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Extracellular vesicles (EVs) are membrane-delimited particles secreted by nearly all cell types. EVs mediate critical physiological functions and pathophysiological processes in the central nervous system (CNS). As carriers of diverse bioactive cargo (e.g., proteins, lipids and nucleic acids) that can be modified in response to external stimuli, EVs have emerged as pathological mediators after neurotrauma, such as spinal cord injury (SCI). Here, we discuss the roles of endogenous EVs within the CNS as well as crosstalk with peripheral EVs in relation to neurotrauma, with particular focus on SCI. We then summarize the status of EV-based therapeutic advances in preclinical animal models for these conditions. Finally, we discuss new bioengineering strategies that are poised to enhance CNS-specific therapeutic capabilities of EVs.

Patients with spinal cord injury(SCI) are suffering disability and accompanying complications. Due to the complex biological processes and inhibitory microenvironment after SCI, advances in clinical treatment show obvious limitations for achieving a successful repair. Herein, we summarize recent advances in engineering strategies of using electrospun nanofibers to promote the neural regeneration and functional recovery after SCI. We firstly introduce the pathological mechanism of SCI and thus point out the challenges on the regeneration of the nerve. We then discuss the regenerative approaches by combining electrospun nanofibrous scaffolds with physical cues, biochemical cues(e.g., cells, growth factors and other biomolecules), external stimuli, and supporting materials filling in the inner lumen of the scaffolds. All these strategies have indicated their potentials to enhance the efficacy of repairing the SCI. At last, we provide a perspective on the future direction for designing the electrospun nanofibrous scaffolds in combination with imaging systems to realize the in-situ monitoring of regeneration progress for further improving the treatment outcome.

A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane (n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping (n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes-Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes-Weinstein monofilament examination. The ratio (percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differences in the results of routine blood tests, liver and renal function tests, coagulation function tests, or immunoglobulin tests at 14 and 180 days postoperatively between the two groups. These findings suggest that the novel nerve matrix membrane is similar in efficacy to the commercially-available bovine-derived collagen membrane in the repair of peripheral nerve injury, and it may therefore serve as an alternative in the clinical setting. The clinical trial was approved by the Institutional Ethics Committee of Beijing Jishuitan Hospital, China (approval No. 20160902) on October 8, 2016, the Institutional Ethics Committee of the First Bethune Hospital of Jilin University, China (approval No. 160518-088) on December 14, 2016, and the Institutional Ethics Committee of Yantai Yuhuangding Hospital, China (approval No. 2016-10-01) on December 9, 2016. The clinical trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000033324) on May 28, 2020.

Traumatic brain injury (TBI) is recognized as the disease with high morbidity and disability around world in spite of the work ongoing in neural protection. Due to heterogeneity among the patients, it's still hard to acquire satisfying achievements in clinic. Neuroinflammation, which exists since primary injury occurs, with elusive duality, appear to be of significance from recovery of injury to neurogenesis. In recent years, studied have revealed that communication in neurogenic niche is more than “cell to cell” communication, and study on NSCs represent it as central role in the progress of neural regeneration. Hence, the neuroinflammation-affecting crosstalk after TBI, and clarifying definitive role of NSCs in the course of regeneration is a promising subject for researchers, for its great potential in overcoming the frustrating status quo in clinic, promoting welfare of TBI patient.

Spinal cord injury (SCI) is a devastating health condition that may lead to permanent disabilities and death. Understanding the pathophysiological perspectives of traumatic SCI is essential to define mechanisms that can help in designing recovery strategies. Since central nervous system tissues are notorious for their deficient ability to heal, efforts have been made to identify solutions to aid in restoration of the spinal cord tissues and thus its function. The two main approaches proposed to address this issue are neuroprotection and neuro-regeneration. Neuroprotection involves administering drugs to restore the injured microenvironment to normal after SCI. As for the neuro-regeneration approach, it focuses on axonal sprouting for functional recovery of the injured neural tissues and damaged axons. Despite the progress made in the field, neural regeneration treatment after SCI is still unsatisfactory owing to the disorganized way of axonal growth and extension. Nanomedicine and tissue engineering are considered promising therapeutic approaches that enhance axonal growth and directionality through implanting or injecting of the biomaterial scaffolds. One of these recent approaches is nanofibrous scaffolds that are used to provide physical support to maintain directional axonal growth in the lesion site. Furthermore, these preferable tissue-engineered substrates can afford axonal regeneration by mimicking the extracellular matrix of the neural tissues in terms of biological, chemical, and architectural characteristics. In this review, we discuss the regenerative approach using nanofibrous scaffolds with a focus on their fabrication methods and their properties that define their functionality performed to heal the neural tissue efficiently.

Recently, tissue engineering has developed into a powerful tool for repairing and reconstructing damaged tissues and organs. Tissue engineering scaffolds play a vital role in tissue engineering, as they not only provide structural support for targeted cells but also serve as templates that guide tissue regeneration and control the tissue structure. Over the past few years, owing to unique physicochemical properties and excellent biocompatibility, various types of two-dimensional (2D) nanomaterials have been developed as candidates for the construction of tissue engineering scaffolds, enabling remarkable achievements in bone repair, wound healing, neural regeneration, and cardiac tissue engineering. These efforts have significantly advanced the development of tissue engineering. In this review, we summarize the latest advancements in the application of 2D nanomaterials in tissue engineering. First, each typical 2D nanomaterial is introduced briefly, followed by a detailed description of its applications in tissue engineering. Finally, the existing challenges and prospects for the future of the application of 2D nanomaterials in tissue engineering are discussed.

Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients’ quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine.

Objective: An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury, and that regulating autophagy can enhance recovery from spinal cord injury. However, the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear. Therefore, in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison, in an effort to provide a basis for further research. Data source: Relevant literature published from inception to February 1, 2018 were included by searching Wanfang, CNKI, Web of Science, MEDLINE (OvidSP), PubMed and Google Scholar in English and Chinese. The keywords included “autophagy”, “spinal cord injury”, and “rat”. Data selection: The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury (including intervention pre- and post-spinal cord injury). Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy, and subgroup analyses were also conducted. Outcome measure: Basso, Beattie, and Bresnahan scores. Results: Of the 622 studies, 33 studies of median quality were included in the analyses. Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 1.80, 95% CI: 0.81–2.79, P = 0.0004), 3 days (MD = 0.92, 95% CI: 0.72–1.13, P < 0.00001), 1 week (MD = 2.39, 95% CI: 1.85–2.92, P < 0.00001), 2 weeks (MD = 3.26, 95% CI: 2.40–4.13, P < 0.00001), 3 weeks (MD = 3.13, 95% CI: 2.51–3.75, P < 0.00001) and 4 weeks (MD = 3.18, 95% CI: 2.43–3.92, P < 0.00001) after spinal cord injury with upregulation of autophagy compared with the control group (drug solvent control, such as saline group). Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 6.48, 95% CI: 5.83–7.13, P < 0.00001), 2 weeks (MD = 2.43, 95% CI: 0.79–4.07, P = 0.004), 3 weeks (MD = 2.96, 95% CI: 0.09–5.84, P = 0.04) and 4 weeks (MD = 4.41, 95% CI: 1.08–7.75, P = 0.01) after spinal cord injury with downregulation of autophagy compared with the control group. Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso, Beattie, and Bresnahan scores at 1 day (MD = −4.68, 95% CI: –5.840 to −3.496, P = 0.94644), 3 days (MD = −0.28, 95% CI: −2.231–1.671, P = 0.99448), 1 week (MD = 1.83, 95% CI: 0.0076–3.584, P = 0.94588), 2 weeks (MD = 0.81, 95% CI: −0.850–2.470, P = 0.93055), 3 weeks (MD = 0.17, 95% CI: −2.771–3.111, P = 0.99546) or 4 weeks (MD = –1.23, 95% CI: −4.647–2.187, P = 0.98264) compared with the control group. Conclusion: Regulation of autophagy improves neurological function, whether it is upregulated or downregulated. There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury. The variability in results among the studies may be associated with differences in research methods, the lack of clearly defined autophagy characteristics after spinal cord injury, and the limited autophagy monitoring techniques. Thus, methods should be standardized, and the dynamic regulation of autophagy should be examined in future studies.

Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the role of adrenomedullin in neuropathological disorders, including pathological pain, brain injury and nerve regeneration, and their treatment. As a newly characterized pronociceptive mediator, adrenomedullin has been shown to act as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. Initiation of glia-neuron signaling networks in the peripheral and central nervous system by adrenomedullin is involved in the formation and maintenance of morphine tolerance. Adrenomedullin has been shown to exert a facilitated or neuroprotective effect against brain injury including hemorrhagic or ischemic stroke and traumatic brain injury. Additionally, adrenomedullin can serve as a regulator to promote nerve regeneration in pathological conditions. Therefore, adrenomedullin is an important participant in nervous system diseases.

Many studies have shown that bio-scaffolds have important value for promoting axonal regeneration of injured spinal cord. Indeed, cell transplantation and bio-scaffold implantation are considered to be effective methods for neural regeneration. This study was designed to fabricate a type of three-dimensional collagen/silk fibroin scaffold (3D-CF) with cavities that simulate the anatomy of normal spinal cord. This scaffold allows cell growth in vitro and in vivo. To observe the effects of combined transplantation of neural stem cells (NSCs) and 3D-CF on the repair of spinal cord injury. Forty Sprague-Dawley rats were divided into four groups: sham (only laminectomy was performed), spinal cord injury (transection injury of T10 spinal cord without any transplantation), 3D-CF (3D scaffold was transplanted into the local injured cavity), and 3D-CF + NSCs (3D scaffold co-cultured with NSCs was transplanted into the local injured cavity. Neuroelectrophysiology, imaging, hematoxylin-eosin staining, argentaffin staining, immunofluorescence staining, and western blot assay were performed. Apart from the sham group, neurological scores were significantly higher in the 3D-CF + NSCs group compared with other groups. Moreover, latency of the 3D-CF + NSCs group was significantly reduced, while the amplitude was significantly increased in motor evoked potential tests. The results of magnetic resonance imaging and diffusion tensor imaging showed that both spinal cord continuity and the filling of injury cavity were the best in the 3D-CF + NSCs group. Moreover, regenerative axons were abundant and glial scarring was reduced in the 3D-CF + NSCs group compared with other groups. These results confirm that implantation of 3D-CF combined with NSCs can promote the repair of injured spinal cord. This study was approved by the Institutional Animal Care and Use Committee of People's Armed Police Force Medical Center in 2017 (approval No. 2017-0007.2).

Objectives: The optimal surgical approach to treat recurrent laryngeal nerve (RLN) infiltration by differentiated thyroid cancer (DTC) remains a subject of debate. This study explored the feasibility and efficiency of immediate ansa cervicalis nerve (ACN)-to-RLN anastomosis for the management of RLN infiltration by DTC. Material and Methods: Fifty-three patients who underwent immediate ACN-to-RLN anastomosis during DTC extirpation were enrolled in the present study. Thirty-seven cases presented with unilateral vocal cord paralysis before the operation (Group A), and another 16 patients presented with normal vocal cord mobility preoperatively (Group B). Multidimensional assessments, videostroboscopy, voice assessment, and laryngeal electromyography (LEMG) were performed preoperatively and postoperatively. Results: All videostroboscopy, voice assessment and LEMG parameters in Group A deteriorated 1 month after the operation and improved 1 year after the operation compared with preoperative data. In Group B, all parameters 1 year after the operation improved significantly compared with the corresponding parameters 1 month after the operation. LEMG in Group A and B provided substantial evidence for the maturation of neural regeneration from ACN and demonstrated that the laryngeal muscles were reinnervated successfully by this procedure. Conclusions: If the RLN is infiltrated by DTC, immediate ACN-to-RLN anastomosis during complete excision of DTC could restore satisfactory phonatory function and does not compromise oncological radicality.

Hypertension is a risk factor for a large number of vision-threatening eye disorders. In this study, we investigated for the first time the retinal neural structure of the hypertensive BPH/2J mouse (Schlager mouse) and compared it to its control counterpart, the normotensive BPN/3J strain. The BPH/2J mouse is a selectively inbred mouse strain that develops chronic hypertension due to elevated sympathetic nervous system activity. When compared to the BPN/3J strain, the hypertensive BPH/2J mice showed a complete loss of outer layers of the neural retina at 21 weeks of age, which was indicative of a severe vision-threatening disease potentially caused by hypertension. To elucidate whether the retinal neural phenotype in the BPH/2J strain was attributed to increased BP, we investigated the neural retina of both BPN/3J and BPH/2J mice at 4 weeks of age. Our preliminary results showed for the first time that the BPH/2J strain develops severe retinal neural damage at a young age. Our findings suggest that the retinal phenotype in the BPH/2J mouse is possibly due to elevated blood pressure and may be contributed by an early onset spontaneous mutation which is yet to be identified or a congenital defect occurring in this strain. Further characterization of the BPH/2J mouse strain is likely to i) elucidate gene defects underlying retinal disease; ii) understand mechanisms leading to neural retinal disease and iii) permit testing of molecules for translational research to interfere with the progression of retinal disease. The animal experiments were performed with the approval of the Royal Perth Hospital Animal Ethics Committee (R535/17-18) on June 1, 2017.

