Interdisciplinary and Collaborative Training in Neuroscience: Insights from the Human Brain Project Education Programme.

Neuroscience education is challenged by rapidly evolving technology and the development of interdisciplinary approaches for brain research. The Human Brain Project (HBP) Education Programme aimed to address the need for interdisciplinary expertise in brain research by equipping a new generation of researchers with skills across neuroscience, medicine, and information technology. Over its ten year duration, the programme engaged over 1,300 experts and attracted more than 5,500 participants from various scientific disciplines in its blended learning curriculum, specialised schools and workshops, and events fostering dialogue among early-career researchers. Key principles of the programme's approach included fostering interdisciplinarity, adaptability to the evolving research landscape and infrastructure, and a collaborative environment with a focus on empowering early-career researchers. Following the programme's conclusion, we provide here an analysis and in-depth view across a diverse range of educational formats and events. Our results show that the Education Programme achieved success in its wide geographic reach, the diversity of participants, and the establishment of transversal collaborations. Building on these experiences and achievements, we describe how leveraging digital tools and platforms provides accessible and highly specialised training, which can enhance existing education programmes for the next generation of brain researchers working in decentralised European collaborative spaces. Finally, we present the lessons learnt so that similar initiatives may improve upon our experience and incorporate our suggestions into their own programme.

CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.

Genetic and molecular correlates of cortical thickness alterations in adults with obsessive-compulsive disorder: a transcription-neuroimaging association analysis.

BACKGROUND: Although numerous neuroimaging studies have depicted neural alterations in individuals with obsessive-compulsive disorder (OCD), a psychiatric disorder characterized by intrusive cognitions and repetitive behaviors, the molecular mechanisms connecting brain structural changes and gene expression remain poorly understood. METHODS: This study combined the Allen Human Brain Atlas dataset with neuroimaging data from the Meta-Analysis (ENIGMA) consortium and independent cohorts. Later, partial least squares regression and enrichment analysis were performed to probe the correlation between transcription and cortical thickness variation among adults with OCD. RESULTS: The cortical map of case-control differences in cortical thickness was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms preferentially expressed across different cell types and cortical layers. These genes were specifically expressed in brain tissue, spanning all cortical developmental stages. Protein-protein interaction analysis revealed that these genes coded a network of proteins encompassing various highly interactive hubs. CONCLUSIONS: The study findings bridge the gap between neural structure and transcriptome data in OCD, fostering an integrative understanding of the potential biological mechanisms.

Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.

Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny.

A measles virus collective infectious unit that caused lethal human brain disease includes many locally restricted and few widespread copy-back defective genomes.

During virus replication in cultured cells, copy-back defective viral genomes (cbDVGs) can arise. CbDVGs are powerful inducers of innate immune responses in vitro, but their occurrence and impact on natural infections of human hosts remain poorly defined. We asked whether cbDVGs were generated in the brain of a patient who succumbed to subacute sclerosing panencephalitis (SSPE) about 20 years after acute measles virus (MeV) infection. Previous analyses of 13 brain specimens of this patient indicated that a collective infectious unit (CIU) drove lethal MeV spread. In this study, we identified 276 replication-competent cbDVG species, each present in over 100 copies in the brain. Six species were detected in multiple forebrain locations, implying that they travelled long-distance with the CIU. The cbDVG to full-length genomes ratio was often close to 1 (0.6-1.74). Most cbDVGs were 324-2,000 bases in length, corresponding to 2%-12% of the full-length genome; all are predicted to have complementary terminal sequences. If improperly encapsidated, these sequences have the potential to form double-stranded structures that can induce innate immune responses. To assess this, we examined the transcriptome of all brain specimens. Several interferon and inflammatory response genes were upregulated, but upregulation levels did not correlate with cbDVG levels in the specimens. Thus, the CIU that drove MeV pathogenesis in this brain includes, in addition to two complementary full-length genome populations, many locally restricted and few widespread cbDVG species. The widespread cbDVG species may have been positively selected but how they impacted pathogenesis remains to be determined.IMPORTANCECopy-back defective viral genomes (cbDVGs) can drive virus-host interactions. They can suppress virus replication directly, by competing with full-length genomes, or indirectly by stimulating antiviral immunity. In vitro, cbDVG can slow down infections and promote persistence, but there is limited documentation of their presence in human hosts or of their impact on disease. We had the unique opportunity to analyze the brain of a patient who succumbed to subacute sclerosing panencephalitis, a rare but lethal consequence of measles. We detected more than 270 distinct cbDVG species; most were restricted to one specimen, but several reached all lobes of the forebrain, suggesting positive selection. Our analyses provide the missing knowledge of the diversity of cbDVG in a natural infection of a human host. They also reveal that a collective infectious unit that caused lethal human brain disease includes few widespread cbDVG, in addition to two ubiquitous complementary full-length genome populations.

