Neuroscience Research Community Research Articles

The Promise and Practicality of Addressing Sex as a Biological Variable and the Ovarian Cycle in Preclinical Epilepsy Research

Seizures and epilepsy affect people of all sexes and genders. In the last several years, funding agency initiatives such as the U.S. National Institutes of Health policy on sex as a biological variable (SABV) have intended to encourage researchers to study both males and females from cell to tissue to organism and analyze and report the resulting data with sex as a factor. Preclinical epilepsy research, however, continues to be plagued by confusion regarding both the SABV policy and its implementation, reflecting similar beliefs in the larger neuroscience research community. This article aims to address some common misconceptions and provide practical tools and suggestions for preclinical epilepsy researchers in implementing SABV and analysis of the female ovarian cycle (estrous cycle in rodents) in their research programs, with a focus on studies using rodent models. Examples of recent publications in preclinical epilepsy research highlighting the value of incorporating SABV and information on the estrous cycle are included. The specifics of how best to address SABV and the estrous cycle can vary depending on the needs and goals of a particular research program, but an embrace of these physiological factors by the preclinical epilepsy research community promises to yield more rigorous research and improved treatment strategies for all people with epilepsy.

SCAN: Spatiotemporal Cloud Atlas for Neural cells.

The nervous system is one of the most complicated and enigmatic systems within the animal kingdom. Recently, the emergence and development of spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) technologies have provided an unprecedented ability to systematically decipher the cellular heterogeneity and spatial locations of the nervous system from multiple unbiased aspects. However, efficiently integrating, presenting and analyzing massive multiomic data remains a huge challenge. Here, we manually collected and comprehensively analyzed high-quality scRNA-seq and ST data from the nervous system, covering 10 679 684 cells. In addition, multi-omicdatasets from more than 900 species were included for extensive data mining from an evolutionary perspective. Furthermore, over 100 neurological diseases (e.g. Alzheimer's disease, Parkinson's disease, Down syndrome) were systematically analyzed for high-throughput screening of putative biomarkers. Differential expression patterns across developmental time points, cell types and ST spots were discerned and subsequently subjected to extensive interpretation. To provide researchers with efficient data exploration, we created a new database with interactive interfaces and integrated functions called the Spatiotemporal Cloud Atlas for Neural cells (SCAN), freely accessible at http://47.98.139.124:8799 or http://scanatlas.net. SCAN will benefit the neuroscience research community to better exploit the spatiotemporal atlas of the neural system and promote the development of diagnostic strategies for various neurological disorders.

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

Trends and Treatment Approaches for Complications in Neuroscience Experiments with Monkey Species.

Our goal in this manuscript is to advance the assessment and treatment of monkey species in neuroscience research. We hope to begin a discussion and establish baseline data on how complications are identified and treated. We surveyed the neuroscience research community working with monkeys and compiled responses to questions about investigator demographics, assessment of animal wellbeing, treatment choices, and approaches to mitigate risks associated with CNS procedures and promote monkey health and wellbeing. The majority of the respondents had worked with nonhuman primates (NHP) for over 15 y. Identification of procedure-related complications and efficacy of treatment generally rely on common behavioral indices. Treatments for localized inflammatory responses are generally successful, whereas the treatment success for meningitis or meningoencephalitis, abscesses, and hemorrhagic stroke are less successful. Behavioral signs of pain are treated successfully with NSAIDs and opioids. Our future plans are to collate treatment protocols and develop best practices that can be shared across the neuroscience community to improve treatment success rates and animal welfare and therefore science. Human protocols can be used to develop best practices, assess outcomes, and promote further refinements in treatment practices for monkeys to enhance research outcomes.

Interdisciplinary views of fNIRS: Current advancements, equity challenges, and an agenda for future needs of a diverse fNIRS research community.

