Author(s): Surendra Barshikar, MD, MBA, Chiamaka Sonubi, MD, Nedha Kinnare, MD
Originally published: November 5, 2012 Last updated: July 23, 2026
Jump to:

Overview and Description

While long-established scientific doctrine has held that central nervous system (CNS) axons have limited regenerative capacity following stroke, brain injury, cerebral palsy, degenerative brain diseases, or spinal cord injury, emerging evidence suggests that this potential can be enhanced through modulation of intrinsic neuronal growth programs and the surrounding cellular environment. These advances represent important developments in the fields of physiatry and neurorehabilitation. Current research focuses on axon regeneration, neuronal survival, immune signaling, and remyelination. Studies of the spinal cord and visual system continue to provide insight into neural circuits and molecular pathways involved in recovery and regeneration.1,2 Understanding how nerve injury and repair differ between the CNS and peripheral nervous system (PNS) helps identify the intrinsic and extrinsic factors that influence neural repair and regeneration.

The nervous system consists of the CNS and PNS, the latter of which has the ability to regenerate. During development, CNS neurons lose the ability to regenerate. This limited regeneration is partly due to inhibitory molecular signals and poor clearance of myelin debris, creating an environment that restricts repair.3 Neurogenesis, the formation of new neurons from neural progenitor stem cells, begins during prenatal development and continues in limited regions of the adult brain, particularly in the hippocampus and subventricular zones. Neurogenesis is one of three mechanisms of plasticity in the brain, together with synaptic plasticity and functional compensatory processing.4 Synaptic plasticity strengthens communication between neurons by strengthening synaptic connections, whereas, functional compensatory processing recruits previously inactive brain regions to support recovery after injury. Compared with other mechanisms of plasticity, neurogenesis offers the unique potential to replace damaged tissue with new cells in both structure and function.

In spinal cord injury research, emphasis has historically been placed on  neuroprotection rather than regeneration because due to the limited regenerative capacity of CNS axons following injury.5 However, more recently, studies in animal models have shown that CNS axons in the mammalian spinal cord can regenerate provided they are given a permissive environment, such as one supported by neural stem cell grafts, that does not inhibit regrowth.6,7 Neural progenitor cell grafts can assist corticospinal motor axons to reinnervate neurons distal to the lesion. This suggests that reinnervation of neurons is possible without typical guidance cueing.8 In addition, growing research has examined combinatorial approaches- including stem cell transplantation, neurotrophic factors, biomaterial scaffolds, and genetic modulation to promote axonal regeneration after spinal cord injury.9 After neural injury, the immune system removes damaged axons and cellular debris, though this process differs in the CNS and PNS. In the CNS, microglia and astrocytes participate in debris clearance and regulate inflammatory signaling, whereas in the PNS Schwann cells play a central role Activated microglia release cytokines such as TNF-alpha and IL-1beta, that contribute to the inflammatory response but can also promote tissue remodeling and repair. In contrast, Schwann cells not only assist macrophages in clearing debris but also differentiate into repair cells that support axonal regeneration, contributing to faster recovery after PNS injury. Oligodendrocytes myelinate CNS axons but have limited regenerative capacity following injury. Debris clearance occurs more slowly in the CNS often taking several months compared with the PNS, where clearance typically occurs within weeks. In spinal cord injury models, depletion of microglia results in disorganized astrocytic scarring and impaired recovery, suggesting that microglia contribute to the formation of a protective scar that may support neural repair and regeneration.10

Successful neurogenesis requires that undifferentiated neural progenitor or stem cells survive and differentiate appropriately within existing structural and functional neural circuits. Much of the research on CNS regeneration has focused on multipotent mesenchymal stromal cell (MSC) and neural stem cell (NSC) therapies. MSCs may be obtained from bone marrow, cord blood, placenta, and adipose tissues and are thought to promote recovery by creating a supportive microenvironment that enhances endogenous neurogenesis and angiogenesis following CNS injury. These effects are largely mediated through paracrine signaling, immunomodulation, and reduction of inflammation.10 By comparison, NSCs may be obtained via direct extraction from primary CNS tissues, including fetal brain, adult brain, and spinal cord tissue, differentiation from pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, and trans-differentiation from somatic cells.11