Objective: To judge the efficacies of neural stem cell (NSC) transplantation on functional recovery following contusion spinal cord injuries (SCIs). Data sources: Studies in which NSCs were transplanted into a clinically relevant, standardized rat model of contusion SCI were identified by searching the PubMed, Embase and Cochrane databases, and the extracted data were analyzed by Stata 14.0. Data selection: Inclusion criteria were that NSCs were used in in vivo animal studies to treat contusion SCIs and that behavioral assessment of locomotor functional recovery was performed using the Basso, Beattie, and Bresnahan lo-comotor rating scale. Exclusion criteria included a follow-up of less than 4 weeks and the lack of control groups. Outcome measures: The restoration of motor function was assessed by the Basso, Beattie, and Bresnahan locomotor rating scale. Results: We identified 1756 non-duplicated papers by searching the aforementioned electronic databases, and 30 full-text articles met the inclusion criteria. A total of 37 studies reported in the 30 articles were included in the meta-analysis. The meta-analysis results showed that transplanted NSCs could improve the motor function recovery of rats following contusion SCIs, to a moderate extent (pooled standardized mean difference (SMD) = 0.73; 95% confidence interval (CI): 0.47–1.00; P < 0.001). NSCs obtained from different donor species (rat: SMD = 0.74; 95% CI: 0.36–1.13; human: SMD = 0.78; 95% CI: 0.31–1.25), at different donor ages (fetal: SMD = 0.67; 95% CI: 0.43–0.92; adult: SMD = 0.86; 95% CI: 0.50–1.22) and from different origins (brain-derived: SMD = 0.59; 95% CI: 0.27–0.91; spinal cord-derived: SMD = 0.51; 95% CI: 0.22–0.79) had similar efficacies on improved functional recovery; however, adult induced pluripotent stem cell-derived NSCs showed no significant efficacies. Furthermore, the use of higher doses of transplanted NSCs or the administration of immunosuppressive agents did not promote better locomotor function recovery (SMD = 0.45; 95% CI: 0.21–0.70). However, shorter periods between the contusion induction and the NSC transplantation showed slightly higher efficacies (acute: SMD = 1.22; 95% CI: 0.81–1.63; subacute: SMD = 0.75; 95% CI: 0.42–1.09). For chronic injuries, NSC implantation did not significantly improve functional recovery (SMD = 0.25; 95% CI: –0.16 to 0.65). Conclusion: NSC transplantation alone appears to be a positive yet limited method for the treatment of contusion SCIs.

There is no effective treatment for hemiplegia after hypertensive intracerebral hemorrhage. Considering that the branches of L4 nerve roots in the lumbar plexus root control the movement of the lower extremity anterior and posterior muscles, we investigated a potential method of nerve repair using the L4 nerve roots. Rat models of hindlimb hemiplegia after a hypertensive intracerebral hemorrhage were established by injecting autogenous blood into the posterior limb of internal capsule. The L4 nerve root on the healthy side of model rats was transferred and then anastomosed with the L4 nerve root on the affected side to drive the extensor and flexor muscles of the hindlimbs. We investigated whether this method can restore the flexible movement of the hindlimbs of paralyzed rats after hypertensive intracerebral hemorrhage. In a beam-walking test and ladder rung walking task, model rats exhibited an initial high number of slips, but improved in accuracy on the paretic side over time. At 17 weeks after surgery, rats gained approximately 58.2% accuracy from baseline performance and performed ankle motions on the paretic side. At 9 weeks after surgery, a retrograde tracing test showed a large number of fluoro-gold-labeled motoneurons in the left anterior horn of the spinal cord that supports the L4-to-L4 nerve roots. In addition, histological and ultramicrostructural findings showed axon regeneration of motoneurons in the anterior horn of the spinal cord. Electromyography and paw print analysis showed that denervated hindlimb muscles regained reliable innervation and walking coordination improved. These findings suggest that the L4-to-L4 nerve root transfer method for the treatment of hindlimb hemiplegia after hypertensive intracerebral hemorrhage can improve the locomotion of hindlimb major joints, particularly of the distal ankle. Findings from study support that the L4-to-L4 nerve root transfer method can effectively repair the hindlimb hemiplegia after hypertensive intracerebral hemorrhage. All animal experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (No. IACUC-1906009) in June 2019.

Oscillating field stimulation (OFS) is a potential method for treating spinal cord injury. Although it has been used in spinal cord injury (SCI) therapy in basic and clinical studies, its underlying mechanism and the correlation between its duration and nerve injury repair remain poorly understood. In this study, we established rat models of spinal cord contusion at T10 and then administered 12 weeks of OFS. The results revealed that effectively promotes the recovery of motor function required continuous OFS for more than 6 weeks. The underlying mechanism may be related to the effects of OFS on promoting axon regeneration, inhibiting astrocyte proliferation, and improving the linear arrangement of astrocytes. This study was approved by the Animal Experiments and Experimental Animal Welfare Committee of Capital Medical University (supplemental approval No. AEEI-2021-204) on July 26, 2021.

Central nervous system injury, specifically traumatic brain and spinal cord injury, can have significant long lasting effects. There are no comprehensive treatments to combat the injury and sequalae of events that occurring following a central nervous system trauma. Herein we discuss the potential for the epothilone family of microtubule stabilizing agents to improve outcomes following experimentally induced trauma. These drugs, which are able to cross the blood-brain barrier, may hold great promise for the treatment of central nervous system trauma and the current literature presents the extensive range of beneficial effects these drugs may have following trauma in animal models. Importantly, the effect of the epothilones can vary and our most recent contributions to this field indicate that the efficacy of epothilones following traumatic brain injury is dependent upon the age of the animals. Therefore, we present a case for a greater emphasis to be placed upon age when using an intervention aimed at neural regeneration and highlight the importance of tailoring the therapeutic regime in the clinic to the age of the patient to promote improved patient outcomes.

Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.

Extracellular vesicles (EVs) present a great potential for the development of new treatments in the biomedical field. To be used as therapeutics, many different sources have been used for EVs obtention, while only a few studies have addressed the use of platelet-derived EVs (pEVs). In fact, pEVs have been shown to intervene in different healing responses, thus some studies have evaluated their regenerative capability in wound healing or hemorrhagic shock. Even more, pEVs have proven to induce cellular differentiation, enhancing musculoskeletal or neural regeneration. However, the obtention and characterization of pEVs is widely heterogeneous and differs from the recommendations of the International Society for Extracellular Vesicles. Therefore, in this review, we aim to present the main advances in the therapeutical use of pEVs in the regenerative medicine field while highlighting the isolation and characterization steps followed. The main goal of this review is to portray the studies performed in order to enhance the translation of the pEVs research into feasible therapeutical applications.

Spinal cord injury (SCI) destroys the sensorimotor pathway and blocks the information flow between the peripheral nerve and the brain, resulting in autonomic function loss. Numerous studies have explored the effects of obstructed information flow on brain structure and function and proved the extensive plasticity of the brain after SCI. Great progress has also been achieved in therapeutic strategies for SCI to restore the “re-innervation” of the cerebral cortex to the limbs to some extent. Although no thorough research has been conducted, the changes of brain structure and function caused by “re-domination” have been reported. This article is a review of the recent research progress on local structure, functional changes, and circuit reorganization of the cerebral cortex after SCI. Alterations of structure and electrical activity characteristics of brain neurons, features of brain functional reorganization, and regulation of brain functions by reconfigured information flow were also explored. The integration of brain function is the basis for the human body to exercise complex/fine movements and is intricately and widely regulated by information flow. Hence, its changes after SCI and treatments should be considered.

