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 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 4  |  Page : 166-172

Neural rewiring from peripheral to central: a narrative review

1 School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China
2 Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee, WI, USA

Date of Submission05-Dec-2022
Date of Decision12-Dec-2022
Date of Acceptance23-Dec-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Ji-Geng Yan
Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.365026

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Peripheral nerve injury and reconstruction would lead to alteration of neural pathways. This is regarded as rewiring peripheral nerves, which could also be a trigger for the corresponding neural rewiring process in the brain. Brain plasticity subsequent to peripheral nerve reconstruction plays an important role in the functional recovery of limbs, which has attracted increasing concerns. The present study aimed to overview recent progress in neuroregeneration-related brain plasticity. Nerve transfer is a special technique of nerve reconstruction that usually leads to substantial peripheral neural rewiring and cortical reorganization. Nerve transfer-related shifting of motor representation was particularly discussed. We also emphasized rehabilitation strategies based on the current peripheral-central rewiring theory. Specific strategies based on neural plasticity were proposed for corresponding recovery stages.

Keywords: brain plasticity; nerve repair; nerve rewiring; peripheral nerve injury; rehabilitation

How to cite this article:
Lu HY, Yan JG. Neural rewiring from peripheral to central: a narrative review. Brain Netw Modulation 2022;1:166-72

How to cite this URL:
Lu HY, Yan JG. Neural rewiring from peripheral to central: a narrative review. Brain Netw Modulation [serial online] 2022 [cited 2023 Jun 7];1:166-72. Available from: http://www.bnmjournal.com/text.asp?2022/1/4/166/365026

  Introduction Top

Peripheral nerve injury (PNI) refers to the injury caused by external force on the trunk or branches of a peripheral nerve, which causes damage to the function or structure of the peripheral nervous system, including nerve conduction dysfunction, axon interruption or nerve rupture. PNI occurs in about 2.8% of all trauma patients and there are more than 1 million new cases worldwide every year (Li et al., 2018; Boecker et al., 2019). It is reported that 25% of patients with upper limb PNI are still unable to return to work until 1.5 years after injury (Mika et al., 2013; Kouyoumdjian et al., 2017). Clinical features of PNI include sensorimotor dysfunction, pain, skin nutritional changes, vascular dysfunction, and osteoporosis. It usually seriously impacts the activities of daily living and brings about huge medical and economic burdens. Although microsurgical techniques and nerve regeneration promotion researches have greatly advanced, further breakthrough in nerve reconnection and regeneration is extremely difficult (Xing et al., 2021). Recently, research in PNI-related brain plasticity has been a great concern. Brain plasticity is a continuous process throughout the recovery period following PNI. It starts even minutes following nerve injury (Wall et al., 1986). These plastic changes would be more greatly involved in the functional recovery following reinnervation (Shen, 2022). Although the human brain has the potential for spontaneous compensation through the mechanism of synaptic plasticity in specific brain regions or neural circuits, its efficacy and extent may still be limited (Jara et al., 2020). Spontaneous compensation might even be maladaptive, sometimes leading to intractable complications, such as neuropathic pain and phantom pain (Navarro et al., 2007; Takeuchi and Izumi, 2012). Facilitating adaptive brain plasticity and inhibiting maladaptive plasticity through appropriate rehabilitation approaches may be a rewarding strategy to further improve functional recovery.

With the continuous development of neuroimaging techniques, such as functional magnetic resonance imaging, we are able to explore dynamic plasticity of the brain. The present study overviewed recent progress in brain plasticity related to PNI and nerve reconstruction procedures. Particularly, neural plasticity rules related to specific nerve reconstruction methods were summarized. We also proposed appropriate rehabilitation strategies based on brain plasticity mechanisms both functionally and structurally.

  Search Strategy Top

We searched PubMed for relevant articles published from 1980 to 2022. The search terms included “peripheral nerve injury” AND “neural rewiring” OR “brain plasticity” OR “nerve repair” OR “nerve transfer” OR “rehabilitation.”

