Adaptive functional changes in the cerebral cortex during multiple sclerosis
Adaptive functional changes in the cerebral cortex during multiple sclerosis
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.
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.
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
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)
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.
Arnold DL, Wolinsky JS, Matthews PM and Falini A (1998). The use of magnetic resonance spectroscopy in the evaluation of the natural history of multiple sclerosis, Journal of Neurology, Neurosurgery and Psychiatry, 64, 94–101.
Blinkenberg M, Jensen CV, Holm S, Paulson OB and Sorensen PS (1999). A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS. Neurology, 53, 149–53.
Cramer SC, Nelles G, Benson RR, Kaplan JD, Parker RA, Kwong KK, Kennedy DN, Finklestein SP and Rosen BR (1997), A functional MRI study of subjects recovered from hemiparetic stroke. Stroke, 28, 2518–27.
De Stefano N, Matthews PM and Arnold DL (1995). Reversible decreases in N-acetylaspartate after acute brain injury. Magnetic Resonance in Medicine, 34, 721–7.
De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP and Arnold DL (1998). Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study, Brain, 121(8), 1469–77.
Evangelou N, Esiri MM, Smith S, Palace J and Matthews PM (2000). Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Annals of Neurology,47, 391–5.
(p.330) Filippi M, Horsfield MA, Ader HJ, Barkhof F, Bruzzi P, Evans A, Frank JA, Grossman RI, McFarland HF, Molyneux P, Paty DW, Simon J, Tofts PS, Wolinsky JS and Miller DH (1998). Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis. Annals of Neurology, 43, 499–506.
Filippi M, Rocca MA, Colombo B, Falini A, Codella M, Scotti G and Comi G (2002a). Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. Neuroimage, 15, 559–67.
Filippi M, Rocca MA, Falini A, Caputo D, Ghezzi A, Colombo B, Scotti G and Comi G (2002b). Correlations between structural CNS damage and functional MRI changes in primary progressive MS. Neuroimage, 15, 537–46.
Fu L, Matthews P M, De Stefano N, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C and Arnold DL (1998). Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain, 121 (1), 103–13.
Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S and Matthews PM (2002). The role of ipsilateral premotor cortex in hand movement after stroke. Proceedings of the National Academy of Science of the United States of America, 99, 14518–23.
Lee M, Reddy H, Johansen-Berg H, Pendlebury S, Jenkinson M, Smith S, Palace J and Matthews PM (2000). The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Annals of Neurology, 47, 606–13.
Matthews PM, De Stefano N, Narayanan S, Francis GS, Wolinsky JS, Antel JP and Arnold DL (1998). Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Seminars in Neurology, 18, 327–36.
Moffett JR, Namboodiri MA, Cangro CB and Neale JH (1991). Immunohistochemical localization of N-acetylaspartate in rat brain. NeuroReport, 2, 131–4.
Pantano P, Iannetti GD, Caramia F, Mainero C, Di Legge S, Bozzao L, Pozzilli C and Lenzi GL (2002). Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain, 125, 1607–15.
Rao SM, Binder JR, Bandettini PA, Hammeke TA, Yetkin FZ, Jesmanowicz A, Lisk LM, Morris G L, Mueller WM and Estkowski LD (1993). Functional magnetic resonance imaging of complex human movements. Neurology, 43, 2311–18.
Reddy H, Floyer A, Donaghy M and Matthews PM (2001). Altered cortical activation with finger movement after peripheral denervation: comparison of active and passive tasks. Experimental Brain Research, 138, 484–91.
Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM and Arnold DL (2000a). Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain, 123 (11), 2314–20.
Reddy H, Narayanan S, Matthews PM, Hoge RD, Pike GB, Duquette P, Antel J and Arnold DL (2000b). Relating axonal injury to functional recovery in MS. Neurology, 54, 236–9.
Reddy H, Narayanan S, Woolrich M, Mitsumori T, Lapierre Y, Arnold DL and Matthews PM (2002). Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain, 125, 2646–57.
Rocca MA, Matthews PM, Caputo D, Ghezzi A, Falini A, Scotti G, Comi G and Filippi M (2002). Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology, 58, 866–72.
Roelcke U, Kappos L, Lechner-Scott J, Brunnschweiler H, Huber S, Ammann W, Plohmann A, Dellas S, Maguire RP, Missimer J, Radu EW, Steck A and Leenders KL (1997). Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology, 48, 1566–71.
Rovaris M and Filippi M (2000). The value of new magnetic resonance techniques in multiple sclerosis. Current Opinion on Neurology, 13, 249–54.
Seil FJ (1997). Recovery and repair issues after stroke from the scientific perspective. Current Opinion on Neurology, 10, 49–51.
Shibasaki H, Sadato N, Lyshkow H, Yonekura Y, Honda M, Nagamine T, Suwazono S, Magata Y, Ikeda A and Miyazaki M (1993). Both primary motor cortex and supplementary motor area play an important role in complex finger movement. Brain, 116 (6), 1387–98.
Staffen W, Mair A, Zauner H, Unterrainer J, Niederhofer H, Kutzelnigg A, Ritter S, Golaszewski S, Iglseder B and Ladurner G (2002). Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain, 125 (6), 1275–82.
Sun X, Tanaka M, Kondo S, Okamoto K and Hirai S (1998). Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study. Annals of Nuclear Medicine, 12 (2), 89–94.
Weiller C, Juptner M, Fellows S, Rijntjes M, Leonhardt G, Kiebel S, Muller S, Diener HC and Thilmann AF (1996). Brain representation of active and passive movements. Neuroimage, 4 (2), 105–10.
Werring DJ, Bullmore ET, Toosy AT, Miller DH, Barker GJ, MacManus DG, Brammer MJ, Giampietro VP, Brusa A, Brex PA, Moseley IF, Plant GT, McDonald WI and Thompson AJ (2000). Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study. Journal of Neurology, Neurosurgery and Psychiatry, 68 (4), 441–9.
Wexler BE, Fulbright RK, Lacadie CM, Skudlarski P, Kelz MB, Constable RT and Gore JC (1997). An fMRI study of the human cortical motor system response to increasing functional demands. Magnetic Resonance Imaging, 15, 385–96.