Large Brain Research Articles

Methodology and Neuromarkers for Cetaceans' Brains.

Cetacean brain sampling may be an arduous task due to the difficulty of collecting and histologically preparing such rare and large specimens. Thus, one of the main challenges of working with cetaceans’ brains is to establish a valid methodology for an optimal manipulation and fixation of the brain tissue, which allows the samples to be viable for neuroanatomical and neuropathological studies. With this in view, we validated a methodology in order to preserve the quality of such large brains (neuroanatomy/neuropathology) and at the same time to obtain fresh brain samples for toxicological, virological, and microbiological analysis (neuropathology). A fixation protocol adapted to brains, of equal or even three times the size of human brains, was studied and tested. Finally, we investigated the usefulness of a panel of 20 antibodies (neuromarkers) associated with the normal structure and function of the brain, pathogens, age-related, and/or functional variations. The sampling protocol and some of the 20 neuromarkers have been thought to explore neurodegenerative diseases in these long-lived animals. To conclude, many of the typical measures used to evaluate neuropathological changes do not tell us if meaningful cellular changes have occurred. Having a wide panel of antibodies and histochemical techniques available allows for delving into the specific behavior of the neuronal population of the brain nuclei and to get a “fingerprint” of their real status.

Deep Learning in Large and Multi-Site Structural Brain MR Imaging Datasets.

Large, multi-site, heterogeneous brain imaging datasets are increasingly required for the training, validation, and testing of advanced deep learning (DL)-based automated tools, including structural magnetic resonance (MR) image-based diagnostic and treatment monitoring approaches. When assembling a number of smaller datasets to form a larger dataset, understanding the underlying variability between different acquisition and processing protocols across the aggregated dataset (termed “batch effects”) is critical. The presence of variation in the training dataset is important as it more closely reflects the true underlying data distribution and, thus, may enhance the overall generalizability of the tool. However, the impact of batch effects must be carefully evaluated in order to avoid undesirable effects that, for example, may reduce performance measures. Batch effects can result from many sources, including differences in acquisition equipment, imaging technique and parameters, as well as applied processing methodologies. Their impact, both beneficial and adversarial, must be considered when developing tools to ensure that their outputs are related to the proposed clinical or research question (i.e., actual disease-related or pathological changes) and are not simply due to the peculiarities of underlying batch effects in the aggregated dataset. We reviewed applications of DL in structural brain MR imaging that aggregated images from neuroimaging datasets, typically acquired at multiple sites. We examined datasets containing both healthy control participants and patients that were acquired using varying acquisition protocols. First, we discussed issues around Data Access and enumerated the key characteristics of some commonly used publicly available brain datasets. Then we reviewed methods for correcting batch effects by exploring the two main classes of approaches: Data Harmonization that uses data standardization, quality control protocols or other similar algorithms and procedures to explicitly understand and minimize unwanted batch effects; and Domain Adaptation that develops DL tools that implicitly handle the batch effects by using approaches to achieve reliable and robust results. In this narrative review, we highlighted the advantages and disadvantages of both classes of DL approaches, and described key challenges to be addressed in future studies.

Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex.

One of the most salient features defining modern humans is our remarkable cognitive capacity, which is unrivaled by any other species. Although we still lack a complete understanding of how the human brain gives rise to these unique abilities, the past several decades have witnessed significant progress in uncovering some of the genetic, cellular, and molecular mechanisms shaping the development and function of the human brain. These features include an expansion of brain size and in particular cortical expansion, distinct physiological properties of human neurons, and modified synaptic development. Together they specify the human brain as a large primate brain with a unique underlying neuronal circuit architecture. Here, we review some of the known human-specific features of neuronal connectivity, and we outline how novel insights into the human genome led to the identification of human-specific genetic modifiers that played a role in the evolution of human brain development and function. Novel experimental paradigms are starting to provide a framework for understanding how the emergence of these human-specific genomic innovations shaped the structure and function of neuronal circuits in the human brain.