  Brain Plasticity Following Peripheral Nerve Injury Top

Evidence of brain plasticity following PNI is usually collected from those suffering from amputation or before reinnervation of transected nerves. In the early stage of peripheral neural pathway interruption, the representative area of cerebral cortex corresponding to the target becomes non-responsive (i.e., the “silence” phenomenon). Adjacent areas that respond to other parts of the body expand and invade into the area that originally responds to the injured nerve (Sanes et al., 1988; Wu and Kaas, 1999). The outcomes of function restoration following reinnervation are suggested to be related to whether the “silence” phenomenon is reversed (Wu and Kaas, 1999). In a study reported by Merzenich et al. (1983), the cortex within parietal somatosensory areas 3b and 1 was “silenced” after median nerve transection in adult squirrel and owl monkeys, and completely invaded by representations of ulnar and radial nerves within 2-9 months. Elbert et al. (1994) provided further evidence that extensive cortical reorganization occurred in humans following upper extremity amputation in which afferentation from the upper extremity was completely shut off. Their study indicated that the cortical representation of the chin invades or shiftes toward the area that normally represents the digits. According to the above findings, protecting the cortex from being occupied may be an important basis for rehabilitation strategies.

  Brain Plasticity Following Direct Repair of Peripheral Nerves Top

When PNI can be sutured directly or bridged by an autograft nerve, structural continuity between the target organ and the corresponding cortex is reconstructed directly through axonal regeneration. The “silence” phenomenon can be partially reversed, although its accuracy is incompletely or disorderly restored (Lundborg, 2000). Due to incompleteness and mismatch of axons within the nerve bundle during regeneration, initial restoration of cortical representation would be incomplete and disarranged as well. When the median nerve is reconnected following neurorrhaphy, its primitive somatosensory cortex is largely restored but with a disordered arrangement of different fingers (Lundborg, 2000). This disorganization in the brain is also related to incomplete recovery of accurate sensory and fine movement following repair of musculocutaneous, radial, median and ulnar nerves (Bao et al., 2021). It may result from a higher degree of loss and/or misdirected sensory input after nerve axonal regeneration and a more serious mismatch between the cortical representation and the reinnervated extremities. Moreover, cortical representation corresponding to the injured hand is encroached by adjacent cortex to a greater extent due to its larger size of representative area than the arm. In a hand transplantation study by Giraux et al. (2001), the motor cortices of hands were reactivated while regaining grasping function. Therefore, the brain has the compensating potential to spontaneously restore the original control over extremities even when axonal regeneration is incomplete and mismatched. Even though, external interventions may be still needed to achieve more satisfactory accuracy and refinement.

  Brain Plasticity Following Nerve Transfer Top

Nerve transfer is a special nerve reconstruction strategy that is applied when the injured nerve cannot be sutured directly. It is originally used for treating brachial plexus avulsion injury or other proximal peripheral nerve injuries. With the evolution of the concept and microsurgical techniques, it is also utilized in the treatment of other neuropathies, such as spinal cord injury, stroke, and cerebral palsy (Berger et al., 2022; Feng et al., 2022).

Briefly, in a nerve transfer surgery, a nerve with less important functions (or partially taken without affecting its original major function) is used as a donor to repair an injured nerve that executes more important functions (Nagano et al., 1992). In the brain, a directional “shifting” process of the representative sensorimotor cortex is generally observed. The cortical representation of the affected limb shifts from the area of donor nerve to the original area of the injured nerve. The original representation of the injured nerve is reconnected to the affected limb and finally reactivated through neural plasticity. The underlying mechanism may be related to the activation of pre-existing connections between these two cortical areas. Cortical plasticity features in different nerve transfer approaches are reviewed as follows:

Ipsilateral nerve transfer

Donors ipsilateral to the affected limb are most commonly used for nerve transfer, such as accessory nerves, phrenic nerves, and intercostal nerves (Gu et al., 1989; Nagano et al., 1992; Gu and Ma, 1996; Songcharoen et al., 1996). Cortical plasticity following intercostal nerve and phrenic nerve transfer has been largely explored. In patients receiving intercostal nerves to musculocutaneous nerves transfer, synkinetic elbow flexion during inspiration is observed at the initial recovery stage. Finally, most of the patients could flex their elbows freely without the help of respiratory activities (Sokki et al., 2012). At the early stage after nerve transfer, the reinnervated biceps is controlled by the cortical representation related to posture and breathing. At the later stage, the representative area of the biceps shifts back to those original functional areas (Malessy et al., 1998, 2003). The principal mechanism underlying this process may be to uncover or strengthen previously silent or subthreshold synaptic connections between ICNs and musculocutaneous nerve neurons by neural plasticity.