Direct coaptation of contralateral C7 to the upper trunk could avoid the interposition of nerve grafts. We have successfully shortened the gap and graft lengths, and even achieved direct coaptation. However, direct repair can only be performed in some selected cases, and partial procedures still require autografts, which are the gold standard for repairing neurologic defects. As symptoms often occur after autografting, human acellular nerve allografts have been used to avoid concomitant symptoms. This study investigated the quality of shoulder abduction and elbow flexion following direct repair and acellular allografting to evaluate issues requiring attention for brachial plexus injury repair. Fifty-one brachial plexus injury patients in the surgical database were eligible for this retrospective study. Patients were divided into two groups according to different surgical methods. Direct repair was performed in 27 patients, while acellular nerve allografts were used to bridge the gap between the contralateral C7 nerve root and upper trunk in 24 patients. The length of the harvested contralateral C7 nerve root was measured intraoperatively. Deltoid and biceps muscle strength, and degrees of shoulder abduction and elbow flexion were examined according to the British Medical Research Council scoring system; meaningful recovery was defined as M3-M5. Lengths of anterior and posterior divisions of the contralateral C7 in the direct repair group were 7.64 ± 0.69 mm and 7.55 ± 0.69 mm, respectively, and in the acellular nerve allografts group were 6.46 ± 0.58 mm and 6.43 ± 0.59 mm, respectively. After a minimum of 4-year follow-up, meaningful recoveries of deltoid and biceps muscles in the direct repair group were 88.89% and 85.19%, respectively, while they were 70.83% and 66.67% in the acellular nerve allografts group. Time to C5/C6 reinnervation was shorter in the direct repair group compared with the acellular nerve allografts group. Direct repair facilitated the restoration of shoulder abduction and elbow flexion. Thus, if direct coaptation is not possible, use of acellular nerve allografts is a suitable option. This study was approved by the Medical Ethical Committee of the First Affiliated Hospital of Sun Yat-sen University, China (Application ID: [2017] 290) on November 14, 2017.

Quantitative assessment of the recovery of nerve function, especially sensory and autonomic nerve function, remains a challenge in the field of nerve regeneration research. We previously found that neural control of vasomotor activity could be potentially harnessed to evaluate nerve function. In the present study, five different models of left sciatic nerve injury in rats were established: nerve crush injury, nerve transection/suturing, nerve defect/autografting, nerve defect/conduit repair, and nerve defect/non-regeneration. Laser Doppler perfusion imaging was used to analyze blood perfusion of the hind feet. The toe pinch test and walking track analysis were used to assess sensory and motor functions of the rat hind limb, respectively. Transmission electron microscopy was used to observe the density of unmyelinated axons in the injured sciatic nerve. Our results showed that axonotmesis-evoked vasodilatation in the foot 6 months after nerve injury/repair recovered to normal levels in the nerve crush injury group and partially in the other three repair groups; whereas the nerve defect/non-regeneration group exhibited no recovery in vasodilatation. Furthermore, the recovery index of axonotmesis-evoked vasodilatation was positively correlated with toe pinch reflex scores and the density of unmyelinated nerve fibers in the regenerated nerve. As C-fiber afferents are predominantly responsible for dilatation of the superficial vasculature in the glabrous skin in rats, the present findings indicate that axonotmesis-evoked vasodilatation can be used as a novel way to assess C-afferent function recovery after peripheral nerve injury. This study was approved by the Ethics Committee for Laboratory Animals of Nantong University of China (approval No. 20130410-006) on April 10, 2013.

Hearing loss is very common and economically burdensome. No accepted therapeutic modality for sensorineural hearing loss is yet available; most clinicians emphasize rehabilitation, placing hearing aids and cochlear implants. Photobiomodulation (PBM) employs light energy to enhance or modulate the activities of specific organs, and is a popular non-invasive therapy used to treat skin lesions and neurodegenerative disorders. Efforts to use PBM to improve hearing have been ongoing for several decades. Initial in vitro studies using cell lines and ex vivo culture techniques have now been supplanted by in vivo studies in animals; PBM protects the sensory epithelium and triggers neural regeneration. Many reports have used PBM to treat tinnitus. In this brief review, we introduce PBM applications in hearing research, helpful protocols, and relevant background literature.

Background/purpose: Far-infrared (FIR) therapy is a safe and noninvasive source for medical applications. Animal study has shown the effects of FIR in promoting nerve repair. However, the cellular mechanism is not well known. Nerve growth factor (NGF) treated neuron-like PC12 cells for neurite outgrowth have been widely employed as the in vitro model for neural regeneration. Methods: In this study, we tried to evaluate the potential of FIR in promoting neurite outgrowth and related mechanism by using NGF-treated neuron-like PC12 cells as a cellular model. We found that FIR could promote neurites outgrowth of neuron-like PC12 cells at earlier culture period. Results: The neurite outgrowth-enhancing effect of FIR irradiation was more obvious when lower NGF concentration (1 ng/ml and 10 ng/ml) was added into the medium. We also found that FIR had no thermal effects on culture medium. The effects of FIR in promoting neurite outgrowth were dose dependent, and higher power density of FIR provided more effects for improving neurite outgrowth. The mechanism of FIR in promoting neurite outgrowth was through AKT1 pathway. Conclusion: The effects of FIR irradiation on promoting neurite outgrowth and neural regeneration of NGF-treated neuron-like PC12 cells are dose dependent and through activation of AKT1 phosphorylation. This study provided important information for understanding the cellular mechanism of FIR in promoting neurite outgrowth and possible neural regeneration for further clinical applications. Keywords: Far-infrared, Neurite outgrowth, Neural regeneration, Neuron-like PC12 cells

Recently, we have reported that Oenanthe javanica extract (OJE) displays strong neuroprotective effect against ischemic damage after transient global cerebral ischemia. However, neuroprotective mechanisms of OJE have not been fully identified. Thus, this study investigated the neuroprotection of OJE in the hippocampal CA1 area and its anti-inflammatory activity in gerbils subjected to 5 minutes of transient global cerebral ischemia. We treated the animals by intragastrical injection of OJE (100 and 200 mg/kg) once daily for 1 week prior to transient global cerebral ischemia. Neuroprotection of OJE was observed by immunohistochemistry for neuronal nuclear antigen and histofluorescence staining for Fluoro-Jade B. Immunohistochemistry of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 was done for astrocytosis and microgliosis, respectively. To investigate the neuroprotective mechanisms of OJE, we performed immunohistochemistry of tumor necrosis factor-alpha and interleukin-2 for pro-inflammatory function and interleukin-4 and interleukin-13 for anti-inflammatory function. When we treated the animals by intragastrical administration of 200 mg/kg of OJE, hippocampal CA1 pyramidal neurons were protected from transient global cerebral ischemia and cerebral ischemia-induced gliosis was inhibited in the ischemic hippocampal CA1 area. We also found that interleukin-4 and -13 immunoreactivities were significantly increased in pyramidal neurons of the ischemic CA1 area after OJE pretreatment, and the increased immunoreactivities were sustained in the CA1 pyramidal neurons after transient global cerebral ischemia. However, OJE pretreatment did not increase interleukin-2 and tumor necrosis factor-alpha immunoreactivities in the CA1 pyramidal neurons. Our findings suggest that pretreatment with OJE can protect neurons and attenuate gliosis from transient global cerebral ischemia via increasing expressions of interleukin-4 and -13. The experimental plan of this study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) in Kangwon National University (approval No. KW-160802-1) on August 10, 2016.

