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Mechanisms o f neurological recovery: the concept o f cerebral plasticity

Recovery is common following many types of neurological injury but, until recently, the mechanisms have been difficult to study in humans in vivo. With non-invasive functional neuroimaging, it is now possible to investigate how the

human brain responds following damage. In contrast to longstanding concepts of “hardwired” functional pathways, evidence has emerged for functional reorganization (or “plasticity”) in the adult CNS following injury (see, for

example, Benecke et ah, 1991; Chollet et ah, 1991; Frackowiak, 1998). The basic

underlying mechanisms underlying CNS plasticity and its role in recovery remain speculative. In animal studies, changes in the expression of presynaptic protein

markers of axonal sprouting have been described local to a focal ischaemic lesion

(Li et ah, 1998); similar synaptic remodelling may also contribute to neurological recovery in humans.

In its most general sense, plasticity in the nervous system means a change in structure or function due to development, experience or injury; to be relevant to recovery, reorganization should occur in a pattern that may plausibly help to

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compensate for the deficit induced by injury. A working definition of the concept

of plasticity has been proposed by Frackowiak as a “long-term alteration in patterns of behaviour-related activity in distributed brain systems.” (Frackowiak,

1998). This defines a phenomenon that can be investigated with functional

imaging methods, which are able to map the distribution of cerebral activity

during performance of a task involving appropriate brain systems after injury. There are likely to be a number of general mechanisms involved in

neurological recovery. Changes at the site of tissue injury may contribute,

particularly in the very early stages, and include the resolution of inflammation and oedema, and the re-absorption of necrotic tissue. However, considerable

recovery is often observed for months or years after CNS injury, a phenomenon not explicable by these acute local changes. Other processes occurring over a longer period must therefore contribute: in MS, for example, remyelination of damaged fibres may occur over weeks to months. However, restitution of function

in MS and other neurological conditions may occur despite the destruction or degeneration of some of the axons in affected pathways. Recovery must therefore

depend, at least in part, on adaptive changes in surviving components of either the

damaged pathway, or other intact systems. Plasticity in this context implies that undamaged brain regions can somehow compensate by “taking over” the function

of the damaged tissue. Proposed mechanisms include the strengthening or

unmasking of existing functional connections (perhaps linked with bilateral cerebral representation of function); the formation of new connections; or the

release of inhibition from cerebral areas local to, or remote from, the injury. For example, lost brain function due to a cortical injury might be engaged by tissue adjacent to the lesion, by areas in the unaffected hemisphere, or by connected

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subcortical structures. To illustrate the concept of plasticity, and the way in which

functional imaging may be used to investigate it, some of the evidence obtained following two types of CNS injury - motor stroke and spinal cord injury - will be

discussed.

Motor stroke

Motor stroke is a common cause of neurological disability, often followed by a variable ftmctional recovery, which has been widely studied with functional

neuroimaging. A series of studies used PET to measure regional cerebral blood flow (rCBF) changes in patients who had recovered from a first hemiplegic stroke.

On moving the recovered hand, a bilateral activation of motor cortices occurred, in contrast to the unilateral pattern observed for the unaffected hand (Chollet et al., 1991); this observation suggests that pathways between the affected limb and the ipsilateral motor cortex contribute to the recovery process. A number of possible

confounding explanations of the observed result have been put forward, including the presence of involuntary ‘mirror movements’ of the unaffected hand when

moving the recovered hand. Neurophysiological work has also cast doubt on the

role of fast ipsilateral descending pathways in recovery (Palmer et al., 1992), although this does not exclude a contribution from slower, polysynaptic pathways.

In a second paper, Weiller et al. (1992) compared recovered motor stroke patients

with normal subjects, and reported a widespread increase in activation in areas including motor cortex ipsilateral to the hand performing the task, contralateral

cerebellum, bilateral lower parietal cortex and insula in patients compared to controls. A third paper examined the individual patterns of activation in patients

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compared to a group of 10 normal controls (Weiller et al., 1993) and found a large

variability in the areas of significant activation differences between individuals and the control group. Bilateral motor cortex activation was observed in four

patients (though these all exhibited involuntary synkinetic “mirror movements” of the unaffected arm). Another observation in this study was that of an expansion of

the hand field o f the normal contralateral motor cortex representation ventrally

(i.e. toward the face area) in four patients with posterior capsular limb damage.

fMRI is a relatively recent technology, and at the time of writing there have been few published data on neurological recovery. One study (Cramer et al.,

1997) demonstrated patterns of reorganization after hemiparetic stroke that were largely consistent with those seen with earlier PET studies, including activation

contralateral to the deficit in unaffected hemisphere motor cortex, and in the ipsilateral cerebellum. This study noted that in general recovered finger tapping by patients activated similar motor regions to controls, but to a larger extent.

The role o f changes in cerebral activation patterns in recovery is difficult to

investigate. There is some experimental evidence that motor recovery from a small cortical infarct is associated with an expansion of representation of the affected

hand into adjacent cortical areas, but only in the context of rehabilitative training

(Nudo et al., 1996). An exciting direction for future functional imaging research will be to investigate the effect of rehabilitation on patterns o f functional

C hapter 3________________________fMRI studies o f recovery m echanism s fo llo w im o ptic neuritis Spinal cord injury

Spinal cord injury may damage pathways ascending to or descending from the

cerebrum, and the degree of functional recovery is variable. Alteration in input or

output pathways might be expected to cause a functional reorganization of brain

sensorimotor areas. A study using fluorodeoxyglucose PET (Roelcke et al.,

1997) examined 11 patients with complete paraplegia or tetraplegia following spinal cord injury (between six months and 16 years prior to the study) and

compared them to healthy controls. Reduced global cerebral metabolism was

found in patients at rest, as expected from a loss of afferent and efferent cortical projections. However areas of increased glucose metabolism in brain regions involved in movement preparation or execution, including supplementary motor cortex, putamen and anterior cingulate cortex were seen, which were thought to

reflect a release of inhibition to these areas. Another study investigated a single patient following a near-complete spinal cord transection sparing only a part of one anterolateral quadrant (Danziger et al., 1996), 18 years following the injury.

The patient had retained some sensory functions classically believed to depend upon intact dorsal spinal cord pathways, including light touch and joint position

sense. Furthermore, PET activation studies of vibration of the hand or foot showed

a very abnormal pattern, with activation of cerebral areas beyond the usual

somatotopic representations. The data from these studies suggest that injury to the spinal cord may cause a reorganization of the cortical areas connected with

ascending or descending pathways, although the functional significance of these changes remains unclear.

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These studies illustrate the following general points: firstly, functional imaging techniques are powerful tools with which to investigate plasticity or

“functional reorganization” associated with recovery from CNS injury; secondly,

the interpretation of the data may be complex due to factors including artefactual causes of altered activation patterns and the heterogeneity of response between

individuals; and thirdly, the contribution of altered activation patterns to

neurological recovery may be difficult to establish.

Recovery in demyelinating disease

The remarkable capacity for full recovery is a hallmark of relapses in the early

stages of MS. The mechanisms have been discussed in detail in chapter 1, but will briefly be reiterated here. In the acute phase, contributory factors include the resolution of oedema and inflammation and the release of conduction block (Youl et al., 1991). However, a slower process of recovery continues in spite of

persistent structural damage to myelinated axons in affected pathways. Part of the

explanation may be that functional conduction can be restored in persistently demyelinated axons (McDonald et al., 1976; Smith et al., 1994), probably due to changes in the distribution and concentration of ionic sodium channels.

Nevertheless, recovery of function after demyelination may occur despite

persistent significant axonal degeneration or conduction disturbance in the

affected pathway. In patients following an excellent recovery from optic neuritis, atrophy of the retinal nerve fibre layer (MacFayden et al., 1988; Steel and

Waldock, 1998), and persistent VEP delay (Halliday et al., 1972) are frequent. In certain peripheral demyelinating neuropathies, clinical recovery may also occur

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despite enduring neurophysiological evidence of conduction block (McLeod, 1981; Lewis et al., 1982).

Experimental studies provide further evidence for functional recovery

despite axonal loss in eloquent pathways (see chapter 1). Jacobson et al. (1979)

describe a delayed phase of visual recovery following experimental optic

neuropathy, despite extensive destruction of fibres in the affected nerves. In the

absence of regeneration or remyelination of fibres traversing the experimental lesion (Eames et al., 1977) these data raise the possibility that adaptive synaptic

changes in the brain (or retina) may contribute to the slow phase of visual recovery after optic neuritis. Since axonal loss probably occurs to some extent in the

majority of MS lesions, regardless of their location (Adams and Kublik, 1952) or the stage of disease (Trapp et al., 1998), compensatory plastic changes may also contribute to the recovery from lesions in other systems, for example in

corticospinal pathways.

Hypothesis

The data discussed in the previous section suggest that local changes in a

demyelinated pathway cannot fully account for the temporal pattern and extent of functional recovery commonly observed. In the absence of significant functionally

effective regeneration, recovery, despite persistent conduction block or axonal loss, may depend on adaptive changes in the cerebral cortex or surviving

pathways. With functional neuroimaging, it is now possible to begin to investigate this possibility. As a first step, we have generated a hypothesis that is testable using functional magnetic resonance imaging:

C h avter 3_________________________fM Rl studies o f recovery mechanism s follow in s o ptic neuritis Following an episode o f demyelination in an eloquent CNS pathway, the pattern o f activation o f the brain induced by a task involving that pathway is different from that induced by a task involving a comparable, unaffected pathway.