Pain generator-based lumbar spinal decompression surgery is the backbone of modern spine care. In contrast to traditional image-based medical necessity criteria for spinal surgery, assessing the severity of neural element encroachment, instability, and deformity, staged management of common painful degenerative lumbar spine conditions is likely to be more durable and cost-effective. Targeting validated pain generators can be accomplished with simplified decompression procedures associated with lower perioperative complications and long-term revision rates. In this perspective article, the authors summarize the current concepts of successful management of spinal stenosis patients with modern transforaminal endoscopic and translaminar minimally invasive spinal surgery techniques. They represent the consensus statements of 14 international surgeon societies, who have worked in collaborative teams in an open peer-review model based on a systematic review of the existing literature and grading the strength of its clinical evidence. The authors found that personalized clinical care protocols for lumbar spinal stenosis rooted in validated pain generators can successfully treat most patients with sciatica-type back and leg pain including those who fail to meet traditional image-based medical necessity criteria for surgery since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte and cyst, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. The position of the key opinion authors of the perspective article is that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Limitations of this care model are dictated by appropriate patient selection and mastering the learning curve of modern MIS procedures. Decompensated deformity and instability will likely continue to be treated with open corrective surgery. Vertically integrated outpatient spine care programs are the most suitable setting for executing such pain generator-focused programs. Lumbar spinal stenosis (LSS) is defined as a narrowing of the lumbar spinal canal caused by age-related degeneration of the spinal motion segment. It causes encroachment of neural elements and may contribute to back and leg pain. It is a leading cause of disability from lack of mobility due to neurogenic claudication worldwide . Spinal Spondylolisthesis  and decoIn this review perspective article, the authors take a fresh, consensus look at the available evidence including their own professional expertise and experiences on using minimally invasive and endoscopic lumbar decompression techniques in a more targeted and personalized care model. 14 professional societies reviewed recent articles on the topic and through their related committees and subcommittees express their professional position. This perspective paper is coordinated by the Interamerican Society For Minimally Invasive Spine Surgery–La Sociedad Interamericana de Cirugía de Columna Mínimamente Invasiva (SICCMI) and the Spine Subcommittee of the Society For Brain Mapping & Therapeutics (SBMT), and endorsed by the International Society For Minimal Intervention In Spinal Surgery (ISMISS), the Korean Minimally Invasive Spine Society (KOMISS), the Minimally Invasive Surgery Section of the Chinese Orthopaedic Association (COA-MIS SECTION), The Colombian Spine Society, the Bolivian Spine Association, the Iberolatinoamerican Spine Society–La Sociedad Iberolatinoamericana de Columna (SILACO), the Mexican Association of Spinal Surgeons–Associacion Mexicana de Cirujanos de Columna (AMCICO), the Federation of Latinamerican Neurosurgical Societies–Federación Latino-Americana de Sociedades de Neurocirugía (FLANC), the Latin American Society of Neurosurgeons of USA & Canada (SLANC), the Brazilian Spine Society–Sociedade Brasiliiera de Columna (SBC), the Brazilian Society For Thoracic Surgery—Sociedade Brasileira de Cirurgia Torácica (SBCT), and the International Intradiscal Therapy Society (IITS).The annual incidence of adult spine disease is estimated at 266 million people globally . The higIn the 2010 Global Burden of Disease (GBD) Study ,23, LBP Most contemporary medical necessity criteria for spinal decompression are based on analyzing advanced imaging studies such as MRI or CT. Using these image-based criteria reserves decompression surgery only for patients with progressive disease ,38,39,40Whoever does not fit these medical necessity criteria is often committed to repetitive cycles of spinal injections, physical therapy, and non-steroidal anti-inflammatory treatments. Those who are so disabled that they cannot even participate in these programs in a meaningful way or have poorly controlled co-morbidities which preclude medical management often cannot get much help. An exemplary summary of traditional Review Clinical Guidelines For Spinal Stenosis affecting coverage decisions is shown in In this perspective paper, SICCMI, in collaboration with 12 other international surgeons’ societies, is confronting the increased scrutiny on the appropriateness of spine care spending by payers, government, and patients in an attempt to deliver on simplified, innovative, less costly, more effective, and more durable treatments for common degenerative and painful spine conditions associated with lower complication and revision rates. Resolution to these problems is needed to meet the increasing demand by the aging baby-boomer population for such simplified treatments.The treatment of the painful degenerative disease process of the spinal motion segment with traditional open spine surgery is dictated by the application of MRI and CT image criteria of spinal stenosis, instability, and deformity. The clinical decision-making for surgery focuses on treating the end-stage of the disease, leaving many patients without timely treatment or no treatment at all. With the backdrop of recent clinical studies describing the limited utility of the lumbar MRI scan and its reporting suffering from relatively low sensitivity and specificity to diagnose the painful spine condition , key opiTraditional open spine surgery in the lumbar spine includes laminectomy. A translaminar decompression is performed by removing the posterior spinal elements, including the spinous process, the lamina, and part of the bilateral facet joints. The benefit of lumbar decompression for symptomatic herniated disc and spinal stenosis has been demonstrated in several prospective randomized clinical trials, including the original study by Weber , the MaiMinimally invasive surgery (MIS) for the treatment of common degenerative conditions of the spine is increasingly practiced. It encompasses a portfolio of surgical techniques that are aimed to alleviate patients’ pain via reduced surgical access resulting in less blood loss and reduced peri- and postoperative problems including pain, nausea, and vomiting. The introduction of tubular retractors and microsurgical dissection techniques simplified the very nature of spine surgery by transforming it through the implementation of less burdensome and more simplified protocols. Over the last 40 years, open spine surgery has established a track record that is interpreted by most patients, employers, and payers as aggressive and too costly due to high out-of-work complications and reoperation rates.Quality of life and cost-effectiveness of minimally invasive surgery (MIS) for spinal stenosis in patients with degenerative lumbar spondylolisthesis (DLS) has been calculated relative to failed medical management and compared to the cost-effectiveness of hip and knee arthroplasty for matched cohorts of patients with osteoarthritis . IncremeSelect pain generators in the lumbar spine are not diagnosed on routine lumbar MRI scan . A recenCommon pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte, and