For severe cubital tunnel syndrome, patients with absent sensory nerve action potential tend to have more severe nerve damage than those without. Thus, it is speculated that such patients generally have a poor prognosis. How absent sensory nerve action potential affects surgical outcomes remains uncertain owing to a scarcity of reports and conflicting results. This retrospective study recruited one hundred and fourteen cases (88 patients with absent sensory nerve action potential and 26 patients with present sensory nerve action potential) undergoing either subcutaneous transposition or in situ decompression. The minimum follow-up was set at 2 years. Primary outcome measures of overall hand function included their McGowan grade, modified Bishop score, and Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH) score. For patients with absent sensory nerve action potential, 71 cases (80.7%) achieved at least one McGowan grade improvement, 76 hands (86.4%) got good or excellent results according to the Bishop score, and the average DASH score improved 49.5 points preoperatively to 13.1 points postoperatively. When compared with the present sensory nerve action potential group, they showed higher postoperative McGowan grades and DASH scores, but there was no statistical difference between the modified Bishop scores of the two groups. Following in situ decompression or subcutaneous transposition, great improvement in hand function was achieved for severe cubital tunnel syndrome patients with absent sensory nerve action potential. The functional outcomes after surgery for severe cubital tunnel syndrome are worse in patients with absent sensory nerve action potential than those without. This study was approved by the Ethical Committee of Huashan Hospital, Fudan University, China (approval No. 2017142).

The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease. However, the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear. To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex, a model of Parkinson’s disease was established by injecting 8 µg 6-hydroxydopamine into the substantia nigra compacta of rats. After 1 or 3 weeks, 0.3 µg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain. At 3 or 5 weeks after the initial injury, neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically. The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining. Results demonstrated that after injury, the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats. Compared with normal medial prefrontal cortical neurons, at 3 and 5 weeks after substantia nigra compacta injury, the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge, with an increased discharge interval. The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge, but the discharge interval was only higher at 3 weeks. At 3 weeks after the combined lesions, the discharge frequency, discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex. These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex. The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal cortex neurons after substantia nigra compacta injury. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University, China (approval No. XJTULAC2017-067) on August 26, 2017.

Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A, RhoA, and Rho-associated kinase (ROCK) in the ischemic boundary zone. However, it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke. In addition, it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling. Here, a stroke model was established by middle cerebral artery occlusion and reperfusion. Seven days after stroke, the following treatments were initiated and continued for 3 weeks: forced limb use in constraint-induced movement therapy rats (constraint-induced movement therapy group), intraperitoneal infusion of fasudil (a ROCK inhibitor) in fasudil rats (fasudil group), or lateral ventricular injection of NEP1-40 (a specific antagonist of the Nogo-66 receptor) in NEP1-40 rats (NEP1-40 group). Immunohistochemistry and western blot assay results showed that, at 2 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone. However, at 4 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups, but there was no difference between these two groups. Compared with the ischemia/reperfusion group, modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion, especially in the constraint-induced movement therapy group. Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers (BrdU in combination with CD31 (platelet endothelial cell adhesion molecule), Nestin, doublecortin, NeuN, and glial fibrillary acidic protein) in the subventricular zone and ischemic boundary zone ipsilateral to the infarct. After 3 weeks of constraint-induced movement therapy, the number of regenerated nerve cells was noticeably increased, and was accompanied by an increased immune response of tight junctions (claudin-5), a pericyte marker (α-smooth muscle actin), and vascular endothelial growth factor receptor 2. Taken together, the results demonstrate that, compared with fasudil, constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion. In addition, constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40. Therefore, constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury, at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, China on December 9, 2015 (approval No. 2015PS326K).

While animal models of controlled cortical impact often display short-term motor dysfunction after injury, histological examinations do not show severe cortical damage. Thus, this model requires further improvement. Mice were subjected to injury at three severities using a Pin-Point™-controlled cortical impact device to establish secondary brain injury mouse models. Twenty-four hours after injury, hematoxylin-eosin staining, Fluoro-Jade B histofluorescence, and immunohistochemistry were performed for brain slices. Compared to the uninjured side, we observed differences of histopathological findings, neuronal degeneration, and glial cell number in the CA2 and CA3 regions of the hippocampus on the injured side. The Morris water maze task and beam-walking test verified long-term (14–28 days) spatial learning/memory and motor balance. To conclude, the histopathological responses were positively correlated with the degree of damage, as were the long-term behavioral manifestations after controlled cortical impact. All animal procedures were approved by the Institutional Animal Care and Use Committee at Shanghai Jiao Tong University School of Medicine.

Some studies have suggested that early surgical treatment can effectively improve the prognosis of cervical spinal cord injury without radiological abnormality, but no research has focused on the development of a prognostic model of cervical spinal cord injury without radiological abnormality. This retrospective analysis included 43 patients with cervical spinal cord injury without radiological abnormality. Seven potential factors were assessed: age, sex, external force strength causing damage, duration of disease, degree of cervical spinal stenosis, Japanese Orthopaedic Association score, and physiological cervical curvature. A model was established using multiple binary logistic regression analysis. The model was evaluated by concordant profiling and the area under the receiver operating characteristic curve. Bootstrapping was used for internal validation. The prognostic model was as follows: logit(P) = -25.4545 + 21.2576VALUE + 1.2160SCORE - 3.4224TIME, where VALUE refers to the Pavlov ratio indicating the extent of cervical spinal stenosis, SCORE refers to the Japanese Orthopaedic Association score (0-17) after the operation, and TIME refers to the disease duration (from injury to operation). The area under the receiver operating characteristic curve for all patients was 0.8941 (95% confidence interval, 0.7930-0.9952). Three factors assessed in the predictive model were associated with patient outcomes: a great extent of cervical stenosis, a poor preoperative neurological status, and a long disease duration. These three factors could worsen patient outcomes. Moreover, the disease prognosis was considered good when logit(P) ≥ -2.5105. Overall, the model displayed a certain clinical value. This study was approved by the Biomedical Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University, China (approval number: 2018063) on May 8, 2018.

Hyperglycemia reduces the number of circulating endothelial progenitor cells, accelerates their senescence and impairs their function. However, the relationship between blood glucose levels and endothelial progenitor cells in peripheral blood of patients with traumatic brain injury is unclear. In this study, 101 traumatic brain injury patients admitted to the Department of Neurosurgery, Tianjin Medical University General Hospital or the Department of Neurosurgery, Tianjin Huanhu Hospital, China, were enrolled from April 2005 to March 2007. The number of circulating endothelial progenitor cells and blood glucose levels were measured at 1, 4, 7, 14 and 21 days after traumatic brain injury by flow cytometry and automatic biochemical analysis, respectively. The number of circulating endothelial progenitor cells and blood sugar levels in 37 healthy control subjects were also examined. Compared with controls, the number of circulating endothelial progenitor cells in traumatic brain injury patients was decreased at 1 day after injury, and then increased at 4 days after injury, and reached a peak at 7 days after injury. Compared with controls, blood glucose levels in traumatic brain injury patients peaked at 1 day and then decreased until 7 days and then remained stable. At 1, 4, and 7 days after injury, the number of circulating endothelial progenitor cells was negatively correlated with blood sugar levels (r = -0.147, P < 0.05). Our results verify that hyperglycemia in patients with traumatic brain injury is associated with decreased numbers of circulating endothelial progenitor cells. This study was approved by the Ethical Committee of Tianjin Medical University General Hospital, China (approval No. 200501) in January 2015.

