Brain communications最新文献

Incision pain is a prevalent condition in clinical practice, affecting approximately 50% of patients and significantly diminishing their quality of life. However, the central mechanisms underlying incision pain remain unclear. Here, we established a paw incision model that increased neuronal excitability in the paraventricular thalamic nucleus (PVT). Multiple tracing methods revealed an inhibitory ascending neural pathway from the dorsal raphe nucleus (DRN) to the PVT, with external nociceptive stimuli enhancing the activity of this pathway. Inhibition of the DRN^GABA-PVT pathway induced nociceptive sensitivity in normal mice, while activation of this pathway alleviated incision pain. Notably, antagonists targeting GABA_A receptors-not GABA_B receptors-administered into the PVT blocked DRN^GABA-PVT activation and produced significant analgesic effects on incision pain. Collectively, these findings suggest that GABAergic neurons in the DRN play an analgesic role by acting on GABA_A receptors in the PVT.

While some anatomical brain asymmetries are seen across primates, the earlier appearance and larger depth of the right superior temporal sulcus (STS) is specific to human foetuses. Interestingly, the degree of STS asymmetry varies between foetuses, and it has been shown that this interindividual variability is related to the functional lateralization of the language network in school-aged children. It remains unclear, however, whether it is also indicative of language localization and functioning shortly after birth. In the present longitudinal study, we prospectively examined the predictive value of foetal STS asymmetry for neonates' language lateralization and neural speech discrimination. We measured the STS depths and volumes in neurotypical foetuses (N = 35) using foetal MRI. After birth, we investigated the neonates' haemodynamic response to forward and backward speech using functional near-infrared spectroscopy. We hypothesized that less rightward asymmetry of the STS depths in the foetal brain is related to increased left language lateralization and to a greater haemodynamic difference between speech conditions in the left hemisphere in neonates. While the foetuses demonstrated an overall rightward asymmetry of the STS depths and volumes, the degree of asymmetry varied between individuals. After birth, the group activated left frontal and right temporal regions during the speech discrimination paradigm. Again, there was variability in the degree of neural activation in response to speech. Importantly, we found that children with a foetal STS depth asymmetry towards the left hemisphere activated their right hemisphere less for forward speech (r = -0.58, P = 0.002) and differentiated less between forward and backward speech in their right hemisphere (r = -0.48, P = 0.014). Contrary to our initial hypothesis, the results suggest that an earlier structural development of the left temporal lobe goes along with reduced involvement of the right hemisphere, rather than an increased involvement of the left hemisphere, during neural speech discrimination. Given that rightward asymmetry of language-related brain areas has been associated with weaker language abilities, the present study provides important preliminary data regarding the neural underpinnings of language development during the prenatal and early postnatal period.

Following traumatic brain injury, the ability of conventional diffusion-weighted MRI analysis techniques to resolve tract-specific white matter damage, particularly in crossing fibre regions, is limited. Using fixel-based analysis, this study aimed to identify white matter abnormalities in chronic traumatic brain injury patients and to resolve the effects of traumatic brain injury on distinct white matter tracts, especially in crossing fibre regions. In this cross-sectional study, diffusion-weighted MRI were acquired from adults with chronic moderate-to-severe traumatic brain injury (N = 29; median time since injury 1.9 years) and matched healthy controls (N = 17). Whole-brain and tract-of-interest analyses compared differences in white matter connectivity represented by fixel-wise metrics (fibre density, fibre bundle cross-section and combined fibre density and bundle cross-section) between groups. Regions where crossing white matter fibres demonstrates differential damage were identified. Significant reductions were found in all corrected fixel-wise metrics in traumatic brain injury patients, with distinct spatial distributions between metrics. Combined fibre density and bundle cross-section demonstrated the highest sensitivity out of the fixel-wise metrics and fractional anisotropy, detecting abnormalities in 73.6% of examined tracts. Fixel-based analysis resolved the distinct effects of traumatic brain injuries on crossing fibres with 14% of tract pairings containing crossing fibres (131/927) demonstrating robust evidence of differential damage (i.e. significant difference between groups in the fixel-wise metric of one tract in the pair but not the other tract within the same voxel). Fixel-based analysis identified variabilities in white matter abnormalities in traumatic brain injury patients. Crucially, fixel-based analysis was able to resolve injury-related tract-specific alterations even in crossing fibre regions, supporting further exploration of fixel-wise metrics as more specific biomarkers of white matter alterations in traumatic brain injury.

