The Interplay Between Neuromodulation and Stem Cell Therapy for Sensory-Motor Neuroplasticity After Spinal Cord Injury: A Perspective View

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

GENERAL COMMENTS:

• This review manuscript would benefit from discussing:

1. the pathogenesis of the disease initiated by SCI. A systematic study in the rat model is a good start
2. preclinical studies testing anti-inflammatory treatments in the acute SCI models. While clinical studies are not published yet, this type of treatment shows exciting and unprecedented results indicating much increased need for electrophysiological, etc., methodology reviewed in the paper.
3. Studies on axonal regeneration and creation of novel white matter in dysmyelinated models. There is much misconception and wishful thinking with using stem cells to achieve neuroregeneration.
4. Barriers to axonal regeneration in normally myelinated models.

 

Also; a glial/astrocytic scar does not exist, the persistent use of this term arises from ignorance of the pathogenesis of the disease initiated by SCI.  Arachnoiditis is a better term.  Astrogliosis, the most obvious cellular plasticity in injured in SCI is a spinal cord tissue response to pathology designed to limit damage, destructive power of severe inflammation and to restore homeostasis.

Author Response

Please see the attached report. We truly appreciate your time and effort. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The review article offers a comprehensive overview of neuromodulation and stem cell-based therapies aimed at sensorimotor recovery. It is well written, features numerous figures and tables, and advocates for combining neuromodulation, rehabilitation, and stem cell implantation as synergistic treatment approaches. However, it primarily discusses a limited set of neuromodulation techniques—such as spinal stimulation and epidural interventions—while omitting consideration of other clinically approved neuromodulation strategies like vagus nerve stimulation (FDA approved for stroke recovery and currently in clinical trials for SCI), deep brain stimulation in the midbrain, and paired associative stimulation. Expanding the discussion to encompass these additional aspects of neuromodulation would be beneficial.

Additionally, the article seems to operate under the assumption that neuroplasticity is always advantageous and that merging multiple therapies invariably leads to synergistic recovery. In reality, this is not always true; the effectiveness of each intervention can depend on the specific context in which it is applied, and interactions among the therapies may affect outcomes differently. Further comments are attached for your consideration.

• Please clarify what you mean by “restoring somatosensory control.” If you are referring to perception, please specify this in your statement.

 

• Neuroplasticity refers not only to the restoration of intraspinal pathways but also to changes in functional connectivity throughout the entire central nervous system, including supraspinal areas and the cortex. Please ensure appropriate citations are included to support these statements.

 

 

• Please remove the equation concept: “Neuroplasticity = Neuromodulation + Task Specific Training (TsT).” This is an oversimplification. Neither neuromodulation nor task-specific training alone may be sufficient to induce neuroplasticity. Numerous factors can impact neuroplasticity, such as the timing of therapy relative to the injury and the behavioral context in which neuromodulation is applied. For example, typical FES or TMS-based approaches rely on spike timing-dependent plasticity and are tightly paired with movements. Vagus nerve stimulation (VNS), when delivered alone, is ineffective, but when paired with movement, it enhances neuroplasticity. Administering therapy in the chronic phase of injury may not be as effective (see Detloff et al., 2016, MR Neurorehabilitation & Repair; Detloff et al., 2013, Experimental Neurology). The dose of therapy may also vary depending on injury severity and can differentially affect neuroplasticity (see Nandakumar et al., 2023, Experimental Neurology).

 

• The suggestion that neuroplasticity is always beneficial is misleading. In some cases, neuroplasticity may become maladaptive with task-specific training or neuromodulation, potentially hindering functional improvement and contributing to the development of neuropathic pain or spasticity. Please extend your discussion to address these issues (refer to Moxon et al., 2014, Neuroscience).

 

 

• While the review focuses on the role of epidural stimulation in restoring movement by enabling central pattern generators (CPGs) to initiate standing and stepping, it does not discuss how epidural stimulation facilitates transmission from supraspinal centers (such as the cortex and brainstem) to regions below the lesion. This transmission is crucial for volitional locomotion after spinal injury, highlighting the need to involve the cortex and movement intent through advances like brain-spinal interfaces (see Asboth et al., 2018, Nature Neuroscience; Bonizzato et al., 2021, Nature Communications).
• Figure 1 is well done; however, the earliest documented use of epidural stimulation to improve function dates back to 1976, in the context of multiple sclerosis, where recovery of voluntary function was reported (see Cook 1976, PMID 1088368). Please ensure the history of epidural electrical stimulation (EES) is reported accurately. Also, include landmark contributions from the groups led by Susan Harkema, Reggie Edgerton, and Grégoire Courtine, which have been instrumental in advancing this technology. Consider referencing these landmark articles directly in the figure, rather than citing them. Additionally, the text in the figure is currently small and difficult to read; please revise for better clarity.

