The Cerebellum and Motor Recovery

A potentially important brain region mediating recovery is the cerebellum. Contralesional cerebellar activity shows increased or sustained activity after an acute ischemic lesion associated with hemiparesis (Feydy et al., 2002; Fraser et al., 2002; Calautti and Baron, 2003). Increased cerebellar activity may distinguish patients with a more favorable outcome after stroke (Small et al., 2002). Cerebellar pathways have been implicated in circuitry mediating recovery and could be particularly important for adaptive responses to injury because of their high intrinsic synaptic plasticity (Voogd and Glickstein, 1998). The cerebellum has a well-described and key role in functional plasticity of the motor system during skill learning by the healthy brain, for example (Doyon et al., 2002; Lafleur et al., 2002; Ungerleider et al., 2002). Cerebellar activation may be critical for sensory processing (Ito, 1993), specifically in monitoring and optimizing movements based on proprioceptive feedback. This role could link these changes to those in secondary somatosensory areas, recalling the specifically disability-associated activations reported by Reddy et al. (2002) (Fig. 5).

Figure 5 To test whether behavioral changes associated with increased disability and greater disease burden make independent contributions to altered patterns of brain activity in patients with multiple sclerosis, patients were matched for either disability or burden of disease, and fMRI was performed with a finger flexion task. (A) For all subjects, the task was associated with activation in a distributed motor control network, including the primary sensorimotor and premotor cortex and the supplementary motor area. (B) Patients with greater corticospinal tract injury who were matched for disability showed relatively increased activation in the dorsal premotor cortex and supplementary motor area. (C) In contrast, patients matched for corticospinal tract injury, but with greater disability, showed relatively increased activation in secondary somatosensory and parietal cortex. 1 = ipsilateral dorsal premotor cortex; 2 = supplementary motor cortex; 3 = contralateral sensorimotor cortex; 4 = primary somatosensory cortex; 5 = secondary somatosensory cortex.

Figure 5 To test whether behavioral changes associated with increased disability and greater disease burden make independent contributions to altered patterns of brain activity in patients with multiple sclerosis, patients were matched for either disability or burden of disease, and fMRI was performed with a finger flexion task. (A) For all subjects, the task was associated with activation in a distributed motor control network, including the primary sensorimotor and premotor cortex and the supplementary motor area. (B) Patients with greater corticospinal tract injury who were matched for disability showed relatively increased activation in the dorsal premotor cortex and supplementary motor area. (C) In contrast, patients matched for corticospinal tract injury, but with greater disability, showed relatively increased activation in secondary somatosensory and parietal cortex. 1 = ipsilateral dorsal premotor cortex; 2 = supplementary motor cortex; 3 = contralateral sensorimotor cortex; 4 = primary somatosensory cortex; 5 = secondary somatosensory cortex.

A recent study explored the potential role of cerebellar-cortical interactions in patients with MS through a measure of functional connectivity that was defined as the strength of the correlation between regional time courses for brain BOLD responses (Saini et al., 2004). Predominantly patients with early relapsing-remitting MS were studied, along with age-matched, healthy controls. The control group showed the expected strong "crossed" correlation between activation changes in the left primary motor cortex and right cerebel-lar dentate nuclei (DiPiero et al., 1990; Meyer et al., 1994). This was not found in patients with MS. In contrast, increased connectivity was found between the left premotor cortex (contralateral to the hand moved) and the cerebellar cortex (the input region for the cortico-ponto-cerebellar projection system) on the same side. Increases in activity in the cerebellar hemisphere contralateral to the hand moved are also found with motor learning in healthy subjects (Doyon et al., 2002). This may reflect recruitment of uncrossed pontocerebellar projections. In studies of the cat, although the majority of pontocerebellar projections are crossed, almost a quarter were found to project to the same side (Brodal, 1983). One possible role for activity in the cerebellum contralateral to the hand moved would be changing excitability of premotor cortex ipsilateral to the hand moved via crossed dentate-thalamo-cortical projections. A subcortical pathway linking activity in motor cortices of the two hemispheres is suggested by observations such as that showing motor cortex activation ipsilateral to the hand moved does not require an intact corpus callosum (Reddy et al., 2000a, 2000b).

