Plasticity In Central Nervous System Research Articles

Role of Microglia in Central Nervous System Development and Plasticity.

The nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS, and highlight exciting new discoveries about their contributions to CNS development, maintenance, and plasticity.

From Control to Chaos: Visual-Cognitive Progression During Recovery from ACL Reconstruction.

BACKGROUND: Anterior cruciate ligament tear is a serious knee injury with implications for central nervous system (CNS) plasticity. To perform simple knee movements, people with a history of ACL reconstruction (ACL-R) engage cross-modal brain regions and when challenged with cognitive-motor dual-tasks, physical performance deteriorates. Therefore, people with ACL-R may increase visual-cognitive neural processes for motor control. CLINICAL QUESTION: What components of CNS plasticity should the rehabilitation practitioner target with interventions, and how can practitioners augment rehabilitation exercises to target injury associated plasticity? KEY RESULTS: This clinical commentary (1) describes the neurophysiological foundation for visual-cognitive compensation after ACL-R, (2) provides a theoretical rationale for implementing visual-cognitive challenges throughout the return to sport (RTS) continuum, and (3) presents a framework for implementing visual-cognitive challenges from the acute phases of rehabilitation. The 'Visual-Cognitive Control Chaos Continuum (VC-CCC) framework consists of five training difficulties that progress visual-cognitive challenges from high control to high chaos, to better represent the demands of sport. CLINICAL APPLICATION: The VC-CCC framework augments traditional rehabilitation so that each exercise can progress to increase difficulty and promote sensorimotor and visual-cognitive adaptation after ACL-R.

Perineuronal Nets in the CNS: Architects of Memory and Potential Therapeutic Target in Neuropsychiatric Disorders.

The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.

Single-Nucleus RNA-Seq Characterizes the Cell Types Along the Neuronal Lineage in the Adult Human Subependymal Zone and Reveals Reduced Oligodendrocyte Progenitor Abundance with Age.

The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during postnatal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between four youth (age 16-22) and four middle-aged adults (age 44-53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons, and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of oligodendrocyte progenitors and microglia decreased in middle-age, indicating that the cellular composition of human SEZ is remodeled between youth and adulthood. The expression of genes related to nervous system development was higher across different cell types, including NSCs, in youth as compared with middle-age. These transcriptional changes suggest ongoing central nervous system plasticity in the SEZ in youth, which declined in middle-age.

A Review of Current Perspectives on Motoric Insufficiency Rehabilitation following Pediatric Stroke.

Pediatric stroke (PS) is an injury caused by the occlusion or rupture of a blood vessel in the central nervous system (CNS) of children, before or after birth. Hemiparesis is the most common motoric deficit associated with PS in children. Therefore, it is important to emphasize that PS is a significant challenge for rehabilitation, especially since the consequences may also appear during the child's growth and development, reducing functional capacity. The plasticity of the child's CNS is an important predecessor of recovery, but disruption of the neural network, specific to an immature brain, can have harmful and potentially devastating consequences. In this review, we summarize the complexity of the consequences associated with PS and the possibilities and role of modern rehabilitation. An analysis of the current literature reveals that Constraint-Induced Movement Therapy, forced-use therapy, repetitive transcranial magnetic stimulation, functional electrical stimulation and robot-assisted therapy have demonstrated at least partial improvements in motor domains related to hemiparesis or hemiplegia caused by PS, but they are supported with different levels of evidence. Due to the lack of randomized controlled studies, the optimal rehabilitation treatment is still debatable, and therefore, most recommendations are primarily based on expert consensuses, opinions and an insufficient level of evidence.

Tryptophan metabolism as a 'reflex' feature of neuroimmune communication: Sensor and effector functions for the indoleamine-2, 3-dioxygenase kynurenine pathway.

