disease. A corollary of this is that interventions to promote cortical plasticity could provide an important new target for interventions in this disease.


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