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ABSTRACT 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. [ABSTRACT FROM AUTHOR]

The ambiguous set theory has recently been introduced to characterize ambiguities inherent in information. Based on ambiguous set and ambiguous entropy (AE), this study presents a clustering algorithm called ambiguous-entropy clustering algorithm (AECA). The proposed AECA applies to analyze the resting-state fMRI signals (RSfMRISs). For the experimental purpose, this study considers RSfMRISs data obtained from resting-state of human brain. Three different data clusters related to RSfMRIS are identified and their statistical significance is analyzed using AECA. We perform the autocorrelation analysis for the clustered RSfMRISs. We test the statistical significance of the results using the Ljung-Box test. The results show that AECA is able to identify the activation of RSfMRISs despite the resting state of the brain. To discover the activation patterns of neurons in the resting state, functional connections in RSfMRISs are investigated. For this purpose, an algorithm called ambiguous-entropy functional connection algorithm (AEFCA) is presented in this study. Using this algorithm, a weighted graph is constructed to show the functional connections. Such a graph is called functional connection network graph (FCNG). [ABSTRACT FROM AUTHOR]

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 HbO2 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. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a subclass of non-coding RNAs which have demonstrated potential as biomarkers for Alzheimer’s disease (AD). In this study, we conducted a comprehensive exploration of the circRNA transcriptome within AD brain tissues. Specifically, we assessed circRNA expression patterns in the dorsolateral prefrontal cortex collected from nine AD-afflicted individuals and eight healthy controls. Utilising two circRNA detection tools, CIRI2 and CIRCexplorer2, we detected thousands of circRNAs and performed a differential expression analysis. CircRNAs which exhibited statistically significantly differential expression were identified as AD-specific differentially expressed circRNAs. Notably, our investigation revealed 120 circRNAs with significant upregulation and 1325 circRNAs displaying significant downregulation in AD brains when compared to healthy brain tissue. Additionally, we explored the expression profiles of the linear RNA counterparts corresponding to differentially expressed circRNAs in AD-afflicted brains and discovered that the linear RNA counterparts exhibited no significant changes in the levels of expression. We used CRAFT tool to predict that circUBE4B had potential to target miRNA named as hsa-miR-325-5p, ultimately regulated CD44 gene. This study provides a comprehensive overview of differentially expressed circRNAs in the context of AD brains, underscoring their potential as molecular biomarkers for AD. These findings significantly enhance our comprehension of AD’s underlying pathophysiological mechanisms, offering promising avenues for future diagnostic and therapeutic developments. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility of downfield MR spectroscopic imaging (DF‐MRSI) in the human brain at 7T. Methods: A 7T DF‐MRSI pulse sequence was implemented based on the previously described methodology at 3T, with 3D phase‐encoding, 13‾31‾$$ 1\overline{3}3\overline{1} $$ spectral‐spatial excitation, and frequency selective refocusing. Data were pre‐processed followed by analysis using the "LCModel" software package, and metabolite maps created from the LCModel results. Total scan time, including brain MRI and a water‐reference MRSI, was 24 min. The sequence was tested in 10 normal volunteers. Estimated metabolite levels and uncertainty values (Cramer Rao lower bounds, CRLBs) for nine downfield peaks were compared between seven different brain regions, anterior cingulate cortex (ACC), centrum semiovale (CSO), corpus callosum (CC), cerebellar vermis (CV), dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC), and thalamus (Thal). Results: DF peaks were relatively uniformly distributed throughout the brain, with only a small number of peaks showing any significant regional variations. Most DF peaks had average CRLB<25% in most brain regions. Average SNR values were higher for the brain regions ACC and DLPFC (˜7 ± 0.95, mean ± SD) while in a range of 3.4–6.0 for other brain regions. Average linewidth (FWHM) values were greater than 35 Hz in the ACC, CV, and Thal, and 22 Hz in CC, CSO, DLPFC, and PCC. Conclusion: High‐field DF‐MRSI is able to spatially map exchangeable protons in the human brain at high resolution and with near whole‐brain coverage in acceptable scan times, and in the future may be used to study metabolism of brain tumors or other neuropathological disorders. [ABSTRACT FROM AUTHOR]

Purpose: In vivo quantification of lactate has numerous applications in studying the pathology of both cerebral and musculoskeletal systems. Due to its low concentration (~0.5–1 mM), and overlap with lipid signals, traditional 1H MR spectra acquired in vivo using a small voxel and short echo time often result in an inadequate signal to detect and resolve the lactate peak, especially in healthy human volunteers. Methods: In this study, using a semi‐LASER acquisition with long echo time (TE = 288 ms) and large voxel size (80 × 70 × 20 mm3), we clearly visualize the combined signal of lactate and threonine. Therefore, we call the signal at 1.33 ppm Lac+ and quantify Lac+ concentration from water suppressed spectra in healthy human brains in vivo. Four participants (22–37 years old; mean age = 28 ± 5.4; three male, one female) were scanned on four separate days, and on each day four measurements were taken. Intra‐day values are calculated for each participant by comparing the four measurements on a single day. Inter‐day values were calculated using the mean intra‐day measurements. Results: The mean intra‐participant Lac+ concentration, standard deviation (SD), and coefficient of variation (CV) ranged from 0.49 to 0.61 mM, 0.02 to 0.07 mM, and 4% to 13%, respectively, across four volunteers. The inter‐participant Lac+ concentration, SD, and CV was 0.53 mM, ±0.06 mM, and 11%. Conclusion: Repeatability is shown in Lac+ measurement in healthy human brain using a long echo time semi‐LASER sequence with a large voxel in about 3.5 min at 3 T. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function. Methods: At in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal–Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn's or Sidak's test. Results: We show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1–42)/Aβ(1–40) ratio (particularly in their oligomeric forms) in a sex-dependent manner. Conclusions: Our unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture. [ABSTRACT FROM AUTHOR]