The intermingling of regenerated nerve fibers inside nerve grafts is the main reason for mismatched nerve fibers. This is one of the key factors affecting limb function recovery after nerve injury. Previous research has shown that the accuracy of axon regeneration can be improved by a bionic structural implant. To this aim, iodine and freeze-drying high-resolution micro-computed tomography was performed to visualize the 3D topography of the New Zealand rabbit sciatic nerve (25 mm). A series of 1-, 2-, 3-, and 4-custom anatomy-based nerve conduits (CANCs) were fabricated based on the anatomical structure of the nerve fascicle. The match index, luminal surface, and mechanical properties of CANCs were evaluated before implanting in a 10-mm gap of the sciatic nerve. Recovery was evaluated by histomorphometric analyses, electrophysiological study, gastrocnemius muscle weight recovery ratio, and behavioral assessments at 12 and 24 weeks postoperatively. The accuracy of nerve regeneration was determined by changes in fluorescence-labeled profile number during simultaneous retrograde tracing. Our results showed that the optimal preprocessing condition for high-resolution micro-computed tomography visualization was treatment of the sciatic nerve with 40% Lugol's solution for 3 days followed by lyophilization for 2 days. In vitro experiments demonstrated that the match index was highest in the 3-CANC group, followed by the 2-, 1-, and 4-CANC groups. The luminal surface was lowest in the 1-CANC group. Mechanical properties (transverse compressive and bending properties) were higher in the 3- and 4-CANC groups than in the 1-CANC group. In vivo experiments demonstrated that the recovery (morphology of regenerated fibers, compound muscle action potential, gastrocnemius muscle weight recovery ratio, pain-related autotomy behaviors, and range of motion) in the 3-CANC group was superior to the other CANC groups, and achieved the same therapeutic effect as the autograft. The simultaneous retrograde tracing results showed that the percentages of double-labeled profiles of the 2-, 3-, and 4-CANC groups were comparatively lower than that of the 1-CANC group, which indicates that regenerated nerve fascicles were less intermingled in the 2-, 3-, and 4-CANC groups. These findings demonstrate that the visualization of the rabbit sciatic nerve can be achieved by iodine and freeze-drying high-resolution micro-computed tomography, and that this method can be used to design CANCs with different channels that are based on the anatomical structure of the nerve. Compared with the 1-CANC, 3-CANC had a higher match index and luminal surface, and improved the accuracy of nerve regeneration by limiting the intermingling of the regenerated fascicles. All procedures were approved by the Animal Care and Use Committee, Xinjiang Medical University, China on April 4, 2017 (ethics approval No. IACUC20170315-02).

Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cerebral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 term-born infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children's Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children's Hospital (approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016409) and the protocol version is 1.0.

The G-protein-coupled purinergic receptor P2Y2 (P2RY2) plays an important role in the mechanism of atherosclerosis, which is relevant to ischemic stroke. This retrospective case-control study aimed to assess the relationship between P2RY2 gene polymorphisms and ischemic stroke risk in the northern Han Chinese population. In this study, clinical data and peripheral blood specimens were collected from 378 ischemic stroke patients and 344 controls. The ischemic stroke participants were recruited from the First Affiliated Hospital of China Medical University and the First Affiliated Hospital of Liaoning Medical University. The controls were recruited from the Health Check Center at the First Affiliated Hospital of China Medical University. Ischemic stroke patients were divided into two subgroups according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification: large-artery atherosclerosis (n = 178) and small-artery occlusion (n = 200) strokes. All subjects were genotyped for three single nucleotide polymorphisms (rs4944831, rs1783596, and rs4944832) in the P2RY2 gene using peripheral venous blood samples. The distribution of the dominant rs4944832 phenotype (GG vs. GA+AA) differed significantly between small-artery occlusion patients and control subjects (odds ratio (OR) = 1.720, 95% confidence interval (CI): 1.203–2.458, P < 0.01). Multivariable logistic regression analysis revealed that the GG genotype of rs4944832 was significantly more prevalent in small-artery occlusion patients than in control subjects (OR = 1.807, 95% CI: 1.215–2.687, P < 0.01). The overall distribution of the haplotype established by rs4944831-rs1783596-rs4944832 was significantly different between ischemic stroke patients and controls (P < 0.01). In ischemic stroke patients, the frequency of the G-C-G haplotype was significantly higher than in control subjects (P = 0.028), whereas the frequency of the T-C-A haplotype was lower than in control subjects (P = 0.047). These results indicate that the G-C-G haplotype of P2RY2 is a susceptibility haplotype for ischemic stroke. In addition, the GG genotype of rs4944832 may be associated with the development of small-artery occlusion in the northern Han Chinese population. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of China Medical University on February 20, 2012 (No. 2012-38-1) and the First Affiliated Hospital of Liaoning Medical University, China, on March 1, 2013 (No. 2013-03-1). All participants gave their informed consent. This trial was registered with the ISRCTN Registry (ISRCTN11439124) on October 24, 2018. Protocol version (1.0).

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer’s disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aβ). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.

Constraint-induced movement therapy is an effective rehabilitative training technique used to improve the restoration of impaired upper extremity movement after stroke. However, whether constraint-induced movement therapy is more effective than conventional rehabilitation in acute or sub-acute stroke remains controversial. The aim of the present study was to identify the optimal time to start constraint-induced movement therapy after ischemic stroke and to explore the mechanisms by which constraint-induced movement therapy leads to post-stroke recovery. Sixty-four adult male Sprague-Dawley rats were randomly divided into four groups: sham-surgery group, cerebral ischemia/reperfusion group, early constraint-induced movement therapy group, and late constraint-induced movement therapy group. Rat models of left middle cerebral artery occlusion were established according to the Zea Longa line embolism method. Constraint-induced movement therapy was conducted starting on day 1 or day 14 in the early constraint-induced movement therapy and late constraint-induced movement therapy groups, respectively. To explore the effect of each intervention time on neuromotor function, behavioral function was assessed using a balance beam walking test before surgery and at 8 and 21 days after surgery. The expression levels of brain-derived neurotrophic factor, nerve growth factor and Nogo receptor were evaluated using real time-polymerase chain reaction and western blot assay to assess the effect of each intervention time. The results showed that the behavioral score was significantly lower in the early constraint-induced movement therapy group than in the cerebral ischemia/reperfusion and late constraint-induced movement therapy groups at 8 days. At 21 days, the scores had significantly decreased in the early constraint-induced movement therapy and late constraint-induced movement therapy groups. At 8 days, only mild pyknosis appeared in neurons of the ischemic penumbra in the early constraint-induced movement therapy group, which was distinctly better than in the cerebral ischemia/reperfusion group. At 21 days, only a few vacuolated cells were observed and no obvious inflammatory cells were visible in late constraint-induced movement therapy group, which was much better than at 8 days. The mRNA and protein expression levels of brain-derived neurotrophic factor and nerve growth factor were significantly higher, but expression levels of Nogo receptor were significantly lower in the early constraint-induced movement therapy group compared with the cerebral ischemia/reperfusion and late constraint-induced movement therapy groups at 8 days. The changes in expression levels at 21 days were larger but similar in both the early constraint-induced movement therapy and late constraint-induced movement therapy groups. Besides, the protein nerve growth factor level was higher in the late constraint-induced movement therapy group than in the early constraint-induced movement therapy group at 21 days. These results suggest that both early (1 day) and late (14 days) constraint-induced movement therapy induces molecular plasticity and facilitates functional recovery after ischemic stroke, as illustrated by the histology. The mechanism may be associated with downregulation of Nogo receptor expression and upregulation of brain-derived neurotrophic factor and nerve growth factor expression.

Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is related to anti-oxidative stress is not clear. To reveal its mechanism, we established the optic nerve transection injury model by transecting 1 mm behind the left eyeball of adult male Sprague-Dawley rats. The rats received an intraperitoneal injection of etomidate (4 mg/kg) once per day for 7 days. The results showed that etomidate significantly enhanced the number of retinal ganglion cells retrogradely labeled with Fluorogold at 7 days after optic nerve transection. Etomidate also significantly reduced the levels of nitric oxide and malonaldehyde in the retina and increased the level of glutathione at 12 hours after optic nerve transection. Thus, etomidate can protect retinal ganglion cells after optic nerve transection in adult rats by activating an anti-oxidative stress response. The study was approved by the Animal Ethics Committee at Air Force Medical University, China (approval No. 20180305) on March 5, 2018.

Suture and autologous nerve transplantation are the primary therapeutic measures for completely severed nerves. However, imbalances in the microenvironment and adhesion of surrounding tissues can affect the quality of nerve regeneration and repair. Previous studies have shown that human amniotic membrane can promote the healing of a variety of tissues. In this study, the right common peroneal nerve underwent a 5-mm transection in rats. Epineural nerve repair was performed using 10/0 non-absorbable surgical suture. The repair site was wrapped with a two-layer amniotic membrane with α-cyanoacrylate rapid medical adhesive after suture. Hindlimb motor function was assessed using footprint analysis. Conduction velocity of the common peroneal nerve was calculated by neural electrical stimulation. The retrograde axoplasmic transport of the common peroneal nerve was observed using fast blue BB salt retrograde fluorescent staining. Hematoxylin-eosin staining was used to detect the pathological changes of the common peroneal nerve sputum. The mRNA expression of axon regeneration-related neurotrophic factors and inhibitors was measured using real-time polymerase chain reaction. The results showed that the amniotic membrane significantly improved the function of the injured nerve; the toe spread function rapidly recovered, the nerve conduction velocity was restored, and the number of fast blue BB salt particles were increased in the spinal cord. The amniotic membrane also increased the recovery rate of the tibialis anterior muscle and improved the tissue structure of the muscle. Meanwhile, mRNA expression of nerve growth factor, growth associated protein-43, collapsin response mediator protein-2, and brain-derived neurotrophic factor recovered to near-normal levels, while Lingo-1 mRNA expression decreased significantly in spinal cord tissues. mRNA expression of glial-derived neurotrophic factor did not change significantly. Changes in mRNA levels were more significant in amniotic-membrane-wrapping-treated rats compared with model and nerve sutured rats. These results demonstrate that fresh amniotic membrane wrapping can promote the functional recovery of sutured common peroneal nerve via regulation of expression levels of neurotrophic factors and inhibitors associated with axonal regeneration. The study was approved by the Committee on Animal Research and Ethics at the Affiliate Hospital of Zunyi Medical University, China (approval No. 112) on December 1, 2017.

During peripheral nerve transposition repair, if the diameter difference between transposed nerves is large or multiple distal nerves must be repaired at the same time, traditional epineurial neurorrhaphy has the problem of high tension at the suture site, which may even lead to the failure of nerve suture. We investigated whether a small gap bio-sleeve suture with different inner diameters at both ends can be used to repair a 2-mm tibial nerve defect by proximal transposition of the common peroneal nerve in rats and compared the results with the repair seen after epineurial neurorrhaphy. Three months after surgery, neurological function, nerve regeneration, and recovery of nerve innervation muscle were assessed using the tibial nerve function index, neuroelectrophysiological testing, muscle biomechanics and wet weight measurement, osmic acid staining, and hematoxylin-eosin staining. There was no obvious inflammatory reaction and neuroma formation in the tibial nerve after repair by the small gap bio-sleeve suture with different inner diameters at both ends. The conduction velocity, muscle strength, wet muscle weight, cross-sectional area of muscle fibers, and the number of new myelinated nerve fibers in the bio-sleeve suture group were similar to those in the epineurial neurorrhaphy group. Our findings indicate that small gap bio-sleeve suture with different inner diameters at both ends can achieve surgical suture between nerves of different diameters and promote regeneration and functional recovery of injured peripheral nerves.

The neuroprotective function of macrophage migration inhibitory factor (MIF) in ischemic stroke was rarely evaluated. This study aimed to investigate the effects of early treadmill exercise on recovery from ischemic stroke and to determine whether these effects are associated with the expression levels of MIF and brain-derived neurotrophic factor (BDNF) in the ischemic area. A total of 40 male Sprague-Dawley rats were randomly assigned to the ischemia and exercise group [middle cerebral artery occlusion (MCAO)-Ex, n = 10), ischemia and sedentary group (MCAO-St, n = 10), sham-surgery and exercise group (Sham-Ex, n = 10), or sham-surgery and sedentary group (Sham-St, n = 10). The MCAO-Ex and MCAO-St groups were subjected to MCAO for 60 minutes, whereas the Sham-Ex and Sham-St groups were subjected to an identical operation without MCAO. Rats in the MCAO-Ex and Sham-Ex groups then ran on a treadmill for 30 minutes once a day for 5 consecutive days. After reperfusion, the hanging time tested by the wire hang test was longer and the relative fractional anisotropy determined by MRI was higher in the peri-infarct region of the MCAO-Ex group compared with the MCAO-St group. The expression levels of MIF and BDNF in the peri-infarct region were upregulated in the MCAO-Ex group. Increased MIF and BDNF levels were positively correlated with relative fractional anisotropy changes in the peri-infarct region. There was no significant difference in the levels of MIF and BDNF in the peri-infarct region between the Sham-Ex and Sham-St groups. Our study demonstrated that early exercise (initiated 48 hours after the MCAO) could improve motor and neuronal recovery after ischemic stroke. Furthermore, the increased levels of MIF and BDNF in the peri-infarct region (penumbra) may be one of the mechanisms of enhanced neurological function recovery. All experiments were approved by the Institutional Animal Care and Use Committee in Asan Medical Center in South Korea (2016-12-126).