Hypoxia-Induced Inflammation in In Vitro Model of Human Blood-Brain Barrier: Modulatory Effects of the Olfactory Ensheathing Cell-Conditioned Medium.

Hypoxia compromises the integrity of the blood-brain barrier (BBB) and increases its permeability, thereby inducing inflammation. Olfactory ensheathing cells (OECs) garnered considerable interest due to their neuroregenerative and anti-inflammatory properties. Here, we aimed to investigate the potential modulatory effects of OEC-conditioned medium (OEC-CM) on the response of human brain microvascular endothelial cells (HBMECs), constituting the BBB, when exposed to hypoxia. HBMECs were utilized to establish the in vitro BBB model. OECs were isolated from mouse olfactory bulbs, and OEC-CM was collected after 48 h of culture. The effect of OEC-CM treatment on the HBMEC viability was evaluated under both normoxic and hypoxic conditions at 6 h, 24 h, and 30 h. Western blot and immunostaining techniques were employed to assess NF-κB/phospho-NF-κB expression. HIF-1α, VEGF-A, and cPLA2 mRNA expression levels were quantified using digital PCR. ELISA assays were performed to measure PGE2, VEGF-A, IL-8 secretion, and cPLA2 specific activity. The in vitro formation of HBMEC capillary-like structures was examined using a three-dimensional matrix system. OEC-CM attenuated pro-inflammatory responses and mitigated the HIF-1α/VEGFA signaling pathway activation in HBMECs under hypoxic condition. Hypoxia-induced damage of the BBB can be mitigated by novel therapeutic strategies harnessing OEC potential.

Parameter quantification for oxygen transport in the human brain.

BACKGROUND AND OBJECTIVE: Oxygen is carried to the brain by blood flow through generations of vessels across a wide range of length scales. This multi-scale nature of blood flow and oxygen transport poses challenges on investigating the mechanisms underlying both healthy and pathological states through imaging techniques alone. Recently, multi-scale models describing whole brain perfusion and oxygen transport have been developed. Such models rely on effective parameters that represent the microscopic properties. While parameters of the perfusion models have been characterised, those for oxygen transport are still lacking. In this study, we set to quantify the parameters associated with oxygen transport and their uncertainties. METHODS: Effective parameter values of a continuum-based porous multi-scale, multi-compartment oxygen transport model are systematically estimated. In particular, geometric parameters that capture the microvascular topologies are obtained through statistically accurate capillary networks. Maximum consumption rates of oxygen are optimised to uniquely define the oxygen distribution over depth. Simulations are then carried out within a one-dimensional tissue column and a three-dimensional patient-specific brain mesh using the finite element method. RESULTS: Effective values of the geometric parameters, vessel volume fraction and surface area to volume ratio, are found to be 1.42% and 627 [mm2/mm3], respectively. These values compare well with those acquired from human and monkey vascular samples. Simulation results of the one-dimensional tissue column show qualitative agreement with experimental measurements of tissue oxygen partial pressure in rats. Differences between the oxygenation level in the tissue column and the brain mesh are observed, which highlights the importance of anatomical accuracy. Finally, one-at-a-time sensitivity analysis reveals that the oxygen model is not sensitive to most of its parameters; however, perturbations in oxygen solubilities and plasma to whole blood oxygen concentration ratio have a considerable impact on the tissue oxygenation. CONCLUSIONS: The findings of this study demonstrate the validity of using a porous continuum approach to model organ-scale oxygen transport and draw attention to the significance of anatomy and parameters associated with inter-compartment diffusion.

SHARD: an improved method for staining and visualizing multiplex immunofluorescence in optically cleared postmortem human brain tissue.

