Brain communications最新文献

Inflammatory bowel disease (IBD) is associated with neuroinflammation, which may contribute to an increased risk of neurodegenerative disorders. This research investigated the potential of transcranial low-intensity pulsed ultrasound (LIPUS) to mitigate colonic inflammation induced by dextran sulphate sodium (DSS), focusing on its effects via the brain-gut axis. Colitis and neuroinflammation were induced in mice by administering 3% (wt/vol) DSS for 7 days. Subsequently, the brain was subjected to LIPUS stimulation at intensities of 0.5 or 1.0 W/cm² for 3 days. Biological samples were analyzed using real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and histological observation. Behavioural dysfunctions were assessed using the open field test, novel object recognition task, and Y-maze test. The alteration in gut microbiota composition was assessed through 16S rRNA sequencing. LIPUS therapy notably alleviated colitis symptoms and suppressed inflammation in both the colon and hippocampus of DSS-exposed mice. Compared with the group treated only with DSS, the LIPUS treatment showed decreased crypt destruction and partial epithelial barrier preservation. Moreover, LIPUS preserved intestinal barrier function by upregulating the levels of occludin and zonula occludens, decreasing the levels of lipopolysaccharide (LPS) and LPS-binding protein in serum, and ameliorating behavioural disorders. Further analysis indicated that LIPUS did not significantly transform the composition of the intestinal microbiota, but the microbial community showed some differences from the community in the DSS-only treatment group. This study demonstrates that transcranial LIPUS stimulation could be a novel therapeutic strategy for IBD and neuroinflammation via regulation of inflammatory interactions across brain-gut axis.

Intracranial pressure (ICP) is typically measured with the head in a neutral position whilst the body is in an upright or supine posture. The effect of body position on ICP is well studied, with ICP greater when supine than when upright. In daily life the head is frequently moved away from the neutral position but how this impacts ICP dynamics is unclear. Knowledge of ICP dynamics in different head-on-body positions may improve future treatments that restore normal ICP dynamics such as CSF drainage shunts. We recruited 57 relatively well, ambulatory patients undergoing clinical ICP monitoring for investigation of possible CSF dynamics disturbances to a single-centre, cross-sectional study. Forty-one patients were non-shunted, seven had a working shunt and nine had a malfunctioning shunt. We measured ICP and ICP pulsatility (pulse amplitude) over 10 or 20 s in different combinations of head and body positions. Positions included right and left head turn and forward tilt in upright (seated, standing) and supine body positions, and right and left lateral tilt and backward tilt in upright body positions. ICP increased by 3-9 mmHg, on average, when the head moved away from neutral to each head position in upright and supine body positions, except for head forward tilt when supine, where ICP did not change. The increase in ICP with head turn and forward tilt in upright body positions was larger in patients with a malfunctioning shunt than with no shunt or a functioning shunt. Pulsatility also increased by 0.5-2 mmHg on average when the head moved away from neutral to each head position in upright and supine body positions, except for head forward tilt in upright body positions where pulsatility slightly decreased by 0.7 mmHg on average. ICP and pulsatility generally increase when the head is moved away from the neutral position, but this depends on a combination of head and body position and shunt status. We propose our results can be explained by a combination of changes to neck vasculature and head orientation relative to gravity. Our findings provide potential reason for patient reports that ICP-related symptoms can be induced and/or exacerbated by head movement and could explain behaviours that avoid excess head movement, such as turning the body rather than the head when looking to the side. Our data describe the predicted change in ICP in different head and body positions and could underpin future smart shunt design.

Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.