Retinal ganglion cells, (RGC’s) are CNS neurons that exhibit subtype-specific differences in vulnerability following injury – while some subtypes undergo rapid cell death, others demonstrate resilience and survive for about 8 days post injury. Single- cell transcriptomic studies have identified differential expression of growth factors, neuroprotective genes, and transcription factors across RGC subtypes, offering insight into the molecular mechanisms underlying this resilience and highlighting potential therapeutic targets10 Beyond acute CNS injury, numerous studies have also investigated the role of physical activity in facilitating neurogenesis in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and age-related cognitive decline.12-14

Relevance to Clinical Practice

While significant research milestones suggest a future where neurogenesis can be pharmacologically or cellularly stimulated post-CNS injury to drive functional recovery,14 a stark translational gap remains between the bench and bedside. Currently PM&R physicians lack commercially available, and FDA approved regenerative treatments. Practice remains anchored in high-intensity task-specific training, compensatory strategies, and the optimization of secondary health factors (e.g., glycemic control, sleep hygiene, and aerobic exercise) known to support endogenous brain-derived neurotrophic factor (BDNF) expression- a protein crucial for neuron survival and synaptic plasticity. Even though animal studies have yielded successes at curing some CNS disorders, there has not been a successful transition to cure the same CNS disorders in humans. Consequently, the clinician’s role has evolved into that of an educator and navigator. As patients increasingly seek out experimental trials, clinicians must critically appraise the validity of these interventions. Furthermore, the focus has shifted toward “priming” the CNS. Emerging neuromodulation therapies like Repetitive Transcranial Magnetic Stimulation (rTMS) are being utilized not as cures, but as adjuncts to enhance the “readiness” of neural circuits to reorganize in response to traditional rehabilitation Interventions aimed at stimulating neuroplasticity within the injured CNS to enhance motor and cognitive recovery are characterized as ‘top-down’ approaches. This therapeutic category encompasses a broad spectrum of modalities, ranging from pharmacological agents and stem cell therapies to various forms of neuromodulation. Currently, in the arena of cell-based therapies, the landscape is shifting toward novel small-molecule inhibitors and biological messengers that target the inhibitory microenvironment. An example is the development of peptides like NVG-291, which targe the sigma-receptor to modulate chondroitin sulfate proteoglycan (CSPG) inhibition, effectively allowing for axonal sprouting and remyelination.15 Early Phase 2 data (e.g., the CONNECT SCI study) has demonstrated unprecedented durable improvements in hand function and autonomic control in chronic spinal cord injury, signaling a move toward the first viable pharmacological neurorepair agents. In tandem, the focus of stem cell therapy has evolved from simple cell replacement to paracrine modulation. Rather than expecting transplanted cells to integrate as new neurons, current trials—such as those utilizing engineered neural stem cell mixtures (e.g., SuNR1se II) or Olfactory Ensheathing Cells (OECs)—leverage these cells as “biological factories.” These cells secrete neurotrophic factors and exosomes (extracellular vesicles) that reduce neuroinflammation and “prime” the endogenous environment for repair.16 Notably, exosome-based therapies are gaining traction as “cell-free” regenerative options, offering reduced immunogenicity and the ability to cross the blood-brain barrier via non-invasive delivery methods like intranasal administration.

To bridge the gap between structural repair and functional reactivation, neurorehabilitation has expanded from cellular regeneration to the electrical modulation of surviving neural circuits with methods such as Transcranial Magnetic Stimulation (TMS), Deep Brain Stimulation (DBS), Vagus Nerve Stimulation (VNS) and Transcranial Direct Current Stimulation (TDCS).

TMS is a non-invasive neuromodulation technique that utilizes high-intensity electrical currents passed through conducting coils to generate a focal magnetic field. This field penetrates the cranium to induce secondary electrical currents within excitable cortical tissue. Axons, being the primary conductors of the CNS, are preferentially depolarized by the TMS pulse, which can selectively activate both inhibitory and excitatory interneurons.17

Repetitive TMS (rTMS) induces plasticity through mechanisms analogous to long-term potentiation (LTP) and long-term depression (LTD). The direction of effect is frequency dependent. Lower frequencies down-regulate hyperactive lesions. While higher frequencies increase cortical excitability, facilitating motor sequence learning and functional reorganization.17

