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Cervical ossification of the posterior longitudinal ligament (OPLL) is a contributing factor to spinal cord injury or trauma-induced myelopathy in the elderly. To reduce the incidence of these traumas, it is essential to diagnose OPLL at an early stage and to educate patients how to prevent falls. We thus evaluated the ability of our convolutional neural network (CNN) to differentially diagnose cervical spondylosis and cervical OPLL. We enrolled 250 patients with cervical spondylosis, 250 patients with cervical OPLL, and 180 radiographically normal controls. We evaluated the ability of our CNN model to distinguish cervical spondylosis, cervical OPLL, and controls, and the diagnostic accuracy was compared to that of 5 board-certified spine surgeons. The accuracy, average recall, precision, and F1 score of the CNN for classification of lateral cervical spine radiographs were 0.86, 0.86, 0.87, and 0.87, respectively. The accuracy was higher for CNN compared to any expert spine surgeon, and was statistically equal to 4 of the 5 experts and significantly higher than that of 1 expert. We demonstrated that the performance of the CNN was equal or superior to that of spine surgeons.

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.

The purpose of this study was to compare the short-term clinical outcomes between extreme lateral interbody fusion (XLIF) and minimally invasive surgery (MIS)–transforaminal interbody fusion (TLIF) in patients with degenerative spondylolisthesis with stenosis. One hundred-six patients were enrolled; 44 were treated with MIS–TLIF (direct decompression group; DP), and 62 were treated with XLIF (indirect decompression group; IDP). Perioperative indexes included operation time and intraoperative bleeding. Perioperative indexes preoperative and postoperative numeric rating scale (NRS) scores for low back pain (NRS-BP), leg pain (NRS-LP), and leg numbness (NRS-LN), and the preoperative score on the Japanese version of the painDETECT questionnaire (PDQ-J) were also assessed. The average follow-up period for the collection of NRS scores was 12.6 months. The operation time was significantly shorter in the IDP than in the DP group (109.9 ± 35.4 vs. 153.3 ± 50.9 min; p p p

Despite the importance of sleep and the evidence on its relationship with various chronic diseases, quality of sleep is not considered in patients with lumbar spinal stenosis (LSS). This prospective comparative study aimed to investigate the changes in sleep disturbance after treatment in patients with LSS. Patients with LSS and sleep disturbance (n = 201; 147 conservatively treated and 54 patients with surgical treatment) were included. The Pittsburgh sleep quality index (PSQI) was used to evaluate sleep quality. Propensity score matching was used to attenuate the potential bias. Clinical outcome of surgery, as determined by the Oswestry disability index, and the PSQI was compared between the two groups at 6 weeks, 3 months, and 6 months after enrollment. Multivariate logistic analysis was performed to adjust for possible confounders within the matched cohorts. Among the 201 patients, 96 (47.7%) patients were finally matched (48 patients in each group). Sleep quality was initially improved after treatment, regardless of the treatment method. Sleep quality in the surgical group was improved by 6 weeks after surgery and consistently improved during the 6-month follow-up period, despite less use of pain killer. Conversely, the improvement in sleep quality at 6-weeks following conservative treatment was not maintained during the follow-up, although the treatment outcome for LSS measured by ODI was continuously improved. After multivariate logistic regression analysis within propensity score matched cohorts, surgical treatment had a significantly greater chance to improve sleep quality compared to conservative treatment. The failure of sleep improvement in conservative group was significantly associated with depression presented by worse score in Hamilton depression rating scale, and more severe degree of foraminal-type stenosis, which should be carefully considered for conservative treatment of LSS patients with sleep disturbance.

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability., Fragile X syndrome and autism spectrum disorders are associated with circuit hyperexcitability, however, its cellular and synaptic bases are not well understood. Here, the authors report abnormal synaptogenesis with an increased prevalence of polysynaptic spines with normal morphology in a mouse model of fragile X.

Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2+/−) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2+/− rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning., Synaptic pruning is important during development and synaptic plasticity. Here, the authors show that the dopamine D2 receptor (Drd2) in the anterior cingulate cortex regulates synaptic pruning, affecting LTD and behaviour in transgenic rats.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization., This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant IJCI-2016-27658 to PMS, Grant PGC2018-094307-B-I00), the Cajal Blue Brain Project (the Spanish partner of the Blue Brain Project initiative from EPFL, Switzerland) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0066, Spain). JBP is currently supported by Grants from the Swedish Research Council (#2018-02201), Hjärnfonden (#FO2019-0289), Alzheimerfonden (#AF-930827) and the Strategic Research Programme in Neuroscience at Karolinska Institutet (Stratneuro Startup Grant).

A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorders after injury or disease insults to the CNS. Here, we used an adeno-associated viral (AAV)-mediated Cre-Lox system to knockout Rac1 protein expression in motor neurons after SCI. Three weeks after AAV9-Cre delivery into the soleus/gastrocnemius of Rac1-“floxed” adult mice to retrogradely infect spinal alpha-motor neurons, we observed significant restoration of RDD and reduced H-reflex excitability in SCI animals. Additionally, viral-mediated Rac1 knockdown reduced presence of dendritic spine dysgenesis on motor neurons. In control SCI animals without Rac1 knockout, we continued to observe abnormal dendritic spine morphology associated with hyperexcitability disorder, including an increase in mature, mushroom dendritic spines, and an increase in overall spine length and spine head size. Taken together, our results demonstrate that viral-mediated disruption of Rac1 expression in ventral horn motor neurons can mitigate dendritic spine morphological correlates of neuronal hyperexcitability, and reverse hyperreflexia associated with spasticity after SCI. Finally, our findings provide evidence of a putative mechanistic relationship between motor neuron dendritic spine dysgenesis and SCI-induced spasticity.

Radiotherapy has played an important role in the treatment of spinal metastases. One of the major complications of radiotherapy is vertebral compression fracture (VCF). Although the spinal instability neoplastic score (SINS) was developed for evaluating spinal instability in patients with spinal metastases, it is also commonly used to predict VCF after radiotherapy in patients with spinal metastases. However, its accuracy for predicting radiotherapy-induced VCF and precision remain controversial. The aim of this study was to clarify the diagnostic value of the SINS to predict radiotherapy-induced VCF and to make recommendations for improving its diagnostic power. We searched core databases and identified 246 studies. Fourteen studies were analyzed, including 7 studies (with 1269 segments) for accuracy and 7 studies (with 280 patients) for precision. For accuracy, the area under the summary receiver operating characteristic curve was 0.776. When a SINS cut-off value of 7 was used, as was done in the included studies, the pooled sensitivity was 0.790 and the pooled specificity was 0.546. For precision, the summary estimate of interobserver agreement was the highest dividing 2 categories based on a cut-off value of 7, and the value was 0.788. The body collapse showed moderate relationship and precision with the VCF. The lytic tumor of bone lesion showed high accuracy and fair reliability, while location had excellent reliability, but low accuracy. The SINS system can be used to predict the occurrence of VCF after radiotherapy in spinal metastases with moderate accuracy and substantial reliability. Increasing the cut-off value and revising the domains may improve the diagnostic performance to predict the VCF of the SINS.

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.

Cerebrospinal fluid (CSF) circulation relies on the beating of motile cilia projecting in the lumen of the brain and spinal cord cavities Mutations in genes involved in cilia motility disturb cerebrospinal fluid circulation and result in scoliosis-like deformities of the spine in juvenile zebrafish. However, these defects in spine alignment have not been validated with clinical criteria used to diagnose adolescent idiopathic scoliosis (AIS). The aim of this study was to describe, using orthopaedic criteria the spinal deformities of a zebrafish mutant model of AIS targeting a gene involved in cilia polarity and motility, cfap298tm304. The zebrafish mutant line cfap298tm304, exhibiting alteration of CSF flow due to defective cilia motility, was raised to the juvenile stage. The analysis of mutant animals was based on micro-computed tomography (micro-CT), which was conducted in a QUANTUM FX CALIPER, with a 59 µm-30 mm protocol. 63% of the cfap298tm304 zebrafish analyzed presented a three-dimensional deformity of the spine, that was evolutive during the juvenile phase, more frequent in females, with a right convexity, a rotational component and involving at least one dislocation. We confirm here that cfap298tm304 scoliotic individuals display a typical AIS phenotype, with orthopedic criteria mirroring patient’s diagnosis.

The actin binding protein drebrin plays a key role in dendritic spine formation and synaptic plasticity. Decreased drebrin protein levels have been observed in temporal lobe epilepsy, suggesting the involvement of drebrin in the disease. Here we investigated the effect of drebrin knockout on physiological and pathophysiological neuronal network activities in mice by inducing gamma oscillations, involved in higher cognitive functions, and by analyzing pathophysiological epileptiform activity. We found that loss of drebrin increased the emergence of spontaneous gamma oscillations suggesting an increase in neuronal excitability when drebrin is absent. Further analysis showed that although the kainate-induced hippocampal gamma oscillations were unchanged in drebrin deficient mice, seizure like events measured in the entorhinal cortex appeared earlier and more frequently. The results suggest that while drebrin is not essential for normal physiological network activity, it helps to protect against the formation of seizure like activities during pathological conditions. The data indicate that targeting drebrin function could potentially be a preventive or therapeutic strategy for epilepsy treatment.

Intervertebral disc (IVD) degeneration with chronic low back pain is associated with neo-vascularisation into the deeper IVD regions. During this process, endothelial cells (ECs), which are primarily responsible for angiogenesis, interact with the adjacent annulus fibrosus (AF) cells, which are the first line of defence against the invasion of vascular structures into deeper IVD regions. However, the accumulation of inflammatory and catabolic enzymes that results from this interaction promotes matrix degradation and an inflammatory response. Thus, regulating the production of these mediators and catabolic enzymes could ameliorate IVD degeneration. Photobiomodulation (PBM) therapy is a non-invasive stimulation known to have biologically beneficial effects on wound healing, tissue repair, and inflammation. Here, we examined the effects of PBM, administered at various wavelengths (645, 525, and 465 nm) and doses (16, 32, and 64 J/cm2), on EC-stimulated human AF cells. Our results show that PBM selectively inhibited the EC-mediated production of inflammatory mediators, catabolic enzymes, and neurotrophins by human AF cells in a dose- and wavelength-dependent manner. These results suggest that PBM could be a superior and advanced treatment strategy for IVD degeneration.

This work for funded by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/M021793/1), RS MacDonald Charitable Trust, Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Engineering and Physical Sciences Research Council (EPSRC; EP/P030017/1), Welcome Trust (202932/Z/16/Z), European Research Council (ERC; 695568) and the Simons Initiative for the Developing Brain. Functionally distinct synapses exhibit diverse and complex organisation at molecular and nanoscale levels. Synaptic diversity may be dependent on developmental stage, anatomical locus and the neural circuit within which synapses reside. Furthermore, astrocytes, which align with pre and post-synaptic structures to form “tripartite synapses”, can modulate neural circuits and impact on synaptic organisation. In this study, we aimed to determine which factors impact the diversity of excitatory synapses throughout the lumbar spinal cord. We used PSD95-eGFP mice, to visualise excitatory postsynaptic densities (PSDs) using high-resolution and super-resolution microscopy. We reveal a detailed and quantitative map of the features of excitatory synapses in the lumbar spinal cord, detailing synaptic diversity that is dependent on developmental stage, anatomical region and whether associated with VGLUT1 or VGLUT2 terminals. We report that PSDs are nanostructurally distinct between spinal laminae and across age groups. PSDs receiving VGLUT1 inputs also show enhanced nanostructural complexity compared with those receiving VGLUT2 inputs, suggesting pathway-specific diversity. Finally, we show that PSDs exhibit greater nanostructural complexity when part of tripartite synapses, and we provide evidence that astrocytic activation enhances PSD95 expression. Taken together, these results provide novel insights into the regulation and diversification of synapses across functionally distinct spinal regions and advance our general understanding of the ‘rules’ governing synaptic nanostructural organisation. Publisher PDF

While ephrin-B ligands and EphB receptors are expressed to high levels in the learning centers of the brain, it remains largely unknown how their trans-synaptic interactions contribute to memory. We find that EphB2 forward signaling is needed for contextual and sound-evoked memory recall and that constitutive over-activation of the receptor’s intracellular tyrosine kinase domain results in enhanced memory. Loss of EphB2 expression does not affect the number of neurons activated following encoding, although a reduction of neurons activated after the sound-cued retrieval test was detected in the auditory cortex and hippocampal CA1. Further, spine density and maturation was reduced in the auditory cortex of mutants especially in the neurons that were dual-activated during both encoding and retrieval. Our data demonstrates that trans-synaptic ephrin-B-EphB2 interactions and forward signaling facilitate neural activation and structural plasticity in learning-associated neurons involved in the generation of memories., Talebian and Henkemeyer show that the Ephrin B receptor 2 (EphB2) is important for memory. They reveal that loss of EphB2 in mice leads to fewer neurons being activated during memory retrieval, reduced synaptic complexity and a reduction in context recall and tone recall memories.

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO+-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues., The lymphatic vasculature is essential to maintain fluid homeostasis and immune surveillance, including in the brain where lymphatic vessels were only recently identified. Here, Jacob et al. provide an anatomical map of lymphatic vessels in the vertebral column, where they find these contribute to fluid drainage and immune responses.

Activity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT4 (5-HT4R) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction. In neuroblastoma cells, this leads to cell rounding and neurite retraction. In hippocampal neurons in situ, 5-HT4R-mediated RhoA activation triggers maturation of dendritic spines. This is paralleled by RhoA-dependent, transient alterations in cell excitability, as reflected by increased spontaneous synaptic activity, apparent shunting of evoked synaptic responses, and enhanced long-term potentiation of excitatory transmission. The 5-HT4R/G13/RhoA signaling thus emerges as a previously unrecognized molecular pathway underpinning use-dependent functional remodeling of excitatory synaptic connections., Schill, Bijata, Kopach et al. show that 5-HT4R activation leads to maturation of dendritic spines in hippocampal neurons via G13/RhoA signaling. The dendritic changes are complemented with corresponding changes in excitatory transmission, suggesting a role for 5-HT4R in dendritic spine remodeling.