Contralateral nerve transfer

Transferring donors from the contralateral side is another important approach for nerve transfer and provides an opportunity for exploring cortical plasticity in a complex peripheral nerve rewiring pattern. Contralateral C7 nerve transfer is a commonly used procedure for brachial plexus avulsion injury, in which the seventh cervical nerve from the healthy side is sacrificed as a donor to reconstruct the injured nerves (Gu et al., 1992). At the early stage after neurotization, patients can only move the affected limb with the assistance of the contralateral healthy limb. As the recovery progresses, patients are capable of controlling the affected limb independently (Gu, 1997; Gu et al., 1998). In the investigation of brain plasticity, cross-hemispheric remodeling occurs in the primary motor cortices after contralateral C7 transfer (Jiang et al., 2010). Initially, the affected upper limb is dominated by the ipsilateral motor cortex. The cortical representation of the affected upper limb shifts from the ipsilateral hemisphere to the contralateral hemisphere in the final stage of regeneration. By reactivating the “silenced” area corresponding to the affected upper limb, the cross-hemispheric remodeling occurs. Finally, the contralateral cortex is exclusively responsible for controlling the affected upper limb (Hua et al., 2013; Liu et al., 2013; Stephenson et al., 2013). This remodeling process is supposed to be mediated by fibers in the corpus callosum. In a rat model, corpus callosotomy was performed to explore its effecton this cross-hemispheric plasticity. The cross-hemispheric plasticity of motor cortex did not occur while the corpus callosum was transected, indicating an essential role of the corpus callosum in the cross-hemispheric plasticity (Hua et al., 2012).

As for the somatosensory cortex, the cross-hemispheric phenomenon was absent. Researchers have reported that following contralateral C7 transfer, the somatosensory representations of bilateral forelimbs both located in the hemisphere ipsilateral to the affected side although their overlapping area showed a trend of separation (Wang et al., 2010a).

Nerve transfer with end-to-side neurorrhaphy

End-to-side neurorrhaphy is an alternative method for nerve transfer, in which the donor nerve is preserved or partially injured while the recipient nerve is reinnervated by collateral sprouting of the donor nerve (Ballance et al., 1903). Phrenic nerve is considered a feasible donor for end-to-side transfer due to its great regeneration ability and continuous discharge of impulses (Viterbo et al., 1995; Wang et al., 2011; Yan et al., 2011; Zheng et al., 2012). Beisteiner et al. (2011) demonstrated that patients with brachial plexus avulsion injury who underwent phrenic nerve-to-musculocutaneous nerve transfer with end-to-side neurorrhaphy could independently flex their elbows. Zheng et al. (2012) conducted an intracranial microstimulation study in a rat model of phrenic-nerve-to-musculocutaneous-nerve transfer with end-to-side neurorrhaphy. They found that the original cortical representation could still be reactivated even when two separate targets (diaphragm and biceps) were reinnervated by a single nerve (phrenic nerve). Recently, a new repair of the musculocutaneous nerve using the vagus nerve side as a donor by helicoid end-to-side technique has been studied in rats and a useful biceps muscle function has been obtained (Yan et al., 2017), indicating that the autonomic nerve can be converted to the non-autonomic nerve.

  Brain Plasticity-Based Rehabilitation Top

Recovery from PNI is a long-lasting process. Patients usually suffer from persistent and serious disabilities (Taylor et al., 2008). Rehabilitation is an important component of treatment throughout the whole course of recovery. The traditional concept of rehabilitation focuses on the treatment of local complications, including axonal regeneration, inflammation, swelling, and joint contraction. As our understanding of neuroscience progresses, rehabilitation strategies based on the rules of brain plasticity are attracting increasing concern. Accordingly, we proposed staged rehabilitation strategies based on brain plasticity at different recovery stages [Figure 1].
Figure 1: Rehabilitation strategies based on brain plasticity at different recovery stages in different nerve reconstruction methods.