Postmortem human brain tissue is a critical resource for studying neurodegenerative disease, providing critical insights into cellular morphology, pathology, and network connectivity. To improve standard microscopy and enable high-resolution, three-dimensional (3D) images of tissues at the subcellular level, tissue-clearing methods have been developed. These 3D images allow for the analysis of large regions of interest and can be used to study structural and spatial changes that occur during neurodegeneration. Additionally, 3D imaging facilitates the visualization of whole-cell morphology, especially in cells with long processes that would otherwise be truncated in single-plane images. Human brain tissue is especially challenging for tissue clearing due to the abundance of lipids in myelin and the need for optimal fixation and low postmortem intervals. Formaldehyde-based fixatives, commonly used in preserving tissue, hinder antibody binding by crosslinking important antibody epitopes, and fluorescent microscopy requires the incorporation of fluorescent labels through passive diffusion or electrophoresis. Recent studies have focused on optimally fixed human brain tissue with short postmortem intervals, limiting the general applicability of these methods. To address these challenges, we developed SHARD (SHIELD, antigen retrieval, and delipidation), a simple and widely applicable method for clearing and labeling human brain tissue, which can be applied to long-term banked human brain tissue preserved in formaldehyde. SHARD is a novel addition to the SHIELD tissue clarification method, combining antigen retrieval, tissue clearing, and staining of 200-µm sections from long-term banked human brain tissue. The SHARD method is effective for postmortem intervals (PMIs) ranging from 10 to 72 h in multiple neurodegenerative diseases and control samples. In this study, we demonstrate that the SHARD method significantly enhances the immunostaining of glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal marker. Overall, the combination of antigen retrieval and tissue delipidation holds great potential for achieving detailed 3D immunostaining in long-term formaldehyde-fixed postmortem human brain tissue, opening new avenues for research and discovery.

Cryopreservation of Neuroectoderm on a Pillar Plate and In Situ Differentiation into Human Brain Organoids.

Cryopreservation in cryovials extends cell storage at low temperatures, and advances in organoid cryopreservation improve reproducibility and reduce generation time. However, cryopreserving human organoids presents challenges due to the limited diffusion of cryoprotective agents (CPAs) into the organoid core and the potential toxicity of these agents. To overcome these obstacles, we developed a cryopreservation technique using a pillar plate platform. To demonstrate cryopreservation application to human brain organoids (HBOs), early stage HBOs were produced by differentiating induced pluripotent stem cells (iPSCs) into neuroectoderm (NE) in an ultralow attachment (ULA) 384-well plate. The NE was transferred and encapsulated in Matrigel on the pillar plate. The NE on the pillar plate was exposed to four commercially available CPAs, including the PSC cryopreservation kit, CryoStor CS10, 3dGRO, and 10% DMSO, before being frozen overnight at -80 °C and subsequently stored in a liquid nitrogen dewar. We examined the impact of the CPA type, organoid size, and CPA exposure duration on cell viability post-thaw. Additionally, the differentiation of NE into HBOs on the pillar plate was assessed using RT-qPCR and immunofluorescence staining. The PSC cryopreservation kit proved to be the least toxic for preserving the early stage HBOs on the pillar plate. Notably, smaller HBOs showed higher cell viability postcryopreservation than larger ones. An incubation period of 80 min with the PSC kit was essential to ensure optimal CPA diffusion into HBOs with a diameter of 400-600 µm. These cryopreserved early stage HBOs successfully matured over 30 days, exhibiting gene expression patterns akin to noncryopreserved HBOs. The cryopreserved early stage HBOs on the pillar plate maintained high viability after thawing and successfully differentiated into mature HBOs. This on-chip cryopreservation method could extend to other small organoids, by integrating cryopreservation, thawing, culturing, staining, rinsing, and imaging processes within a single system, thereby preserving the 3D structure of the organoids.

A Map of Transcriptomic Signatures of Different Brain Areas in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches.

Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Background: Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms that underlie the development and progression of AUD remains limited. Here, we investigated AUD-associated DNA methylation changes within and across 2 addiction-relevant brain regions, the nucleus accumbens and dorsolateral prefrontal cortex. Methods: Illumina HumanMethylation EPIC array data from 119 decedents (61 cases, 58 controls) were analyzed using robust linear regression with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public annotation data and published genetic and epigenetic studies. We also tested for brain region-shared and brain region-specific associations using mixed-effects modeling and assessed implications of these results using public gene expression data from human brain. Results: At a false discovery rate of ≤.05, we identified 105 unique AUD-associated CpGs (annotated to 120 genes) within and across brain regions. AUD-associated CpGs were enriched in histone marks that tag active promoters, and our strongest signals were specific to a single brain region. Some concordance was found between our results and those of earlier published alcohol use or dependence methylation studies. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors, some of which also overlapped with previous addiction-related methylation studies. Conclusions: Our findings identify AUD-associated methylation signals and provide evidence of overlap with previous genetic and methylation studies. These signals may constitute predisposing genetic differences or robust methylation changes associated with AUD, although more work is needed to further disentangle the mechanisms that underlie these associations and their implications for AUD.