Astrocyte heterogeneity and its relation to aging in the normal human brain remain poorly understood. We here analyzed astrocytes in gray and white matter brain tissues obtained from donors ranging in age between the neonatal period to over 100 years. We show that astrocytes are differently distributed with higher density in the white matter. This regional difference in cellular density becomes less prominent with age. Additionally, we confirm the presence of morphologically distinct astrocytes, with gray matter astrocytes being morphologically more complex. Notably, gray matter astrocytes morphologically change with age, while white matter astrocytes remain relatively consistent in morphology. Using regional mass spectrometry-based proteomics, we did, however, identify astrocyte specific proteins with regional differences in abundance, reflecting variation in cellular density or expression level. Importantly, the expression of some astrocyte specific proteins region-dependently decreases with age. Taken together, we provide insights into region- and age-related differences in astrocytes in the human brain. [Display omitted] • White matter astrocyte density becomes less during aging. • Gray matter astrocytes become morphologically more complex during aging. • Region- and age-related differences in astrocyte protein expression. [ABSTRACT FROM AUTHOR]

Abstract Background Alzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function. Methods At in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal–Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn’s or Sidak’s test. Results We show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1–42)/Aβ(1–40) ratio (particularly in their oligomeric forms) in a sex-dependent manner. Conclusions Our unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture.

Proton (1H) Magnetic Resonance Spectroscopy (MRS) is a non-invasive tool capable of quantifying brain metabolite concentrations in vivo. Prioritization of standardization and accessibility in the field has led to the development of universal pulse sequences, methodological consensus recommendations, and the development of open-source analysis software packages. One on-going challenge is methodological validation with ground-truth data. As ground-truths are rarely available for in vivo measurements, data simulations have become an important tool. The diverse literature of metabolite measurements has made it challenging to define ranges to be used within simulations. Especially for the development of deep learning and machine learning algorithms, simulations must be able to produce accurate spectra capturing all the nuances of in vivo data. Therefore, we sought to determine the physiological ranges and relaxation rates of brain metabolites which can be used both in data simulations and as reference estimates. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we've identified relevant MRS research articles and created an open-source database containing methods, results, and other article information as a resource. Using this database, expectation values and ranges for metabolite concentrations and T2 relaxation times are established based upon a meta-analyses of healthy and diseased brains.

Currently, brain iron content represents a new neuromarker for understanding the physiopathological mechanisms leading to Parkinson's disease (PD). In vivo quantification of biological iron is possible by reconstructing magnetic susceptibility maps obtained using quantitative susceptibility mapping (QSM). Applying QSM is challenging, as up to now, no standardization of acquisition protocols and phase image processing has emerged from referenced studies. Our objectives were to compare the accuracy and the sensitivity of 10 QSM pipelines built from algorithms from the literature, applied on phantoms data and on brain data. Two phantoms, with known magnetic susceptibility ranges, were created from several solutions of gadolinium chelate. Twenty healthy volunteers from two age groups were included. Phantoms and brain data were acquired at 1.5 and 3 T, respectively. Susceptibility‐weighted images were obtained using a 3D multigradient‐recalled‐echo sequence. For brain data, 3D anatomical T1‐ and T2‐weighted images were also acquired to segment the deep gray nuclei of interest. Concerning in vitro data, the linear dependence of magnetic susceptibility versus gadolinium concentration and deviations from the theoretically expected values were calculated. For brain data, the accuracy and sensitivity of the QSM pipelines were evaluated in comparison with results from the literature and regarding the expected magnetic susceptibility increase with age, respectively. A nonparametric Mann–Whitney U‐test was used to compare the magnetic susceptibility quantification in deep gray nuclei between the two age groups. Our methodology enabled quantifying magnetic susceptibility in human brain and the results were consistent with those from the literature. Statistically significant differences were obtained between the two age groups in all cerebral regions of interest. Our results show the importance of optimizing QSM pipelines according to the application and the targeted magnetic susceptibility range, to achieve accurate quantification. We were able to define the optimal QSM pipeline for future applications on patients with PD. [ABSTRACT FROM AUTHOR]

Abstract 3D reconstruction of human brain volumes at high resolution is now possible thanks to advancements in tissue clearing methods and fluorescence microscopy techniques. Analyzing the massive data produced with these approaches requires automatic methods able to perform fast and accurate cell counting and localization. Recent advances in deep learning have enabled the development of various tools for cell segmentation. However, accurate quantification of neurons in the human brain presents specific challenges, such as high pixel intensity variability, autofluorescence, non-specific fluorescence and very large size of data. In this paper, we provide a thorough empirical evaluation of three techniques based on deep learning (StarDist, CellPose and BCFind-v2, an updated version of BCFind) using a recently introduced three-dimensional stereological design as a reference for large-scale insights. As a representative problem in human brain analysis, we focus on a $$4~\text {-cm}^3$$ 4 -cm 3 portion of the Broca’s area. We aim at helping users in selecting appropriate techniques depending on their research objectives. To this end, we compare methods along various dimensions of analysis, including correctness of the predicted density and localization, computational efficiency, and human annotation effort. Our results suggest that deep learning approaches are very effective, have a high throughput providing each cell 3D location, and obtain results comparable to the estimates of the adopted stereological design.

Abstract We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer’s disease (AD, n = 8), Pick’s disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.

Purpose: The utilization of functional magnetic resonance imaging (fMRI) in studying the mechanisms and treatment of chronic pain has gained significant popularity. However, there is currently a dearth of literature conducting bibliometric analysis on fMRI studies focused on chronic pain. Methods: All the literature included in this study was obtained from the Science Citation Index Expanded of Web of Science Core Collection. We used CiteSpace and VOSviewer to analyze publications, authors, countries or regions, institutions, journals, references and keywords. Additionally, we evaluated the timeline and burst analysis of keywords, as well as the timeline and burst analysis of references. The search was conducted from 2004 to 2023 and completed within a single day on October 4th, 2023. Results: A total of 1,327 articles were retrieved. The annual publication shows an overall increasing trend. The United States has the highest number of publications and the main contributing institution is Harvard University. The journal PAIN produces the most articles. In recent years, resting-state fMRI, the prefrontal cortex, nucleus accumbens, thalamus, and migraines have been researched hotspots of fMRI studies on chronic pain. Conclusions: This study provides an in-depth perspective on fMRI for chronic pain research, revealing key points, research hotspots and research trends, which offers valuable ideas for future research activities. It concludes with a summary of advances in clinical practice in this area, pointing out the need for critical evaluation of these findings in the light of guidelines and expert recommendations. It is anticipated that further high-quality research outputs will be generated in the future, which will facilitate the utilization of fMRI in clinical decision-making for chronic pain. [ABSTRACT FROM AUTHOR]

