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Traumatic spinal cord injury occurs when an external physical impact damages the spinal cord and leads to permanent neurological dysfunction and disability, and it is associated with a high socioeconomic burden. Conventional MRI plays a crucial role in the diagnostic workup as it reveals extrinsic compression of the spinal cord and disruption of the discoligamentous complex. Additionally, it can reveal macrostructural evidence of primary intramedullary damage such as haemorrhage, oedema, post-traumatic cystic cavities, and tissue bridges. Quantitative MRI, such as magnetisation transfer, magnetic resonance relaxation mapping, and diffusion imaging, enables the tracking of secondary changes across the neuraxis at the microstructural level. Both conventional MRI and quantitative MRI metrics, obtained early after spinal cord injury, are predictive of clinical outcome. Thus, neuroimaging biomarkers could serve as surrogate endpoints for more efficient future trials targeting acute and chronic spinal cord injury. The adoption of neuroimaging biomarkers in centres for spinal cord injury might lead to personalised patient care.

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that remains difficult to treat because underlying mechanisms are not yet fully understood. In part, this is due to limitations of evaluating neuropathic pain in animal models in general, and SCI rodents in particular. Though pain in patients is primarily spontaneous, with relatively few patients experiencing evoked pains, animal models of SCI pain have primarily relied upon evoked withdrawals. Greater use of operant tasks for evaluation of the affective dimension of pain in rodents is needed, but these tests have their own limitations such that additional studies of the relationship between evoked withdrawals and operant outcomes are recommended. In preclinical SCI models, enhanced reflex withdrawal or pain responses can arise from pathological changes that occur at any point along the sensory neuraxis. Use of quantitative sensory testing for identification of optimal treatment approach may yield improved identification of treatment options and clinical trial design. Additionally, a better understanding of the differences between mechanisms contributing to at- versus below-level neuropathic pain and neuropathic pain versus spasticity may shed insights into novel treatment options. Finally, the role of patient characteristics such as age and sex in pathogenesis of neuropathic SCI pain remains to be addressed.

Purpose: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T 1 , T 2 and T 3A ), minimal postoperative residual tumor, and no evidence of dissemination (Mo). Methods and Materials: Between June 1986 and November 1990, the Children’s Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm 3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose. Results: Following an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation. Conclusions: In patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

The molecular mechanisms that produce the full array of neuronal subtypes in the vertebrate nervous system are incompletely understood. Here, we provide evidence of a global temporal patterning program comprising sets of transcription factors that stratifies neurons based on the developmental time at which they are generated. This transcriptional code acts throughout the central nervous system, in parallel to spatial patterning, thereby increasing the diversity of neurons generated along the neuraxis. We further demonstrate that this temporal program operates in stem cell−derived neurons and is under the control of the TGFβ signaling pathway. Targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their functional requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal transcriptional program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning mechanisms diversifies and organizes neuronal subtypes in the vertebrate nervous system.

Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.

