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Manipulation of Central Nervous System Plasticity: A New Dimension in the Care of Neurologically Impaired Patients

      Research in the neurosciences in recent decades has shown that the central nervous system is not a structurally static organ as was believed previously, but instead is a dynamic system that constantly undergoes structural and functional reorganization. The term brain plasticity refers to the constant cellular and intercellular modifications that occur during normal development and after neurologic injury and result in changes in neurologic function. The discovery that central nervous system plasticity after injury can be directed toward functional improvement with use of specific modalities has opened up a new dimension in the care of the neurologically impaired patient, termed restorative neurology.
      Research in the neurosciences in recent decades has revealed that the brain is not a structurally static organ as was believed previously, but instead is a dynamic system that continuously changes in structure and function. The term brain plasticity refers to the inherent capacity and resiliency of the brain to undergo structural and functional modifications. These changes are especially evident during development and after neurologic injury and can be best conceptualized as spanning throughout various levels: brain level (glial and vascular support), network level (changes in interconnection between neurons), intercellular level (qualitative and quantitative changes at the synaptic level, including synaptic sprouting), intracellular level (changes in mitochondrial and ribosomal function), biochemical level (protein conformation, enzyme mobilization), and genetic level (transcription, translation, and post-translation modifications).
      • Teskey GC
      A general framework for neuroplasticity theories and models.
      Because the brain is the source and end organ for neurologic, cognitive, and psychological functions, modifications in the brain's structure and function are mirrored by changes in these areas.
      Brain plasticity is of particular interest to neurologists because plastic changes are seen clearly after neurologic injury, and these changes correlate with either improvement or deterioration of neurologic function. Function is the cognitive and/or physical activity through which individuals interact with self and the external world and includes mobility, communication, cognition, and sexual activity. From a functional perspective, it is helpful to divide cortical reorganization after neurologic injury into functionenabling plasticity, which leads to an improvement in neurologic function, or function-disabling plasticity, which results in deterioration of function. Examples of function-enabling plasticity include changes in cortical representation and improved function seen with forced use of the affected extremity after injury. Examples of function-disabling plasticity include modifications in the cortical representation for a specific motor function after nonuse, which results in decreased motor capabilities. Other examples include late development of dystonias and other movement disorders seen after injury. Also, phantom limb and phantom sensation after spinal cord injury can be attributed to cortical reorganization after injury
      • Moore C
      • Stern CE
      • Dunbar C
      • Kostyk SK
      • Gehi A
      • Corkin S
      Referred phantom sensations and cortical reorganization after spinal cord injury in humans.
      and are examples of “sensory” function-disabling plasticity.
      An exciting offshoot of research in this area involves nervous system plasticity that can be driven or directed to flow in a desired direction, ie, improvement of function. Enhancement of function-enabling plasticity and prevention of function-disabling plasticity can be accomplished through numerous modalities that have received considerable attention, such as specific rehabilitation modalities, pharmacological interventions, stem cell transplantation, and environmental enrichment.
      The term restorative neurology refers to caring for neurologically impaired patients to restore function after neurologic injury. Restorative neurology deals less with the management of underlying disease process and more with strategies for functional improvement by ameliorating neurologic deficits regardless of their etiology. If prevention, diagnosis, and management are considered the first 3 phases in the care of the neurologically impaired patient, perhaps restorative neurology can be conceptualized as the fourth phase of care. The fact that cortical plasticity can be manipulated toward a desired direction has opened up a new dimension in the care of neurologically impaired patients and provides a creative new set of tools for the restorative neurologist. In fact, a major aspect of restorative neurology involves engineering of the brain's intrinsic plasticity to improve neurologic function.