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Early stage

Before reinnervation, the cerebral cortex of the injured nerve becomes non-responsive to original targets and gradually occupied by adjacent areas. Following successful nerve regeneration, the connectivity between the cortex and targets is reestablished. Whether the original area regains control over the affected limb is a crucial process for satisfactory functional recovery. The principal purpose of neural plasticity-based rehabilitation at this stage is to protect the original cortical representation of the affected limb from being occupied.

A direct way to deliver peripheral stimulation to the injured nerve is electrical stimulation. The application of electrical stimulation after nerve injury not only facilitates correct projection of regenerated axons but also provides continuous peripheral signal input to the brain (Geremia et al., 2007; Chu et al., 2022). Use of myoelectric prosthesis is beneficial for functional recovery due to reduced cortical reorganization and preserved representative area of the affected limb (Lotze et al., 1999). It is thought to contribute to ongoing peripheral stimulation, muscular training of the stump and visual feedback (Winslow et al., 2018; Guémann et al., 2022).

Motor imagery (MI) is considered another way to activate relevant circuits when actions are absent. MI refers to an active process in which the representation of a human action is internally reproduced in their working memory without resulting in any overt output (Di Rienzo et al., 2014; Lu et al., 2016). As imagination and execution are supposed to share similar signal transduction processes and call similar brain regions, MI is believed to catalyze the recovery process through activation or modulation of cortical maps in spite of the condition that the injured limb cannot move voluntarily (Lu et al., 2016). MI is particularly important for nerve transfer surgeries. Imagination is an essential process for patients to regain independent control over the target motion and get rid of donor nerve assistance.

Mirror therapy is another feasible treatment for patients at this stage. In the initial period of sensory loss, mirror therapy is an alternative stimulus that supplies the somatosensory cortex with reflex images of the intact limb to preserve the representation of the somatosensory cortex and reduce or inhibit cortical reorganization that may occur without early interventions (Grünert-Plüss et al., 2008; Svens and Rosén, 2009). Researchers propose that mirror therapy help to regrow nerves and achieve well-organized connections between body and cortical maps by means of action observation or visual illusion (Zink and Philip, 2020; Chen et al., 2022).

Virtual reality is another new technique that has been increasingly used in rehabilitation. It enhances the input of vision, hearing, and touch, and allows patients to interact and train in an interesting pattern. A vivid and relatively realistic three-dimensional environment is generated to ensure multi-modal input is transmitted to the brain (Georgiev et al., 2021).

Late stage

Due to the lack of afferent stimuli in the cortical representation area of the injured nerve, the overlapping of adjacent cortical areas occurs within minutes after PNI (Lundborg, 2000). After reinnervation, both anatomic and physiological neural pathways between the cerebral cortex and target tissue have been reconstructed. Neural plasticity-based rehabilitation therapies at this stage are supposed to accelerate restoration of the original cortex corresponding to the injured nerve.

Constraint-induced movement therapy (CIMT) and brain-computer interface (BCI) are especially suggested at this stage of recovery. CIMT is a package of training techniques designed to restrain the movement of the healthy limb and conduct repetitive exercises and activities related to daily life with the affected limb. Continuous use of the affected limb may serve to maintain the cortical area of the contralateral hemisphere that innervates the limb, as well as increase the recruitment of other cortical areas (Sutcliffe et al., 2007; Lin et al., 2010). Werner et al. (2021) treated 21 children with neonatal brachial plexus palsy with CIMT intervention or routine care for 8 weeks, indicating favored results of CIMT over routine care for bimanual activity performance. BCI is a human-computer interaction tool between the human brain and external devices, independent of conventional information output pathways of the brain which refer to peripheral nerves and muscle tissue (Wang et al., 2010b). MI is a classical paradigm used in BCI and motor function recovery (Chen et al., 2019). MI-based BCI does not depend on any sensory stimulation. When patients imagine their own limb movements but do not have actual motor output, relevant electroencephalogram signals could still be recorded from the specific area of the brain (Zhang et al., 2014). MI-based BCI enables patients to perform tasks in specific virtual scenes through continuous MI training to facilitate reconstruction of the damaged cerebral cortex and repair functional control connections between external limbs and the brain (Ren et al., 2020). Takemi et al. (2018) suggested that MI-based BCI makes effector-specific training possible for patients with motor paralysis by selectively disinhibiting the corticomotor output to the agonist muscle.