Alcohol use disorder (AUD) has a profound public health impact, but understanding of the molecular mechanisms that underlie its development and progression remains limited. In the current study, which is the largest of its kind, we examined DNA methylation changes in the brains of 119 individuals with and without AUD. In 2 brain regions key to the addiction cycle, the nucleus accumbens and dorsolateral prefrontal cortex, we identified 105 methylation markers (CpGs) associated with AUD across 120 genes. We also integrated these results with previously published genetic and epigenetic studies, highlighting potential targets for better understanding how AUD develops, progresses, and someday may be treated.

Exploring the role of different cell types on cortical folding in the developing human brain through computational modeling.

The human brain's distinctive folding pattern has attracted the attention of researchers from different fields. Neuroscientists have provided insights into the role of four fundamental cell types crucial during embryonic development: radial glial cells, intermediate progenitor cells, outer radial glial cells, and neurons. Understanding the mechanisms by which these cell types influence the number of cortical neurons and the emerging cortical folding pattern necessitates accounting for the mechanical forces that drive the cortical folding process. Our research aims to explore the correlation between biological processes and mechanical forces through computational modeling. We introduce cell-density fields, characterized by a system of advection-diffusion equations, designed to replicate the characteristic behaviors of various cell types in the developing brain. Concurrently, we adopt the theory of finite growth to describe cortex expansion driven by increasing cell density. Our model serves as an adjustable tool for understanding how the behavior of individual cell types reflects normal and abnormal folding patterns. Through comparison with magnetic resonance images of the fetal brain, we explore the correlation between morphological changes and underlying cellular mechanisms. Moreover, our model sheds light on the spatiotemporal relationships among different cell types in the human brain and enables cellular deconvolution of histological sections.

C3a Mediates Endothelial Barrier Disruption in Brain-Derived, but Not Retinal, Human Endothelial Cells.

Neuromyelitis optica spectrum disorder (NMOSD) is associated with pathological aquaporin-4 immunoglobulin G (AQP4-IgG), which cause brain damage. However, the impact of AQP4-IgG on retinal tissue remains unclear. Additionally, dysregulated complement anaphylatoxins C3a and C5a, known to modulate the endothelial barrier, are implicated in NMOSD. This study evaluates the susceptibility of human brain microvascular endothelial cells (HBMEC) and human retinal endothelial cells (HREC) to C3a- and C5a-mediated stress using real-time cell barrier analysis, immunocytochemical staining, qPCR and IgG transmigration assays. The findings reveal that C3a induced a concentration-dependent paracellular barrier breakdown and increased transcellular permeability in HBMEC, while HREC maintained barrier integrity under the same conditions. C5a attenuated C3a-induced disruption in HBMEC, indicating a protective role. Anaphylatoxin treatment elevated transcript levels of complement component C3 and increased C5 gene and protein expression in HREC, with no changes observed in HBMEC. In HBMEC, C5a treatment led to a transient upregulation of C3a receptor (C3AR) mRNA and an early decrease in C5a receptor 1 (C5AR1) protein detection. Conversely, HREC exhibited a late increase in C5aR1 protein levels. These results indicate that the retinal endothelial barrier is more stable under anaphylatoxin-induced stress compared to the brain, potentially offering better protection against paracellular AQP4-IgG transport.

Testing the expensive-tissue hypothesis' prediction of inter-tissue competition using causal modelling with latent variables.

The expensive-tissue hypothesis (ETH) posited a brain-gut trade-off to explain how humans evolved large, costly brains. Versions of the ETH interrogating gut or other body tissues have been tested in non-human animals, but not humans. We collected brain and body composition data in 70 South Asian women and used structural equation modelling with instrumental variables, an approach that handles threats to causal inference including measurement error, unmeasured confounding and reverse causality. We tested a negative, causal effect of the latent construct 'nutritional investment in brain tissues' (MRI-derived brain volumes) on the construct 'nutritional investment in lean body tissues' (organ volume and skeletal muscle). We also predicted a negative causal effect of the brain latent on fat mass. We found negative causal estimates for both brain and lean tissue (-0.41, 95% CI, -1.13, 0.23) and brain and fat (-0.56, 95% CI, -2.46, 2.28). These results, although inconclusive, are consistent with theory and prior evidence of the brain trading off with lean and fat tissues, and they are an important step in assessing empirical evidence for the ETH in humans. Analyses using larger datasets, genetic data and causal modelling are required to build on these findings and expand the evidence base.