      RECOVERY OF FUNCTION AFTER NEUROLOGIC INJURY

      Damage to the nervous system frequently results in loss of neurologic function. For instance, a left middle cerebral artery stroke can result in aphasia, right hemiparesis, and hemianopsia. These neurologic deficits can affect the patient's ability to communicate, walk, and see, among other impairments. Damage to the neural substrate responsible for a particular function causes an alteration in that function; eg, damage to the language areas in the left hemisphere results in alterations in language. Functional impairment may not always be due to structural damage but instead may be due to diaschisis. The concept of diaschisis was introduced to describe the phenomenon in which structurally intact brain areas become functionally impaired because of the loss of input from an anatomically connected injured area of the brain.
      • Von Monakow C
      Diaschisis.
      • Feeney DM
      • Baron JC
      Diaschisis.
      Occasionally after unilateral brain injury, disruption of either contralateral or bilateral function can be observed. This disturbance of function can be observed as decreased blood flow and metabolism detected by techniques such as single-photon emission computed tomography (SPECT). For example, we reported a patient with cortical blindness and a unilateral occipital lesion visualized on structural brain imaging (magnetic resonance imaging). However, functional imaging by single-photon emission computed tomography showed bilateral parieto-occipital hypometabolism despite the unilateral structural lesion. The functional involvement of the visual cortex causing bilateral blindness was considered secondary to diaschisis.
      • Drubach DA
      • Carmona S
      • Meyerrose GE
      • Peralta LM
      • Sostre S
      Brain SPECT in a case of cortical blindness.
      After maximal neurologic compromise, a certain degree of restoration of function can occur in the subsequent “critical” time span, which can range from seconds to years. The neurobiology behind this recovery of function has only recently become better understood. Numerous factors have been identified and can be placed schematically into 2 categories. The first is recovery of the original neural substrate for a particular function. The second is utilization of the existing inactive neuronal network or creation of neuronal networks that can perform the lost function.
      Factors that result in the restoration of the original substrate for a specific function include resolution of edema, immediate reperfusion of ischemic areas, and resolution of other complications that temporarily and reversibly disrupt neuronal function. In these circumstances, partial or full recovery of function is possible. The second mechanism for functional recovery, the creation or recruitment of a “new” neural substrate to perform that same function, has become better understood in recent years. An extreme example of this is seen in children who have acquired language, subsequently undergo partial left hemispherectomy, and then fully recover language up to a certain age. Recent functional magnetic resonance imaging studies revealed that the right hemisphere becomes active during language tasks after surgery, indicating that a new, previously inactive neural substrate has become active in the function of language.
      • Hertz-Pannier L
      • Chiron C
      • Jambaque I
      • et al.
      Late plasticity for language in a child's non-dominant hemisphere: a pre- and post-surgery fMRI study.
      A likely mechanism for the restoration of function is a combination of the 2 processes: partial recovery of the substrate responsible for the function, as well as creation of a new substrate to “aid” the lost component.
      The timing of recovery should provide some clues about the responsible underlying neurobiological factors. Previously, it was generally accepted that early recovery was probably due to resolution of factors temporarily interfering with neuronal function such as those described. Later, recovery was believed to be caused by plastic processes. However, the explanation is more complicated. Plastic changes, including synaptic potentiation or depression,
      • Zucker RS
      • Regehr WG
      Short-term synaptic plasticity.
      synaptic pruning and sprouting, and dendritic arborization can occur within milliseconds to hours. Functional imaging and transcranial magnetic stimulation studies after neurologic injury have shown that the brain “recruits” areas, frequently distant and at times contralateral to the damaged area, to perform the function of the lesioned region, and that this recruitment can be seen within hours or days. For example, functional plasticity of the somatosensory cortex can be detected as early as 10 days after a person's finger is amputated.
      • Weiss T
      • Miltner WH
      • Huonker R
      • Friedel R
      • Schmidt I
      • Taub E
      Rapid functional plasticity of the somatosensory cortex after finger amputation.
      Thus, plastic changes become active shortly after injury and may contribute to early as well as late recovery.
      A number of “extrinsic” variables can affect the speed and degree of neurologic recovery after injury. Approaching this subject from a restorative neurologic perspective, we can divide these factors into independent variables (not amenable to manipulation) and modifiable variables (subject to certain manipulations). The modifiable factors are of particular interest to the restorative neurologist.