Novel large scale brain network models for EEG epileptic pattern generations

BackgroundUnlike normal EEG patterns, the epileptiform abnormal pattern is characterized by different morphologies such as the high-frequency oscillations (HFOs) of ripples on spikes, spikes and waves, continuous and sporadic spikes, and ploy2 spikes. Several studies have reported that HFOs can be novel biomarkers in human epilepsy study. MethodTo regenerate and investigate these patterns, we have proposed three large scale brain network models (BNMS) by linking the neural mass model (NMM) of Stefanescu-Jirsa 2D (S-J 2D) with our own structural connectivity derived from the realistic biological data, so called, large-scale connectivity connectome. These models include multiple network connectivity of brain regions at different lobes from both hemispheres (left and right). The network nodes of these models were simulated based on the local dynamics of the S-J 2D model, which were generated by adjusting the global coupling between the excitatory and inhibitory populations. The connection strength between the inhibitory and excitatory neurons of the local model was also adjusted to investigate different morphology patterns. ResultsThe proposed network models were developed and evaluated by simulations. Different abnormal patterns of EEG brain activities such as HFOS ripples on spikes, spikes, continuous spikes, sporadic spikes and ploy2 spikes ranging from 94 to 144 Hz were regenerated. Different morphology patterns of abnormality were generated from novel BNMs and the epileptiform abnormal pattern obtained in actual EEG and other computational models were also compared. SignificantThis study is able to assist researchers and clinical doctors in the field of epilepsy to better understand the complex neural mechanisms behind the abnormal oscillatory activities, which may lead to the discovery of new clinical interventions in epilepsy.

THE ROLE OF NEURO LINGUISTICS IN CREATIVE WRITING SHORT STORIES THROUGH AN INTERDISCIPLINARY APPROACH

This study aims to explore the role of neurolinguistics in writing creative short stories for students through an interdisciplinary approach. neurolinguistics is a field of study consisting of linguistics and medicine which studies the relationship between language and the human brain which is linked to cognitive neuroscience and sensory and cellular movement. The method used in this research is literature review or literature review. There are four stages or four phases in conducting this research (1) designing a review, (2) conducting a review, (3) analyzing and (4) writing a review. In neurolinguistics, the parts of the human brain are also studied. The brain has 3 main parts, namely the cerebrum (cerebrum), cerebellum (cerebellum), and brainstem (brainstem). There are six factors that must be considered in creative writing, namely general knowledge and cognition, creative cognition, process, motivation and conative, linguistics and literacy, and psychomotor. There are also four-pillar factors of neurolinguistics, namely outcome, rapport, sensory acuity, and flexibility. Neurolinguistics also studies the structure and parts of the human brain, including the cerebrum (large brain), cerebellum (cerebellum), brainstem (brain stem) and limbic system (limbic system). The part that is closely related to writing is the cerebellum (cerebellum).

BRAIN 2.0: Transforming neuroscience

The NIH BRAIN Initiative is entering a new phase. Three large new projects-a comprehensive human brain cell atlas, a whole mammalian brain microconnectivity map, and tools for precision access to brain cell types-promise to transform neuroscience research and the treatment of human brain disorders.

Preliminary safety assessment of CIGB-210, an investigational peptide for HIV infection.

Current human immunodeficiency virus treatments need to be periodically administered lifelong. In this study we assess the effect of repeated doses of an anti-HIV peptide drug candidate in C57BL6 strain. Two schemes of up to 15 administrations and one of 30, daily dosing for 5days per week, all by the subcutaneous route were evaluated. Different dose concentrations of the peptide were assayed. CIGB-210 treated animals showed no symptoms or abnormal behavior as compared with placebo. All the animals gained weight during the study. Macroscopic evaluation showed no alterations in any of the organs studied. Microscopic analysis of the tissues did not show morphological changes in thymus, stomach, small and large intestines, kidney, brain, or cerebellum. The proliferative response of splenocytes and their capacity to secrete gamma interferon were not compromised by the repeated administration of CIGB-210. There were not statistically significant differences for any of the parameters evaluated during the study among treated and non-treated groups. We can conclude that CIGB-210 is well tolerated in C57BL6 mice in the dose concentration range explored and merits subsequent toxicological studies.

How to dose-stage large or high risk brain metastases - an alternative two-fraction radiosurgical treatment approach

How to dose-stage large or high risk brain metastases - an alternative two-fraction radiosurgical treatment approach

Hypofractionated Radiosurgery Re-Irradiation in Large Solitary Brain Metastasis from HER2 Positive Breast Carcinoma

Hypofractionated Radiosurgery Re-Irradiation in Large Solitary Brain Metastasis from HER2 Positive Breast Carcinoma

Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.