Bilingual language process is a key factor in left side of the brain. The cognition of the learning modalities is very crucial for assimilation, organization, and interpretation of knowledge. The neurochemical events like estrogen, testosterone, dopamine 5HT, Oxytocin, nerve growth factor (NGF) play as neuro-endocrine brain axis for learning to cognition. The human cognition recognises the language in five stages that is input, status of language, getting access over the literature of that language, interaction with family, and finally social network communication. The factors influence the bilingual aspects include language exposure, genes, perception and receiving, neurochemical pathways, social communication, and environmental conditions. Apart from these elements the other external influencing factors like health humanities and technological advances and make a lot of impact on cognition processes and mental health. [ABSTRACT FROM AUTHOR]

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol−1sec−1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism—the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions. [ABSTRACT FROM AUTHOR]

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aß) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aß. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human postmortem AD and control (CTL) frontal cortex (FC; AD n = 22, CTL n = 23) and hippocampus (HP; AD n = 34, CTL n = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aß pathology at different timepoints during aging and disease progression by immunoblot (n = 5-8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days in vitro. Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aß accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression. [ABSTRACT FROM AUTHOR]

Finite element (FE) simulations of the brain undergoing neurosurgical procedures present us with the great opportunity to better investigate, understand, and optimize surgical techniques and equipment. FE models provide access to data such as the stress levels within the brain that would otherwise be inaccessible with the current medical technology. Brain retraction is often a dangerous but necessary part of neurosurgery, and current research focuses on minimizing trauma during the procedure. In this work, we present a simulation-based comparison of different types of retraction mechanisms. We focus on traditional spatulas and tubular retractors. Our results show that tubular retractors result in lower average predicted stresses, especially in the subcortical structures and corpus callosum. Additionally, we show that changing the location of retraction can greatly affect the predicted stress results. As the model predictions highly depend on the material model and parameters used for simulations, we also investigate the importance of using region-specific hyperelastic and viscoelastic material parameters when modelling a three-dimensional human brain during retraction. Our investigations demonstrate how FE simulations in neurosurgical techniques can provide insight to surgeons and medical device manufacturers. They emphasize how further work into this direction could greatly improve the management and prevention of injury during surgery. Additionally, we show the importance of modelling the human brain with region-dependent parameters in order to provide useful predictions for neurosurgical procedures. [ABSTRACT FROM AUTHOR]

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Despite significant achievements in the artificial narrow intelligence sphere, the mechanisms of human-like (general) intelligence are still undeveloped. There is a theory stating that the human brain extracts the meaning of information rather than recognizes the features of a phenomenon. Extracting the meaning is finding a set of transformation rules (context) and applying them to the incoming information, producing an interpretation. Then, the interpretation is compared to something already seen and is stored in memory. Information can have different meanings in different contexts. A mathematical model of a context processor and a differential contextual space which can perform the interpretation is discussed and developed in this paper. This study examines whether the basic principles of differential contextual spaces work in practice. The model is developed with Rust programming language and trained on black and white images which are rotated and shifted both horizontally and vertically according to the saccades and torsion movements of a human eye. Then, a picture that has never been seen in the particular transformation, but has been seen in another one, is exposed to the model. The model considers the image in all known contexts and extracts the meaning. The results show that the program can successfully process black and white images which are transformed by shifts and rotations. This research prepares the grounding for further investigations of the contextual model principles with which general intelligence might operate. [ABSTRACT FROM AUTHOR]

Human brain organoids are emerging as translationally relevant models for the study of human brain health and disease. However, it remains to be shown whether human-specific protein processing is conserved in human brain organoids. Herein, we demonstrate that cell fate and composition of unguided brain organoids are dictated by culture conditions during embryoid body formation, and that culture conditions at this stage can be optimized to result in the presence of glia-associated proteins and neural network activity as early as three-months in vitro. Under these optimized conditions, unguided brain organoids generated from induced pluripotent stem cells (iPSCs) derived from male-female siblings are similar in growth rate, size, and total protein content, and exhibit minimal batch-to-batch variability in cell composition and metabolism. A comparison of neuronal, microglial, and macroglial (astrocyte and oligodendrocyte) markers reveals that profiles in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples, providing the first demonstration that human-specific protein processing is largely conserved in unguided brain organoids. Thus, our organoid protocol provides four major cell types that appear to process proteins in a manner very similar to the human brain, and they do so in half the time required by other protocols. This unique copy of the human brain and basic characteristics lay the foundation for future studies aiming to investigate human brain-specific protein patterning (e.g., isoforms, splice variants) as well as modulate glial and neuronal processes in an in situ-like environment. [ABSTRACT FROM AUTHOR]

• VGLUT1 and VGLUT2 are generally preserved in AD across the medial temporal lobe. • We report a lower density of VGLUT1 in the dentate gyrus stratum moleculare in AD. • VGLUT2 expression is lower in the AD subiculum and superior temporal gyrus. • VGLUT1 and VGLUT2 expression show a brain region-specific vulnerability in AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate. Thus, expressional changes in disease can have implications for aberrant neuronal activity, raising the possibility of a therapeutic target. There is no information regarding the expression of VGLUTs in the human medial temporal lobe in AD, one of the earliest and most severely affected brain regions. This study aimed to quantify and compare the layer-specific expression of VGLUT1 and VGLUT2 between control and AD cases in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Free-floating fluorescent immunohistochemistry was used to label VGLUT1 and VGLUT2 in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Sections were imaged using laser-scanning confocal microscopy and transporter densitometric analysis was performed. VGLUT1 density was not significantly different in AD tissue, except lower staining density observed in the dentate gyrus stratum moleculare (p = 0.0051). VGLUT2 expression was not altered in the hippocampus and entorhinal cortex of AD cases but was significantly lower in the subiculum (p = 0.015) and superior temporal gyrus (p = 0.0023). This study indicates a regionally specific vulnerability of VGLUT1 and VGLUT2 expression in the medial temporal lobe and superior temporal gyrus in AD. However, the causes and functional consequences of these disturbances need to be further explored to assess VGLUT1 and VGLUT2 as viable therapeutic targets. [ABSTRACT FROM AUTHOR]

Diffusion MRI with free gradient waveforms, combined with simultaneous relaxation encoding, referred to as multidimensional MRI (MD‐MRI), offers microstructural specificity in complex biological tissue. This approach delivers intravoxel information about the microstructure, local chemical composition, and importantly, how these properties are coupled within heterogeneous tissue containing multiple microenvironments. Recent theoretical advances incorporated diffusion time dependency and integrated MD‐MRI with concepts from oscillating gradients. This framework probes the diffusion frequency, ω$$ \omega $$, in addition to the diffusion tensor, D$$ \mathbf{D} $$, and relaxation, R1$$ {R}_1 $$, R2$$ {R}_2 $$, correlations. A Dω−R1−R2$$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ clinical imaging protocol was then introduced, with limited brain coverage and 3 mm3 voxel size, which hinder brain segmentation and future cohort studies. In this study, we introduce an efficient, sparse in vivo MD‐MRI acquisition protocol providing whole brain coverage at 2 mm3 voxel size. We demonstrate its feasibility and robustness using a well‐defined phantom and repeated scans of five healthy individuals. Additionally, we test different denoising strategies to address the sparse nature of this protocol, and show that efficient MD‐MRI encoding design demands a nuanced denoising approach. The MD‐MRI framework provides rich information that allows resolving the diffusion frequency dependence into intravoxel components based on their Dω−R1−R2$$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ distribution, enabling the creation of microstructure‐specific maps in the human brain. Our results encourage the broader adoption and use of this new imaging approach for characterizing healthy and pathological tissues. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex chronic metabolic disorder characterized by hyperglycemia because of insulin resistance. Diabetes with chronic hyperglycemia may alter brain metabolism, including brain glucose and neurotransmitter levels; however, detailed, longitudinal studies of metabolic alterations in T2D are lacking. To shed insight, here, we characterized the consequences of poorly controlled hyperglycemia on neurochemical profiles that reflect metabolic alterations of the brain in both humans and animal models of T2D. Using in vivo 1 H magnetic resonance spectroscopy, we quantified 12 metabolites cross-sectionally in T2D patients and 20 metabolites longitudinally in T2D db/db mice versus db+ controls. We found significantly elevated brain glucose (91%, p< 0.001), taurine (22%, p= 0.02), glucose+taurine (56%, p< 0.001), myo-inositol (12%, p= 0.02), and choline-containing compounds (10%, p= 0.01) in T2D patients versus age- and sex-matched controls, findings consistent with measures in T2D db/db versus control db+ littermates. In mice, hippocampal and striatal neurochemical alterations in brain glucose, ascorbate, creatine, phosphocreatine, γ-aminobutyric acid, glutamate, glutamine, glutathione, glycerophosphorylcholine, lactate, myo-inositol, and taurine persisted in db/db mice with chronic disease progression from 16 to 48 weeks of age, which were distinct from control db+ mice. Overall, our study demonstrates the utility of 1 H magnetic resonance spectroscopy as a non-invasive tool for characterizing and monitoring brain metabolic changes with T2D progression. [ABSTRACT FROM AUTHOR]

The probabilistic topography and inter-individual variability of the pituitary gland (PG) remain undetermined. The absence of a standardized reference atlas hinders research on PG volumetrics. In this study, we aimed at creating maximum probability maps for the anterior and posterior PG in young female adults. We manually delineated the anterior and posterior parts of the pituitary glands in 26 healthy subjects using high-resolution MRI T1 images. A three-step procedure and a cost function-masking approach were employed to optimize spatial normalization for the PG. We generated probabilistic atlases and maximum probability maps, which were subsequently coregistered back to the subjects' space and compared to manual delineations. Manual measurements led to a total pituitary volume of 705 ± 88 mm³, with the anterior and posterior volumes measuring 614 ± 82 mm³ and 91 ± 20 mm³, respectively. The mean relative volume difference between manual and atlas-based estimations was 1.3%. The global pituitary atlas exhibited an 80% (± 9%) overlap for the DICE index and 67% (± 11%) for the Jaccard index. Similarly, these values were 77% (± 13%) and 64% (± 14%) for the anterior pituitary atlas and 62% (± 21%) and 47% (± 17%) for the posterior PG atlas, respectively. We observed a substantial concordance and a significant correlation between the volume estimations of the manual and atlas-based methods for the global pituitary and anterior volumes. The maximum probability maps of the anterior and posterior PG lay the groundwork for automatic atlas-based segmentation methods and the standardized analysis of large PG datasets. [ABSTRACT FROM AUTHOR]