Objective: To assess whether dietary fat intake influences Parkinson’s disease risk. Data Sources: We systematically surveyed the Embase and PubMed databases, reviewing manuscripts published prior to October 2018. The following terms were used: (“Paralysis agitans” OR “Parkinson disease” OR “Parkinson” OR “Parkinson’s” OR “Parkinson’s disease”) AND (“fat” OR “dietary fat” OR “dietary fat intake”). Data Selection: Included studies were those with both dietary fat intake and Parkinson’s disease risk as exposure factors. The Newcastle-Ottawa Scale was adapted to investigate the quality of included studies. Stata V12.0 software was used for statistical analysis. Outcome Measures: The primary outcomes included the relationship between high total energy intake, high total fat intake, and Parkinson’s disease risk. The secondary outcomes included the relationship between different kinds of fatty acids and Parkinson’s disease risk. Results: Nine articles met the inclusion criteria and were incorporated into this meta-analysis. Four studies scored 7 and the other five studies scored 9 on the Newcastle-Ottawa Scale, meaning that all studies were of high quality. Meta-analysis results showed that high total energy intake was associated with an increased risk of Parkinson’s disease (P = 0.000, odds ratio (OR) = 1.49, 95% confidence interval (CI): 1.26–1.75); in contrast, high total fat intake was not associated with Parkinson’s disease risk (P = 0.123, OR = 1.07, 95% CI: 0.91–1.25). Subgroup analysis revealed that polyunsaturated fatty acid intake (P = 0.010, OR = 1.03, 95% CI: 0.88–1.20) reduced the risk of Parkinson’s disease, while arachidonic acid (P = 0.026, OR = 1.15, 95% CI: 0.97–1.37) and cholesterol (P = 0.002, OR = 1.09, 95% CI: 0.92–1.29) both increased the risk of Parkinson’s disease. Subgroup analysis also demonstrated that, although the results were not significant, consumption of n-3 polyunsaturated fatty acids (P = 0.071, OR = 0.88, 95% CI: 0.73–1.05), α-linolenic acid (P = 0.06, OR = 0.86, 95% CI: 0.72–1.02), and the n-3 to n-6 ratio (P = 0.458, OR = 0.89, 95% CI: 0.75–1.06) were all linked with a trend toward reduced Parkinson’s disease risk. Monounsaturated fatty acid (P = 0.450, OR = 1.06, 95% CI: 0.91–1.23), n-6 polyunsaturated fatty acids (P = 0.100, OR = 1.15, 95% CI: 0.96–1.36) and linoleic acid (P = 0.053, OR = 1.11, 95% CI: 0.94–1.32) intakes were associated with a non-significant trend toward higher PD risk. Saturated fatty acid (P = 0.619, OR = 1.01, 95% CI: 0.87–1.18) intake was not associated with Parkinson’s disease. Conclusion: Dietary fat intake affects Parkinson’s disease risk, although this depends on the fatty acid subtype. Higher intake of polyunsaturated fatty acids may reduce the risk of Parkinson’s disease, while higher cholesterol and arachidonic acid intakes may elevate Parkinson’s disease risk. However, further studies and evidence are needed to validate any link between dietary fat intake and Parkinson’s disease.

Kai Xin San (KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups (which received physiological saline), the doses of KXS (0.7, 1.4 and 2.8 g/kg per day) and donepezil (3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following. (1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze. (2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze. (3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies. (4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus. (5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.

Combinations of biomaterials and cells can effectively target delivery of cells or other therapeutic factors to the brain to rebuild damaged nerve pathways after brain injury. Porous collagen-chitosan scaffolds were prepared by a freeze-drying method based on brain tissue engineering. The scaffolds were impregnated with rat bone marrow mesenchymal stem cells. A traumatic brain injury rat model was established using the 300 g weight free fall impact method. Bone marrow mesenchymal stem cells/collagen-chitosan scaffolds were implanted into the injured brain. Modified neurological severity scores were used to assess the recovery of neurological function. The Morris water maze was employed to determine spatial learning and memory abilities. Hematoxylin-eosin staining was performed to measure pathological changes in brain tissue. Immunohistochemistry was performed for vascular endothelial growth factor and for 5-bromo-2-deoxyuridine (BrdU)/neuron specific enolase and BrdU/glial fibrillary acidic protein. Our results demonstrated that the transplantation of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds to traumatic brain injury rats remarkably reduced modified neurological severity scores, shortened the average latency of the Morris water maze, increased the number of platform crossings, diminished the degeneration of damaged brain tissue, and increased the positive reaction of vascular endothelial growth factor in the transplantation and surrounding areas. At 14 days after transplantation, increased BrdU/glial fibrillary acidic protein expression and decreased BrdU/neuron specific enolase expression were observed in bone marrow mesenchymal stem cells in the injured area. The therapeutic effect of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds was superior to stereotactic injection of bone marrow mesenchymal stem cells alone. To test the biocompatibility and immunogenicity of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds, immunosuppressive cyclosporine was intravenously injected 12 hours before transplantation and 1–5 days after transplantation. The above indicators were similar to those of rats treated with bone marrow mesenchymal stem cells and collagen-chitosan scaffolds only. These findings indicate that transplantation of bone marrow mesenchymal stem cells in a collagen-chitosan scaffold can promote the recovery of neuropathological injury in rats with traumatic brain injury. This approach has the potential to be developed as a treatment for traumatic brain injury in humans. All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medical University, China (approval No. AEEI-2015-035) in December 2015.

Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regeneration of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some regenerative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness.

Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton’s jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients (16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton’s Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland (approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov (identifier: NCT02881476) on August 29, 2016.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.

Peripheral nerve injury is a common clinical problem and affects the quality of life of patients. Traditional restoration methods are not satisfactory. Researchers increasingly focus on the field of tissue engineering. The three key points in establishing a tissue engineering material are the biological scaffold material, the seed cells and various growth factors. Understanding the type of nerve injury, the construction of scaffold and the process of repair are necessary to solve peripheral nerve injury and promote its regeneration. This review describes the categories of peripheral nerve injury, fundamental research of peripheral nervous tissue engineering and clinical research on peripheral nerve scaffold material, and paves a way for related research and the use of conduits in clinical practice.

The specific mechanisms by which acupuncture affects the central nervous system are unclear. In the International Standard Scalp Acupuncture system, acupuncture needles are applied at the middle line of the vertex, anterior parietal-temporal oblique line, and the posterior parietal-temporal oblique line. We conducted a single-arm prospective clinical trial in which seven healthy elderly volunteers (three men and four women; 50-70 years old) received International Standard Scalp Acupuncture at MS5 (the mid-sagittal line between Baihui (DU20) and Qianding (DU21)), the left MS6 (line joining Sishencong (EX-HN1) and Xuanli (GB6)), and the left MS7 (line joining DU20 and Qubin (GB7)). After acupuncture, resting-state functional magnetic resonance imaging demonstrated changes in the fractional amplitude of low frequency fluctuations and regional homogeneity in various areas, showing remarkable enhancement of regional homogeneity in the bilateral anterior cingulate, left medial frontal gyrus, supramarginal gyrus, right middle frontal gyrus, and inferior frontal gyrus. Functional connectivity based on a seed region at the right middle frontal gyrus (42, 51, 9) decreased at the bilateral medial superior frontal gyrus. Our data preliminarily indicates that the international standard scalp acupuncture in healthy elderly participants specifcally enhances the correlation between the brain regions involved in cognition and implementation of the brain network regulation system and the surrounding adjacent brain regions. The study was approved by the Ethics Committee of the China-Japan Union Hospital at Jilin University, China, on July 18, 2016 (approval No. 2016ks043).

Glaucoma is a chronic, progressive optic neuropathy characterized by the loss of peripheral vision first and then central vision. Clinically, normal tension glaucoma is considered a special subtype of glaucoma, in which the patient’s intraocular pressure is within the normal range, but the patient experiences typical glaucomatous changes. However, increasing evidence has challenged the traditional pathophysiological view of normal tension glaucoma, which is based only on intraocular pressure, and breakthroughs in central nervous system imaging may now greatly increase our knowledge about the mechanisms underlying normal tension glaucoma. In this article, we review the latest progress in understanding the pathogenesis of normal tension glaucoma and in developing imaging techniques to detect it, to strengthen the appreciation for the connection between normal tension glaucoma and the brain.