Functional Near-Infrared Spectroscopy (fNIRS) is an innovative and promising neuroimaging modality for studying brain activity in real-world environments. While fNIRS has seen rapid advancements in hardware, software, and research applications since its emergence nearly 30 years ago, limitations still exist regarding all three areas, where existing practices contribute to greater bias within the neuroscience research community. We spotlight fNIRS through the lens of different end-application users, including the unique perspective of a fNIRS manufacturer, and report the challenges of using this technology across several research disciplines and populations. Through the review of different research domains where fNIRS is utilized, we identify and address the presence of bias, specifically due to the restraints of current fNIRS technology, limited diversity among sample populations, and the societal prejudice that infiltrates today's research. Finally, we provide resources for minimizing bias in neuroscience research and an application agenda for the future use of fNIRS that is equitable, diverse, and inclusive.

Standard metadata for 3D microscopy

Recent advances in fluorescence microscopy techniques and tissue clearing, labeling, and staining provide unprecedented opportunities to investigate brain structure and function. These experiments’ images make it possible to catalog brain cell types and define their location, morphology, and connectivity in a native context, leading to a better understanding of normal development and disease etiology. Consistent annotation of metadata is needed to provide the context necessary to understand, reuse, and integrate these data. This report describes an effort to establish metadata standards for three-dimensional (3D) microscopy datasets for use by the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative and the neuroscience research community. These standards were built on existing efforts and developed with input from the brain microscopy community to promote adoption. The resulting 3D Microscopy Metadata Standards (3D-MMS) includes 91 fields organized into seven categories: Contributors, Funders, Publication, Instrument, Dataset, Specimen, and Image. Adoption of these metadata standards will ensure that investigators receive credit for their work, promote data reuse, facilitate downstream analysis of shared data, and encourage collaboration.

Simplifying the hardware requirements for fast neural EIT of peripheral nerves

Objective. The main objective of this study was to assess the feasibility of lowering the hardware requirements for fast neural electrical impedance tomography (EIT) in order to support the distribution of this technique. Specifically, the feasibility of replacing the commercial modules present in the existing high-end setup with compact and cheap customized circuitry was assessed. Approach. Nerve EIT imaging was performed on rat sciatic nerves with both our standard ScouseTom setup and a customized version in which commercial benchtop current sources were replaced by custom circuitry. Electrophysiological data and images collected in the same experimental conditions with the two setups were compared. Data from the customized setup was subject to a down-sampling analysis to simulate the use of a recording module with lower specifications. Main results. Compound action potentials (573 ± 287 μV and 487 ± 279 μV, p=0.28) and impedance changes (36 ± 14 μV and 31 ± 16 μV, p=0.49) did not differ significantly when measured using commercial high-end current sources or our custom circuitry, respectively. Images reconstructed from both setups showed neglibile (<1voxel, i.e. 40 μm) difference in peak location and a high degree of correlation (R 2 = 0.97). When down-sampling from 24 to 16 bits ADC resolution and from 100 to 50 KHz sampling frequency, signal-to-noise ratio showed acceptable decrease (<−20%), and no meaningful image quality loss was detected (peak location difference <1voxel, pixel-by-pixel correlation R 2 = 0.99). Significance: The technology developed for this study greatly reduces the cost and size of a fast neural EIT setup without impacting quality and thus promotes the adoption of this technique by the neuroscience research community.

BRAIN UK: Accessing NHS tissue archives for neuroscience research.

