7 NERVE INJURY AND BRAIN DAMAGE

Neuroplastic changes of various kinds occur in response to nerve injury and brain damage caused by stroke and other insults. Nerve injury leads to changes in the damaged nerve fibers, as well as to functional reorganization of neuronal circuitry in both the brain and spinal cord. These effects can persist for many months or years. The changes that occur following nerve injury and amputation do not lead to any significant recovery of function, especially after a serious injury, but rather can be maladaptive, causing neuropathic pain, or the “phantom” sensations and pain experienced by amputees. By contrast, the spontaneous plastic changes that occur after a stroke can help the brain to compensate for the damage that has occurred.

Investigations of injury-induced brain changes are done in rats, monkeys, and humans. In rats, they focus largely on an area of the brain called the barrel cortex, which receives sensory information from the whiskers. In monkeys and humans, studies are focused on the primary somatosensory cortex, which receives sensory information from the skin surface, and on the primary motor cortex, which executes movements by sending commands down the spinal cord to the muscles. Sensory brain regions are said to be organized topographically. For example, touch information from adjacent areas of the skin surface is processed in adjacent patches of the primary somatosensory cortex, while adjacent groups of body muscles are controlled by cells in adjacent patches of the primary motor cortex. In this way, the body is “mapped” onto the surface of the primary somatosensory and motor cortices.

The size of these cortical representations is determined by the number of nerve endings or muscles in the corresponding body part, rather than by its actual size. Therefore, the vast majority of neural tissue in the primary somatosensory and motor cortices is devoted respectively to processing information from, and sending movement commands to, the face and hands, which are the most sensitive and articulated parts of the body. These cortical representations can be altered by experience, shrinking when they are deprived of sensory information or expanding with increased use of their corresponding part. This process, called remapping, takes place after nerve injury and brain damage, and in some cases it can be induced artificially, using various methods of noninvasive brain stimulation, to facilitate rehabilitation.

Peripheral Nerve Injury

Some of the earliest direct evidence for neuroplasticity came from animal studies of nerve injury, performed in the early 1980s. When the median nerve in monkeys’ arms is severed, corresponding regions of the primary somatosensory cortex are deprived of inputs, but those regions do not lie dormant. In the weeks following the injury the primary somatosensory cortex reorganizes itself so that neighboring patches of brain tissue, which receive inputs from adjacent body parts, expand and encroach upon the deprived area.

In rats, severing the sciatic nerve causes a threefold expansion of the somatosensory area normally devoted to inputs from the adjacent saphenous nerve, which begins one to two days after the nerve has been severed and persists for up to six months. And two to eight months after monkeys have a finger amputated, the patch of primary somatosensory cortex that previously responded to the amputated digit responds instead when adjacent digits are touched.¹

Reorganization of the motor cortex happens along similar lines, but with different consequences. In rats, the facial nerve normally controls whisker movements, and when it is severed, the corresponding motor area initially sits silent and does not respond to electrical stimulation. A few hours later, however, stimulation produces muscle contractions in the forearm and eyelid.

Two to eight months after monkeys have a finger amputated, the patch of primary somatosensory cortex that previously responded to the amputated digit responds instead when adjacent digits are touched.

Researchers can now detect changes such as these taking place in the human brain, using noninvasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These changes begin to take place minutes after transient nerve blockade, and weeks after spinal cord injury. Immediately after nerve block by local anesthetic, for example, the patch of motor cortex corresponding to the paralyzed area falls silent, and neighboring areas increase their output to the spinal motor neurons. This effect is reversible, however, and disappears about 20 minutes after the anesthetic has worn off.

The same sort of cortical reorganization also takes place following arm amputation. As is the case in animal studies, the somatosensory cortical region corresponding to the amputated arm gradually shrinks, and the surrounding areas begin to expand and encroach upon it. The vast majority of amputees experience phantom limb, the vivid sensation that the missing limb is still attached to their body, which can often be extremely painful. Phantom limbs are believed to occur at least partly because of the cortical reorganization that occurs following amputation. In the somatosensory and motor cortices, the neural representation of the hands lies immediately next to that of the face; after amputation of an arm, therefore, it is the area representing the face that expands and invades its deprived neighbor. Consequently, touching certain parts of the amputee’s face may trigger vivid phantom sensations, suggesting that the deprived area somehow retains a memory of its previous function.²

Phantom limbs are believed to occur at least partly because of the cortical reorganization that occurs following amputation.