DBS is an invasive neuromodulation technique that utilizes implanted electrodes to deliver high-frequency electrical impulses to the subcortical nuclei, thereby modulating dysfunctional neural circuitry. While long-established for movement disorders and refractory epilepsy, its application in TBI represents a “top-down” paradigm shift. Preclinical rodent models suggest that precisely timed, task-matched DBS of the nucleus accumbens (NAc) can enhance learning and induce lasting neurobiological adaptations, including upregulated synaptogenesis and neurogenesis.18 In human applications, the focus has shifted toward two primary domains: disorders of consciousness and cognitive/executive dysfunction, with the central thalamus being the most common target. The CENTURY-S trial is a first-in-human phase 1 clinical trial investigating the safety and feasibility of using DBS to restore cognitive function in patients with chronic, moderate-to-severe traumatic brain injury (TBI) using bilateral stimulation of the central thalamus. All subjects demonstrated quantitative gains in processing speed, attention, and executive functioning. Qualitatively, families reported significant restorations in personal identity and emotional regulation, suggesting that DBS may reactivate dormant frontal-striatal-thalamic loops.19 Recent longitudinal data from a 10-year single-center, investigation in Croatia evaluated the efficacy of deep brain stimulation (DBS) in a cohort of21 patients with severe disorders of consciousness (DoC). While only 21% of the total cohort achieved significant restoration of consciousness, the Minimally Conscious State (MCS) subgroup showed a notably higher response rate, with 60% (3 of 5) who emerged.20. These results highlight a growing therapeutic window for neuromodulation in the chronic phase of brain injury.

Vagal nerve simulation (VNS) has emerged as a potential therapeutic approach for ischemic strokes. It works by delivering electrical pulses to the vagus nerve, which travel to the nucleus tractus solitarius in the brain stem – a key relay hub that broadly influences the autonomic nervous system. VNS can be delivered through two systems: surgically implanted devices or non-invasive transcutaneous auricular devices.21When paired with intensive rehabilitation, VNS is designed to help patients regain upper limb motor function. Beyond motor recovery, VNS has also been shown to reduce reperfusion injury and promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulate release of neurotransmitters. Together, these effects are thought to stimulate neuroplasticity and facilitate broader functional recovery.22

Transcranial Direct Current Stimulation (tDCS) is a portable, non-invasive adjuvant therapy that utilizes weak direct currents (1–2 mA) to modulate resting membrane potentials. Unlike the suprathreshold pulses of TMS, tDCS shifts cortical excitability in a polarity-dependent manner: anodal stimulation increases excitability, while cathodal stimulation decreases it, with effects persisting up to 90 minutes post-treatment. In stroke rehabilitation, tDCS is used to restore interhemispheric balance by upregulating the lesioned hemisphere or downregulating the hyperexcitable, unaffected side. Clinical trials combining tDCS with occupational therapy demonstrate motor improvements lasting at least one week, particularly in patients with preserved pyramidal tract integrity. Its safety, ease of use, and compatibility with sham-controlled designs make it an ideal candidate for integrated clinical and home-based recovery protocols.23

To establish a therapeutic alliance around the complex topic of experimental medicine, clinicians should adopt a transparent and engaging posture when discussing novel treatments with patients and their families. This requires maintaining working knowledge of current clinical trials and evidence-based resources of information. Ultimately, the role of the physiatrist is to serve as the essential architect of recovery, strategically integrating these emerging neuromodulatory and regenerative therapies into the foundational principles of high-volume, task-specific training to ensure that cellular-level plasticity is successfully translated into meaningful functional independence.

Cutting Edge/Unique Concepts/ Emerging Issues

While novel treatments to promote neurogenesis are increasingly available to participants in clinical research trials, several emerging issues remain. The field is currently transitioning from proof-of-concept to optimization of precision delivery. Research has yet to establish the definitive therapeutic window- the optimal dosage, timing, and delivery route for cell-based therapies and novel biomaterials. Furthermore, the pharmacokinetics of pharmaceutical compounds within the injured CNS microenvironment remain poorly understood, leading to concerns regarding localized toxicities and unintended systemic effects that have yet to be established conclusively.24 A primary concern is the long-term risk of tumorigenesis. Trials utilizing undifferentiated neural progenitor or stem cells based must contend with the potential for iatrogenic mass formation, a risk highlighted in both animal models and rare human case reports.25-27 Because the upregulation of pro-growth factors can trigger oncogenic pathways, many studies are shifting their focus to targeted axonal repair. This approach aims to restore connectivity through site-specific regeneration and remyelination without the mitogenic risks associated with generalized cellular proliferation.

