Randolph J. Nudo

Extensive Cortical Rewiring after Brain Injury

Previously, we showed that the ventral premotor cortex (PMv) underwent neurophysiological remodeling after injury to the primary motor cortex (M1). In the present study, we examined cortical connections of PMv after such lesions. The neuroanatomical tract tracer biotinylated dextran amine was injected into the PMv hand area at least 5 months after ischemic injury to the M1 hand area. Comparison of labeling patterns between experimental and control animals demonstrated extensive proliferation of novel PMv terminal fields and the appearance of retrogradely labeled cell bodies within area 1/2 of the primary somatosensory cortex after M1 injury. Furthermore, evidence was found for alterations in the trajectory of PMv intracortical axons near the site of the lesion. The results suggest that M1 injury results in axonal sprouting near the ischemic injury and the establishment of novel connections within a distant target. These results support the hypothesis that, after a cortical injury, such as occurs after stroke, cortical areas distant from the injury undergo major neuroanatomical reorganization. Our results reveal an extraordinary anatomical rewiring capacity in the adult CNS after injury that may potentially play a role in recovery.

Motor learning-dependent synaptogenesis is localized to functionally reorganized motor cortex.

The regional specificity and functional significance of learning-dependent synaptogenesis within physiologically defined regions of the adult motor cortex are described. In comparison to rats in a motor activity control group, rats trained on a skilled reaching task exhibited an areal expansion of wrist and digit movement representations within the motor cortex. No expansion of hindlimb representations was seen. This functional reorganization was restricted to the caudal forelimb area, as no differences in the topography of movement representations were observed within the rostral forelimb area. Paralleling the physiological changes, trained animals also had significantly more synapses per neuron than controls within layer V of the caudal forelimb area. No differences in the number of synapses per neuron were found in either the rostral forelimb or hindlimb areas. This is the first demonstration of the co-occurrence of functional and structural plasticity within the same cortical regions and provides strong evidence that synapse formation may play a role in supporting learning-dependent changes in cortical function.

Postinfarct Cortical Plasticity and Behavioral Recovery

Plasticity phenomena in the cerebral cortex after ischemic injury have been documented repeatedly over the past 2 decades both in animal models and in human stroke survivors. This review highlights many of the major neuroanatomic and neurophysiological changes that characterize poststroke plasticity in experimental animals. Spared regions adjacent to the infarct and far removed from the infarct undergo functional alterations that are modified by behavioral experience. Recent evidence is also reviewed, demonstrating that long-range intracortical pathways can be rerouted to completely novel territories. The implications of this new finding for understanding the brain’s capacity for recovery are discussed.

Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans

Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans?

Mechanisms for recovery of motor function following cortical damage

Recent studies of focal injury to the cerebral cortex have demonstrated that the remaining, intact tissue undergoes structural and functional changes that could play a substantial role in neurological recovery. New information regarding the molecular and cellular environment in the adjacent, intact tissue has suggested that waves of growth promotion and inhibition modulate the self-repair processes of the brain. Furthermore, recent studies have documented widespread neurophysiological and neuroanatomical changes in regions remote from a focal cortical injury, suggesting that entire cortical networks participate in the recovery process.

Recovery after damage to motor cortical areas.

Until recently, the neural bases underlying recovery of function after damage to the cerebral cortex were largely unknown. Recent results from neuroanatomical and neurophysiological studies in animal models have demonstrated that after cortical damage, long-term and widespread structural and functional alterations take place in the spared cortical tissue. These presumably adaptive changes may play an important role in functional recovery.

Recovery after brain injury: Mechanisms and principles

The past 20 years have represented an important period in the development of principles underlying neuroplasticity, especially as they apply to recovery from neurological injury. It is now generally accepted that acquired brain injuries, such as occur in stroke or trauma, initiate a cascade of regenerative events that last for at least several weeks, if not months. Many investigators have pointed out striking parallels between post-injury plasticity and the molecular and cellular events that take place during normal brain development. As evidence for the principles and mechanisms underlying post-injury neuroplasticity has been gleaned from both animal models and human populations, novel approaches to therapeutic intervention have been proposed. One important theme has persisted as the sophistication of clinicians and scientists in their knowledge of neuroplasticity mechanisms has grown: behavioral experience is the most potent modulator of brain plasticity. While there is substantial evidence for this principle in normal, healthy brains, the injured brain is particularly malleable. Based on the quantity and quality of motor experience, the brain can be reshaped after injury in either adaptive or maladaptive ways. This paper reviews selected studies that have demonstrated the neurophysiological and neuroanatomical changes that are triggered by motor experience, by injury, and the interaction of these processes. In addition, recent studies using new and elegant techniques are providing novel perspectives on the events that take place in the injured brain, providing a real-time window into post-injury plasticity. These new approaches are likely to accelerate the pace of basic research, and provide a wealth of opportunities to translate basic principles into therapeutic methodologies.

Functional and structural plasticity in motor cortex: implications for stroke recovery

Several studies have now demonstrated that the motor cortical representations are dynamically maintained in both normal and brain-injured animals. Functional plasticity in the motor cortex of normal animals is accompanied by changes in synaptic morphology; these changes are skill-dependent rather than simply use-dependent. Finally, motor cortical areas undergo substantial functional alterations after focal ischemic infarcts; motor experience is a potent and adaptive modulator of injury-related plasticity. These recent neuroscientific advances set the stage for the development of new, more effective interventions in chronic stroke populations that are based on the basic mechanisms underlying neuroplasticity.

Recovery of motor function after focal cortical injury in primates: compensatory movement patterns used during rehabilitative training

The recovery of skilled hand use after cortical injury was assessed in adult squirrel monkeys. Specific movement patterns used to perform a motor task requiring fine manual skill were analyzed before and after a small ischemic infarct (2.6-3.8 mm2) to the electrophysiologically identified hand area of the primary motor cortex (M1). After 1-3 weeks of pre-infarct training, each monkey stereotypically used one specific movement pattern to retrieve food pellets. After injury to the hand area of M1, the monkeys were required to retrieve the pellets using their impaired forelimb. Immediately after the injury, the number of finger flexions used by the monkeys to retrieve the pellets increased, indicating a deficit in skilled finger use. After approximately 1 month of rehabilitative training, skilled use of the fingers appeared to recover, indicated by a reduction in the number of finger flexions per retrieval. The monkeys again retrieved the pellets using one specific movement pattern in most trials. Despite the apparent recovery of skilled finger use after rehabilitative training, three of five monkeys retrieved the pellets using stereotypic movement patterns different from those used before the injury. Thus, this study provides evidence that compensatory movement patterns are used in the recovery of motor function following cortical injury, even after relatively small lesions that produce mild, transient deficits in motor performance. Examination of electrophysiological maps of evoked movements suggests that the mode of recovery (re-acquisition of pre-infarct movement strategies vs development of compensatory movement strategies) may be related to the relative size of the lesion and its specific location within the M1 hand representation.

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke A Critical Appraisal

BACKGROUND AND PURPOSE Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. SUMMARY OF REVIEW Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. CONCLUSIONS Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs.