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Microglial Dynamics across the Human Lifespan
Microglial cells appear in the brain rudiment at about 4 postconceptional weeks (pcw) (Carnegie stage (CS) 10) and are thought to derive from yolk-sac progenitors similarly to the rodent. By 22 pcw, colonisation of the brain is speculated to be complete. In the adult, these cells turnover at a slow rate (reported between 0.08% and 2% at any one time). Microglial spatiotemporal dynamics have not been carefully examined in the human developing brain particularly in the context of co-occurring developmental processes. It is also unclear when their regional heterogeneity is first established nor how their developmental dynamics contribute to the adult pool. We also do not have a baseline characterisation of microglial cells in old age in the absence of overt pathology. With the appropriate ethical approval, we have obtained frontal and temporal tissues from 10 participating centres in the UK and Europe to study microglial cell dynamics across the human lifespan. 145 individuals aged between the 4th pcw and 90 years are being studied. Transcriptomic data available from the early and mid-fetal periods made it possible to examine the spatiotemporal establishment of the transcriptional signature of microglia in the human. In this presentation we will report on the preliminary findings of our study and how these inform our understanding of microglial function in the developing human brain.
Microglial contribution to the pathology of neurodevelopmental disorders in humans
AbstractMicroglia are the brain’s resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.
Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.
Mapping cellular organization in the developing brain presents significant challenges due to the multidimensional nature of the data, characterized by complex spatial patterns that are difficult to interpret without high-throughput tools. Here, we present DeepCellMap, a deep-learning-assisted tool that integrates multi-scale image processing with advanced spatial and clustering statistics. This pipeline is designed to map microglial organization during normal and pathological brain development and has the potential to be adapted to any cell type. Using DeepCellMap, we capture the morphological diversity of microglia, identify strong coupling between proliferative and phagocytic phenotypes, and show that distinct spatial clusters rarely overlap as human brain development progresses. Additionally, we uncover an association between microglia and blood vessels in fetal brains exposed to maternal SARS-CoV-2. These findings offer insights into whether various microglial phenotypes form networks in the developing brain to occupy space, and in conditions involving haemorrhages, whether microglia respond to, or influence changes in blood vessel integrity. DeepCellMap is available as an open-source software and is a powerful tool for extracting spatial statistics and analyzing cellular organization in large tissue sections, accommodating various imaging modalities. This platform opens new avenues for studying brain development and related pathologies.
The mouse motor system contains multiple premotor areas and partially follows human organizational principles.
While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.
Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.
Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.
Safety of Nonsteroidal Anti‐inflammatory Drugs in Major Gastrointestinal Surgery: A Prospective, Multicenter Cohort Study
AbstractBackgroundSignificant safety concerns remain surrounding the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) following gastrointestinal surgery, leading to wide variation in their use. This study aimed to determine the safety profile of NSAIDs after major gastrointestinal surgery.MethodsConsecutive patients undergoing elective or emergency abdominal surgery with a minimum one‐night stay during a 3‐month study period were eligible for inclusion. The administration of any NSAID within 3 days following surgery was the main independent variable. The primary outcome measure was the 30‐day postoperative major complication rate, as defined by the Clavien–Dindo classification (Clavien–Dindo III–V). Propensity matching with multivariable logistic regression was used to produce odds ratios (OR) and 95 % confidence intervals.ResultsFrom 9264 patients, 23.9 % (n = 2212) received postoperative NSAIDs. The overall major complication rate was 11.5 % (n = 1067). Following propensity matching and adjustment, use of NSAIDs were not significantly associated with any increase in major complications (OR 0.90, 0.60–1.34, p = 0.560).ConclusionsEarly use of postoperative NSAIDs was not associated with an increase in major complications following gastrointestinal surgery.
Multicentre prospective cohort study of body mass index and postoperative complications following gastrointestinal surgery
Abstract Background There is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications. Methods This was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4-month interval (October–December 2014) were eligible for inclusion. The primary outcome was the 30-day major complication rate (Clavien–Dindo grade III–V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital-level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.). Results Of 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30-day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147). Conclusion Overweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.
High-resolution spatio-temporal bioactivity of a novel peptide revealed by optical imaging in rat orbitofrontal cortex in vitro: possible implications for neurodegenerative diseases.
Acetylcholinesterase (AChE) is now well known to have a secondary, non-enzymatic function independent of cholinergic transmission. In the last decade, the part of the molecule responsible for this action has been identified, i.e. a 14 amino acid peptide fragment ('T14'), deriving from the C-terminus of AChE: this peptide has been shown to be bioactive in a range of preparations and to act at an allosteric site on α₇ nicotinic acetylcholine receptors (α₇-nAChRs). Of particular significance is the finding that AChE-related peptides trigger calcium-induced neurotoxicity that may be pivotal in the process of neurodegenerative diseases, such as Alzheimer's. However to date all studies have been performed on isolated cell preparations. The aim of this study was therefore to characterise the bioactivity of T14 on meso-scale in vitro cortical networks ('neuronal assemblies') from rat brain slices containing orbitofrontal cortex. Local field potential (LFP) recordings showed that the T14 peptide has a selective, holistic action on cortical networks in a modulatory biphasic manner i.e. predisposing excitation at concentrations of up to 1 μM, after which the trend is reversed in favour of inhibition at higher doses (>1 μM). By contrast, a scrambled variant of the T14 peptide sequence (S14), showed no significant changes in neuronal activation. Optical imaging using voltage-sensitive dyes (VSDI) corroborated the electrophysiological findings and also provided further insight into the spatial dynamics of the effects of the peptide: T14 application had a facilitatory effect i.e. increased the time-course of activation at sub-micromolar concentrations only (700 nM) without significantly affecting the spread of evoked assemblies. Moreover: co-applying T14 with the α₇-nAChR competitive antagonist methyllycaconitine (MLA) produced inhibition in activation synchrony not seen with either agent on their own, suggesting an additive inhibitory effect. In conclusion, the T14 peptide derived from AChE produced a dose-dependent biphasic modulation of cortical networks activity dependent on the α₇-nAChR: these findings should thus provide a more comprehensive insight into the immediate actions of a novel bioactive agent of high potential relevance to neurodegenerative disorders such as Alzheimer's disease.
Deep brain stimulation and motor cortex stimulation for central post-stroke pain: a systematic review and meta-analysis
Abstract Introduction Deep brain stimulation (DBS) and motor cortex stimulation (MCS) are invasive interventions in order to treat various neuropathic pain syndromes such as central post-stroke pain (CPSP). While each treatment has varying degree of success, comparative analysis has not yet been performed, and the success rates of these techniques using validated, objective pain scores have not been synthesized. Methods A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Three databases were searched, and articles published from January 2000 to October 2024 were included (last search date October 25, 2024). Meta-Analysis was performed using random effects models. We evaluated the performance of DBS or MCS by assessing studies that reported pain relief using visual analogue scale (VAS) or numerical rating scale (NRS) scores. Results Of the 478 articles identified, 32 were included in the analysis (330 patients—139 DBS and 191 MCS). The improvement in mean VAS score for patients that underwent DBS post-surgery was 48.6% compared to a score of 53.1% for patients that had MCS. The pooled number of patients who improved after DBS was 0.62 (95% CI, 0.51–0.71, I2 = 16%). The pooled number of patients who improved after MCS was 0.64 (95% CI, 0.53–0.74, I2 = 40%). Conclusion The use of neurosurgical interventions such as DBS and MCS are last-resort treatments for CPSP, with limited studies exploring and comparing these two techniques. While our study shows that MCS might be a slightly better treatment option, further research would need to be done to determine the appropriate surgical intervention in the treatment of CPSP.
Early and ultra-early surgical decompression for acute spinal cord injury: bracing for the winds of change.
PURPOSE: Until recently, there has been no consensus on the optimal operative window for decompressive surgery in acute spinal cord injury (aSCI). However, recent evidence is now supporting a role for early intervention in improving outcomes in this type of patients. The purpose of this letter is to discuss the implications for clinical practice within the European community. METHODS: Critical appraisal and interpretation of these results for clinical implementation. RESULTS: Leveraging on the evidence that early (