      VARIABLES

      Independent Variables

      The foremost independent variable is age. Both animal and human studies have shown that age plays a prominent role in recovery of function after injury; increasing age plays a negative role
      • Perez JC
      • Zeilig G
      • Taragano FE
      • Drubach DA
      Efficacy and efficiency in rehabilitation among age groups [abstract].
      due to decreased effectiveness of plasticity with age. Time windows for recovery of specific functions are operant in certain conditions, shown by recovery of language up to a certain age in children with left hemispheric lesions.
      A second independent variable for recovery of function is type of injury. For example, we
      • Drubach DA
      • Perez JC
      • Kelly MP
      • et al.
      Incidence and characteristics of high velocity and low velocity traumatic brain injury [abstract].
      and others have shown that patients admitted to a rehabilitation hospital after traumatic brain injury make a better and faster recovery than patients with hypoxic brain damage. This suggests that injury parameters affect the potential for plasticity.
      A third independent variable is genetics. The wide variety in the speed and degree of recovery seen by rehabilitation specialists among patients of all ages cannot be explained entirely by the injury type and severity. Probable mechanisms of recovery at individual levels may be influenced by genetically determined factors that deal with oxidant stress, inhibition of apoptosis, and other neuroprotective mechanisms.
      Although important in determining functional outcome, independent variables currently are not amenable to manipulation for maximizing recovery of function.