Sequelae stage

At the sequelae stage, nerve regeneration is generally completed, and the new cortical representation of the affected limb has been stably formed. The aim of neural plasticity-based rehabilitation at this stage is to restore skillful motor function and refined sensation. This may involve the integration between different functional regions, circuits and even networks of the brain. Suggested rehabilitation strategies at this stage may include sensory re-education, sensorimotor integration and robot-assisted rehabilitation.

Sensory re-education is a therapy that reestablishes afferent sensation through environmental interaction with discriminant sensory stimulation (Zink and Philip, 2020). In a prospective study, patients who were treated with sensory re-education following median nerve repair showed better outcomes than those without sensory re-education treatment (Antonopoulos et al., 2019). Another study also indicated that sensory re-education was beneficial to the re-education of locognosia (the ability to localize touch) after complete transection and repair of distal median nerves (Mavrogenis et al., 2009).

Skilled movements require coordination between the sensory and motor systems (Asan et al., 2021). Sensorimotor integration is a process that combines the sensations of the body and the external environment to shape body movements, which increases activities of sensorimotor circuits (Asan et al., 2021). Sensory afferents influence the primary motor cortex (M1) either through the intracortical connections between M1 and the primary sensory cortex (S1) or through thalamocortical pathways which reach the M1 (Rocco-Donovan, 2011). Motor flexibility is achieved by ensuring the muscle groups that control a specific joint work in a coordinated and skilled manner after processing the information from the sensory afferents (Pruszynski et al., 2011). Through a sensory-motor integration approach, sensory-motor functions may be further integrated to form a coordinated network.

As an auxiliary means of conventional rehabilitation, robot-assisted rehabilitation has been used in clinical practice. During robot-assisted training, the patient’s brain produces upstream neural signals that drive motor relearning, creating new connections and reorganization between brain regions to restore motor control (Kitago and Krakauer, 2013). Saleh et al. (2017) showed that the improvement through a hybrid of robot-assisted virtual reality rehabilitation training may be attributed to recovery of activity of ipsilesional sensorimotor networks.

Neuropathic pain is one of the main sequelae of PNI, which is thought to be partially related to central sensitization. Repeated transcranial magnetic stimulation has been reported to alleviate neuropathic pain. It is supposed to regulate pain circuits in the brain, which are mainly composed of the anterior cingulate cortex, thalamus, insular lobe, frontal cortex, anterior motor cortex and M1 (Moseley and Flor, 2012). Several studies have confirmed that repeated transcranial magnetic stimulation on M1 could regulate the excitability of pain circuits, thereby producing analgesic effects (Lefaucheur et al., 2010; Moseley and Flor, 2012). Acupuncture is a traditional Chinese medicine practice that has been used for treating neuropathic pain. It is also a technique for suppressing pain-related neural circuits and enhancing analgesic circuits. For example, electroacupuncture can relieve neuropathic pain by simultaneously down-regulating the activation patterns of the somatosensory cortex and pain-related brain regions (Wu et al., 2018).

  Conclusions Top

Brain plasticity following peripheral nerve rewiring has attracted great attention in the recovery of PNI. Spontaneous plasticity is usually insufficient and even maladaptive. Strategies for neurosurgery and rehabilitation should be proposed based on the rules that facilitate adaptive plasticity and/or prevent maladaptive plasticity. Further studies are expected on neuromodulation techniques or other approaches that regulate neural circuits following specific alteration of peripheral neural pathways. The combined peripheral-central rewiring would be a new treatment for the reconstruction of sensorimotor functions.

Author contributions

HYL and JGY designed the literature search strategy, summarized the information of manuscript, and wrote the original version of the manuscript. HYL made the figure. JGY revised the manuscript. Both authors have read and approved the final version of the manuscript.

Conflicts of interest

The author declares no competing financial interests.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[73]

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