Adult hippocampal neurogenesis (AHN), essential for the plasticity of hippocampal structure and function, may be disrupted in Alzheimer's disease (AD). However, the relationship between the changes in AHN and AD‐related pathology in humans remains uncertain. By utilizing advanced immunostaining techniques, we could identify multiple biomarkers representing different stages of AHN in postmortem human hippocampal tissue that exhibited various AD‐related neuropathological changes. In this study, we observed a significant presence of neurogenic cells in the hippocampus's dentate gyrus (DG) region in 30 individuals, including 14 individuals diagnosed with AD‐related neuropathological changes and the remaining 16 individuals without any neurological diseases. Further investigation revealed that patients with AD exhibited pronounced astrogliosis and reduced neurogenesis. Specifically, the number of neuroblasts, immature and early mature granule cells decreased significantly as AD advanced. Although the number of neural stem cells (NSCs) remained unchanged in AD patients compared with mentally healthy individuals, they tended to be more quiescent state regulated by Notch and bone morphogenetic protein (BMP) signaling pathways. These abnormalities were strongly associated with the neuropathological alterations in AD patients. These research findings provide potential insights into the underlying mechanisms that underpin the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Metabolite‐weighted chemical exchange saturation transfer MRI can be used to indirectly image metabolites such as creatine and glutamate. This study aims to further explore the contrast of CEST at 2 ppm in the human brain at 7T and investigate the metabolite correlates of CEST at 2 ppm via correlations with magnetic resonance spectroscopy (MRS). Simulations were performed to establish the optimal acquisition parameters, such as total saturation time (tsat) and B1 root mean squared (B1rms) for CEST at 2 ppm in the human brain. Parameters were validated via in vitro phantom studies at 7T using concentrations, pH and temperature comparable to what is found in the human brain. Finally, 10 healthy volunteers were scanned at 7T for comparison with MRS. Our results show that the optimal parameters to acquire CEST at 2 ppm images are: B1rms = 2.14 μT & tsat = 1500 ms, respectively. Comparison with MRS showed no significant correlation between CEST at 2 ppm and total Creatine measured by MRS (R = 0.19; p‐value = 0.273). However, a significant correlation was found between CEST at 2 ppm and Glu (R = 0.39; p‐value = 0.033), indicating the broad Glutamate‐weighted CEST as the main measurable contributor to CEST at 2 ppm. We identified and confirmed optimal CEST at 2 ppm sequence parameters and validated CEST at 2 ppm measurements in a controlled in vitro environment. Our findings suggest that glutamate is a substantial contributor to the CEST at 2 ppm contrast observed in the human brain, whereas the creatine contribution to CEST at 2 ppm in the brain did not show a measurable contribution. [ABSTRACT FROM AUTHOR]

Magnetic Resonance Spectroscopic Imaging (MRSI) is a powerful technique that can map the metabolic profile in the brain non-invasively. Extracranial lipid contamination and insufficient B0 homogeneity however hampers robustness, and as a result has hindered widespread use of MRSI in clinical and research settings. Over the last six years we have developed highly effective extracranial lipid suppression methods with a second order gradient insert (ECLIPSE) utilizing inner volume selection (IVS) and outer volume suppression (OVS) methods. While ECLIPSE provides > 100-fold in lipid suppression with modest radio frequency (RF) power requirements and immunity to B1+ field variations, axial coverage is reduced for non-elliptical head shapes. In this work we detail the design, construction, and utility of MC-ECLIPSE, a pulsed second order gradient coil with Z2 and X2Y2 fields, combined with a 54-channel multi-coil (MC) array. The MC-ECLIPSE platform allows arbitrary region of interest (ROI) shaped OVS for full-axial slice coverage, in addition to MC-based B0 field shimming, for robust human brain proton MRSI.In vivo experiments demonstrate that MC-ECLIPSE allows axial brain coverage of 92–95 % is achieved following arbitrary ROI shaped OVS for various head shapes. The standard deviation (SD) of the residual B0 field following SH2 and MC shimming were 25 ± 9 Hz and 18 ± 8 Hz over a 5 cm slab, and 18 ± 5 Hz and 14 ± 6 Hz over a 1.5 cm slab, respectively. These results demonstrate that B0 magnetic field shimming with the MC array supersedes second order harmonic capabilities available on standard MRI systems for both restricted and large ROIs. Furthermore, MC based B0 shimming provides comparable shimming performance to an unrestricted SH5 shim set for both restricted, and 5-cm slab shim challenges.Phantom experiments demonstrate the high level of localization performance achievable with MC-ECLIPSE, with ROI edge chemical shift displacements ranging from 1–3 mm with a median value of 2 mm, and transition width metrics ranging from 1–2.5 mm throughout the ROI edge. Furthermore, MC based B0 shimming is comparable to performance following a full set of unrestricted spherical harmonic fields up to order 5. Short echo time MRSI and GABA-edited MRSI acquisitions in the human brain following MC-shimming and arbitrary ROI shaping demonstrate full-axial slice coverage and extracranial lipid artifact free spectra. MC-ECLIPSE allows full-axial coverage and robust MRSI acquisitions, while allowing interrogation of cortical tissue proximal to the skull, which has significant value in a wide range of neurological and psychiatric conditions.

Abstract Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. Graphical Abstract

Abstract Background Herpes simplex virus (HSV) encephalitis (HSE) is a serious and potentially life-threatening disease, affecting both adults and newborns. Progress in understanding the virus and host factors involved in neonatal HSE has been hampered by the limitations of current brain models that do not fully recapitulate the tissue structure and cell composition of the developing human brain in health and disease. Here, we developed a human fetal organotypic brain slice culture (hfOBSC) model and determined its value in mimicking the HSE neuropathology in vitro. Methods Cell viability and tissues integrity were determined by lactate dehydrogenase release in supernatant and immunohistological (IHC) analyses. Brain slices were infected with green fluorescent protein (GFP-) expressing HSV-1 and HSV-2. Virus replication and spread were determined by confocal microscopy, PCR and virus culture. Expression of pro-inflammatory cytokines and chemokines were detected by PCR. Cell tropism and HSV-induced neuropathology were determined by IHC analysis. Finally, the in situ data of HSV-infected hfOBSC were compared to the neuropathology detected in human HSE brain sections. Results Slicing and serum-free culture conditions were optimized to maintain the viability and tissue architecture of ex vivo human fetal brain slices for at least 14 days at 37 °C in a CO2 incubator. The hfOBSC supported productive HSV-1 and HSV-2 infection, involving predominantly infection of neurons and astrocytes, leading to expression of pro-inflammatory cytokines and chemokines. Both viruses induced programmed cell death—especially necroptosis—in infected brain slices at later time points after infection. The virus spread, cell tropism and role of programmed cell death in HSV-induced cell death resembled the neuropathology of HSE. Conclusions We developed a novel human brain culture model in which the viability of the major brain-resident cells—including neurons, microglia, astrocytes and oligodendrocytes—and the tissue architecture is maintained for at least 2 weeks in vitro under serum-free culture conditions. The close resemblance of cell tropism, spread and neurovirulence of HSV-1 and HSV-2 in the hfOBSC model with the neuropathological features of human HSE cases underscores its potential to detail the pathophysiology of other neurotropic viruses and as preclinical model to test novel therapeutic interventions.