Parallel to cellular regeneration is the emerging field of functional circuit modulation. Current evidence suggests that Deep Brain Stimulation (DBS) for brain injury remains experimental, yet promising. The strongest support exists for carefully selected patients (e.g., those in a minimally conscious state) treated within the first-year post-injury, typically targeting the central thalamic nuclei. Emerging evidence suggests that DBS may also play a role in mitigating refractory executive deficits in chronic TBI, shifting the clinical goal from structural repair to the optimization of surviving neural networks.

Ultimately, the physiatrist serves as the essential bridge between these emerging biotechnologies and real-world functional outcomes. As we move toward an era of “Biorehabilitation,” the clinical focus must shift towards actively coordinating the timing of regenerative interventions with high-intensity, task-specific training.

Gaps in Knowledge/Evidence Base

Clinical trials of stem cell therapy for neurogenesis following CNS injury have largely focused on establishing safety and dosing parameters, with a growing but still limited number of studies progressing to efficacy outcomes. Large scale, population-based studies remain difficult to conduct due to patient selection restrictions in preliminary investigations and the significant heterogeneity in injury level and severity across individuals (scope). Clinicians may face practical challenges when discussing novel treatments with individuals who have sustained a CNS injury, particularly as patients are increasingly exposed to commercially marketed, direct-to-consumer stem cell interventions that lack safety oversight, have not undergone rigorous clinical testing, and are not subject to the monitoring protections afforded by formal clinical trial participation.25 Clinicians and researchers working with this population much therefore must maintain current awareness of established informed consent standards, ethical considerations surrounding experimental trial participation, and consumer-facing educational resources available to patients.28-30