      Modifiable Variables

      Perhaps one of the most exciting discoveries about brain plasticity is that numerous factors, including environmental interaction, pharmacological agents, trophic factors, and environmental enrichment, can be manipulated to drive plastic changes in the desired direction. Nervous system tissue transplantation is another exciting area that is receiving much attention; however, because it is a topic unto itself, we will not discuss it in this article.
      Environmental Interaction.—Environmental interaction involves 2 distinct, although interrelated, processes: acting upon the environment and being acted upon by the environment. Acting upon the environment is performed through motor systems and motor supporting systems. Being acted upon by the environment involves receipt of data through sensory systems and sensorial systems. This separation is somewhat artificial because acting upon and being acted upon are constantly interrelated; however, it is a good framework for our discussion of plasticity. Although sensory deafferentation, even if temporary,
      • Brasil-Neto JP
      • Cohen LG
      • Pascual-Leone A
      • Jabir FK
      • Wall RT
      • Hallett M
      Rapid reversible modulation of human motor outputs after transient deafferentation of the forearm: a study with transcranial magnetic stimulation.
      has been shown clearly to produce cortical reorganization, we limit our discussion to motor plasticity.
      Acting upon the environment by means of motor activity is one of the most powerful drivers of cortical reorganization and an instigator of both function-enabling plasticity and function-disabling plasticity. Acting upon the environment includes cortical reorganization that occurs in normal conditions, such as with skill acquisition, as well as reorganization that occurs after neurologic injury. Research findings on motor plasticity underscore one of the most fundamental aspects of brain activity: the fundamental role played by environmental interaction and experience in defining the characteristics of brain structure and function. In particular, motor plasticity stresses a circular relationship between motor activity and brain structure; the repeated performance of a motor act results in cortical reorganization, which in turn increases the efficiency of the motor act. Thus, the brain motor system is both the cause and the effect of motor activity.
      Multiple studies in recent years involving both functional imaging and stimulation have shown the effect of motor practice on motor system reorganization in both normal conditions and after injury. For example, motor skill learning in primates results in plastic changes in the primary motor cortex.
      • Nudo RJ
      • Milliken GW
      • Jenkins WM
      • Merzenich MM
      Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys.
      Sustained performance of a specific motor task involving the thumb in human subjects induced cortical motor area reorganization within minutes, providing data on the neural mechanisms for skill acquisition.
      • Elbert T
      • Pantev C
      • Wienbruch C
      • Rockstroh B
      • Taub E
      Increased cortical representation of the fingers of the left hand in string players.
      Those who play stringed instruments have increased cortical representation for the fingers of the left hand compared with the right hand,
      • Classen J
      • Liepert J
      • Wise SP
      • Hallett M
      • Cohen LG
      Rapid plasticity of human cortical movement representation induced by practice.
      corresponding to the increased dexterity of the left hand in playing such instruments. Regarding plasticity after injury, postischemic reorganization of the motor cortex after rehabilitative training has been documented in animals
      • Nudo RJ
      • Wise BM
      • SiFuentes F
      • Milliken GW
      Neural substrates for the effects of rehabilitative training in motor recovery after ischemic infarct.
      and in humans.
      • Liepert J
      • Bauder H
      • Wolfgang HR
      • Miltner WH
      • Taub E
      • Weiller C
      Treatment-induced cortical reorganization after stroke in humans.
      Examples of function-disabling plasticity in motor systems have been provided by numerous studies showing that nonuse of an extremity leads to changes in cortical structures, which presumably further compound difficulties in using that limb.
      • Levy CE
      • Nichols DS
      • Schmalbrock PM
      • Keller P
      • Chakeres DW
      Functional MRI evidence of cortical reorganization in upper-limb stroke hemiplegia treated with constraint-induced movement therapy.
      This has important implications for the rehabilitation process. Rehabilitation professionals frequently encourage patients with disabilities to use compensation techniques to improve function. Thus, patients with a right hemiparesis are taught to use the left upper extremity to perform tasks previously performed by the paretic limb. Some researchers suggest that this approach may be contraindicated because nonuse of the paretic limb may further contribute to function-disabling plasticity. This notion has led to perhaps one of the most novel theories of rehabilitation, frequently referred to as constraint-induced rehabilitation
      • Kopp B
      • Kunkel A
      • Muhlnickel W
      • Villringer K
      • Taub E
      • Flor H
      Plasticity in the motor system related to therapy-induced improvement of movement after stroke.
      • Liepert J
      • Miltner WH
      • Bauder H
      • et al.
      Motor cortex plasticity during constraint-induced movement therapy in stroke patients.
      ; this approach uses several techniques, including restraint of the healthy limb, to stimulate use of the paretic extremity in an effort to encourage function-enabling plasticity. This technique, used for rehabilitation of motor impairments, has been proposed for other functional impairments as well, such as language rehabilitation in aphasic patients.
      • Pulvermuller F
      • Neininger B
      • Elbert T
      • et al.
      Constraint-induced therapy of chronic aphasia after stroke.
      Although numerous studies using this approach to rehabilitation have shown promising results, to our knowledge it is not yet widely accepted among rehabilitation professionals.
      Pharmacological Agents.—The role of pharmacological interventions in modulating plasticity is an exciting topic that has generated much interest. Almost 2 decades ago, Feeney et al
      • Feeney DM
      • Gonzales A
      • Law WA
      Amphetamine restores locomotor function after motor cortex injury in the rat.
      • Feeney DM
      • Gonzalez A
      • Law WA
      Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury.
      showed that administration of amphetamines to animals after neurologic injury resulted in a faster and more complete recovery than that achieved in nonmedicated animals. In contrast, dopamine-blocking agents had a negative effect on recovery. Use of amphetamines in conjunction with rehabilitation resulted in a better recovery than that achieved in animals that received amphetamines alone or rehabilitation alone. Numerous other studies using different animal species and similar experimental paradigms have confirmed these findings. Although large-scale human studies are scant, pharmacological agents (particularly dopaminergic and noradrenergic drugs) have been beneficial in treating several neurologic impairments including neglect,