The field of diffuse optics has provided a rich set of neurophotonic tools to measure the human brain noninvasively. Interferometric detection is a recent, exciting methodological development in this field. The approach is especially promising for the measurement of diffuse fluctuation signals related to blood flow. Benefitting from inexpensive sensor arrays, the interferometric approach has already dramatically improved throughput, enabling the measurement of brain blood flow faster and deeper. The interferometric approach can also achieve time-of-flight resolution, improving the accuracy of acquired signals. We provide a historical perspective and summary of recent work in the nascent area of interferometric diffuse optics. We predict that the convergence of interferometric technology with existing economies of scale will propel many advances in the years to come.

The proteins in the cell membrane of the brain are modified by glycans in highly interactive regions. The glycans and glycoproteins are involved in cell-cell interactions that are of fundamental importance to the brain. In this study, the comprehensive N-glycome and N-glycoproteome of the brain were determined in 11 functional brain regions, some of them known to be affected with the progression of Alzheimer's disease. N-glycans throughout the regions were generally highly branched and highly sialofucosylated. Regional variations were also found with regard to the glycan types including high mannose and complex-type structures. Glycoproteomic analysis identified the proteins that differed in glycosylation in the various regions. To obtain the broader representation of glycan compositions, four subjects with two in their 70s and two in their 90s representing two Alzheimer's disease subjects, one hippocampal sclerosis subject, and one subject with no cognitive impairment were analyzed. The four subjects were all glycomically mapped across 11 brain regions. Marked differences in the glycomic and glycoproteomic profiles were observed between the samples.

Background: Brain banks provide small tissue samples to researchers, while gross anatomy laboratories could provide larger samples, including complete brains to neuroscientists. However, they are preserved with solutions appropriate for gross-dissection, different from the classic neutral-buffered formalin (NBF) used in brain banks. Our previous work in mice showed that two grossanatomy laboratory solutions, a saturated-salt-solution (SSS) and an alcoholformaldehyde-solution (AFS), preserve antigenicity of the main cellular markers (neurons, astrocytes, microglia, and myelin). Our goal is now to compare the quality of histology and antigenicity preservation of human brains fixed with NBF by immersion (practice of brain banks) vs. those fixed with a SSS and an AFS by whole body perfusion, practice of gross-anatomy laboratories. Methods: We used a convenience sample of 42 brains (31 males, 11 females; 25-90 years old) fixed with NBF (N = 12), SSS (N = 13), and AFS (N = 17). One cm3 tissue blocks were cut, cryoprotected, frozen and sliced into 40 µm sections. The four cell populations were labeled using immunohistochemistry (Neurons = neuronal-nuclei = NeuN, astrocytes = glial-fibrillary-acidicprotein = GFAP, microglia = ionized-calcium-binding-adaptor-molecule1 = Iba1 and oligodendrocytes = myelin-proteolipid-protein = PLP). We qualitatively assessed antigenicity and cell distribution, and compared the ease of manipulation of the sections, the microscopic tissue quality, and the quality of common histochemical stains (e.g., Cresyl violet, Luxol fast blue, etc.) across solutions. Results: Sections of SSS-fixed brains were more difficult to manipulate and showed poorer tissue quality than those from brains fixed with the other solutions. The four antigens were preserved, and cell labeling was more often homogeneous in AFS-fixed specimens. NeuN and GFAP were not always present in NBF and SSS samples. Some antigens were heterogeneously distributed in some specimens, independently of the fixative, but an antigen retrieval protocol successfully recovered them. Finally, the histochemical stains were of sufficient quality regardless of the fixative, although neurons were more often paler in SSS-fixed specimens. Conclusion: Antigenicity was preserved in human brains fixed with solutions used in human gross-anatomy (albeit the poorer quality of SSS-fixed specimens). For some specific variables, histology quality was superior in AFS-fixed brains. Furthermore, we show the feasibility of frequently used histochemical stains. These results are promising for neuroscientists interested in using brain specimens from anatomy laboratories. [ABSTRACT FROM AUTHOR]

Introduction: The red nucleus is part of the motor system controlling limb movements. While this seems to be a function common in many vertebrates, its organization and circuitry have undergone massive changes during evolution. In primates, it is sub-divided into the magnocellular and parvocellular parts that give rise to rubrospinal and rubro-olivary connection, respectively. These two subdivisions are subject to striking variation within the primates and the size of the magnocellular part is markedly reduced in bipedal primates including humans. The parvocellular part is part of the olivo-cerebellar circuitry that is prominent in humans. Despite the well-described differences between species in the literature, systematic comparative studies of the red nucleus remain rare. Methods: We therefore mapped the red nucleus in cytoarchitectonic sections of 20 primate species belonging to 5 primate groups including prosimians, new world monkeys, old world monkeys, non-human apes and humans. We used Ornstein-Uhlenbeck modelling, ancestral state estimation and phylogenetic analysis of covariance to scrutinize the phylogenetic relations of the red nucleus volume. Results: We created openly available high-resolution cytoarchitectonic delineations of the human red nucleus in the microscopic BigBrain model and human probabilistic maps that capture inter-subject variations in quantitative terms. Further, we compared the volume of the nucleus across primates and showed that the parvocellular subdivision scaled proportionally to the brain volume across the groups while the magnocellular part deviated significantly from the scaling in humans and non-human apes. These two groups showed the lowest size of the magnocellular red nucleus relative to the whole brain volume and the largest relative difference between the parvocellular and magnocellular subdivision. Discussion: That is, the red nucleus has transformed from a magnocellulardominated to a parvocellular-dominated station. It is reasonable to assume that these changes are intertwined with evolutionary developments in other brain regions, in particular the motor system. We speculate that the interspecies variations might partly reflect the differences in hand dexterity but also the tentative involvement of the red nucleus in sensory and cognitive functions. [ABSTRACT FROM AUTHOR]

• Electrocorticography reveals a two-stage face processing in the human brain. • The human brain shows a "detection-first, recognize-later" face procession pattern. • Convolutional neural networks exhibit brain-like face processing pattern. • This sequential organization of face processing is a computational optimization. Face processing includes two crucial processing levels – face detection and face recognition. However, it remains unclear how human brains organize the two processing levels sequentially. While some studies found that faces are recognized as fast as they are detected, others have reported that faces are detected first, followed by recognition. We discriminated the two processing levels on a fine time scale by combining human intracranial EEG (two females, three males, and three subjects without reported sex information) and representation similarity analysis. Our results demonstrate that the human brain exhibits a "detection-first, recognition-later" pattern during face processing. In addition, we used convolutional neural networks to test the hypothesis that the sequential organization of the two face processing levels in the brain reflects computational optimization. Our findings showed that the networks trained on face recognition also exhibited the "detection-first, recognition-later" pattern. Moreover, this sequential organization mechanism developed gradually during the training of the networks and was observed only for correctly predicted images. These findings collectively support the computational account as to why the brain organizes them in this way. [ABSTRACT FROM AUTHOR]

Indirect correlational evidence suggests that the posteromedial sector of the human parietal cortex (area hV6A) is involved in reaching corrections. We interfered with hV6A functions using repetitive transcranial magnetic stimulation (rTMS) while healthy participants performed reaching movements and in-flight adjustments of the hand trajectory in presence of unexpected target shifts. rTMS over hV6A specifically altered action reprogramming, causing deviations of the shifted trajectories, particularly along the vertical dimension (i.e., distance). This study provides evidence of the functional relevance of hV6A in action reprogramming while a sudden event requires a change in performance and shows that hV6A also plays a role in state estimation during reaching. These findings are in line with neurological data showing impairments in actions performed along the distance dimension when lesions occur in the dorsal posterior parietal cortex. [ABSTRACT FROM AUTHOR]

Due to advancements in data collection, storage, and processing techniques, machine learning has become a thriving and dominant paradigm. However, one of its main shortcomings is that the classical machine learning paradigm acts in isolation without utilizing the knowledge gained through learning from related tasks in the past. To circumvent this, the concept of Lifelong Machine Learning (LML) has been proposed, with the goal of mimicking how humans learn and acquire cognition. Human learning research has revealed that the brain connects previously learned information while learning new information from a single or small number of examples. Similarly, an LML system continually learns by storing and applying acquired information. Starting with an analysis of how the human brain learns, this paper shows that the LML framework shares a functional structure with the brain when it comes to solving new problems using previously learned information. It also provides a description of the LML framework, emphasizing its similarities to human brain learning. It also provides citation graph generation and scientometric analysis algorithms for the LML literatures, including information about the datasets and evaluation metrics that have been used in the empirical evaluation of LML systems. Finally, it presents outstanding issues and possible future research directions in the field of LML. [ABSTRACT FROM AUTHOR]

Single‐voxel proton magnetic resonance spectroscopy (SV 1H‐MRS) is an in vivo noninvasive imaging technique used to detect neurotransmitters and metabolites. It enables repeated measurements in living participants to build explanatory neurochemical models of psychiatric symptoms and testing of therapeutic approaches. Given the tight link among glutamate, gamma‐amino butyric acid (GABA), glutathione and glutamine within the cellular machinery, MRS investigations of neurocognitive and psychiatric disorders must quantify a network of metabolites simultaneously to capture the pathophysiological states of interest. Metabolite‐selective sequences typically provide improved metabolite isolation and spectral modelling simplification for a single metabolite at a time. Non‐metabolite‐selective sequences provide information on all detectable human brain metabolites, but feature many signal overlaps and require complicated spectral modelling. Although there are short‐echo time (TE) MRS sequences that do not use spectral editing and are optimised to target either glutamate, GABA or glutathione, these approaches usually imply a precision tradeoff for the remaining two metabolites. Given the interest in assessing psychiatric and neurocognitive diseases that involve excitation‐inhibition imbalances along with oxidative stress, there is a need to survey the literature on the quantification precision of current metabolite‐selective MRS techniques. In this review, we locate and describe 17 studies that report on the quality of simultaneously acquired MRS metabolite data in the human brain. We note several factors that influence the data quality for single‐shot acquisition of multiple metabolites of interest using metabolite‐selective MRS: (1) internal in vivo references; (2) brain regions of interests; (3) field strength of scanner; and/or (4) optimised acquisition parameters. We also highlight the strengths and weaknesses of various SV spectroscopy techniques that were able to quantify in vivo glutamate, GABA and glutathione simultaneously. The insights from this review will assist in the development of new MRS pulse sequences for simultaneous, selective measurements of these metabolites and simplified spectral modelling. [ABSTRACT FROM AUTHOR]