Large improvement in RF magnetic fields and imaging SNR with whole-head high-permittivity slurry helmet for human-brain MRI applications at 7 T.

PURPOSE: To optimize the design and demonstrate the integration of a helmet-shaped container filled with a high-permittivity material (HPM) slurry with RF head coil arrays to improve RF coil sensitivity and SNR for human-brain proton MRI. METHODS: RF reception magnetic fields ( B 1 - $$ {\mathrm{B}}_1^{-} $$ ) of a 32-channel receive-only coil array with various geometries and permittivity values of HPM slurry helmet are calculated with electromagnetic simulation at 7 T. A 16-channel transmit-only coil array, a 32-channel receive-only coil array, and a 2-piece HPM slurry helmet were constructed and assembled. RF transmission magnetic field ( B 1 + $$ {\mathrm{B}}_1^{+} $$ ), B 1 - $$ {\mathrm{B}}_1^{-} $$ , and MRI SNR maps from the entire human brain were measured and compared. RESULTS: Simulations showed that averaged B 1 - $$ {\mathrm{B}}_1^{-} $$ improvement with the HPM slurry helmet increased from 57% to 87% as the relative permittivity (εr) of HPM slurry increased from 110 to 210. In vivo experiments showed that the average B 1 + $$ {\mathrm{B}}_1^{+} $$ improvement over the human brain was 14.5% with the two-piece HPM slurry (εr ≈ 170) helmet, and the average B 1 - $$ {\mathrm{B}}_1^{-} $$ and SNR were improved 63% and 34%, respectively, because the MRI noise level was increased by the lossy HPM. CONCLUSION: The RF coil sensitivity and MRI SNR were largely improved with the two-piece HPM slurry helmet demonstrated by both electromagnetic simulations and in vivo human head experiments at 7 T. The findings demonstrate that incorporating an easily producible HPM slurry helmet into the RF coil array significantly enhances human-brain MRI SNR homogeneity and quality at ultrahigh field. Greater SNR improvement is anticipated using the less lossy HPM and optimal design.

Recurrent neural network-aided processing of incomplete free induction decays in 1H-MRS of the brain.

In the case of limited sampling windows or truncation of free induction decays (FIDs) for artifact removal in proton magnetic resonance spectroscopy (1H-MRS) and spectroscopic imaging (1H-MRSI), metabolite quantification needs to be performed on incomplete FIDs. Given that FIDs are naturally time-domain sequential data, we investigated the potential of recurrent neural network (RNN)-types of neural networks (NNs) in the processing of incomplete human brain FIDs with or without FID restoration prior to quantitative analysis at 3.0T. First, we employed an RNN encoder-decoder and developed it to restore incomplete FIDs (rRNN) with different amounts of sampled data. The quantification of metabolites from the rRNN-restored FIDs was achieved by using LCModel. Second, we modified the RNN encoder-decoder and developed it to convert incomplete brain FIDs into incomplete metabolite-only FIDs without restoration, followed by linear regression using a metabolite basis set for quantitative analysis (cRNN). In consideration of the practical benefit of the FID restoration with respect to pure zero-filling, development and analysis of the NNs were focused particularly on the incomplete FIDs with only the first 64 data points retained. All NNs were trained on simulated data and tested mainly on in vivo data acquired from healthy volunteers (n = 27). Strong correlations were obtained between the NN-derived and ground truth metabolite content (LCModel-derived content on fully sampled FIDs) for myo-inositol, total choline, and total creatine (normalized to total N-acetylaspartate) on the in vivo data using both rRNN (R = 0.83-0.94; p ≤ 0.05) and cRNN (R = 0.86-0.91; p ≤ 0.05). RNN-types of NNs have potential in the quantification of the major brain metabolites from the FIDs with substantially reduced sampled data points. For the metabolites with low to medium SNR, the performance of the NNs needs to be further improved, for which development of more elaborate and advanced simulation techniques would be of help, but remains challenging.

Spectral analysis comparison of pushbroom and snapshot hyperspectral cameras for in vivo brain tissues and chromophore identification.