It is difficult to explain cortical reorganization in terms of cellular mechanisms, however, since brain scanning technologies are still nowhere near sensitive enough to detect such processes in humans. But the animal studies give us a good idea of what might be happening. They show that neurons whose fibers are severed quickly retract their dendrites, so that they become detached from the nerve terminals associated with them and there is an overall reduction in the number of synapses the cell receives. At the injury site, any intact axon fibers may sprout new branches that grow into the damaged area, and the mismatch between the fibers and their new targets can contribute to neuropathic pain.

The earlier stages of cortical reorganization are thought to involve “unmasking” of previously silent connections, including horizontal ones between adjacent patches in corresponding parts of the cortex and vertical ones from the thalamus, an area that relays all types of sensory information from the sense organs to the appropriate area of the cerebral cortex. Unmasked connections are believed to be strengthened by LTP (see chapter 3), but longer-lasting changes are probably consolidated by the sprouting of new axon branches, by elongation and branching of dendrites, and by formation of new synaptic connections. The animal studies suggest that axons and dendrites can grow for distances of up to 3 millimeters during reorganization of the somatosensory cortex, while the boundaries of representations in the motor cortex can shift rapidly by up to 2 millimeters.³

Stroke

Numerous studies have examined the cortical reorganization that takes place after stroke. Stroke is a leading cause of death and disability, and involves an interruption of the blood supply to the brain, due to blocked or broken blood vessels, that leads to death of oxygen-deprived cells. The frontal and temporal lobes of the brain are particularly vulnerable to oxygen deprivation, and so strokes often damage these regions, leading to the characteristic symptoms of speech deficits and muscle weakness or total paralysis one side of the body. Since the left hemisphere of the brain controls the right side of the body, and vice versa, stroke paralyzes the limbs on the side opposite to the damage.

Unlike nerve injury–induced plasticity, which is rarely helpful, the cortical reorganization that occurs after a stroke is believed to contribute significantly to the recovery of motor function. Paralysis occurs because the stroke damage disrupts the neural pathway that descends from the primary motor cortex to the motor neurons in the spinal cord. The brain begins to compensate for this on its own, working around the damage by activating alternative motor pathways that run parallel to the damaged one. These pathways may originate from the primary motor cortex on the opposite side of the brain, or from the secondary motor area immediately adjacent to the damaged area.⁴

Either way, a working connection between the brain and spinal cord can be reestablished. These new pathways are indirect, however. Under normal circumstances, the movement information sent down from the brain to the muscles passes through just one synapse—the connection between the neurons in the primary motor cortex and the motor neurons in the spinal cord. The new motor pathways involve more connections, and they activate whole groups of muscles rather than individual muscle fibers. Thus, although they can lead to an overall improvement in motor function, the recovering patient may still have difficulty moving individual fingers, for example.

Brain scanning studies show that stroke also induces long-term structural and functional changes in the primary somatosensory cortex. Chronic stroke patients exhibit increases in cortical thickness of between 4% and 13%, comparable to the volume increases seen in the mouse motor cortex after motor training and also to the structural changes associated with musical training (see chapter 6). This thickening is associated with increased cortical responses to touch sensations, and heightened sensitivity to touch in stroke patients compared to controls.⁵

Recovery from stroke involves essentially relearning how to control one’s movements with these new neural pathways. The new pathways are less efficient than the damaged ones they replace, but rehabilitation can help to strengthen them and facilitate recovery of the lost functions. Intensive physiotherapy is needed in the months following the stroke, involving repetitive movements of the affected limb, which helps to strengthen the new motor pathways. Patients often lack the motivation to stick to their exercise regimes, however, and physiotherapists are currently in short supply, so in recent years rehabilitation has become increasingly reliant on robotic technology.⁶

Motor functions in stroke patients can be improved by a method called constraint-induced therapy, which involves forcing the patient to use the weakened limbs as much as possible by tying back the unaffected one.⁷ But there are major individual differences in the extent to which stroke patients recover. In about one-third of patients, rehabilitation can lead to significant improvements in both movement and speech; in another third, the improvements are much smaller; and in the remainder, little or no improvement is seen.