Somatic mosaic variants contribute to focal epilepsy, with variants often present only in brain tissue and not in blood or other samples typically assayed for genetic testing. Thus, genetic analysis for mosaic variants in focal epilepsy has been limited to patients with drug-resistant epilepsy who undergo surgical resection and have resected brain tissue samples available. Stereo-EEG (sEEG) has become part of the evaluation for many patients with focal drug-resistant epilepsy, and sEEG electrodes provide a potential source of small amounts of brain-derived DNA. We aimed to identify, validate, and assess the distribution of deleterious mosaic variants in epilepsy-associated genes in DNA extracted from trace brain tissue on individual sEEG electrodes. We enrolled a prospective cohort of 10 paediatric patients with drug-resistant epilepsy who had sEEG electrodes implanted for invasive monitoring. We extracted unamplified DNA and in parallel performed whole-genome amplification from trace brain tissue on each sEEG electrode. We also extracted DNA from resected brain tissue and blood/saliva samples where available. We performed deep sequencing (panel and exome) and analysis for candidate germline and mosaic variants. We validated candidate mosaic variants and assessed the variant allele fraction in amplified and unamplified electrode-derived DNA and across electrodes. We extracted unamplified DNA and performed whole-genome amplification from >150 individual electrodes from 10 individuals. Immunohistochemistry confirmed the presence of neurons in the brain tissue on electrodes. Deep sequencing and analysis demonstrated similar depth of coverage between amplified and unamplified DNA samples but significantly more potential mosaic variants in amplified samples. We validated four deleterious mosaic variants in epilepsy-associated genes in electrode-derived DNA in three patients who underwent laser ablation and did not have resected brain tissue samples available. Three of the four variants were detected in both amplified and unamplified electrode-derived DNA, with higher variant allele fraction observed in DNA from electrodes in closest proximity to the electrical seizure focus in one case. We demonstrate that mosaic variants can be identified and validated from DNA extracted from trace brain tissue on individual sEEG electrodes in patients with drug-resistant focal epilepsy, from both unamplified and amplified electrode-derived DNA. Our findings support a relationship between the extent of regional genetic abnormality and electrophysiology and suggest that with further optimization, this minimally invasive diagnostic approach holds promise for advancing precision medicine for patients with drug-resistant epilepsy as part of the surgical evaluation.

Motor Neuron Disease (MND) is associated with significant non-motor symptoms, including the loss of appetite. Loss of appetite has emerged as a dominant feature of the disease that may contribute to negative energy balance, faster disease progression and earlier death. We examined the prevalence and impact of appetite loss and analysed neural correlates of visual food stimuli with prandial status and appetite in people living with MND (plwMND). 157 plwMND and 120 non-neurodegenerative controls (NND Controls) were assessed for anthropometric, metabolic, appetite and clinical measures. Of these, 35 plwMND and 23 NND Controls underwent further functional MRI assessment of fasting and post-prandial responses to visual food cues. plwMND presented with reduced appetite (P < 0.001), with loss of appetite being more prevalent in plwMND than NND controls [OR = 2.59 (95% CI: = 1.46-4.61)]. Loss of appetite was not associated with hypermetabolism; however, was associated with fat mass loss (P < 0.05). Imaging assessment revealed no overall difference in response between plwMND and NND controls when viewing non-food and food images. In contrast, we found no prandial response in the temporal pole of plwMND compared with NND controls, and decreased activity in the cerebellum relative to appetite in plwMND. Loss of appetite, not hypermetabolism, contributes to negative energy balance in MND. Alterations in the temporal pole and cerebellum could contribute to altered appetite responses in some plwMND-brain regions not widely considered in appetite control-providing additional evidence to support widespread involvement of non-motor areas in the disease.

This scientific commentary refers to 'Edonerpic maleate enhances functional recovery from spinal cord injury with cortical reorganization in non-human primates', by Uramaru et al. (https://doi.org/10.1093/braincomms/fcaf036).

Quantitative susceptibility mapping has been applied to map brain iron distribution after mild traumatic brain injury to understand properties of neural tissue which may be related to cellular dyshomeostasis. However, this is a heterogeneous injury associated with microstructural brain changes, and 'traditional' group-wise statistical approaches may lead to a loss of clinically relevant information, as subtle alterations at the individual level can be obscured by averages and confounded by within-group variability. More precise and individualized approaches are needed to characterize mild traumatic brain injury better and elucidate potential cellular mechanisms to improve intervention and rehabilitation. To address this issue, we use quantitative MRI to build individualized profiles of regional positive (iron-related) magnetic susceptibility across 34 bilateral cortical ROIs following mild traumatic brain injury. Healthy population templates were constructed for each cortical area using standardized Z-scores derived from 25 age-matched male controls aged between 16 and 32 years (M = 21.10, SD = 4.35), serving as a reference against which Z-scores of 35 males with acute (<14 days) sports-related mild traumatic brain injury were compared [M = 21.60 years (range: 16-33), SD = 4.98]. Secondary analyses sensitive to cortical depth and curvature were also generated to approximate the location of iron accumulation in the cortical laminae and the effect of gyrification. Primary analyses indicated that approximately one-third (11/35; 31%) of injured participants exhibited elevated positive susceptibility indicative of abnormal iron profiles relative to the healthy population, a finding that was mainly concentrated in regions within the temporal lobe. Injury severity was significantly higher (P = 0.02) for these participants than their iron-normal counterparts, suggesting a link between injury severity, symptom burden, and elevated cortical iron. Secondary exploratory analyses of cortical depth and curvature profiles revealed abnormal iron accumulation in 83% (29/35) of mild traumatic brain injury participants, enabling better localization of injury-related changes in iron content to specific loci within each region and identifying effects that may be more subtle and lost in region-wise averaging. Our findings suggest that individualized approaches can further elucidate the clinical relevance of iron in mild head injury. Differences in injury severity between iron-normal and iron-abnormal mild traumatic brain injury participants identified in our primary analysis highlight not only why precise investigation is required to understand the link between objective changes in the brain and subjective symptomatology, but also identify iron as a candidate biomarker for tissue pathology after mild traumatic brain injury.