Adaptive staged-dose Gamma Knife Radiosurgery for the treatment of large brain metastases. Report of 40 consecutive cases and review of literature

Adaptive staged-dose Gamma Knife Radiosurgery for the treatment of large brain metastases. Report of 40 consecutive cases and review of literature

Self-tuition as an essential design feature of the brain.

We are curious by nature, particularly when young. Evolution has endowed our brain with an inbuilt obligation to educate itself. In this perspectives article, we posit that self-tuition is an evolved principle of vertebrate brain design that is reflected in its basic architecture and critical for its normal development. Self-tuition involves coordination between functionally distinct components of the brain, with one set of areas motivating exploration that leads to the experiences that train another set. We review key hypothalamic and telencephalic structures involved in this interplay, including their anatomical connections and placement within the segmental architecture of conserved forebrain circuits. We discuss the nature of educative behaviours motivated by the hypothalamus, innate stimulus biases, the relationship to survival in early life, and mechanisms by which telencephalic areas gradually accumulate knowledge. We argue that this aspect of brain function is of paramount importance for systems neuroscience, as it confers neural specialization and allows animals to attain far more sophisticated behaviours than would be possible through genetic mechanisms alone. Self-tuition is of particular importance in humans and other primates, whose large brains and complex social cognition rely critically on experience-based learning during a protracted childhood period.This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.

Experts in action: why we need an embodied social brain hypothesis.

The anthropoid primates are known for their intense sociality and large brain size. The idea that these might be causally related has given rise to a large body of work testing the 'social brain hypothesis'. Here, the emphasis has been placed on the political demands of social life, and the cognitive skills that would enable animals to track the machinations of other minds in metarepresentational ways. It seems to us that this position risks losing touch with the fact that brains primarily evolved to enable the control of action, which in turn leads us to downplay or neglect the importance of the physical body in a material world full of bodies and other objects. As an alternative, we offer a view of primate brain and social evolution that is grounded in the body and action, rather than minds and metarepresentation. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Morphometric indicators of the precentral gyrus of the large brain in boys and girls

The morphology of the precentral gyrus is of particular interest because it is the origin of the pyramidal pathway responsible for voluntary movements. The aim of the study was to determine the width of the precentral gyrus, the thickness of the cerebral cortex in it and X-ray density of neurons in young boys and girls according to X-ray computed tomographic examination.Material and methods.35 male and 37 female with mesocephalic sculls aged 18 to 20 years old with predominance of the right hand and no pathology of the nervous system organs in the anamnesis were examined.Results.The maximal value of the precentral gyrus width was found at the point located above the superior temporal gyrus. Values were lower (p < 0.01) at the point located at the level of the middle frontal gyrus. The smallest precentral gyrus width was found at a point above the cingulate gyrus (p < 0.01). When comparing the indices in each point, there is a tendency for them to be slightly more prevalent in the left hemisphere than in the right. There is a tendency to nonsignificant prevalence in boys compared to girls (p > 0.05). Parameters of cortical thickness in the precentral gyrus in the studied points did not differ statistically significantly, but there was a tendency to their insignificant predominance in the left hemisphere compared to the right, as well as in boys compared to girls (p > 0.05). Values of the X-ray neuron density in the compared points of the precentral gyrus in both hemispheres did not differ statistically significantly for boys and girls.Conclusions.The established results will serve as the initial data as a criterion of age-specific morphological norm in young mesocephals with predominance of the right hand, which is highly demanded in the personalized approach in medical practice. These results can also be used in prospective clinical and basic research.