References

  1. Zuo Z, et al. Interleukin-4 protects retinal ganglion cells and promotes axon regeneration. Cell Commun Signal. 2024;22(1):236. doi:10.1186/s12964-024-01604-y
  2. Zheng B, et al.. Regulation of axonal regeneration after mammalian spinal cord injury. Nat Rev Mol Cell Biol. 2023;24(6):396-413. doi:10.1038/s41580-022-00562-y
  3. Tataranu LG, et al. Neuroplasticity and nervous system recovery: cellular mechanisms, therapeutic advances, and future prospects. Brain Sci. 2025;15(4):400.
  4. Calderone A, et al. The role of neuroinflammation in shaping neuroplasticity and recovery outcomes following traumatic brain injury: a systematic review. Int J Mol Sci. 2024;25(21):11708.
  5. Hosseini SM, et al. Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances. Brain. 2024;147(3):766-793. doi:10.1093/brain/awad392
  6. Lu P, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264-1273.
  7. Moreno-Jiménez EP, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25(4):554-560.
  8. Ceto S, et al. Neural stem cell grafts form extensive synaptic networks that integrate with host circuits after spinal cord injury. Cell Stem Cell. 2020;27(3):430-440.e5.
  9. Harvey AR, et al. Neurotrophic factors for spinal cord repair: which, where, how and when to apply, and for what period of time? Brain Res. 2015;1619:36-71.
  10. Tran NM, et al. Single-cell profiles of retinal ganglion cells differing in resilience to injury reveal neuroprotective genes. Neuron. 2019;104(6):1274-1291.e5.
  11. Ernst M, et al. Physical exercise for people with Parkinson’s disease: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2024;4(4):CD013856. doi:10.1002/14651858.CD013856.pub2
  12. Tsukita K, et al. Long-term effect of regular physical activity and exercise habits in patients with early Parkinson disease. Neurology. 2022;98(8):e859-e871. doi:10.1212/WNL.0000000000013218
  13. Tortosa-Martínez J, et al. Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults. Neurobiol Stress. 2018;9:40-47.
  14. Tetzlaff W, et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma. 2011;28(8):1611-1682.
  15. NervGen Pharma. (2025, November 24). NervGen Pharma announces expanded CONNECT SCI study data demonstrating unprecedented durable improvement in function, independence, and quality of life in chronic spinal cord injury. https://nervgen.com/nervgen-pharma-announces-expanded-connect-sci-study-data-demonstrating-unprecedented-durable-improvement-in-function-independence-and-quality-of-life-in-chronic-spinal-cord-injury/
  16. Huang, Qinqin et al. “Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.” Theranostics vol. 16,1 545-579. 1 Jan. 2026, doi:10.7150/thno.117143
  17. Qian FF, et al. Repetitive transcranial magnetic stimulation promotes neurological functional recovery in rats with traumatic brain injury by upregulating synaptic plasticity-related proteins. Neural Regen Res. 2023;18(2):368-374. doi:10.4103/1673-5374.346548
  18. Aronson JP, Ka, et al. Phasic stimulation in the nucleus accumbens enhances learning after traumatic brain injury. Cereb Cortex Commun. 2022;3(2):tgac016. doi:10.1093/texcom/tgac016
  19. Schiff ND, et al. Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. Nat Med. 2023;29:2062-3174. doi:10.1038/s41591-023-02638-4
  20. Chudy D, et al. Deep brain stimulation in disorders of consciousness: 10 years of a single center experience. Sci Rep. 2023;13:19491. doi:10.1038/s41598-023-46300-y
  21. Wei-Jiang, et al. The effect of VNS on the rehabilitation of stroke: A meta-analysis of randomized controlled studies. J Clin Neurosci. 2020 Nov;81:421-425. doi: 10.1016/j.jocn.2020.09.022. Epub 2020 Oct 26. PMID: 33222954.
  22. Andalib S, et al. Vagus Nerve Stimulation in Ischemic Stroke. Curr Neurol Neurosci Rep. 2023 Dec;23(12):947-962. doi: 10.1007/s11910-023-01323-w. Epub 2023 Nov 27. PMID: 38008851; PMCID: PMC10841711.
  23. Schlaug, Gottfried et al. “Transcranial direct current stimulation in stroke recovery.” Archives of neurology vol. 65,12 (2008): 1571-6. doi:10.1001/archneur.65.12.1571
  24. Center for Regenerative Biotherapeutics. Neuroregeneration. Mayo Clinic. Published February 2, 2017. https://www.mayo.edu/research/centers-programs/center-regenerative-biotherapeutics/focus-areas/neuroregeneration
  25. Jacob KJ, et al. Perspectives on strategies and challenges in the conversation about stem cells for spinal cord injury. Spinal Cord. 2015;53(11):811-815.
  26. Fan X, et al. Stem cell transplantation for spinal cord injury: a meta-analysis of treatment effectiveness and safety. Neural Regen Res. 2017;12(5):815-825.
  27. Lovell-Badge R, et al. ISSCR guidelines for stem cell research and clinical translation: the 2021 update. Stem Cell Reports. 2021;16(6):1398-1408. doi:10.1016/j.stemcr.2021.05.012
  28. Kondiles BR, et al. Lessons learned and recommendations from a SCOPE spinal cord injury neurorestorative clinical trials update. Neurotrauma Rep. 2025;6(1):210-231. doi:10.1089/neur.2024.0163
  29. ClinicalTrials.gov. U.S. National Library of Medicine. Accessed March 13, 2026. https://clinicaltrials.gov
  30. Steeves J, et al. Experimental Treatments for Spinal Cord Injuries: What You Should Know If You Are Considering Participation in a Clinical Trial. ICORD; 2012. Accessed August June 22, 2026. https://icord.org/wp-content/uploads/2014/01/Clinical-Trials-Document-V2-BL-Final.pdf

Original Version of the Topic

Chong Tae Kim, MD. Natural Recovery and Regeneration of the Central Nervous System. 11/05/2012

Previous Revision(s) of the Topic

Chloe Slocum, MD, MPH. Natural Recovery and Regeneration of the Central Nervous System. 10/29/2019

Hillary Ramroop, DO, Rosanna C. Sabini, DO. Natural Recovery and Regeneration of the Central Nervous System. 3/9/2023

Author Disclosure

Surendra Barshikar, MD, MBA
Nothing to Disclose

Chiamaka Sonubi, MD
Nothing to Disclose

Nedha Kinnare, MD
Nothing to Disclose