Significance: Hyperspectral imaging sensors have rapidly advanced, aiding in tumor diagnostics for in vivo brain tumors. Linescan cameras effectively distinguish between pathological and healthy tissue, whereas snapshot cameras offer a potential alternative to reduce acquisition time. Aim: Our research compares linescan and snapshot hyperspectral cameras for in vivo brain tissues and chromophore identification. Approach: We compared a linescan pushbroom camera and a snapshot camera using images from 10 patients with various pathologies. Objective comparisons were made using unnormalized and normalized data for healthy and pathological tissues. We utilized the interquartile range (IQR) for the spectral angle mapping (SAM), the goodness-of-fit coefficient (GFC), and the root mean square error (RMSE) within the 659.95 to 951.42 nm range. In addition, we assessed the ability of both cameras to capture tissue chromophores by analyzing absorbance from reflectance information. Results: The SAM metric indicates reduced dispersion and high similarity between cameras for pathological samples, with a 9.68% IQR for normalized data compared with 2.38% for unnormalized data. This pattern is consistent across GFC and RMSE metrics, regardless of tissue type. Moreover, both cameras could identify absorption peaks of certain chromophores. For instance, using the absorbance measurements of the linescan camera, we obtained SAM values below 0.235 for four peaks, regardless of the tissue and type of data under inspection. These peaks are one for cytochrome b in its oxidized form at λ = 422 nm , two for HbO 2 at λ = 542 nm and λ = 576 nm , and one for water at λ = 976 nm . Conclusion: The spectral signatures of the cameras show more similarity with unnormalized data, likely due to snapshot sensor noise, resulting in noisier signatures post-normalization. Comparisons in this study suggest that snapshot cameras might be viable alternatives to linescan cameras for real-time brain tissue identification.

Advances in Human Cellular Mechanistic Understanding and Drug Discovery of Brain Organoids for Neurodegenerative Diseases.

The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.

Cerebral Microcirculation: Progress and Outlook of Laser Doppler Flowmetry in Neurosurgery and Neurointensive Care.

Laser Doppler flowmetry (LDF) is a well-established technique for the investigation of tissue microcirculation. Compared to skin, the use in the human brain is sparse. The measurement of cerebral microcirculation in neurointensive care and during neurosurgery is challenging and requires adaptation to the respective clinical setting. The aim of the review is to present state of the art and progress in neurosurgery and neurointensive care where LDF has proven useful and can find clinical importance in the investigation of cerebral microcirculation. The literature in the field is summarized and recent technical improvements regarding LDF systems and fiber optical probe designs for neurosurgical and neurocritical care described. By combining two signals from the LDF unit, the measurement of the microcirculation (Perfusion) and gray whiteness (TLI) of the brain tissue, the full potential of the device is achieved. For example, a forward-looking LDF-probe detects high-risk hemorrhage areas and gray-white matter boundaries along intraoperative trajectories during stereotactic neurosurgery. Proof of principles are given for LDF as a guidance tool in deep brain stimulation implantation, brain tumor needle biopsies, and as long-term monitoring device in neurocritical care. With well-designed fiber optical probes, surgical fixation, and signal processing for movement reduction, LDF monitoring of the cerebral microcirculation is successful up to 10 days. The use of LDF can be combined with other physiological measurement techniques, for example, fluorescence spectroscopy for identification of glioblastoma during tumor surgery. Fiber optics can also be used during magnetic resonance imaging (MRI). Despite the many advantages, fiber optical LDF has not yet reached its full potential in clinical neuro-applications. Multicenter studies are required to further evaluate LDF in neurosurgery and neurointensive care. In conclusion, the present status of LDF in neurosurgery and neurointensive care has been reviewed. By combining Perfusion and TLI with tailored probe designs the full potential of LDF can be achived in measuring cerebral microcirculation. This includes guidance during DBS implantation and needle biopsies, and long-term monitoring in neurocritical care.

Integrated analysis of circRNA regulation with ADARB2 enrichment in inhibitory neurons.

This study investigates the regulation of circular RNAs (circRNAs) with Adenosine Deaminase RNA Specific B2 (ADARB2) enrichment specifically in inhibitory neurons. Using an integrated analysis combining high-throughput sequencing and bioinformatics approaches, we identified a group of circRNAs that are potentially enhanced by ADARB2. Our findings highlight the pivotal role of ADARB2 in circRNA synthesis within inhibitory neurons, likely through its specific binding to precursor RNAs, which facilitates circRNA biogenesis.