many others examples, as shown in One example is highlighted by the INTRACEPT prospective, open-label, 1:1 randomized controlled trial. This trial tests the efficacy of basivertebral nerve (BVN) ablation technology compared to a standard care control treatment of vertebrogenic chronic low back pain . ConceptThe authors take the position that direct visualization and treatment of pain generators is the foundation for surgical pain management of the lumbar spine. Spinal endoscopy enables the surgeon to diagnose and treat the painful condition during the same operation ,66,67,68Objective measurements of the foraminal or lateral canal dimensions are rarely given. Surgical stenosis classifications use measurable parameters such as height and width of the posterior disc, lateral recess, or neuroforamen to stratify patients for the most appropriate MIS approach and technique . The lacTreating pain generators involves identifying those structural problems in the lumbar spine that cause the majority of the patient’s symptoms as implicated in the symptoms by history and physical examination or by advanced imaging studies such as MRI or CT scan. Most patients have unilateral or mono-segmental radiculopathy symptoms. When confirmed with diagnostic selective nerve root blocks, these clinical observations highlight that many structural changes in a degenerative spine are multilevel but may not be painful, even if the MRI or CT scan suggests a similar degree of stenosis as within the symptomatic spinal motion segment. For example, exiting and traversing nerve root pain syndromes may or may not exist within the same lumbar motion segment simultaneously. However, when they do, the surgeon can easily be confused with patients whose MRI suggests multilevel disease. Identifying the correct source level of axial facet joint pain in multilevel degeneration may even be more difficult without a radicular component. The staged management concept is the central element of the clinical spine care model. It implies treating validated symptomatic pain generators and ignoring all degenerative changes or injuries that do not hurt.While it is easier to rely on MRI-based criteria of compression, instability, and deformity when deducting a plan of surgical care—certainly within the mainstream of traditionally trained surgeons, and perhaps a coincidence between the radiologist’s confirmation of compressive pathology and the surgical plan of care invites less scrutiny during the health insurance preauthorization process for surgery—identifying the predominant pain generator can be a daunting task. Recommending a targeted surgical treatment plan to a patient in pain is as much of an art as it is a science and relies heavily on judgment and clinical experience. Less aggressive treatment recommendations are often sufficient to substantially reduce pain, all while ignoring traditional decompression and lumbar fusion criteria.What to treat and, more importantly, what to ignore requires attention to detail and utilization of preoperative diagnostic tools of high positive predictive value. For the endoscopic spine surgeon, the plan of care is derived from identifying those pain generators that impair the patient the most. Minimizing the risk-taking and maximizing the benefit, all while managing patients’ expectations about the desired outcome, are the key to achieving high patient satisfaction . The staA new subspecialty is emerging: “Surgical Pain Management.” The term implies a blend of diagnostic and patient management strategies employed by interventional pain physicians comprised of physiatrists, anesthesiologists, and spine surgeons consisting of orthopedic and neurosurgeons. This new emerging subspeciality is a grassroots development driven by enthusiast physicians who invested their careers into a more personalized approach to spine care. Thus, surgical pain management integrates needle-based non-visualized interventions into MIS and endoscopic surgical procedures by tailoring the treatment based on the individual patient’s symptoms and the functional context when the spine care is delivered. Examples of this development include the integration of radiofrequency and laser into endoscopic surgeries. The continued use of rule-based medical necessity criteria for lumbar spine care seems increasingly inappropriate. It invites the delivery of costly, ineffective therapies and treatments which ultimately do not lower the societal burden of spine care. Ignoring individual pain generators stemming from the underlying disease causing cumulative disability does not address the root cause and precludes the patient from definitive care or leads to patient entrapment in repetitive yet ineffective treatment cycles. In the opinion of the KOL authors of this lead perspective article in the JPM special issue “The Path To Personalized Pain Management,” the staged approach to surgical pain management is poised to lower disability and the direct and indirect costs with all of its hidden unintended consequences of repetitive treatments. Its implementation has the potential for diminishing the burden of failed medical pain management and opioid addiction, delayed returned to work, and disrupted social reintegration. While the authors do not suggest abandoning traditional open spine surgery, we propose integrating staged surgical pain management of directly visualized pain generators early in the disease process into existing spine care programs.The authors of this perspective paper arrived at the consensus statement on the indications for surgical treatment for symptomatic lumbar spinal stenosis based on validated pain generators rather than traditional image-based medical necessity criteria. This approach to treating patients with claudication and sciatica-type low back and leg symptoms represents the authors’ views and their respective surgeon societies. The most published individuals on this team of authors are accomplished and passionate endoscopic spinal surgeons. In experienced hands, approximately 80% of patients with painful degenerative spine conditions may be treated successfully with a targeted outpatient MIS or endoscopic decompression procedure ,82,83. WJudiciously and skillfully executed modern targeted MIS surgeries can provide more cost-effective and less burdensome spine care with shorter treatment cycles as the underlying structural correlate for the patient’s pain is treated causally. Lateral recess and foraminal stenosis are the most common clinically relevant indications for primary surgery and revision surgery after decompression in the lumbar spine. The personalized clinical protocols for treating lumbar spinal stenosis based on validated pain generators are a break with traditional population management protocols that employ image-based medical necessity criteria for intervention since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. It is the authors position, that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Clinical judgment of appropriate patient selection and mastering the learning curve of modern MIS procedures will likely lead to a broadening of the accepted indications for such a pain generator-based approach to patient care. Limitations of this care model are dictated by decompensated deformity and instability, for which open corrective surgery will likely continue to be the treatment of choice. Vertically integrated outpatient spine care programs are probably the most suitable setting for executing such a pain generator focused program since physicians who have complete custody of their patients can minimize protocol breaches by other providers who are not invested in the personalized care model proposed by the authors.