Although the central nervous system (CNS) and immune system were regarded as independent entities, it is now clear that immune system cells can influence the CNS, and neuroglial activity influences the immune system. Despite the many clinical implications for this 'neuroimmune interface', its detailed operation at the molecular level remains unclear. This narrative review focuses on the metabolism of tryptophan along the kynurenine pathway, since its products have critical actions in both the nervous and immune systems, placing it in a unique position to influence neuroimmune communication. In particular, since the kynurenine pathway is activated by pro-inflammatory mediators, it is proposed that physical and psychological stressors are the stimuli of an organismal protective reflex, with kynurenine metabolites as the effector arm co-ordinating protective neural and immune system responses. After a brief review of the neuroimmune interface, the general perception of tryptophan metabolism along the kynurenine pathway is expanded to emphasize this environmentally driven perspective. The initial enzymes in the kynurenine pathway include indoleamine-2,3-dioxygenase (IDO1), which is induced by tissue damage, inflammatory mediators or microbial products, and tryptophan-2,3-dioxygenase (TDO), which is induced by stress-induced glucocorticoids. In the immune system, kynurenic acid modulates leucocyte differentiation, inflammatory balance and immune tolerance by activating aryl hydrocarbon receptors and modulates pain via the GPR35 protein. In the CNS, quinolinic acid activates N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, whereas kynurenic acid is an antagonist: the balance between glutamate, quinolinic acid and kynurenic acid is a significant regulator of CNS function and plasticity. The concept of kynurenine and its metabolites as mediators of a reflex coordinated protection against stress helps to understand the variety and breadth of their activity. It should also help to understand the pathological origin of some psychiatric and neurodegenerative diseases involving the immune system and CNS, facilitating the development of new pharmacological strategies for treatment.

Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y12 receptor expression in the spinal cord.

During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y12 receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y12 receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of Rhizoma Corydalis, inhibited the P2Y12/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y12 receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.

Echinoderm radial glia in adult cell renewal, indeterminate growth, and regeneration.

Echinoderms are a phylum of marine deterostomes with a range of interesting biological features. One remarkable ability is their impressive capacity to regenerate most of their adult tissues, including the central nervous system (CNS). The research community has accumulated data that demonstrates that, in spite of the pentaradial adult body plan, echinoderms share deep similarities with their bilateral sister taxa such as hemichordates and chordates. Some of the new data reveal the complexity of the nervous system in echinoderms. In terms of the cellular architecture, one of the traits that is shared between the CNS of echinoderms and chordates is the presence of radial glia. In chordates, these cells act as the main progenitor population in CNS development. In mammals, radial glia are spent in embryogenesis and are no longer present in adults, being replaced with other neural cell types. In non-mammalian chordates, they are still detected in the mature CNS along with other types of glia. In echinoderms, radial glia also persist into the adulthood, but unlike in chordates, it is the only known glial cell type that is present in the fully developed CNS. The echinoderm radial glia is a multifunctional cell type. Radial glia forms the supporting scaffold of the neuroepithelium, exhibits secretory activity, clears up dying or damaged cells by phagocytosis, and, most importantly, acts as a major progenitor cell population. The latter function is critical for the outstanding developmental plasticity of the adult echinoderm CNS, including physiological cell turnover, indeterminate growth, and a remarkable capacity to regenerate major parts following autotomy or traumatic injury. In this review we summarize the current knowledge on the organization and function of the echinoderm radial glia, with a focus on the role of this cell type in adult neurogenesis.

HSPB2 facilitates neural regeneration through autophagy for sensorimotor recovery after traumatic brain injury.