The ε4 allele of the APOE gene, encoding the E4 isoform of apolipoprotein E, is the leading genetic risk factor for late-onset Alzheimer's disease. While many potential mechanisms have been proposed to explain this risk, no dominant or unifying process has yet emerged. Here, we explore the primary function of apolipoprotein E in lipid transport and metabolism, by examining its lipid association properties, to establish whether they show isoform dependence and thereby could mediate Alzheimer's risk. We focus on ethanolamine plasmalogen, a phospholipid subclass known to be depleted in Alzheimer's disease brain. We purified apolipoprotein E from human cerebrospinal fluid by immunoprecipitation using an anti-pan-apolipoprotein E monoclonal antibody bound to magnetic beads, then conducted lipidomic and proteomic analyses of the precipitates by mass spectrometry. The cerebrospinal fluid samples were obtained from cognitively intact, relatively young individuals with no evidence of amyloid pathology and with known apolipoprotein E isoform status (E3E3, n = 5; E3E4, n = 4; E4E4, n = 5). The molar ratio of ethanolamine plasmalogen to apolipoprotein E was 29.5% lower for E4E4 than for E3E3 (P = 0.007) with a biological gradient: E3E3 > E3E4 > E4E4 (P = 0.03). No similar trends and differences were found for phosphatidyl ethanolamine, a chemically related lipid (P = 0.5). Compared to E3E3, the molar ratio of ethanolamine plasmalogen to phosphatidyl ethanolamine was significantly reduced for E3E4 (P = 0.0016) and E4E4 (P = 0.0001). The latter deficiency was similar in magnitude to that found in Alzheimer's disease brain relative to control. The finding that ethanolamine plasmalogen is depleted in apolipoprotein E4 relative to E3 strengthens the view that brain deficiency of this same lipid contributes to Alzheimer's disease causation, rather than being an effect of the neurodegeneration. Simultaneously, these results supply a potential mechanism for the risk of E4 versus E3, the former being less able to counteract the tissue defect. The apolipoprotein E4 lipid depletion cannot itself be a consequence of Alzheimer's disease, since cerebrospinal fluid samples were taken from individuals with no evidence of the condition. The biological gradient in ethanolamine plasmalogen deficiency mirrors the relationship of Alzheimer's disease risk (odds ratio) to E4 allelic dose. Ethanolamine plasmalogen deficiency could be linked to, or indeed drive, several metabolic pathways implicated in Alzheimer's pathogenesis, including amyloid-beta deposition and cholesterol dysregulation. Future studies should extend approaches to therapeutic intervention in Alzheimer's disease which attempt to reverse this lipid abnormality.

[This corrects the article DOI: 10.1093/braincomms/fcaf204.].

The objective of this study was to quantify the variability of cortical blood flow during cognitive load as an indicator of disease-related changes in cerebral capillary blood flow intermittency in patients with post-COVID-19 syndrome. The regulation of cerebral blood flow in the dorsolateral prefrontal cortex under cognitive load was examined using high-resolution functional near-infrared spectroscopy in 36 subjects including 12 patients with post-COVID-19 syndrome and two control groups [12 coronary artery disease patients matched for age and 12 young healthy individuals (CTRL)]. To induce cognitive load, a Flanker task and an N-back task were employed. The structure of temporal variability of local blood flow regulation was assessed using sample entropy at 17 channels spanning both brain hemispheres. The spatial variability of the regional blood flow pattern was evaluated using the coefficient of variation (CV) from sample entropies across all channels. Results revealed a notable discrepancy in that patients with post-COVID-19 syndrome exhibited reduced temporal variability (lower sample entropy) but elevated spatial variability (higher CV) in comparison to coronary artery disease patients during cognitive load (P = 0.02). In the N-back task, the spatial variability increased from healthy individuals to coronary artery disease patients to patients with post-COVID-19 syndrome and was associated with longer reaction time and with lower accuracy. The results confirmed that dynamic cerebral blood flow is altered in patients with post-COVID-19 syndrome, which may be related to fatigue during cognitive tasks. Sample entropy and CV values represent different aspects of blood flow regulation fluctuation. Their simultaneous analysis enabled a meaningful distinction between groups suggesting disease-related changes in brain haemodynamic. The presented method is therefore suitable for describing current states of cortical blood flow regulation and for documenting intervention results in patients with post-COVID-19 syndrome or patients with similar symptoms (e.g. myalgic encephalomyelitis/chronic fatigue syndrome).

Brain arteriovenous malformations (AVMs) are potentially life-threatening vascular anomalies that pose significant clinical challenges due to their heterogeneous anatomy and unpredictable natural history. Existing risk stratification models largely rely on isolated imaging markers and fail to account for the dynamic spatial-temporal complexity of AVMs. Building on our prior work, demonstrating how ontogenesis dictates clinical outcomes of neuroepithelial tumours, we hypothesize that AVMs are similarly influenced by developmental processes that define their spatial distribution, vascular architecture and susceptibility to complications. Here, we present the protocol and pilot data of our multicentre, retrospective and prospective observational study, which introduces a multidimensional approach integrating precise anatomical phenotyping with ontogenetic mapping and the analysis of dynamic structural changes over time. By leveraging unsupervised non-negative matrix factorization, we identified six biologically plausible meta-topologies in our single-centre pilot dataset of 416 patients, supporting the feasibility of this approach. We now seek to expand the study into a multicentre effort with both retrospective and prospective enrollment, aiming for a total sample size of ∼1000 patients. This expansion is essential to enhance the granularity, reproducibility and clinical utility of the meta-topologies. Ultimately, the objective of this integrative framework is to facilitate the development of a robust biologically informed risk-stratifying staging system, enhancing personalized treatment strategies and optimizing patient outcomes.