Leptomeningeal metastatic disease (LMD), encompassing entities of ‘meningeal carcinomatosis’, neoplastic meningitis’ and ‘leukaemic/lymphomatous meningitis’, arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients. Underdiagnosis and misdiagnosis are common, response assessment remains challenging, and the prognosis associated with this disease of whole neuroaxis remains extremely poor. The dearth of effective therapies is further challenged by the difficulties in studying this dynamic disease state. In this Review, a multidisciplinary group of experts describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Drawing upon paradigm-changing advances in mechanistic science, computational approaches, and trial design, the authors discuss domain-specific and cross-disciplinary strategies for optimizing the clinical and translational research landscape for LMD. Advances in diagnostics, multi-agent intrathecal therapies, cell-based therapies, immunotherapies, proton craniospinal irradiation and ongoing clinical trials offer hope for improving outcomes for patients with LMD. Leptomeningeal metastatic disease (LMD) arises secondary to the metastatic dissemination of cancer cells into the leptomeninges and cerebrospinal fluid. Novel therapies against systemic disease have not yet translated into improved outcomes for patients with LMD, in whom median survival after diagnosis remains at 2–6 months. The authors of this Review, a multidisciplinary group of experts, describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Key points The pathogenesis of leptomeningeal metastatic disease (LMD) is distinct from that of brain metastases. Cancer cell dissemination and attachment to the leptomeninges involves remodelling of the blood–choroid plexus barrier and the pia mater. Unique mechanisms for cancer cell survival within the resource-scarce cerebrospinal fluid (CSF) include outcompeting tumour-associated macrophages, elevated levels of branched-chain keto-acids, and exploitation of the complement system. Advances in the development of tools for diagnostic confirmation, disease surveillance and standardized criteria for response assessment will enable the comprehensive longitudinal work-up of LMD, with potential for integration of CSF liquid biopsy. Trials testing the efficacy of novel therapeutic approaches in patients with LMD, such as systemic antibody–drug conjugates, intrathecal targeted therapies and immunotherapies (including dendritic cell-based vaccines), are warranted, whereas promising data are emerging for strategies such as proton-based craniospinal irradiation. Learning from prior failures in neuro-oncology through better-optimized trials and international prospective registries remains essential for the success of future studies, a focus of which should be longitudinal CSF profiling. The implementation of an LMD-specific core outcome set, meticulous pharmacokinetic and pharmacodynamic evaluations prior to late-phase trials, use of CSF flow studies in trials of intrathecal therapies, integration with multi-omics analyses, and use of adaptive designs will help to optimize future trials.

A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months’ time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs. Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses.

Humans are exquisitely sensitive to the microstructure and material properties of surfaces. In the peripheral nerves, texture information is conveyed via two mechanisms: coarse textural features are encoded in spatial patterns of activation that reflect their spatial layout, and fine features are encoded in highly repeatable, texture-specific temporal spiking patterns evoked as the skin moves across the surface. Here, we examined whether this temporal code is preserved in the responses of neurons in somatosensory cortex. We scanned a diverse set of everyday textures across the fingertip of awake macaques while recording the responses evoked in individual cortical neurons. We found that temporal spiking patterns are highly repeatable across multiple presentations of the same texture, with millisecond precision. As a result, texture identity can be reliably decoded from the temporal patterns themselves, even after information carried in the spike rates is eliminated. However, the combination of rate and timing is more informative than either code in isolation. The temporal precision of the texture response is heterogenous across cortical neurons and depends on the submodality composition of their input and on their location along the somatosensory neuraxis. Furthermore, temporal spiking patterns in cortex dilate and contract with decreases and increases in scanning speed, respectively, and this systematic relationship between speed and patterning may contribute to the observed perceptual invariance to speed. Finally, we find that the quality of a texture percept can be better predicted when these temporal patterns are taken into consideration. We conclude that high-precision spike timing complements rate-based signals to encode texture in somatosensory cortex. Neuroscientists seek to understand how neuronal signals carry information and drive perception. Here, the authors show that millisecond-level spike timing in somatosensory cortex is informative about texture and shapes the evoked sensory experience.

The cerebellum is a pivotal centre for the integration and processing of motor and sensory information. Its extended development into the postnatal period makes this structure vulnerable to a variety of pathologies, including neoplasia. These properties have prompted intensive investigations that reveal not only developmental mechanisms in common with other regions of the neuraxis but also unique strategies to generate neuronal diversity. How the phenotypically distinct cell types of the cerebellum emerge rests on understanding how gene expression differences arise in a spatially and temporally coordinated manner from initially homogeneous cell populations. Increasingly sophisticated fate mapping approaches, culminating in genetic-induced fate mapping, have furthered the understanding of lineage relationships between early- versus later-born cells. Tracing the developmental histories of cells in this way coupled with analysis of gene expression patterns has provided insight into the developmental genetic programmes that instruct cellular heterogeneity. A limitation to date has been the bulk analysis of cells, which blurs lineage relationships and obscures gene expression differences between cells that underpin the cellular taxonomy of the cerebellum. This review emphasises recent discoveries, focusing mainly on single-cell sequencing in mouse and parallel human studies that elucidate neural progenitor developmental trajectories with unprecedented resolution. Complementary functional studies of neural repair after cerebellar injury are challenging assumptions about the stability of postnatal cellular identities. The result is a wealth of new information about the developmental mechanisms that generate cerebellar neural diversity, with implications for human evolution.