Autophagy is a promising target for promoting neural regeneration, which is essential for sensorimotor recovery following traumatic brain injury (TBI). Whether neuronal heat shock protein B2 (HSPB2), a small molecular heat shock protein, reduces injury and promotes recovery following TBI remains unclear. In this study, we demonstrated that HSPB2 was significantly increased in the neurons of a TBI mouse model, patients, and primary neuron cultures subjected to oxygen/glucose deprivation and reperfusion treatment. Upon creating a tamoxifen-induced neuron-specific HSPB2 overexpression transgenic mouse model, we found that elevated HSPB2 levels promoted long-term sensorimotor recovery and alleviated tissue loss after TBI. We also demonstrated that HSPB2 enhanced white matter structural and functional integrity, promoted central nervous system (CNS) plasticity, and accelerated long-term neural remodeling. Moreover, we found that autophagy occurred around injured brain tissues in patients, and the pro-regenerative effects of HSPB2 relied on its autophagy-promoting function. Mechanistically, HSPB2 may regulate autophagy possibly by forming the HSPB2/BCL2-associated athanogene 3/sequestosome-1 complex to facilitate the clearance of erroneously accumulated proteins in the axons. Treatment with the autophagy inhibitor chloroquine during the acute stage or delayed induction of HSPB2 remarkably impeded HSPB2's long-term reparative function, indicating the importance of acute-stage autophagy in long-term neuro-regeneration. Our findings highlight the beneficial role of HSPB2 in neuro-regeneration and functional recovery following acute CNS injury, thereby emphasizing the therapeutic potential of autophagy regulation for enhancing neuro-regeneration.

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein's structure and function.

GRIN2A is a gene that encodes NMDA receptors found in the central nervous system and plays a pivotal role in excitatory synaptic transmission, plasticity and excitotoxicity in the mammalian central nervous system. Changes in this gene have been associated with a spectrum of neurodevelopmental disorders such as epilepsy. Previous studies on GRIN2A suggest that non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein's structure and function. To gain a better understanding of the impact of potentially deleterious variants of GRIN2A, a range of bioinformatics tools were employed in this study. Out of 1320 nsSNPs retrieved from the NCBI database, initially 16 were predicted as deleterious by 9 tools. Further assessment of their domain association, conservation profile, homology models, interatomic interaction, and Molecular Dynamic Simulation revealed that the variant I463S is likely to be the most deleterious for the structure and function of the protein. Despite the limitations of computational algorithms, our analyses have provided insights that can be a valuable resource for further in vitro and in vivo research on GRIN2A-associated diseases.

Decoding cerebro-spinal signatures of human behavior: Application to motor sequence learning

Mapping the neural patterns that drive human behavior is a key challenge in neuroscience. Even the simplest of our everyday actions stem from the dynamic and complex interplay of multiple neural structures across the central nervous system (CNS). Yet, most neuroimaging research has focused on investigating cerebral mechanisms, while the way the spinal cord accompanies the brain in shaping human behavior has been largely overlooked. Although the recent advent of functional magnetic resonance imaging (fMRI) sequences that can simultaneously target the brain and spinal cord has opened up new avenues for studying these mechanisms at multiple levels of the CNS, research to date has been limited to inferential univariate techniques that cannot fully unveil the intricacies of the underlying neural states. To address this, we propose to go beyond traditional analyses and instead use a data-driven multivariate approach leveraging the dynamic content of cerebro-spinal signals using innovation-driven coactivation patterns (iCAPs). We demonstrate the relevance of this approach in a simultaneous brain-spinal cord fMRI dataset acquired during motor sequence learning (MSL), to highlight how large-scale CNS plasticity underpins rapid improvements in early skill acquisition and slower consolidation after extended practice. Specifically, we uncovered cortical, subcortical and spinal functional networks, which were used to decode the different stages of learning with a high accuracy and, thus, delineate meaningful cerebro-spinal signatures of learning progression. Our results provide compelling evidence that the dynamics of neural signals, paired with a data-driven approach, can be used to disentangle the modular organization of the CNS. While we outline the potential of this framework to probe the neural correlates of motor learning, its versatility makes it broadly applicable to explore the functioning of cerebro-spinal networks in other experimental or pathological conditions.

Cortical stimulation leads to shortened myelin sheaths and increased axonal branching in spared axons after cervical spinal cord injury.

Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries. We quantified myelin and axonal characteristics by tracing corticospinal axons rostral to and at the lesion epicenter and identifying nodes of Ranvier by immunohistochemistry. Three weeks of daily stimulation induced very short myelin sheaths, axon branching, and thinner axons outside of the lesion zone, where remodeling has not previously been reported. Surprisingly, remodeling was particularly robust rostral to the injury which suggests that electrical stimulation can promote white matter plasticity even in areas not directly demyelinated by the contusion. Stimulation did not alter myelin or axons at the lesion site, which suggests that neuronal activity does not contribute to myelin remodeling near the injury in the sub-chronic period. These data are the first to demonstrate wide-scale remodeling of nodal and myelin structures of a mature, long-tract motor pathway in response to electrical stimulation. This finding suggests that neuromodulation promotes white matter plasticity in intact regions of pathways after injury and raises intriguing questions regarding the interplay between axonal and myelin plasticity.

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhibitory and excitatory input onto PV interneurons enwrapped by PNN, and decreased gamma oscillations in hippocampal CA1. Notably, MMP-9 inhibitor SB-3CT treatment rescued most of these abnormalities. Taken together, our study demonstrates that active MMP-9 mediated PNN remodeling, leading to reduced inhibitory and excitatory input onto PV interneurons and abnormal gamma oscillations in hippocampal CA1, which consequently contributed to cognitive impairments after LPS injection.

Sickle cell disease chronic joint pain: Clinical assessment based on maladaptive central nervous system plasticity.

Chronic joint pain (CJP) is among the significant musculoskeletal comorbidities in sickle cell disease (SCD) individuals. However, many healthcare professionals have difficulties in understanding and evaluating it. In addition, most musculoskeletal evaluation procedures do not consider central nervous system (CNS) plasticity associated with CJP, which is frequently maladaptive. This review study highlights the potential mechanisms of CNS maladaptive plasticity related to CJP in SCD and proposes reliable instruments and methods for musculoskeletal assessment adapted to those patients. A review was carried out in the PubMed and SciELO databases, searching for information that could help in the understanding of the mechanisms of CNS maladaptive plasticity related to pain in SCD and that presented assessment instruments/methods that could be used in the clinical setting by healthcare professionals who manage chronic pain in SCD individuals. Some maladaptive CNS plasticity mechanisms seem important in CJP, including the impairment of pain endogenous control systems, central sensitization, motor cortex reorganization, motor control modification, and arthrogenic muscle inhibition. Understanding the link between maladaptive CNS plasticity and CJP mechanisms and its assessment through accurate instruments and methods may help healthcare professionals to increase the quality of treatment offered to SCD patients.

Targeting CNS Neural Mechanisms of Gait in Stroke Neurorehabilitation.

The central nervous system (CNS) control of human gait is complex, including descending cortical control, affective ascending neural pathways, interhemispheric communication, whole brain networks of functional connectivity, and neural interactions between the brain and spinal cord. Many important studies were conducted in the past, which administered gait training using externally targeted methods such as treadmill, weight support, over-ground gait coordination training, functional electrical stimulation, bracing, and walking aids. Though the phenomenon of CNS activity-dependent plasticity has served as a basis for more recently developed gait training methods, neurorehabilitation gait training has yet to be precisely focused and quantified according to the CNS source of gait control. Therefore, we offer the following hypotheses to the field: Hypothesis 1. Gait neurorehabilitation after stroke will move forward in important ways if research studies include brain structural and functional characteristics as measures of response to treatment. Hypothesis 2. Individuals with persistent gait dyscoordination after stroke will achieve greater recovery in response to interventions that incorporate the current and emerging knowledge of CNS function by directly engaging CNS plasticity and pairing it with peripherally directed, plasticity-based motor learning interventions. These hypotheses are justified by the increase in the study of neural control of motor function, with emerging research beginning to elucidate neural factors that drive recovery. Some are developing new measures of brain function. A number of groups have developed and are sharing sophisticated, curated databases containing brain images and brain signal data, as well as other types of measures and signal processing methods for data analysis. It will be to the great advantage of stroke survivors if the results of the current state-of-the-art and emerging neural function research can be applied to the development of new gait training interventions.

