Parvalbumin gates chronic pain through the modulation of firing patterns in inhibitory neurons.

Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.

Persistence of FoxJ1+ Pax6+ Sox2+ ependymal cells throughout life in the human spinal cord.

Ependymal cells lining the central canal of the spinal cord play a crucial role in providing a physical barrier and in the circulation of cerebrospinal fluid. These cells express the FOXJ1 and SOX2 transcription factors in mice and are derived from various neural tube populations, including embryonic roof and floor plate cells. They exhibit a dorsal-ventral expression pattern of spinal cord developmental transcription factors (such as MSX1, PAX6, ARX, and FOXA2), resembling an embryonic-like organization. Although this ependymal region is present in young humans, it appears to be lost with age. To re-examine this issue, we collected 17 fresh spinal cords from organ donors aged 37-83 years and performed immunohistochemistry on lightly fixed tissues. We observed cells expressing FOXJ1 in the central region in all cases, which co-expressed SOX2 and PAX6 as well as RFX2 and ARL13B, two proteins involved in ciliogenesis and cilia-mediated sonic hedgehog signaling, respectively. Half of the cases exhibited a lumen and some presented portions of the spinal cord with closed and open central canals. Co-staining of FOXJ1 with other neurodevelopmental transcription factors (ARX, FOXA2, MSX1) and NESTIN revealed heterogeneity of the ependymal cells. Interestingly, three donors aged > 75 years exhibited a fetal-like regionalization of neurodevelopmental transcription factors, with dorsal and ventral ependymal cells expressing MSX1, ARX, and FOXA2. These results provide new evidence for the persistence of ependymal cells expressing neurodevelopmental genes throughout human life and highlight the importance of further investigation of these cells.

Litigations following spinal neurosurgery in France: "out-of-court system," therapeutic hazard, and welfare state.

OBJECTIVE: Spinal surgeries carry risks of malpractice litigation due to the random nature of their functional results, which may not meet patient expectations, and the hazards associated with these complex procedures. Claims are frequent and costly. In France, since 2002, a new law, the Patients' Rights Law of March 4, 2002, has created an alternative, out-of-court scheme, which established a simplified, rapid, free-of-charge procedure (Commission for Conciliation and Compensation [CCI]). Moreover, this law has optimized the compensation provided to patients for therapeutic hazards by use of a national solidarity fund. The authors analyzed the consequences of this alternative route in the case of claims against private neurosurgeons in France. METHODS: From the data bank of the insurer Mutuelle d'Assurances du Corps de Santé Français (MACSF), the main insurance company for private neurosurgeons in France, the authors retrospectively analyzed 193 files covering the period 2015-2019. These computerized files comprised the anonymized medical records of the patients, the reports of the independent experts, and the final judgments of the CCI and the entities supporting the compensation, if any. RESULTS: During the 5-year study period (2015-2019), the insurance company recorded 494 complaints involving private neurosurgeons for spinal surgery procedures, of which 126 (25.5%) were in civil court, 123 (24.9%) were under amicable procedure, and 245 (49.6%) were in the out-of-court scheme administered by the CCI. Out of these 245 cases, only 193 were closed due to delays. The conclusions of the commission were rejection/incompetence decisions in 47.2% of the cases, therapeutic hazards in 21.2%, nosocomial infections in 17.6%, and practitioner fault in 13.5%. National solidarity compensated for 48 complaints (24.8%). The final decision of the CCI is not always consistent with the conclusions of the experts mandated by it, illustrating the difficulty in defining the concept of hazards. The authors found that the therapeutic hazards retained and compensated by the national solidarity included decompensated spondylotic myelopathies (15% of the 40 cases) and cauda equina syndromes (30%). As allowed by law, 11.5% of the patients who were not satisfied triggered a classical procedure in a court. CONCLUSIONS: In the French out-of-court system, trial decisions resulting in rulings of proven medical malpractice are rare, but patients can start a new procedure in the classical courts. The therapeutic hazard remains a subtle definition, which may be problematic and require further discussion between experts and magistrates. In spite of the imperfections, this out-of-court system proposes a major evolution to move patients and medical providers from legal battles to reconciliations.

Mortality, complication, and fusion rates of patients with odontoid fracture: the impact of age and comorbidities in 204 cases.

PURPOSE: The French Society of Spine Surgery (SFCR) conducted a prospective epidemiologic multicenter study. The purpose was to investigate mortality, complication, and fusion rates in patients with odontoid fracture, depending on age, comorbidities, fracture type, and treatment. METHODS: Out of 204 patients, 60 were ≤ 70 years and 144 were > 70 years. Demographic data, comorbidities, treatment types and complications (general medical, infectious, neurologic, and mechanical), and death were registered within the first year. Fractures were classified according to Anderson-D'Alonzo and Roy-Camille on the initial CT. A 1-year follow-up CT was available in 144 patients to evaluate fracture consolidation. RESULTS: Type II and oblique-posterior fractures were the most frequent patterns. The treatment was conservative in 52.5% and surgical in 47.5%. The mortality rate in patients ≤ 70 was 3.3% and 16.7% in patients > 70 years (p = 0.0002). Fracture pattern and treatment type did not influence mortality. General medical complications were significantly more frequent > 70 years (p = 0.021) and after surgical treatment (p = 0.028). Neurologic complications occurred in 0.5%, postoperative infections in 2.0%, and implant-related mechanical complications in 10.3% (associated with pseudarthrosis). Fracture fusion was observed in 93.5% of patients ≤ 70 years and in 62.5% >70 years (p < 0.0001). Pseudarthrosis was present in 31.5% of oblique-posterior fractures and in 24.3% after conservative treatment. CONCLUSIONS: Age and comorbidities influenced mortality and medical complication rates most regardless of fracture type and treatment choice. Pseudarthrosis represented the main complication, which increased with age. Pseudarthrosis was most frequent in type II and oblique-posterior fractures after conservative treatment.

Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity.

UNLABELLED: Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains. SIGNIFICANCE STATEMENT: This study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.

Nontraumatic spinal subdural hematoma complicating direct factor Xa inhibitor treatment (rivaroxaban): a challenging management.

PURPOSE: We report on a 72-year-old male patient who developed a nontraumatic spinal subdural hematoma (SSDH) during rivaroxaban therapy, a relatively new orally administered direct factor Xa inhibitor. CASE DESCRIPTION: The patient sustained a sudden onset of interscapular pain, followed by gait impairment and paraplegia. Magnetic resonance imaging (MRI) of the spine demonstrated SSDH from T6 to T8. Laboratory tests revealed a high rivaroxaban level, associated with a major hemorrhagic risk. Surgery was, therefore, performed the following morning, after normalization of coagulation parameters. CONCLUSION: Determining the time of safe surgery remains challenging when hemorrhagic complications happen with direct factor Xa inhibitor, especially when neurological prognosis is engaged. Spinal subdural hematoma has not previously been reported following rivaroxaban therapy.

Robot-assisted spine surgery: feasibility study through a prospective case-matched analysis.

PURPOSE: While image guidance and neuronavigation have enabled a more accurate placement of pedicle implants, they can inconvenience the surgeon. Robot-assisted placement of pedicle screws appears to overcome these disadvantages. However, recent data concerning the superiority of currently available robots in assisting spinal surgeons are conflicting. The aim of our study was to evaluate the percentage of accurately placed pedicle screws, inserted using a new robotic-guidance system. METHOD: 20 Patients were operated on successively by the same surgeon using robotic assistance (ROSA™, Medtech) (Rosa group 10 patients, n = 40 screws) or by the freehand conventional technique (Freehand group 10 patients, n = 50 screws). Patient characteristics as well as the duration of the operation and of exposure to X rays were recorded. RESULTS: The mean age of patients in each group (RG and FHG) was 63 years. Mean BMI and operating time among the RG and FHG were, respectively, 26 and 27 kg/m(2), and 187 and 119 min. Accurate placement of the implant (score A and B of the Gertzbein Robbins classification) was achieved in 97.3% of patients in the RG (n = 36) and in 92% of those in the FHG (n = 50). Four implants in the RG were placed manually following failed robotic assistance. CONCLUSION: We report a higher rate of precision with robotic as compared to the FH technique. Providing assistance by permanently monitoring the patient's movements, this image-guided tool helps more accurately pinpoint the pedicle entry point and control the trajectory. Limitations of the study include its small sized and non-randomized sample. Nevertheless, these preliminary results are encouraging for the development of new robotic techniques for spinal surgery.

Surgical-site infection in spinal injury: incidence and risk factors in a prospective cohort of 518 patients.

PURPOSE: To investigate the incidence of surgical-site infection (SSI) and determinate the risk factors of SSI in the context of spinal injury. METHODS: From February 1, 2011 to July 31, 2011, for a multicentre cohort of patients with acute spinal injury, we prospectively censored those with SSI for at least 12 months. We recorded epidemiologic characteristics and details of surgical procedure and postoperative care for each patient. We calculated the incidence of SSI at 1, 3 and 12 months after surgery. Univariate and multivariate analysis were used to establish the association of risk factors and SSI. We studied clinical outcomes by a visual analog scale for pain and physical and mental component summaries (PCS and MCS) of the Medical Outcomes Survey 36-Item Short Form (SF-36). RESULTS: At 1 year, among 518 patients, we recorded 25 SSI events, with median occurrence at 16 days (25-75 % quartile: 13-44 days). Incidence of SSI was 3.2 % (95 % confidence interval [1.9-5.3 %]) at 1 month, 3.7 % (95 % [2.2-5.8 %]) at 3 months and 4.6 % (95 % CI [3-6.9 %]) at 12 months. On multivariate analysis, age, presence of diabetes and surgical duration were predictors of SSI (p = 0.009, p = 0.047, and p = 0.015 respectively). At 12 months, infected and non-infected patients did not differ in pain (p = 0.58) or SF-36 PCS (p = 0.8) or MCS (p = 0.68). CONCLUSIONS: In this large prospective multicentre study in the context of spinal injury, we obtained an equivalent incidence rate and risk factors of SSI as found in the literature for elective spinal surgery.

Spinal lymphangiomas: Case-based review of a chameleonic disease entity.

Purpose: Lymphangiomas are benign hamartomas in the spectrum of lymphatic malformations, exhibiting multifaceted clinical features. Spinal involvement is exceedingly rare, with only 35 cases reported to date. Both due to their rarity and chameleonic radiologic features, spinal lymphangiomas (SLs) are usually misdiagnosed; postoperatively, surgeons are thus confronted with an unexpected histopathological diagnosis with sparse pertinent literature and no treatment guidelines available. Methods: Here, we report the case of a 67-year-old female who underwent surgery for a T6-T7 epidural SL with transforaminal extension, manifesting with spastic paraparesis. Then, we present the results of the first systematic review of the literature on this subject, delineating the clinical and imaging features and the therapeutic implications of this rare disease entity. Results: Our patient was treated with T6-T7 hemilaminectomy and resection of the epidural mass, with complete recovery of her neurological picture. No recurrence was evident at 18 months. In the literature, 35 cases of SL were reported that can be classified as vertebral SL (n = 18), epidural SL (n = 10), intradural SL (n = 3), or intrathoracic lymphangiomas with secondary spinal involvement (n = 4). Specific treatment strategies (both surgical and nonsurgical) were adopted in relation to each of these categories. Conclusion: Gathering knowledge about SL is fundamental to promote both correct preoperative identification and appropriate perioperative management of this rare disease entity. By reviewing the literature and discussing an exemplary case, we delineate a framework that can guide surgeons facing such an unfamiliar diagnosis.

Safety and efficacy of transvenous embolization of cerebrospinal fluid-venous fistula in patients with spontaneous intracranial hypotension.

BACKGROUND: Transvenous embolization is a recent treatment strategy for cerebrospinal fluid-venous fistulas (CSFVF), which are associated with spontaneous intracranial hypotension (SIH). METHODS: Participants were selected from a prospective database on patients with CSFVF that received transvenous Onyx embolization. All patients underwent a brain magnetic resonance imaging (MRI) before and after embolization with MRI follow-up performed at least 3 months after treatment. Clinical and MRI results after treatment were described. RESULTS: Twenty-one consecutive patients (median age 63 years, IQR = 58-71; females: 15/21 = 71.5%) with 30 CSFVF were included. Most lesions were situated between T9 and L1 (19/30 = 63%), 70% were right-sided, and 38% of the patients had multiples fistulas. Embolization was successful in all cases. The mean MRI SIH score before and after treatment was 6 (±2.5) and 1.4 (±1.6), respectively (p < 0.0001). Twenty patients (90%) experienced improvement of their initial condition, of which 67% reported complete clinical recovery. The mean HIT-6 score decreased from 67 (±15) to 38 (±9) (p < 0.0001), the mean amount of monthly headache days from 23.5 (±10) and 3.2 (±6.6) (p < 0.0001), the visual assessment scale (VAS) for headache severity from 8 (±1.9) to 1.2 (±2) (p < 0.0001), and the mean VAS for perception quality of life improved from 2.6 (±2.5) to 8.6 (±1.8) (p < 0.0001). There were no major complications. The suspected rebound headache rate after treatment was 33%. CONCLUSION: Transvenous embolization of CSFVF allowed high rates of clinical improvement with no morbidity related to the treatment.

Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice.

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

Becoming a neurosurgeon in France: A qualitative study from the trainees' perspective.

Introduction: The training of neurosurgeons is evolving in a world of socio-professional changes, including the technological revolution, administrative pressure on stakeholders, reduced working hours, geographical heterogeneity, generational changes, to name but a few. Research question: This qualitative study aimed to explore experiences and feedback of French neurosurgical trainees concerning their training. Material and methods: The grounded theory approach was used with 23 neurosurgical trainees' interviews. Inclusion was continued until data saturation. Six researchers (an anthropologist, a psychiatrist, and four neurosurgeons) thematically and independently analyzed data collected through anonymized interviews. Results: Data analysis identified three superordinate themes: (1) The Trainee-Senior Dyad, where the respondents describe a similar bipolarity between trainees and faculty (trainees oscillating between those who fit into the system and those who are more reluctant to accept hierarchy, faculty using an ideal pedagogy while others refuse to help or invest in training); (2) The difficulty to learn (describing pressure exercised on trainees that can alter their motivation and degrade their training, including the impact of administrative tasks); (3) A pedagogy of empowerment (trainee' feelings about the pertinent pedagogy in the OR, ideal sequence to progress, progressive empowerment especially during the shifts, and stress of envisioning themselves as a senior neurosurgeon). Discussion and conclusion: Respondents emphasize the heterogeneity of their training both intra- and inter-university-hospital. Their critical analysis, as well as the formalization of their stress to become autonomous seniors, can be an important link with the reforms and optimizations currently being carried out to improve and standardize the training of young French neurosurgeons.

A technique to localize posteriorly located spinal dural leaks associated with spontaneous intracranial hypotension: Dorsal-decubitus dynamic CT myelography.

BACKGROUND: Precise localization and understanding of the origin of cerebrospinal fluid (CSF) leak is crucial to allow targeted treatment. We report the technical feasibility and utility of dorsal-decubitus dynamic computed tomography (DDDCT) myelography to localize posteriorly located dural defects in patients with suspicion of posterolateral dural tears. METHODS: This study reports a series of four consecutive patients with posteriorly located SLEC and suspicion of posterolateral CSF leak who received DDDCT to localize the site of the leak. Patients were collected between October 2022 and October 2023. The technique of DDDCT and its efficacy to detect the site of CSF leak are reported. RESULTS: In all four patients (three females, one male, mean age 39 years), DDDCT myelography was technically successful and precisely demonstrated the site of the CSF leak. In one patient with both anterior and posterior SLEC, DDDCT allowed to exclude the presence of a posteriorly located leak, while a subsequent ventral decubitus dynamic CT myelography localized the leak. Leak sites were all thoracic, except for one that was cervical. Information obtained from the DDDCT myelography was considered useful to target the treatment of the leak. CONCLUSIONS: Based on our experience, DDDCT provided sufficient spatial and temporal resolution to pinpoint fast CSF leaks and it may be considered to localize posterolateral dural defects.

A cellular taxonomy of the adult human spinal cord.

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding of spinal cellular diversity, characterizing human biology directly is important to uncover specialized features of basic function and human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single-nucleus RNA sequencing with spatial transcriptomics and antibody validation. We identified 29 glial clusters and 35 neuronal clusters, organized principally by anatomical location. To demonstrate the relevance of this resource to human disease, we analyzed spinal motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) and other diseases. We found that compared with other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, suggesting a specialized molecular repertoire underlying their selective vulnerability. We include a web resource to facilitate further investigations into human spinal cord biology.

Spine Surgery Infection, Litigation, and Financial Compensation: Analysis of 98 Claims Involving French Spine Surgeons Between 2015 and 2019.

OBJECTIVE: Since 2002, France has adopted the Patients' Rights Law, an alternative malpractice scheme creating a faster, less expensive out-of-court settlement ensuring compensation even in the absence of fault. We aimed to describe the implications of this system by analyzing 5 years of claims for infections related to spinal surgeries collected by the main insurer of French spine surgeons. METHODS: We retrospectively analyzed 98 anonymized malpractice claims from 2015 to 2019 (20% of overall claims), including anonymized medical records of the patients, reports of the independent experts, final judgments, and entities supporting the compensation if any. RESULTS: Claims included 8 deaths and 17 newly acquired neurological sequelae. The conclusions identified 22 faulty cases. The most frequent fault was a delay in diagnosis (10 cases), followed by inadequate surgical management (6 cases), inadequate antibiotic therapy (5 cases), and inadequate follow-up (1 case). Among the 67 cases (68.4%) proved not to be at fault, 10 were covered by the national solidarity fund because of their severity, and the remaining 57 were covered by hospitals. CONCLUSIONS: Since the 2002 Patients' Rights Law, patients with postoperative infections have always received compensation. The out-of-court settlement offers the patients incurring morbidities the assurance of faster compensation. Although certainly subject to selection criteria, this procedure is free and does not necessitate the presence of a lawyer. The analysis of expert reports and the resulting court decisions imply prevention, anticipation, and collaboration of all health care providers and open an opportunity to improve their practices to limit these crucial followings.

Combined video-assisted thoracoscopy surgery and posterior midline incision for en bloc resection of non-small-cell lung cancer invading the spine.

OBJECTIVES: This article aims to evaluate the feasibility and safety of a hybrid video-assisted thoracic surgery (VATS) approach to achieve en bloc lobectomy and spinal resection for non-small-cell lung cancer (NSCLC). METHODS: Between October 2015 and November 2020, 10 patients underwent VATS anatomical lobectomy and en bloc chest wall and spinal resection through a limited posterior midline incision as a single operation for T4 (vertebral involvement) lung cancer. Nine patients had Pancoast syndrome without vascular involvement and 1 patient had NSCLC of the right lower lobe with invasion of T9 and T10. RESULTS: There were 5 men and 5 women. The mean age was 61 years (range: 47-74 years). Induction treatment was administered to 9 patients (90%). The average operative time was 315.5 min (range: 250-375 min). The average blood loss was 665 ml (range: 100-2500 ml). Spinal resection was hemivertebrectomy in 6 patients and wedge corpectomy in 4 patients. Complete resection (R0) was achieved in all patients. The average hospitalization stay was 14 days (range: 6-50 days). There was no in-hospital mortality. The mean follow-up was 32.3 months (range: 6-66 months). Six patients (60%) are alive without recurrence. CONCLUSIONS: VATS is feasible and safe to achieve en bloc resection of NSCLC inviding the spine without compromising oncological efficacy. Further experience and longer follow-up are needed to determine if this approach provides any advantages over thoracotomy.

Isolation and Culture of Precursor Cells from the Adult Human Spinal Cord.

We demonstrated the presence of neural stem cells and/or progenitor cells in the adult human spinal cord. This chapter provides materials and methods to harvest high-quality samples of thoracolumbar, lumbar, and sacral adult human spinal cord and human dorsal root ganglia isolated from brain-dead patients who had agreed before passing to donate their bodies to science for therapeutic and scientific advances. The methods to culture precursor cells from the adult human spinal cord are also described.

Endoscopic transsphenoidal surgery for non-functioning pituitary adenoma: Learning curve and surgical results in a prospective series during initial experience.

Background: To report the initial experience of surgery for non-functioning pituitary adenoma (NFPA) from a neurosurgeon in a dedicated residency training endoscopic transsphenoidal (ETS) program, and detail the surgical and clinical outcomes during this period. Methods: A prospective series of all patients operated for NFPA, using an ETS approach, during the three first years of experience of a newly board-certified neurosurgeon was analysed. Clinical, radiological and peri-operative data were collected. Extent of resection (EOR) was determined by formal volumetric analysis. Impact of the learning curve and predictive factors of gross total resection (GTR) were determined. Results: Fifty-three patients with NFPA were included in this prospective cohort which was divided in two periods of time ("First period": 30 first cases, and "second period": 23 following cases). Baseline characteristics of the patients in the two periods were similar. Overall occurrence of complication was 22% and was not significantly different in the two periods of time. No patient had severe neurological complication. Gross total resection was achieved in 70% of patients. Mean Extent of resection was 96%. In a multiple linear regression model, a higher EOR was positively correlated with experience (p = 0.018) and negatively correlated with Knosp Score equal to 4 (p < 0.001). Predictive factors for GTR were Higher Knosp grade (p = 0,01), higher pre-operative volume (p = 0.03), and second period of time (p = 0.01). Conclusion: NFPA surgery can be safe and efficient during the learning period. Dedicated intensive learning, careful patient selection and multidisciplinary work are key to shorten the learning curve and achieve satisfactory results.

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain.

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.