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Herpes simplex virus (HSV) encephalitis (HSE) is a serious and potentially life-threatening disease, affecting both adults and newborns. Progress in understanding the virus and host factors involved in neonatal HSE has been hampered by the limitations of current brain models that do not fully recapitulate the tissue structure and cell composition of the developing human brain in health and disease. Here, we developed a human fetal organotypic brain slice culture (hfOBSC) model and determined its value in mimicking the HSE neuropathology in vitro. Methods: Cell viability and tissues integrity were determined by lactate dehydrogenase release in supernatant and immunohistological (IHC) analyses. Brain slices were infected with green fluorescent protein (GFP-) expressing HSV-1 and HSV-2. Virus replication and spread were determined by confocal microscopy, PCR and virus culture. Expression of pro-inflammatory cytokines and chemokines were detected by PCR. Cell tropism and HSV-induced neuropathology were determined by IHC analysis. Finally, the in situ data of HSV-infected hfOBSC were compared to the neuropathology detected in human HSE brain sections. Results: Slicing and serum-free culture conditions were optimized to maintain the viability and tissue architecture of ex vivo human fetal brain slices for at least 14 days at 37 °C in a CO2 incubator. The hfOBSC supported productive HSV-1 and HSV-2 infection, involving predominantly infection of neurons and astrocytes, leading to expression of pro-inflammatory cytokines and chemokines. Both viruses induced programmed cell death—especially necroptosis—in infected brain slices at later time points after infection. The virus spread, cell tropism and role of programmed cell death in HSV-induced cell death resembled the neuropathology of HSE. Conclusions: We developed a novel human brain culture model in which the viability of the major brain-resident cells—including neurons, microglia, astrocytes and oligodendrocytes—and the tissue architecture is maintained for at least 2 weeks in vitro under serum-free culture conditions. The close resemblance of cell tropism, spread and neurovirulence of HSV-1 and HSV-2 in the hfOBSC model with the neuropathological features of human HSE cases underscores its potential to detail the pathophysiology of other neurotropic viruses and as preclinical model to test novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Rapid development of artificial intelligence techniques significantly promotes important medical imaging applications such as disease diagnosis, medical image analysis and cross-modality synthesis. It is valuable to synthesize Computed Tomography (CT) scans of human brains from Magnetic Resonance Imaging (MRI) scans because CT images contain particular information for diseases such as malignant tumors, cerebrovascular malformations and aneurysms. Although there has been many studies trying to apply machine learning methods (e.g., fully convolutional neural networks and generative adversarial networks) to predict CT images based on MRI, there are still opportunities to increase the quality of synthesized CT images using the latest machine learning algorithms. In this study, we aim to synthesize high-credibility human brain CT images from MRI images using machine learning approaches. We build a dataset of both CT and MRI images of 41 patients from The Cancer Imaging Archive. A data pre-processing pipeline is designed to guarantee that the processed images are suitable as inputs to machine learning algorithms. The pipeline includes (1) pairing MRI and CT scans according to a certain time interval between CT and MRI exams of the same patient, (2) registering all MRI images to a standard MRI template, (3) registering all CT images to paired MRI images, (4) intensity normalization and (5) extracting 2D slices from 3D CT and MRI volumes. Three deep neural networks with encoder–decoder structure are selected and implemented including U-Net, U-Net++ and pix2pix to synthesize human brain CT images from MRI images. Experimental results illustrate that U-Net++ shows better performance than U-Net and pix2pix in synthesizing CT images from MRI by achieving a Mean Squared Error of 0.025, a Mean Absolute Error of 0.082 and a Peak Signal-to-Noise Ratio of 67.90, respectively. The trained machine learning models from this work can be applied in future human brain CT image prediction where CT images are absent and MRI images are available for specific patients, thereby supporting disease diagnosis based on CT images. [ABSTRACT FROM AUTHOR]

The human brain performs computations via a highly interconnected network of neurons. Taking inspiration from the information delivery and processing mechanism of the human brain in central nervous systems, bioinspired nanofluidic iontronics has been proposed and gradually engineered to overcome the limitations of the conventional electron-based von Neumann architecture, which shows the promising potential to enable efficient brain-like computing. Anomalous and tunable nanofluidic ion transport behaviors and spatial confinement show promising controllability of charge carriers, and a wide range of structural and chemical modification paves new ways for realizing brain-like functions. Herein, a comprehensive framework of mechanisms and design strategy is summarized to enable the rational design of nanofluidic systems and facilitate the further development of bioinspired nanofluidic iontronics. This review provides recent advances and prospects of the bioinspired nanofluidic iontronics, including ion-based brain computing, comprehension of intrinsic mechanisms, design of artificial nanochannels, and the latest artificial neuromorphic functions devices. Furthermore, the challenges and opportunities of bioinspired nanofluidic iontronics in the pioneering and interdisciplinary research fields are proposed, including brain–computer interfaces and artificial neurons. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aβ. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human post-mortem AD and control (CTL) frontal cortex (FC; AD n = 22, CTL n = 23) and hippocampus (HP; AD n = 34, CTL n = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aβ pathology at different timepoints during aging and disease progression by immunoblot (n = 5–8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days in vitro. Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aβ accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression.

Human brain organoids are emerging as translationally relevant models for the study of human brain health and disease. However, it remains to be shown whether human-specific protein processing is conserved in human brain organoids. Herein, we demonstrate that cell fate and composition of unguided brain organoids are dictated by culture conditions during embryoid body formation, and that culture conditions at this stage can be optimized to result in the presence of glia-associated proteins and neural network activity as early as three-months in vitro. Under these optimized conditions, unguided brain organoids generated from induced pluripotent stem cells (iPSCs) derived from male–female siblings are similar in growth rate, size, and total protein content, and exhibit minimal batch-to-batch variability in cell composition and metabolism. A comparison of neuronal, microglial, and macroglial (astrocyte and oligodendrocyte) markers reveals that profiles in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples, providing the first demonstration that human-specific protein processing is largely conserved in unguided brain organoids. Thus, our organoid protocol provides four major cell types that appear to process proteins in a manner very similar to the human brain, and they do so in half the time required by other protocols. This unique copy of the human brain and basic characteristics lay the foundation for future studies aiming to investigate human brain-specific protein patterning (e.g., isoforms, splice variants) as well as modulate glial and neuronal processes in an in situ-like environment.

The human hand is a complex and versatile organ that enables humans to interact with the environment, communicate, create, and use tools. The control of the hand by the brain is a crucial aspect of human cognition and behaviour, but also a challenging problem for both neuroscience and engineering. The aim of this study is to review the current state of the art in hand and grasp control from a neuroscientific perspective, focusing on the brain mechanisms that underlie sensory integration for hand control and the engineering implications for developing artificial hands that can mimic and interface with the human brain. The brain controls the hand by processing and integrating sensory information from vision, proprioception, and touch, using different neural pathways. The user’s intention can be obtained to control the artificial hand by using different interfaces, such as electromyography, electroneurography, and electroencephalography. This and other sensory information can be exploited by different learning mechanisms that can help the user adapt to changes in sensory inputs or outputs, such as reinforcement learning, motor adaptation, and internal models. This work summarizes the main findings and challenges of each aspect of hand and grasp control research and highlights the gaps and limitations of the current approaches. In the last part, some open questions and future directions for hand and grasp control research are suggested by emphasizing the need for a neuroscientific approach that can bridge the gap between the brain and the hand.

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK , and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders. [ABSTRACT FROM AUTHOR]