Protein quality control of N-methyl-D-aspartate receptors.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors.

Aberrant Synaptic Pruning in CNS Diseases: A Critical Player in HIV-Associated Neurological Dysfunction?

Even in the era of effective antiretroviral therapies, people living with Human Immunodeficiency Virus (HIV) are burdened with debilitating neurological dysfunction, such as HIV-associated neurocognitive disorders (HAND) and HIV-associated pain, for which there are no FDA approved treatments. Disruption to the neural circuits of cognition and pain in the form of synaptic degeneration is implicated in developing these dysfunctions. Glia-mediated synaptic pruning is a mechanism of structural plasticity in the healthy central nervous system (CNS), but recently, it has been discovered that dysregulated glia-mediated synaptic pruning is the cause of synaptic degeneration, leading to maladaptive plasticity and cognitive deficits in multiple diseases of the CNS. Considering the essential contribution of activated glial cells during the development of HAND and HIV-associated pain, it is possible that glia-mediated synaptic pruning is the causative mechanism of synaptic degeneration induced by HIV. This review will analyze the known examples of synaptic pruning during disease in order to better understand how this mechanism could contribute to the progression of HAND and HIV-associated pain.

Synaptic pathology in multiple sclerosis: a role for Nogo-A signaling in astrocytes?

Synaptic pathology in multiple sclerosis: a role for Nogo-A signaling in astrocytes?

Mapping brain structure and function in professional fencers: Amodel to study training effects on central nervous system plasticity.

Brain magnetic resonance imaging (MRI) studies have shown different patterns of structural and functional reorganization in high‐level athletes compared with controls, but little is known about their relationship with interlimb coordination mechanisms. To this aim, we investigated brain structural and functional differences in high‐level fencers compared with nonathlete controls and the MRI substrates of interlimb coordination in elite athletes. Fourteen right‐handed male fencers (median age = 22.3 years) and 15 right‐handed age‐ and sex‐matched healthy subjects (median age = 22.4 years) underwent structural and functional MRI acquisition during the execution of cyclic bimanual‐movements as well as during in‐phase and antiphase hand/foot‐movements of the dominant‐right limbs. No between‐group differences were found in gray matter volumes and white matter architecture. Active‐fMRI showed that controls versus fencers had higher activations in parietal and temporal areas during bimanual‐task; whereas fencers versus controls had higher activations in the basal ganglia. During in‐phase task, controls versus fencers showed higher activation of right cerebellum, whereas fencers had higher activity mainly in frontal areas. The functional‐connectivity (FC) analysis showed that fencers versus controls had an increased FC between left motor cortex and fronto‐temporal areas as well as bilateral thalami during the different tasks. Intensive and prolonged fencing activity is associated with brain functional changes mainly involving frontal regions related to high‐level motor control and planning of complex tasks. These modifications are likely to reflect an optimization of brain networks involved in motor activities, including interlimb coordination tasks, occurring after intensive training.

Plasticity of the Central Nervous System Involving Peripheral Nerve Transfer.

Peripheral nerve injury can lead to partial or complete loss of limb function, and nerve transfer is an effective surgical salvage for patients with these injuries. The inability of deprived cortical regions representing damaged nerves to overcome corresponding maladaptive plasticity after the reinnervation of muscle fibers and sensory receptors is thought to be correlated with lasting and unfavorable functional recovery. However, the concept of central nervous system plasticity is rarely elucidated in classical textbooks involving peripheral nerve injury, let alone peripheral nerve transfer. This article is aimed at providing a comprehensive understanding of central nervous system plasticity involving peripheral nerve injury by reviewing studies mainly in human or nonhuman primate and by highlighting the functional and structural modifications in the central nervous system after peripheral nerve transfer. Hopefully, it will help surgeons perform successful nerve transfer under the guidance of modern concepts in neuroplasticity.