Epidemics in the Pacific Islands noted flu-like symptoms and complications following human ZIKV infection. However, after a severe outbreak in 2015, Latin American studies reported fetal birth defects with maternal infection but reports in other developing countries where outbreaks occurred were not fully characterized. This study aims to review current reports on birth outcomes associated with maternal ZIKV infection .Zika Virus became an emerging health threat in the early 21This narrative review evaluated birth outcomes of Zika positive pregnant women. Research articles were found using Google Scholar, PubMed, and MEDLINE. The inclusion criteria were publication between 2012 to 2022, availability as full text in English, categorization as original research, meta-analyses or case reports. Exclusion criteria were studies that were part of a book chapter or encyclopedia and studies that cited results from developed nations. The articles were studied and 20 methodologically sound studies were selected for review, and the data was classified in themes based on birth outcomes.18 studies reported that infants born to some laboratory-confirmed zika-positive mothers had abnormal birth outcomes after delivery including microcephaly, stillbirth, neurological abnormalities and hearing loss. Maternal ZIKV infection is associated with an increased risk of abnormal birth outcomes in newborns in developing countries. In the countries of studies that did not report abnormal outcomes there may have been a protective factor from previous maternal Dengue Virus (DENV) infection adding protection for their infants.Overall, there appears a difference in birth outcomes of infants born to mothers infected with ZIKV, however more research is needed on environmental factors and prior arboviral infection as additional factors contributing to these outcomes.All Authors: No reported disclosures


Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI. Spinal cord injury (SCI) leads to long-term dysfunction and lifelong disability. There are hundreds of thousands of new patients suffering an SCI each year worldwide, and ninety percent of these SCIs are caused by traumatic events, including traffic accidents, falling, sports injuries, violence, etc. . SCI intThe pathophysiology of SCI involves primary injury and secondary injury. The primary injury is caused by acute mechanical trauma and results in vascular disruption, blood–spinal cord barrier rupture, cell death , and interruption of neural fiber tracts in the spinal cord. The secondary injury references the consecutive pathological events triggered by the primary injury, such as hemorrhage, excitotoxicity, neuroinflammation, demyelination, astrogliosis and extracellular matrix (ECM) remodeling, which aggravate tissue damage, and compromise neuroplasticity . The curIn this review, we provide an overview of recent advances and challenges in SCI research and treatment. We summarize the recent progress regarding interventions after SCI in preclinical rodent and non-human primate models as well as in the clinical settings. We then discuss the current status and challenges with respect to clinical translation, prospect the future of SCI repair, and we highlight combinatory approaches and multidisciplinary cooperation are imperative to optimize clinical outcomes after SCI. This review provides an update of current strategies following SCI and provide researchers with new insights to develop more effective and targeted interventions to facilitate clinically meaningful recovery after SCI.The originally narrow concept of regeneration referred to the regrowth of transected axons across the lesion core to form functional synapses with their original pre-injury targets after SCI. The broad definition of regeneration now encompasses multiple forms of axon growth, including long-distance axon regrowth, compensatory sprouting of injured and spared supraspinal axons as well as propriospinal neurons, synapse remodeling, and circuit reorganization  Fig. 1)Fig. 1). Axon outgrowth is driven by the growth cone, a motile structure located at the tip of the growing axon. Growth cone motility and axon growth are determined by the neuronal cytoskeleton, which includes microtubule and actin filament (F-actin) . MicrotuCytoskeletal dynamics and rearrangements are mainly modulated by two intracellular signaling pathways: glycogen synthase kinase 3β (GSK3β) and Rho GTPases. GSK3β is downstream of PI3K signaling and is inactivated through serine-9 phosphorylation within its amino-terminal region upon activation of the PI3K pathway. GSK3β has been shown to be a crucial negative regulator of microtubule dynamics by phosphorylating multiple microtubule binding proteins (MBPs), such as collapsin response mediator protein 2 (CRMP-2), adenomatous polyposis coli (APC), and microtubule-associated protein-1B (MAP1B) . InhibitEnhancing cytoskeletal dynamics in the growth cone supports axon growth, whereas aberrant cytoskeletal dynamics following injury represents a major obstacle to axon regeneration. Therefore, manipulations targeting cytoskeletal dynamics may be potential strategies to induce axon regeneration of adult neurons following injury.Socs3 in adult retinal ganglion cells magnified JAK/STAT signaling, thereby inducing axon regeneration after optic nerve injury  axons in the mouse spinal cord (Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in regulating axon regeneration and cell survival. JAK is activated by growth factors and cytokines ) and then phosphorylates STATs, which transduce the signals to the nucleus and promote transcription of regeneration-associated genes (RAGs). Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK/STAT pathway. Ablation of e injury . Activatnal cord .Pten promotes mTOR activation and positively modulates regeneration of facial nerve and CST axons  pathway plays a crucial role in regulating fundamental cell processes, including cell growth and metabolism, gene transcription, protein synthesis, and cytoskeletal remodeling . mTOR fuST axons . Activatneration .dlk-1 is sufficient to enhance regrowth capacity of injured axons in C. elegans , a highly conserved mitogen-activated protein kinase kinase kinase (MAP3K), plays a vital role in injury response, apoptosis, axon transport, and regeneration following injury both in the peripheral nervous system (PNS) and in the central nervous system (CNS) . Upon ax elegans . Germina elegans .Klfs), Sox11, Stat3, cAMP-response element binding protein (Creb), and hypoxia inducible factor-1a (Hif-1a) , which initiate pro-regenerative transcriptional programs and enable the reacquisition of regenerative potential. Previous studies have identified multiple pro-regenerative TFs, such as Krüppel-like factors ((Hif-1a) . ManipulEpigenetic modifications, which include histone acetylation, DNA demethylation and hydroxymethylation, as well as modification of non-coding RNAs, facilitate access to gene regulatory regions by TFs, thus enabling active transcription of genomic regions and RAG expression. Epigenetic modifications play a key role in embryonic and adult neurogenesis . In receIt is difficult to achieve frank regeneration of injured axons beyond the lesion site in the adult mammalian CNS. Apart from limited intrinsic regenerative competence, multiple extrinsic barriers contribute to the axon regeneration failure. Among these, myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) represent the major inhibitors to axon regeneration following SCI. Nogo A, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are three prototypical myelin-associated inhibitory molecules that exert inhibition on axon regeneration after injury in the adult CNS. These MAIs initiate intracellular Rho and ROCK signaling pathways through multiple receptors  and eventually lead to growth cone collapse and prevent neurite extension . CSPGs aSpinal cord injury interrupts the connectivity of the spinal cord and leads to devastating neurological deficits. In addition, concomitant complications, including respiratory and urinary infections, gastrointestinal disorders, muscle atrophy, and chronic pain exacerbate clinical outcomes. Numerous novel approaches have been emerged to ameliorate SCI outcomes that can be divided into two parts: (i) relieving secondary damage via neuroprotection and (ii) fostering neuroplasticity and axon regeneration by triggering intrinsic regenerative mechanisms, ameliorating the extrinsic environment, and applying cell transplantation and neuromodulation technologies . Each ofThe primary mechanical injury to the spinal cord triggers a cascade of complex biological processes, termed the secondary injury, which cause further damage to the spared tissue and exacerbate neurological impairment and regeneration failure. Therefore, interventions that confer neuroprotection during the acute phase are crucial to suppress the spread of the secondary injury and to protect the spinal cord tissue from further damage. Several strategies have been deployed to attenuate the secondary damage. Pharmacological agents like methylprednisolone, minocycline, and cyclosporine A have been used to in patients with SCI to suppress secondary damage . HoweverIn recent years, a large number of novel neuroprotective approaches have emerged designed to counteract the progression of secondary injury. These therapies have demonstrated neuroprotective effects in preclinical studies and provide new perspectives for the treatment of clinical SCI. Oxidative stress following SCI leads to excess release of reactive oxygen species (ROS), which exacerbates secondary injury and results in axon degeneration and permanent neurological dysfunction. Antioxidant enzymes encapsulated in biodegradable nanoparticles have been shown to significantly reduce ROS activity and neuronal cell apoptosis, attenuate mitochondrial dysfunction, and improve locomotor recovery following severe contusive SCI in rats . In a moOveractivation of microglia after SCI exacerbates the inflammatory response and results in loss of neurons, gliosis, and synaptic damage. Inhibition of microglia proliferation by oral administration of the CSF1R inhibitor, GW2580, reduced neuroinflammation and improved locomotor function in mice and non-human primates following lateral spinal cord hemisection . MicroglWhile self-repair spontaneously occurs after injury in the adult mammalian PNS, mature neurons in the CNS fail to regain regenerative competence after SCI. Axon regeneration failure is mostly attributed to the poor intrinsic growth competence of the adult CNS neurons. Axon growth capacity sharply declines with age and is switched off upon maturation. However, over the last few decades, accumulating evidence suggests that axon regeneration and remodeling of neural circuits are possible via pharmacological, molecular, or genetic manipulations in the adult mammalian CNS . SubstanMicrotubule destabilization and actin disassembly following SCI lead to growth cone collapse and retraction bulb formation. The reformation of a growth cone-like structure from severed axon stumps is the first step in axon regeneration. Most manipulations aiming to augment axon regenerative ability eventually converge on cytoskeletal dynamics and remodeling within the growth cone.Rhoa knockdown was shown to enhance axon regeneration and reduce apoptosis, cavity formation, and astrogliosis in a rat compression SCI model , which is mainly produced in the mitochondria. SCI-induced mitochondrial dysfunction and energy deficits exacerbate axon regeneration failure. Syntaphilin (Snph) is a static anchor protein that holds axonal mitochondria stationary on microtubules via its microtubule-binding domain. Enhancing mitochondrial transport by  in mice . The mit in mice .Intracellular signaling pathways, such as mTOR, JAK/STAT/SOCS3 and DLK regulate neuronal survival and axon growth. Accumulating evidence suggests that manipulating these pathways could enhance intrinsic growth competence and neuroplasticity after SCI.Socs3 triggered collateral sprouting of intact CST axons to the denervated spinal cord after unilateral pyramidotomy. Moreover, co-deletion of Pten and Socs3 further enhanced CST sprouting with significant restoration of skilled locomotion function, suggesting the reformation of functional circuits mediated by sprouting axons  concentration by extruding Cl− from the cytosol. KCC2 has important roles in synaptic inhibition as well as in neuronal development and plasticity  directly modulate transcription of RAGs and initiate the switch from the resting state to the robust regrowth state in damaged neurons. TFs have been shown to be an important determinant controlling axon growth potential in the mature CNS. Over the past decades, researchers have identified several candidate TFs that potentiate the regenerative capacity of injured axons after SCI.Klf6 or Klf7 promoted sprouting and regeneration of CST axons in adult mice  promoted histone 3 Lys 9 acetylation (H3K9ac) following peripheral injury, and nal cord . Recent nal cord . These rnal cord . This stIn addition to limited intrinsic growth ability, the hostile microenvironment is another obstacle to axon regeneration after SCI. Indeed, extrinsic growth-inhibitory factors and the deficiency of neurotrophic factors further hamper neuroplasticity and axon regeneration. Therefore, removing inhibitory molecules and augmenting neurotrophic support contribute to render a more permissive environment and promote functional recovery following SCI.The presence of inhibitory factors  surrounding the lesion site appears to be the major environmental obstacle to axon growth that prevents the injured axons from real regeneration. Removal of extrinsic inhibitory components by enzymatic degradation, receptor blocking, or antibody neutralization has demonstrated positive effects on axon regeneration and neurological restoration.Chabc gene expression was shown to promote recovery of skilled reaching and ladder walking performance as well as sensory axon conduction following cervical contusion injury in adult rats  to specifically modulate PTPσ released the inhibitory effect of CSPGs on axon growth and markedly fostered functional recovery of sensory, locomotor, and urinary systems after contusive SCI in rats . InhibitAttenuating MAI-mediated inhibition can be achieved by antibody neutralization, receptor antagonists, and genetic inhibition. Anti-Nogo A treatment ameliorated lower urinary tract dysfunction and restored bladder function in rats with severe SCI . The firLotus overexpression has been proved to enhance axon regeneration of the raphespinal tract and reticulospinal tract fibers, suppress axonal dieback of CST fibers, and promote motor recovery in a mouse contusive SCI model  into neurons and oligodendrocytes, and transplantation of Lingo-1 shRNA-treated NSPCs facilitated locomotor recovery in mice with contusive SCI  are a family of proteins that direct neuronal survival, synaptic function, and axonal growth within the adult nervous system . NFs areBdnf vector into the lesion significantly enhanced sprouting of 5-HT+ axons and increased their synaptic connections with phrenic motor neurons (PhMNs), and contributed to recovery of diaphragm function following cervical SCI  is a secreted protein that fosters neuron survival and synaptic plasticity. Delivery of BDNF mRNA with cationic polymers resulted in improved motor function recovery in a mouse model of contusive SCI . Intraspical SCI . Retrogrical SCI . Sustainical SCI . In addiical SCI . Insulin pathway . Igf-1 o in mice . Subcuta in mice . In addi in mice . Vascula in mice . VEGF wa in mice .The substantial loss of neurons and oligodendrocytes following SCI leads to disruption of neural network and signal transduction. Cell transplantation exhibits multitherapeutic capacities, such as replacement of damaged tissue, formation of relay neural circuits, immunomodulation, neuroprotection, and myelin regeneration, thus emerging as a more promising intervention to promote functional improvement following SCI . A varieNeural stem cells/neural progenitor cells (NSCs/NPCs) are self-renewing cells and can differentiate into specific neurons or glial cells to replace damaged spinal cord tissue. Implantation of NPCs/NSCs has shown great therapeutic potential in axon regeneration and functional restoration after SCI in rodents and primates . The obsMSCs are ideal candidate for cell-based therapies. MSCs raise no ethical concerns and can be acquired from diverse tissue sources like bone marrow, placenta, umbilical cord, and adipose tissue. Therefore, MSC transplantation is one of the most promising candidates for SCI repair. The therapeutic effects MSC transplantation after SCI are primarily due to their paracrine activity and trophic support: MSC-secreted factors modulate the immune response and induce neuroprotection, angiogenesis, and fiber regeneration in the injured spinal cord . In the SCs are another potential candidate for transplantation in patients with SCI. SCs have been shown to promote spinal cord repair through multiple mechanisms; they myelinate axons, reduce tissue injury, enhance neuroprotection, and maintain axonal plasticity. SCs are easily acquired from autologous nerve, thus alleviating the risk of immune rejections and avoiding the need for immunosuppression. SCs have demonstrated potential therapeutic effects in rodent SCI models, and their safety and potential efficacy have also been confirmed in clinical trials. A phase I clinical trial in humans with subacute SCI suggested that autologous human Schwann cell (ahSC) transplantation injected into the epicenter of the spinal lesion was safe and feasible. No serious adverse events or neurological complications were detected within in one year after transplantation . AnotherLike ahSCs, iPSCs derived from somatic cells avoid ethical concerns and immune rejection, and they can be reprogrammed to NPCs/NSCs, supporting human iPSC-derived NSC/NPC transplantation as a viable approach to treat SCI. Transplantation of human iPSC-derived NSCs facilitated axon growth and functional neural circuit reconstruction as well as motor function restoration after cervical spinal cord hemisection in rats . SimilarCollectively, the multiple observed therapeutic benefits associated with cell transplantation makes cell-based therapy an attractive approach that could substantially improve outcomes for patients with SCI. However, some remaining issues may limit their clinical practice, including ethical controversy, cell source, intervention time, uncontrolled cell proliferation, and long-term safety. Continued efforts to resolve these issues and concerns could make cell transplantation a feasible clinical option.The descending motor pathways are severely interrupted after SCI. Although the spinal neural circuits below the injury level remain intact, the absence of supraspinal descending commands leads to the circuits functionally dormant and loss of motor function. Neuromodulation is a bioengineering approach that utilizes electrical or magnetic stimulation, pharmacological agents, optogenetics, and chemogenetics to modulate neuronal activity. Neuromodulation has been successfully applied in a variety of neurological diseases. Neuromodulatory technologies applied for SCI aim to reactivate the spinal intrinsic motor circuits below the lesion and ultimately restore the basic motor function and/or voluntary movements. These neuromodulatory inventions primarily include spinal cord stimulation, brain stimulation, and brain–machine interface.Spinal cord stimulation is emerging as a potential therapy to alleviate neurological deficits and promote functional recovery following SCI. Epidural electrical stimulation (EES), transcutaneous spinal cord stimulation (tcSCS) and intraspinal microstimulation (ISMS) are the three forms of spinal cord stimulation that designed to facilitate functional restoration after SCI.Epidural electrical stimulation (EES) applied to the lumbosacral spinal segments has been shown to substantially restore locomotion and motor control after SCI both in preclinical and clinical studies. Paralyzed rats treated with EES were able to perform continuous stepping, walking, and even climbing staircases . Co-deliContinuous EES may abolish proprioceptive information in humans and restrict locomotion recovery. In contrast, spatiotemporal EES enhanced the active control of motor neurons while preserving the interaction between antagonistic muscles to ensure coordination and stability of lower limb movement . SpatiottcSCS is another well-developed form of spinal cord stimulation and has been demonstrated to restore motor, sensory, and autonomic function when used alone or combined with other interventions . tcSCS iPrevious studies have indicated that even clinically complete SCI spares some descending nerve fibers, but they are dormant and insufficient to trigger movement. Brain stimulation has been used to engage the residual motor circuits to restore voluntary limb movement after SCI. The brain stimulation strategies mainly include deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS).DBS is a well-established technique that activates neural activity of the target brain region via implanted electrode. Motor cortex electrical stimulation was shown to promote CST axon sprouting, and the combination of motor cortex stimulation and transcutaneous spinal direct stimulation (tsDCS) further augmented CST axon plasticity and restored forelimb motor function after rat spinal cord contusion . This coBrain–machine interface (BMI) has emerged as a novel technique that combines engineering, computer science, and neurophysiology to restore sensorimotor functions in patients with severe neurological disability . BMI recA participant with quadriplegia from cervical SCI regained cortical control of dexterous hand movements using BMI. The participant’s forearm muscles were reactivated and controlled by the intracortically recorded signals, ultimately enabling complete functional movement task like grasping, manipulating, and releasing objects . An indiThe wireless brain–spine interface was employed to directly link the intended motor states decoded from leg motor cortex activity to spatiotemporal EES over the lumbosacral segment to re-establish voluntary control of leg activity. This approach alleviated gait deficits and enabled weight-bearing locomotion on a treadmill and overground in rhesus monkeys with unilateral corticospinal tract lesion during the first week post-injury . As obseNeuromodulation therapies have achieved unexpected efficacy in restoring locomotion and volitional control in both SCI animal models and individuals with SCI. Therefore, these neuromodulatory technologies might be the most promising approach to achieve meaningful functional recovery following SCI.Individual treatments are insufficient to restore meaningful locomotion due to the complex pathological responses after SCI. Therefore, combinatory approaches targeting diverse aspects of SCI pathology are warranted to facilitate functional recovery in humans with SCI. Biomaterials serve as physical and structural supports to guide axon outgrowth and have been widely applied in the treatment of SCI. Meanwhile, biomaterials act as a key component of combinatorial approaches, as they provide temporary storage substrates for the long-term release of drugs, bioactive molecules, and transplanted cells to modulate inflammation, neural plasticity, axon regeneration, and cell survival .Combined delivery of multiple growth factors and chemokines released from hydrogel depots elicited robust propriospinal axon regrowth after complete SCI in both mice and rats. The regenerating propriospinal axons formed synapse-like contacts with neurons below the lesion site and restored electrophysiological conduction across lesions . The supLycium barbarum oligosaccharide (LBO) promoted microglia towards M2 polarization. Combination of LBO, nasal mucosa-derived mesenchymal stem cells, and fibronectin hydrogel synergistically enhanced the M2 polarization of microglia and promoted axon remyelination and recovery of hind limb movement after complete spinal cord transection in rats  was shown to promote functional recovery in rodent models of SCI, and its safety and feasibility were confirmed in preliminary phase I/IIa clinical trial. However, the phase 3 clinical trial failed to show significant benefit of G-CSF in the primary end point . A few oAlthough encouraging results have been achieved in SCI animal models, interventions that are effective preclinically demonstrate little efficacy to produce functional improvements when translated into clinical trials. Therefore, the beneficial outcomes from rodent models are not always reproduced in clinical practice. One possible reason is the limitation of rodent models for predicting efficacy in human SCI. The anatomy and size of the spinal cord vary greatly between rodents and primates. For instance, the anatomical characteristics and function of descending pathways involved in motor control  demonstrates pronounced interspecies differences between rodents and primates. In rodents, the CST fibers mostly travel in the dorsal columns of the spinal cord, and no direct connections exist between CST fibers and the cervical motoneurons. By contrast, in humans and non-human primates, the CST fibers are mainly located in the lateral columns and have developed direct connections with motoneurons . In addiFuture clinical trials for the treatment of SCI should be designed after considering several factors that may influence outcomes. Accumulating more data and comprehensive preclinical testing is essential before initiating clinical trials to minimize the risk of patients experiencing adverse effects or undergoing futile treatment. Moreover, the lack of reproducibility and robustness in preclinical experiments is another major issue contributing to the failure of clinical translation . Thus, iIndividual therapeutic interventions are inadequate to resolve the multifaceted pathological processes that occur after SCI and to promote spinal cord repair. Multi-targeted, combinatorial approaches are expected to maximize therapeutic effect. However, this becomes more complicated because many aspects must be taken into account when different strategies are combined. For instance, the optimal temporal window of treatment and whether the treatments are safe, tolerable, and feasible in combination must be determined to identify the most effective synergistic strategies. To optimize combinatorial strategies, determine analytical frameworks and achieve clinically relevant recovery in patients with SCI, it is therefore essential to enhance collaboration and communication between basic researchers and clinicians.Spinal cord injury interrupts the descending motor pathways and ascending sensory fibers within the spinal cord, leading to multi-system dysfunction and permanent disability. To alleviate the devastating effects of SCI, researchers have developed a variety of novel therapeutic approaches in recent years, some of which have shown promising therapeutic efficacy in preclinical studies and are progressing to clinical trials. This review summarizes the recent progress of preclinical and clinical strategies in SCI treatment and discusses the challenges and prospects for spinal cord repair.Despite encouraging results in preclinical experiments, many interventions have failed to translate to clinical application. This translational failure is partially due to the complex and multifaceted features of SCI pathology. Hence, a better understanding of the pathological processes following SCI and thorough investigation of intrinsic and extrinsic mechanisms controlling axon growth are urgently warranted to develop novel strategies to achieve greater beneficial outcomes. Notably, most individual therapeutic strategies targeting a single pathophysiological mechanism are insufficient to achieve relevant efficacy, resulting in clinical translation failure. Combinatorial strategies that act on multiple pathological processes of SCI have been shown to be more effective than individual treatments alone. Therefore, combinatorial approaches are more promising to wok synergistically to overcome multiple regeneration barriers and foster neural repair in patients with SCI. Furthermore, multidisciplinary collaboration and conversations are essential to ensure the accuracy of therapeutic design and predictive analysis.Neuronal regeneration or the formation of relay neural circuits after SCI is not necessarily accompanied by associated functional improvement. Rehabilitation training could augment the adaptive plasticity of residual pathways and is expected to trigger reorganization and integration of neural circuitry to promote longer-lasting functional readouts. Together with appropriate rehabilitation, combinatorial strategies might further enhance recovery of neurological function in clinical SCI. Furthermore, it is vital to select appropriate animal models for preclinical studies, and potential strategies should be extensively investigated preclinically in diverse SCI animal models to validate their therapeutic effects. Pronounced species divergence exists between primates and rodents or carnivores, and non-human primate models are particularly relevant for designing interventions and validating their therapeutic potential before translated to clinical application. In the future, further investigation is warranted to identify the neural regenerative mechanisms of functional recovery after SCI, especially in non-human primate models, as they are more similar to those in humans. These studies might be crucial to develop novel therapeutic interventions targeting particular neural circuits to improve function restoration.


Lacrimal gland enlargement can be a feature of thyroid eye disease (TED). Unilateral or asymmetric lacrimal gland enlargement is poorly described and may impede diagnosis. We present the histological and clinical findings of four patients with asymmetric lacrimal gland enlargement.A retrospective case note review was performed for patients over two tertiary orbital clinics  presenting with an asymmetrical lacrimal gland enlargement with a background of TED that underwent biopsy to exclude alternate diagnoses. Baseline data was collected for each patient and histopathological images and reports were reviewed.All four patients were hyperthyroid at time of lacrimal gland biopsy. Biopsy demonstrated nonspecific, lymphoid aggregates, typically of B cell type, with no diagnostic findings to support lymphocyte clonality or IgG4-related disease. One biopsy specimen demonstrated evidence of some fibrosis.Asymmetrical lacrimal gland enlargement can occur as part of the TED spectrum but may require biopsy to exclude alternate pathology. Histology demonstrates a non-specific lymphocytic infiltrate. Thyroid eye disease (TED) is the commonest cause of orbital inflammation in adults. It can result in expansion and fibrosis of the extraocular muscles and orbital fat . RadioloThe purpose of this study is to report on the histopathological findings of lacrimal gland biopsies in patients with asymmetric lacrimal gland enlargement.A retrospective review of clinical case notes was performed for all patients presenting to two units  between the years 2013 to 2020. Inclusion criteria included patients with known thyroid dysfunction, upper eyelid retraction and/or lid lag in keeping with thyroid eye disease, clinical and/or radiological findings of lacrimal gland enlargement, magnetic resonance imaging (MRI) of the orbits and subsequent lacrimal gland biopsy and serological investigations (eg serum immunoglobulin subclasses) to exclude concurrent disease.Baseline data for each patient was collected including age, sex, ocular comorbidity, laterality, ophthalmic findings, and histopathological findings. Clinical Activity Score (CAS) was obtained for the patient’s initial presentation. The CAS evaluates inflammatory signs and symptoms that are often characteristic of active TED.Ethical approval for this study was not required as per the Human Research Authority (HRA) online decision-making tool. Informed consent was provided by each patient for the procedure and use of clinical information.Four patients were identified through case note review Table . The meaThree of the four patients presented with upper lid retraction. All four patients had inactive disease. Other common presentation features included lid lag and proptosis. MRI had been requested as routine baseline imaging of the orbital contents.All patients were biochemically hyperthyroid and demonstrated asymmetrical lacrimal gland enlargement on MRI (Fig. Histopathological analysis of lacrimal gland biopsy specimens showed nonspecific chronic inflammation composed largely of B lymphocytes in all four cases Figs. , 3, 4. OLacrimal gland enlargement is a common finding in TED and particularly in the active stage of the disease , 6, 7. ARadiological findings may assist the decision-making regarding biopsy of the lacrimal gland. Epithelial neoplasms predominantly involve the orbital lobe whilst inflammatory and lymphoproliferative lesions tend to involve both the orbital and palpebral lobes . LymphopPreviously reported lacrimal gland histopathological findings in TED have also shown nonspecific inflammatory cell infiltration with and without fibrosis , 13, 14.These nonspecific histological changes, to some extent, diagnoses thyroid eye disease by exclusion, given the lack of a specific histopathological marker, although there remains the possibility of other concurrent, non-specific, diseases such as idiopathic dacryoadenitis that tend to present unilaterally.All four patients in the present study were hyperthyroid which contrasts with previous studies which have shown asymmetric TED clinical presentations predominantly in euthyroid or hypothyroid disease states , 18, 19.There are several limitations to this study. Firstly, the retrospective and non-comparative design limit inferences that can be drawn. Secondly, a standard set of immunohistochemical testing was not undertaken due to the retrospective and multi-centre nature of the study. Finally, we have included a small number of patients, although this may reflect the relatively uncommon nature of TED-related, asymmetric lacrimal gland enlargement.This study confirms that those patients with lacrimal gland enlargement presumed secondary to TED typically show nonspecific chronic inflammatory changes on histopathological analysis. Lacrimal gland biopsy is prudent given concurrent malignant or inflammatory disease is possible with asymmetrical enlargement although radiological imaging modalities of the lacrimal gland show promise in diagnosing active TED.


Brain structural and functional alterations have been consistently proposed to be involved in the neurobiological underpinnings of aging and neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease. Given that pathological perturbations of the central nervous system are often intertwined with brain connectivity alteration, it is becoming increasingly accepted that connectome reorganization plays a key role in determining cognitive or motor disability. The advances in connectome-wide association studies (CWAS) have the potential to allow for the identification of novel neural correlates of neurodegeneration at the whole-brain scale, elucidating how brain-network topology can shape neural responses to neurodegenerative damage.This Research Topic aims to encourage the proposal of state-of-the-art methodologies related to CWAS techniques and their applications to neurodegenerative disorders. A total of five studies collected in this topic mainly cover (1) advanced statistical methods to avoid multiple covariates in analyzing brain connectivity; (2) a data-driven CWAS design to clarify and validate brain network findings associated with aging in a large sample of subjects; (3) a virtual analytical approach to describe brain disconnectome reorganization while avoiding the issue of artifacts that are prone to occur in the presence of white matter hyperintensity; (4) advanced dynamic connectivity measurements as novel brain imaging markers to discriminate AD patients at different stages; and (5) the brain structural covariance network analysis and related novel statistical model to unravel pathological progression of AD. In what follows, we summarized the highlights the methodologies and applications in aging and related neurodegeneration of each article.Smith et al. proposed a subject-level regression model to consider multiple covariates, including parcel-wise geographic/homotopic distance and region or network belongings, to move away from reliance on localization assumptions underlying FC comparisons. The key point is to keep each individual's FC in its own geometry, without morphing to a common template. This could be extraordinarily useful when the extent and location of lesions to brain regions varies across subjects. Additionally, the authors demonstrated high repeatability of this model achieved in individual space with test-retest individual scans.Functional connectivity (FC) comparison across individuals can be challenging in CWAS due to complex covariates in inter-subject variations. Du et al. applied a priori-driven independent component analysis, named NeuroMark, on 6,300 healthy adult with an age range of 49–73 years from UK Biobank project. They highlighted multiple significant joint between-network FC changes related to aging occurred in default mode and sub-cortical networks. This spatial diversity of brain network reorganization revealed by CWAS may shed new light on mechanism underlying aging-related brain changes.How aging affects functional networks of the brain in both within-network and between-network connectivity is unclear. To comprehensively explore this effect, Li et al. addressed the focal effect when analyzing brain structural network. To avoid potential confounds of white matter hyperintensity (WMH) in CWAS, the authors proposed a virtual lesion approach to estimate brain connectivity changes in aging. Specifically, WMH frequency maps across age ranges  were used to generate virtual lesion masks for each decade as regions of avoidance in white matter tractography. They quantitatively described the spatial disconnectome evolving patterns in cortical and subcortical areas, which might underlie cognitive and sensorimotor deficits seen in aging. The advancement of this virtual lesion approach can further help identify brain disconnectome features contributing to dementia risk.Another study conducted by Penalba-Sánchez et al. compared multiple FC measurements  and evaluated their corresponding network segregation and integration in mild cognitive impairment and AD. The authors unexpectedly observed an increase in late stage AD and a slight decrease of FC in early MCI, and explained the potential underlying cognitive mechanism. Understanding the dynamic and non-linear nature of FC might be crucial for unraveling the unclear neuropathological factors affecting behavior symptoms along the trajectory of AD.Emerging evidence has supported that abnormal brain structural or functional connectivity could have been observed 10–20 years prior to the onset of clinical symptoms of AD. Aiming to clarify inconsistent brain FC findings in early stage of AD, the study conducted by Xiao et al. applied SCN analysis using T1-weighted MR images from a longitudinal cohort to examine whether and how earlier brain atrophy patterns impact the progressive changes of gray matter atrophy in AD patients over time. After establishing regular structural connectivity by Pearson correlation and causal structural connectivity by Granger causal analysis, they used a new approach named gray matter based spatial statistics to measure the gray matter volume at the core of the cortical plate, aiming to alleviate partial volume effect and inter-subject variability. High discrimination accuracy based on SCN connectivity features suggests that SCN approach may help identify the unique pathological progression of AD and other types of neurodegeneration.Unlike structural connectivity, which is classically represented by the connection strength of white matter tracts on individual level, brain structural covariance network (SCN) analysis highlights synchronized gray matter atrophy undergoing neurological pathological processes across brain regions on population level. In sum, the collective findings represented in these articles reflect the rapidly expanding development of the CWAS field. One could further expect a rising body of brain network analytical tools and statistical models updated in this emerging area, providing new avenues for identification of brain network markers related to aging and neurodegenerative disorders. However, whether and to what degree the brain network construction procedures  affects robustness of findings in neurodegeneration is still in dispute. Therefore, before further translating into clinical applications such as individual auxiliary diagnosis and treatment decision-making, we must be cautious whether the reliability and validity performance of these CWAS approaches has been fully reported and validated in large-sample and multi-center brain imaging data.CY: Writing—original draft. TW: Writing—review & editing. AF: Writing—review & editing.