Brain tumours alter brain structures and functions. However, morphometric alterations induced by unilateral vestibular schwannoma, a benign tumour of the vestibulocochlear nerve, have not been extensively explored. Recent studies have suggested that the tumour does not grow bigger following diagnosis in several patients, suggesting an avenue for conservative therapy. This study aims to comprehensively investigate brain structural re-organizations in vestibular schwannoma patients taking into account the effects of hearing loss and tinnitus-the most common symptoms. To this end, preoperative data from 48 vestibular schwannoma pathology-confirmed patients and a healthy control group of 30 volunteers were retrospectively included in this study. The clinical and imaging data from these participants were processed. General linear models were designed to identify tumour-related brain alterations in grey matter volume and cortical thickness, alongside three other surface measures: sulcal depth, gyrification index and fractal dimension. The differences obtained were further analysed for correlation with tumour size and pure tone audiometry. Interestingly, grey matter volume, cortical thickness and for the first time, fractal dimension measures were increased in vestibular schwannoma patients across key frontal regions (P_FWE < 0.05). The precuneus, superior and inferior frontal gyrus had increased grey matter volumes and cortical thickening in patients compared to controls, among other changes (P _FWE < 0.05). Meanwhile, the sulcal depth and gyrification index measures demonstrated no significant alterations. Furthermore, grey matter volume changes at the paracentral lobule and precuneus were positively correlated to the tumour size, while the fractal dimension at the superior frontal sulcus was negatively correlated. Finally, grey matter volume increase at the inferior frontal gyrus and cortical thickening at the supramarginal gyrus were negatively correlated to pure tone audiometry. These findings suggest that factors beyond hearing loss and tinnitus contribute to brain structural alterations in this tumour, a better understanding of which might pave the way for non-surgical symptomatic therapies.

Brain age gap estimation (BrainAGE), the difference between predicted brain age and chronological age, might be a putative biomarker aiming to detect the transition from healthy to pathological brain ageing. The biomarker primarily models healthy ageing with machine learning models trained with structural magnetic resonance imaging (MRI) data. BrainAGE is expected to translate the deviations in neural ageing trajectory and has been shown to be increased in multiple pathologies, such as Alzheimer's disease (AD), schizophrenia and Type 2 diabetes (T2D). Thus, accelerated ageing seems to be a general feature of neuropathological processes. However, neurobiological constraints remain to be identified to provide specificity to this biomarker. Explainability might be the key to uncovering age predictions and understanding which brain regions lead to an elevated predicted age on a given pathology compared to healthy controls. This is highly relevant to understanding the similarities and differences in neurodegeneration in AD and T2D, which remains an outstanding biological question. Sensitivity maps explain models by computing the importance of each voxel on the final prediction, thereby contributing to the interpretability of deep learning approaches. This paper assesses whether sensitivity maps yield different results across three conditions related to pathological neural ageing: AD, schizophrenia and T2D. Five deep learning models were considered, each model trained with different MRI data types: minimally processed T₁-weighted brain scans, and corresponding grey matter, white matter, cerebrospinal fluid tissue segmentation and deformation fields (after spatial normalization). Our results revealed an increased BrainAGE in all pathologies, with a different mean, which is the smallest in schizophrenia; this is in line with the observation that neural loss is secondary in this early-onset condition. Importantly, our findings suggest that the sensitivity, indexing regional weights, for all models varies with age. A set of regions were shown to yield statistical differences across conditions. These sensitivity results suggest that mechanisms of neurodegeneration are quite distinct in AD and T2D. For further validation, the sensitivity and the morphometric maps were compared. The findings outlined a high congruence between the sensitivity and morphometry maps for age and clinical group conditions. Our evidence outlines that the biological explanation of model predictions is vital in adding specificity to the BrainAGE and understanding the pathophysiology of chronic conditions affecting the brain.