 

• In the table, please add more recent work by Grégoire Courtine (Bonizzato et al., 2018, Nature Communications; Asboth et al., 2018) as well. While this review primarily discusses epidural and spinal stimulation, with some mention of motor cortex stimulation paired with spinal interventions, this does not encompass the full scope of neuromodulation for sensorimotor recovery. Other clinically used and FDA-approved approaches, such as vagus nerve stimulation-based targeted plasticity therapy for spinal cord injury and stroke, should also be discussed (see Ganzer et al., 2018, eLife; Kilgard et al., 2025, Nature; Dawson et al., 2021, Lancet; Khodaparast et al., 2016, Neurorehabilitation and Neural Repair). Please extend your discussion to cover these additional neuromodulation approaches.

 

 

• Consider including a pictorial representation of available neuromodulation treatments for clinical use, along with their mechanisms of action.

 

• In Table 3, the citation “Mestriner et al., 2025” is incorrect, as it refers to an editorial and not a primary research article. Please revise and include the original research article.

 

 

• Please also discuss the use of Schwann cell autografts, which have been shown to be beneficial for functional recovery. Refer to research from Mary Bunge’s group (https://pmc.ncbi.nlm.nih.gov/articles/PMC4929312/), Pearse et al., 2004, Nature Medicine; Anderson et al., 2017, Journal of Neurotrauma; Fouad et al., 2005, Journal of Neuroscience.

 

• Marc Tuszynski’s research group has extensively demonstrated that the implantation of homologous neural stem cells in the spinal cord promotes robust corticospinal regrowth (see Kadoya et al., 2016, Nature Medicine). Their subsequent work has explored the mechanisms underlying regeneration (see Paplowski et al., 2020, Nature; Rosensweig et al., 2018) and investigated how pharmacological agents can induce a regenerative phenotype in injured axons (see Van Niekerk et al., 2025, Nature). The group’s significant contributions to neural stem cell implantation and recovery have been minimally discussed—please expand this section to give readers a comprehensive perspective on recent seminal advances.

 

 

• Clinical trial data indicate that neural stem cell use alone may be insufficient to achieve clinically meaningful recovery. Please include this discussion (see Levi et al., 2019, Journal of Neurotrauma).

 

• Neuromodulation and TST focus on strengthening spared connections and encourage sprouting of new connections whereas Stem cell therapy seems to address the issue of neural regeneration across the gap? This nuance could be discussed.

 

• Stem cell survival is a huge issue in a lot of the implantation studies, often due to rejection by host, and excessive cytotoxicity in the lesion cite with poor environment that promote survival. Cytoskeleton remodeling a dn lack of growth factors also limits axon growth, CSPG degradation has been used by some studies to facilitate growth, please consider adding these into your discussion as well, discussing some of the translational challenges.

Author Response

Please see the attached report. We would like to thank the reviewer for his/her comment. On a personal basis, I, Ashraf S. Gorgey, benefited a lot for your comments. 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors, 

I read with great interest the paper "The Interplay between Neuromodulation and Stem Cell Therapy for Sensory-Motor Neuroplasticity after Spinal Cord Injury: A Perspective View." It is written in a clear, easy-to-read manner. It presents treatment perspectives for regaining lost sensory-motor functions in patients with spinal cord injuries, which are still not fully researched and effective. The authors clearly present what is already known and proven, and what still requires further scientific confirmation, such as stem cell therapy.  

My comments :

In the introduction it would be appropriate to mention other causes of non-traumatic SCI such as myelitis, spinal ischemia, etc. 

In the section 1.1. Neuroplasticity, the authors write, "External stimulation can be induced either chemically or electrically." Can the authors explain what chemical stimulation is? 

ConclusionIn my opinion, it should be emphasized that stem cell therapy is likely the future of treatment for patients with spinal cord injury. However, there is currently no hard data on its effectiveness in people with SCI. 

 

Author Response

Please see the attached report. We would like to thank the reviewer for his/her excellent feedback. 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have substantially improved the manuscript incorporating all feedback, however minor revision is required

Figure 1 highlighting the pictorial representation of FDA approved neuromodulation methods for sensorimotor recovery after SCI is incorrect. Motor cortex stimulation, Tran spinal magnetic stimulation etc. while they are neuromodulation methods actively explored, some of these are not FDA approved, even FDA approved vagal nerve stimulation for stroke recovery is approved for use only open loop. It's recommended that authors change the figure legend appropriately, either discuss only FDA approved technology and cite the phase 2 clinical trial outcome or change the legend 

Also Targeted spatiotemporal stimulation is also another form of epidural stimulation, it's misleading to represent them as an entirely separate stimulation modality

Author Response

Thank you. Please see the attached response,

Author Response File: Author Response.pdf