VI. Distinguishing Functional Changes Related to Altered Patterns of Use

The integration of specific functional systems (e.g., those responsible for cognition, perception, and action) in distributed networks controlling task performance suggests that adaptive functional changes need not be confined to the primary effector system for the task. For example, as described previously, abnormal activation in patients with MS performing a simple motor task may be found not only in primary motor control regions but also in sensory and association cortex including the insula and temporal, parietal, and occipital areas (Filippi et al., 2003; Rocca et al., 2002). However, some of the additional activation in patients may be a consequence of the changes in patterns of use (e.g., associated with disability) that accompany injury in patients rather than adaptive functional responses to injury itself. Altered patterns of somatosensory feedback and use certainly lead to changes in the functional organization of the brain in other contexts (Jenkins et al., 1990; Plautz et al., 2000). One fMRI study directly tested whether the effects of injury and disability could be distinguished (Reddy et al., 2002) (Fig. 5). Patients with greater brain injury but no functional impairment showed larger ipsilateral premotor and bilateral supplementary motor area activations. A separate fMRI testing the effects of greater disability alone, and controlling for the extent of injury, showed greater activation in bilateral primary and secondary somatosensory cortex.

VII. Limitations to Adaptive Plasticity in MS

The observation that functional impairments inevitably progress in most patients leads immediately to the conclusion that adaptive plasticity in MS is limited. What limits this adaptive plasticity? That the brain cannot maintain normal behaviors with even isolated focal lesions, if they are large enough, suggests an intrinsic limitation based on local specializations for processing and connectivity. In the evolution of the brain, a compromise has been achieved between parallelism of structure and functional specializa tions. Thus, there is a limited scope for recovery of function after major damage to a critical functional system.

In a diffuse disease such as MS, other factors also play a role. Principal among these factors must be diffuse cortical injury and neurodegeneration (Peterson et al., 2001; Cifelli et al., 2002; Wylezinska et al., 2003). Several studies have demonstrated that cortical function is impaired in patients with MS. PET measures of resting cerebral blood flow and metabolism have shown decreases of cortical metabolism associated with clinical progression in MS (Blinkenberg et al., 1999). Sun et al. (1998) reported a correlation between decreased oxidative metabolism and increasing disability Flexible connectivity and adaptive functional reorganization demand widely distributed, intact connectivity. As connectivity is progressively impaired or limited by pathology, the potential for recruitment of parallel pathways decreases.

VIII. Studying Brain Recovery and Rehabilitation Using Approaches from Cognitive Neuroscience: Recognizing the Importance of "Context"

Functional imaging has allowed increasingly informative study of motor control and related cognition in the healthy brain. This has provided a framework for understanding functional brain changes associated with injury and recovery in MS. This work has emphasized that there are widespread changes in response to even focal brain injury, consistent with expectations for adaptive changes that may limit clinical expression of the pathology.

These functional observations also provide insights by emphasizing that behavior and function interact in molding brain responses in disease. The use dependence of functional reorganization implies that brain activity itself helps to determine brain functional outcomes in concert with pathology. The "context" of tasks is also important. For example, Ramnani and Matthews (2003) noted distinct differences in the way in which the brain processes meaningful feedback regarding behavior for initial learning and for relearning. Thus, although studies of motor learning offer useful insights into potential mechanisms of neurorehabili-tation, it also must be appreciated that neurorehabilitation (a recovery of movement) is more accurately a specialized form of relearning.

The importance of context has been emphasized in a different way by a study showing that the manner by which the motor cortex becomes activated is important in determining associated functional reorganization: Lotze and Cohen showed that motor learning depends on more than just movement even when alertness and kinematic aspects of training are well controlled (Lotze et al., 2003). Although both active and passive movements led to activation of the same general area within the primary motor cortex, active training led to more prominent increases in the extent of activation in the primary motor cortex over time, as well as changes in TMS recruitment curves, reflecting the relative degree of intracortical facilitation.

The pathological context of the injury is also important. It has long been recognized that the heterogeneity of localization, size, and severity of lesions, for example, has an effect on disability (Riahi et al., 1998). With appreciation of the interacting cognitive systems for perception, movement planning sensorimotor transformation, and execution of a movement and its control by feedback, new approaches to characterizing motor impairment in terms of deficits in specific brain functional systems become possible. This promises the potential for better targeted therapies, moving away from the notion that one therapeutic approach will be optimally suited to all patients.

0 0

Post a comment