The reasons for these varied outcomes are still not clear, but genetic and environmental factors are likely to play a role. The timing of diagnosis and treatment is also crucial—the oxygen deprivation that occurs as the result of a stroke kills millions of brain cells every minute, so quick intervention minimizes the extent of the damage, and it is now clear that the earlier rehabilitation begins, the better the outcome for the patient.

One promising approach to rehabilitating stroke patients involves altering the balance of activity between the left and right hemispheres of the brain. Normally, the hemispheres reciprocally inhibit each other by means of fibers that cross the brain in the corpus callosum, in order to coordinate the movements of all four limbs. Shortly after a stroke, the unaffected hemisphere can become more active, perhaps because of reduced cross-inhibition by the damaged side. By the same token, overactivity of the damaged hemisphere may interfere with rehabilitation.

This balance can be perturbed with TMS, which uses a magnetic coil to deliver magnetic fields to a specific part of the brain. The magnetism generates an electric field that last for about one tenth of a second, which increases or inhibits the activity of cells in the region being targeted. Studies are beginning to show that using TMS to disrupt the activity of one half of the brain can facilitate recovery, but so far the results are variable. In some patients, inhibiting activity on the unaffected side of the brain improves motor function in the affected limbs, but in others it does not.

There is, however, some evidence that the brain hemispheres can switch from inhibiting to exciting each other, at some point after the stroke, in order to facilitate recovery. Thus, using TMS to suppress activity in the damaged hemisphere, or to enhance activity in the unaffected side, can facilitate recovery by enhancing motor activity in the damaged side, but this same treatment could be counterproductive if delivered after the switch to cross-activation.⁸ Learning more about how the brain adapts to a stroke on its own will undoubtedly help clinicians to improve the efficacy of such treatments.

tDCS is another noninvasive method being used to modulate brain activity. This involves using scalp electrodes to apply low-amplitude direct currents to discrete areas of the brain, and we now know that these currents induce LTP in the targeted area.⁹ Both tDCS and TMS are now widely used in the clinic, as adjuncts for rehabilitation treatment and, because they can also be used to evaluate neuronal activity and brain connectivity, for diagnostic and prognostic purposes.¹⁰

Functional neuroimaging is increasingly being used to assess stroke damage and predict the extent to which patients might recover, too. fMRI studies show, for example, that the more a patient’s movements are impaired, the more active are their secondary motor areas on the damaged side during simple gripping tasks. TMS-induced disruption of activity in this brain region impairs movement in stroke patients but not in healthy controls, suggesting that these secondary motor regions make an important contribution to recovery. Conversely, interfering with the activity of secondary motor areas on the unaffected side is far more disruptive in severely affected patients, suggesting that they are more reliant on those new pathways than are patients who suffered less damage.¹¹

Some researchers are also investigating whether noninvasive brain stimulation techniques could be used to rehabilitate language functions. In most people, language functions are localized to specific regions of the left frontal and temporal lobes, and the left hemisphere is said to be the dominant one (see chapter 1). These areas are often damaged by stroke, and consequently about 20% to 40% of patients experience severe language deficits after a stroke.

Compensatory plasticity in the brain’s language networks appears to be similar to that seen in the motor pathways. Damage to the language centers can lead to recruitment of surrounding areas in the damaged left hemisphere, to recruitment of dormant language centers in the right hemisphere, or both. Because language function is usually lateralized to the left hemisphere, and because loss of cross-inhibition between the hemispheres is thought to facilitate recovery, interfering with the balance of activity in the left and right hemispheres may be the key to recovery of language.

This research is still in its early stages, however, and so far the approach has produced conflicting results. As with recovery of motor function, a better understanding of how spontaneous compensatory plasticity changes with time could eventually help to optimize such treatments and improve patients’ outcomes.¹²

Other research shows that early prescription of fluoxetine (Prozac) and related antidepressants enhances motor recovery after three months in stroke patients undergoing physiotherapy. It’s still not clear why this is the case, however. This group of drugs is known to have anti-inflammatory effects, which may protect the patient’s brain from further damage; they may also facilitate relearning by promoting LTP in newly formed motor pathways.¹³