Comparative Immunohistochemical Characteristics of Thalamic Glioarchitectonics of Young and Senile Persons

The aim of the investigation was to establish morphological differences between the human thalamus in young and senile age by using an immunohistochemical marker – glial fibrillary acidic protein (GFAP).Material and methods. The results of the sectional study of both thalami of 94 deceased of both sexes were analyzed. Depending on their age (young and senile), they were divided into two groups. The deceased had no history of diseases and injuries of the central and peripheral nervous system organs as well as alcohol and/or drug addiction, no macroscopic signs of brain tissue pathology were detected when material was taken for microscopic examination. Morphological characterization of thalamic tissue in both hemispheres of the large brain using hematoxylin and eosin staining was given. Immunohistochemical study of the samples used antibodies to GFAP.Results. Histological examination of the thalamus in both young and senile age revealed groups of irregularly arranged neuronal bodies with granular cytoplasm and swollen ectopic nuclei. When the immunohistochemical reaction was performed, the product of the reaction was distributed in the bodies and outgrowths of astrocytes. In young age, single bodies of fibrous astrocytes with a moderate number of poorly visualized outgrowths were found. At senile age, in addition to a statistically significant increase in the numerical density of fibrous astrocyte bodies (p<0.01), there is a clear increase in the number of their outgrowths.Conclusion. The results obtained provide a detailed insight into the morphological characteristics of the thalamic tissue of men and women at young and senile age. The use of antibodies to GFAP is a sensitive marker of age-related changes in thalamic cytoarchitectonics. The increase in the numerical density of astrocytes as well as the outgrowth of their processes allows a more precise understanding of age-related involution of nervous tissue, which will allow to use these data in future prospective basic research.

Comparison of embolization strategies for mixed plexiform and fistulous brain arteriovenous malformations: a computational model analysis of theoretical risks of nidus rupture

BackgroundHigh-flow fistulas related to plexiform nidi are found in 40% of large brain arteriovenous malformations (AVMs). Endovascular occlusion of intranidal fistulas before plexiform components is empirically considered safe, but potential...

MET-6 Neoadjuvant fractionated stereotactic radiotherapy followed by piecemeal resection for metastatic brain tumor

BACKGROUND: Large brain metastases which require resection are treated with surgery followed by whole brain radiation therapy or postoperative stereotactic radiosurgery (SRS). Recently a novel strategy using neoadjuvant stereotactic radiosurgery (Na-SRS) followed by surgery was reported, demonstrating lower rates of postoperative leptomeningeal dissemination (LMD) and symptomatic radiation necrosis (RN). We treated with neoadjuvant fractionated stereotactic radiotherapy (Na-fSRT) followed by surgery for large brain metastasis with piecemeal resection. METHODS: Twelve patients received Na-fSRT followed by surgery between July 2019 and April 2021. Na-fSRT dose was based on lesion size and was standard dosing. Surgery generally followed within 7 days after radiotherapy. RESULTS: The mean age was 68 years (51–79). Sixteen men and five women. Mean follow-up period was 8.5 months (1–24.9). Primary were lung; 10 (NSCLC; 9, SCLC (recurrence); 1), esophagus; 3, colon; 2, melanoma; 2, kidney; 2 (recurrence1), uterus body; 1, and liver; 1. The median maximum tumor diameter was 3.6 cm (2.6–4.9). Median PTV, GTV volume were 21.7ml, 15.5ml, respectively. The median fSRT dose was 30Gy/5fr, and the median time from fSRT to surgery was 4 days (1–7). As preoperative adverse event, intracranial hypertension and partial seizure grade 2 (CTCAE ver.5) were occurred, but controlled with steroid and osmotic diuretics and anticonvulsant. Grade 3 and more adverse events were not occurred. Gross total removal was performed in 95.2%. Event cumulative incidence as follows: cavity local recurrence 4.8% (subtotal removal case); distant brain failure 33%; LMD 4.8%; and symptomatic RN 0%. The median intracranial progression free survival was 7 months, and median overall survival was 8.4 months. CONCLUSIONS: Na-fSRT followed by piecemeal resection is safety and feasible, and may have therapeutic value for deep large brain metastasis and eloquent lesion. Further prospective investigations in multi-institutional settings are warranted.

Analyzing Disparity and Rates of Morphological Evolution with Model-Based Phylogenetic Comparative Methods.

Understanding variation in rates of evolution and morphological disparity is a goal of macroevolutionary research. In a phylogenetic comparative methods framework, we present three explicit models for linking the rate of evolution of a trait to the state of another evolving trait. This allows testing hypotheses about causal influences on rates of phenotypic evolution with phylogenetic comparative data. We develop a statistical framework for fitting the models with generalized least-squares regression and use this to discuss issues and limitations in the study of rates of evolution more generally. We show that the power to detect effects on rates of evolution is low in that even strong causal effects are unlikely to explain more than a few percent of observed variance in disparity. We illustrate the models and issues by testing if rates of beak-shape evolution in birds are influenced by brain size, as may be predicted from a Baldwin effect in which presumptively more behaviorally flexible large-brained species generate more novel selection on themselves leading to higher rates of evolution. From an analysis of morphometric data for 645 species, we find evidence that both macro- and microevolution of the beak are faster in birds with larger brains, but with the caveat that there are no consistent effects of relative brain size.[Baldwin effect; beak shape; behavioral drive; bird; brain size; disparity; phylogenetic comparative method; rate of evolution.]