      • Fleet WS
      • Valenstein E
      • Watson RT
      • Heilman KM
      Dopamine agonist therapy for neglect in humans.
      certain types of aphasias, disorders of consciousness, and motor impairment after cerebrovascular events.
      • Feeney DM
      From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients.
      The effect of pharmacological interventions in modulating plasticity also has been shown at the cellular level in animals.
      • Zhu J
      • Hamm RJ
      • Reeves TM
      • Povlishock JT
      • Phillips LL
      Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury.
      Evidence in human subjects suggests that the combination of pharmacological agents with conventional rehabilitation strategies is especially beneficial. Thus, simultaneous use of amphetamines and physical therapy promotes recovery of motor function after stroke.
      • Crisostomo EA
      • Duncan PW
      • Propst M
      • Dawson DV
      • Davis JN
      Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients.
      The combination of speech and language therapy with amphetamine use also has been shown to facilitate recovery of language after stroke.
      • Walker-Batson D
      • Curtis S
      • Natarajan R
      • et al.
      A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia.
      One study revealed that the statins atorvastatin and simvastatin enhanced functional outcome and induced brain plasticity and neurorestorative activity in rats that had experienced experimental strokes.
      • Chen J
      • Zhang ZG
      • Li Y
      • et al.
      Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke.
      Other pharmacological agents are detrimental to plasticity. Nicotine decreased neurogenesis in the dentate gyrus and increased cell death.
      • Abrous DN
      • Adriani W
      • Montaron M
      • et al.
      Nicotine self-administration impairs hippocampal plasticity.
      The notion that pharmacological interventions can ameliorate functional impairment presents exciting possibilities for restorative neurology. Even more important, this evidence suggests the possibility of “priming” the brain through pharmacological interventions, thereby improving the chances of profiting from other rehabilitation interventions. This underscores the importance of the interdisciplinary approach in rehabilitation with active and constant interaction between physicians and other rehabilitation professionals.
      Trophic Factors.—Interest in neurotrophins and their role in brain plasticity has grown in recent years. These factors may prove to be important tools for driving brain plasticity in the future; currently, however, data about their effects on humans are lacking. Insulinlike growth factors may contribute to plastic changes because they modulate synaptic efficacy by regulating synapse formation, neurotransmitter release, and neuronal excitability.
      • Torres-Aleman I
      Insulin-like growth factors as mediators of functional plasticity in the adult brain.
      Macrophage-stimulating protein (from the family of plasminogen-related growth factors) has been shown to mediate inflammation by repressing production of nitric oxide and may play a role in brain plasticity and regeneration of cranial motoneurons.
      • Stella MC
      • Vercelli A
      • Repici M
      • Follenzi A
      • Comoglio PM
      Macrophage stimulating protein is a novel neurotrophic factor.
      In a study of neonatal brain plasticity, 2 neurotrophins, brain-derived neurotrophic factor and neurotrophin 3, induced climbing fiber reinnervation in a deafferented hemicerebellum in rats and may in fact extend the “critical time” window for brain plasticity and potential therapeutic use after brain trauma.
      • Sherrard RM
      • Bower AJ
      BDNF and NT3 extend the critical period for developmental climbing fibre plasticity.
      • Pham TM
      • Winblad B
      • Granholm AC
      • Mohammed AH
      Environmental influences on brain neurotrophins in rats.
      Nerve growth factor increased in the hippocampus of rats raised in enriched environments (see next section) and therefore may be instrumental in the plastic changes seen in those circumstances.
      • Pham TM
      • Winblad B
      • Granholm AC
      • Mohammed AH
      Environmental influences on brain neurotrophins in rats.
      Environmental Enrichment.—Perhaps one of the most surprising findings involving cortical organization and reorganization is in the area of environmental enrichment. This refers to the paradigm of behavioral modeling wherein the animal is kept in either an open, stimulus-rich environment or a closed, unstimulating environment. Although implications for rehabilitation in humans have been proposed, studies in environmental enrichment have been conducted solely in animals. Plastic processes such as increased dendritic arborization and synaptogenesis, as well as reduced apoptotic hippocampal cellular death, are enhanced in an enriched vs a nonenriched environment.
      • van Praag H
      • Kempermann G
      • Gage FH
      Neural consequences of environmental enrichment.
      These findings were consistent in multiple types of injury in animals. Neurologic outcome after neural grafting is improved by housing rats with neocortical infarctions in an enriched environment
      • Mattsson B
      • Sorensen JC
      • Zimmer J
      • Johansson BB
      Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments.
      vs nonenriched settings. A recent study showed that rats exposed to an enriched environment performed significantly better than those in a nonenriched setting in the water maze test. Neurogenesis increased significantly in the dentate gyrus of those animals exposed to enriched vs nonenriched environments.
      • Faverjon S
      • Silveira DC
      • Fu DD
      • et al.
      Beneficial effects of enriched environment following status epilepticus in immature rats.
      This is an exciting area of restorative neurology that we hope will gain clinical relevance in rehabilitation of humans with neurologic injury.

      STEM CELL RESEARCH

      Work with stem cells has had variable success in animal models of stroke, although overall results seem promising. Grafts of various stem cell lines have been effective in animal models for reversing sensory and motor deficits and reducing lesion volume.
      • Modo M
      • Stroemer RP
      • Tang E
      • Patel S
      • Hodges H
      Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage.
      • Veizovic T
      • Beech JS
      • Stroemer RP
      • Watson WP
      • Hodges H
      Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells.
      • Nakatomi H
      • Kuriu T
      • Okabe S
      • et al.
      Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.
      Human studies are scant, but it is conceivable that in the future, the restorative neurologist will prescribe a regimen of stem cell therapy, using specific cell lines for particular brain regions to influence a particular outcome.

      CONCLUSION

      An exciting phase in neurology is emerging with increased understanding of nervous system reorganization after injury. This gives the physician an unprecedented number of tools for maximizing recovery. Use of these tools to drive function-enabling plasticity and prevent function-disabling plasticity promises to be one of the most important instruments in the management of neurologic disease.

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