Infantile nystagmus (IN) is a common neuro-ophthalmological disorder that presents as early-onset involuntary oscillations of the eyes. Here, we report a novel genotype-phenotype correlation that associates sequence alterations in the calcium voltage-gated channel auxiliary subunit beta 3 (CACNB3) gene, encoding the Ca_Vβ3 protein, with idiopathic infantile nystagmus (IIN). Linkage analysis, whole exome and Sanger sequencing identified a homozygous missense mutation (c.316G>C) in CACNB3 co-segregating with IIN. Our calcium imaging experiments suggest that the p.Gly106Arg mutation in the Src homology 3 domain of Ca_Vβ3 may impair voltage-gated calcium channel function at the plasma membrane and may increase ligand-triggered inositol trisphosphate receptor mediated calcium release at the endoplasmic reticulum. Co-localization studies indicate reduced plasma membrane localization of the calcium channel. We propose CACNB3 to be a novel gene associated with IIN. Our findings point towards an important role of calcium-signalling in IIN and may contribute to deciphering its aetiology.

Down syndrome is commonly associated with a trisomy of chromosome 21 that often presents an accelerated aging profile and higher probability of developing Alzheimer's disease-like symptoms at a relatively early age. However, the physiological changes that may contribute to such symptoms remain poorly understood. To begin to address this knowledge gap, we used magnetoencephalographic neurophysiological imaging to assess the entrainment of occipital cortical neurons to a 15 Hz visual stimulus in a cohort of adults with DS without a dementia diagnosis (N = 26; Age = 27.65 ± 9.55 years) and a demographically matched cohort of neurotypical controls (N = 22; Age = 30.81 ± 8.02 years). Our results indicated that adults with Down syndrome exhibit substantially weaker entrainment of the occipital cortical neurons and elevated spontaneous activity during the prestimulation baseline period compared with the controls. These results suggest that there are alterations in the integrity of occipital neural populations that may be attributable to an imbalance in local GABAergic activity and/or disruption in cholinergic pathways. These changes may affect the strength of resting cortical rhythms, leading to the elevated spontaneous activity observed here, which has been linked to reductions in the dynamic range of neural populations and impairments in perceptual and cognitive processing. These novel results advance our understanding of the occipital cortical physiology seen in adults with Down syndrome and provide foundational knowledge for the development of biomarkers for the early detection of accelerated aging and cognitive decline in those with Down syndrome.

Normal pressure hydrocephalus is a common cause of gait and cognitive impairment in older adults, marked by excessive CSF accumulation. Genetic studies suggest impaired fluid clearance, and clinical symptoms can improve after CSF diversion. However, no fluid biomarkers exist to explore CSF accumulation mechanisms, assist diagnosis, or predict response to treatment. Stable isotope labelling kinetics is a clinical research tool that uses non-radioactive isotopes to label newly translated proteins, enabling measurement of their appearance (synthesis) and disappearance (clearance) in compartments like CSF. This study aimed to develop a novel method to capture protein turnover in CSF and assess whether clearance disruption is evident in normal pressure hydrocephalus with extended follow-up. Proteins of interest were identified via mass spectrometry in human CSF and choroid plexus organoid-derived CSF-like fluid. Protein origin and synthesis rates were evaluated by labelling organoids with ¹³C₆-leucine. Label incorporation was measured using targeted mass spectrometry to determine the ratio of labelled to unlabelled peptide. A proof-of-concept case-control study was then conducted in specialist neuroscience centres. Participants received intravenous ¹³C₆-leucine and underwent serial CSF withdrawal via lumbar drain, with matched blood sampling for up to 72 h. Patients undergoing CSF drainage and controls were recruited sequentially. Targeted mass spectrometry was used to determine protein production and clearance rates. To determine the clinical relevance of these protein turnover rates to CSF flow, they were correlated with direct measurements of CSF production captured using a LiquoGuard machine linked to the lumbar CSF drain. We captured choroid plexus protein kinetics in human organoids and the CSF of participants undergoing CSF drainage (n = 10) or controls (ventricular CSF n = 4; lumbar CSF n = 5). The case and control cohorts varied in sex (NPH = 80% male and controls = 22% male) and in age. There was no significant age difference between NPH and the lumbar control cohort (n = 5) (NPH: 75 (71-78) versus 70 (63-84) years old; P = 0.2438). We found that transthyretin is abundantly secreted by choroid plexus organoids, and observed correlations with CSF transthyretin synthesis rates and volume of CSF production in vivo (P = 0.738; P < 0.05). Clearance rates of transthyretin are ∼10 fold slower in normal pressure hydrocephalus compared with controls, suggesting impaired CSF protein clearance. This method is a novel clinical tool for interrogating CSF protein dynamics and may have utility in tracking CSF flow clinically.