The application of the Human Connectome Project in large scale brain network imaging: A potential biomarker for Alzheimer's disease and related dementias

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) result in progressive dysfunction of large scale brain networks (LSBNs) including the default mode network (DMN). Resting state functional MRI (rs‐fMRI) is an imaging tool offering the potential for tracking LSBN degeneration, but been underutilized as an imaging biomarker. Potential reasons include complexity of imaging protocols and analyzing imaging data. If these steps were simplified and operationalized, further integration of rs‐fMRI into clinical trials as a surrogate endpoint may be feasible. We describe an automated connectome mapping program (Infinitome) that leverages rs‐fMRI scans with standardized protocols, Human Connectome Project (HCP) data, and machine learning to understand longitudinal LSBN degeneration in dementia (figure 1).MethodThe Infinitome program creates a subject specific version of the Human Connectome Project Multimodal Parcellation (HCP‐MMP1) atlas using diffusion tractography (figure 2). Analytics are performed on both diffusion tensor imaging and rs‐fMRI. Outlier detection using a tangent space connectivity matrix is performed by comparing results with a subset of 300 normal HCP subject fMRI samples to determine the range of normal correlations for each regions of interest in a LSBN. Abnormal connectivity is determined as a 3‐sigma outlier for that correlation (figure 3). The imaging protocol for rs‐fMRI is limited to 8 minutes, enabling each study to be readily added on to structural MRI sequences. The program also provides automated image processing and analysis, thus simplifying the process of accessing imaging data and incorporating rs‐fMRI into routine practice.ResultPreliminary work has shown that connectomic analysis using this software in ADRD is feasible and can detect functional anomalies involving regions of interest described by the HCP.ConclusionBy providing support for fMRI processing through a cloud‐based server and incorporating normal control data from the HCP, the Infinitome program addresses the challenges associated with the analysis and interpretation of rs‐fMRI data. Thus, it has the potential to simplify the incorporation of rs‐fMRI into clinical trials as a biomarker for progressive neurodegeneration of vulnerable networks in ADRD. Further studies are planned evaluating LSBNs in AD and dementia with Lewy bodies.

Pathway modeling applied to TREAT-AD proteomic targets demonstrates linkages between AD endophenotypes.

The poor success rate of therapeutic targeting in Alzheimer's disease necessitates the explorations of new biological areas and hypotheses of disease mechanism. The TREAT-AD Consortium is an international group of academic researchers dedicated to identifying novel targets for AD from under-explored areas of disease-linked pathology. However, target identification from genomic and proteomic studies is extremely challenging. Toward that end, we identified 13 core biological domains associated with AD, and created a gene ontology (GO) mapping to each in order to automatically identify genes associated with each endophenotype. The TREAT-AD hits coming from large scale brain proteomic studies were then mapped onto the core biological domains. A novel system of dynamic data driven pathway reconstruction was applied that draws binary relationships from the Pathway Commons data store and builds AD-weighted pathways around the proteomic targets linked to the 13 core biological domains of AD. The dynamic data-driven pathway reconstruction application developed large network objects around the submitted proteomic targets that create hypothetical linkage points across discrete areas of disease biology. The network objects represent a holistic pathway linking the submitted TREAT-AD proteomic hits to each other, through missing elements and disease sentinel genes, to create an interlinked pathway model. This model can be shared and community-mined for significant AD-linked hypotheses. Using this approach, we identified numerous interactions between AD endophenotypes, such as neuroinflammation and endocytosis. One of the primary difficulties with therapeutic target identification is understanding the biological network within which any particular gene resides. The tools we have developed may help examine the biological neighborhood more robustly, as well as assess specific hypothetical mechanist connections between genes that may help identify and optimized AD-drug targets in the future.