The purpose of BRAIN UK (the UK BRain Archive Information Network) is to make the very extensive and comprehensive National Health Service (NHS) Neuropathology archives available to the national and international neuroscience research community. The archives comprise samples of tumours and a wide range of other neurological disorders, not only from the brain but also spinal cord, peripheral nerve, muscle, eye and other organs when relevant. BRAIN UK was founded after the recognition of the importance of this large tissue resource, which was not previously readily accessible for research use. BRAIN UK has successfully engaged the majority of the regional clinical neuroscience centres in the United Kingdom to produce a centralised database of the extensive autopsy and biopsy archive. Together with a simple application process and its broad ethical approval, BRAIN UK offers researchers easy access to most of the national archives of neurological tissues and tumours (http://www.brain-uk.org). The range of tissues available reflects the spectrum of disease in society, including many conditions not covered by disease-specific brain banks, and also allows relatively large numbers of cases of uncommon conditions to be studied. BRAIN UK has supported 141 studies (2010-2020) that have generated 70 publications employing methodology as diverse as morphometrics, genetics, proteomics and methylomics. Tissue samples that would otherwise have been unused have supported valuable neuroscience research. The importance of this unique resource will only increase as molecular techniques applicable to human tissues continue to develop and technical advances permit large-scale high-throughput studies.

BRAIN Initiative: Cutting-Edge Tools and Resources for the Community.

The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.

The Tale of the Dueling Neurosurgeons. A Contribution to the Neurosciences and Neurosurgery

AbstractIn the present article, we elaborate a critical review of the book “The Tale of the Dueling Neurosurgeons: The History of the Human Brain as Revealed by True Stories of Trauma, Madness, and Recovery”, written by Sam Kean. In our opinion, this book can contribute to the dissemination of neurosciences to the lay public, but it can also have an important role: to increase the interest of medicine students in neurosciences and research, since an increasingly lower number of students declare they have this interest. Thus, this book can be an important tool to deal with a pertinent and current issue under debate in the neuroscience research and neurosurgery communities.

Electroencephalograms during Mental Arithmetic Task Performance

This work has been carried out to support the investigation of the electroencephalogram (EEG) Fourier power spectral, coherence, and detrended fluctuation characteristics during performance of mental tasks. To this aim, the presented dataset contains International 10/20 system EEG recordings from subjects under mental cognitive workload (performing mental serial subtraction) and the corresponding reference background EEGs. Based on the subtraction task performance (number of subtractions and accuracy of the result), the subjects were divided into good counters and bad counters (for whom the mental task required excessive efforts). The data was recorded from 36 healthy volunteers of matched age, all of whom are students of Educational and Scientific Centre “Institute of Biology and Medicine”, National Taras Shevchenko University of Kyiv (Ukraine); the recordings are available through Physiobank platform. The dataset can be used by the neuroscience research community studying brain dynamics during cognitive workload.

Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer\u2019s disease-related proteins

BackgroundMicroglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometry methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally relevant molecular insights that are not provided by transcriptomics. However, comprehensive proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed.MethodsWe performed quantitative mass spectrometry based proteomic analyses of purified CD11b+ acutely-isolated microglia from adult (6 mo) mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]). Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains.ResultsOf 4133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized, suggesting a role for Apoe in phagocytic clearance of Aβ.ConclusionsWe report a comprehensive proteomic study of adult mouse microglia derived from acute neuroinflammation and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identify novel roles for microglial proteins in human neurodegeneration.

A Compact Head-Mounted Endoscope for In Vivo Calcium Imaging in Freely Behaving Mice.

Miniaturized fluorescence microscopes for imaging calcium transients are a promising tool for investigating the relationship between behavior and population-level neuronal activity in rodents. However, commercially available miniature microscopes may be costly and, because they are closed source, may not be easily modified based on particular experimental requirements. Here, we describe how to build and use a low-cost compact head-mounted endoscope (CHEndoscope) system for in vivo calcium imaging. The CHEndoscope uses an implanted gradient index lens along with the genetically encoded calcium indicator GCaMP6 to image calcium transients from hundreds of neurons simultaneously in awake behaving mice. This system is affordable, open source, and flexible, permitting modification depending on the particular experiment. This article describes in detail the assembly, surgical implantation, data collection, and processing of calcium signals using the CHEndoscope system. The aim of this open framework is to provide an accessible set of miniaturized calcium imaging tools for the neuroscience research community. © 2018 by John Wiley & Sons, Inc.

Training Studies: An Experimental Design to Advance Educational Neuroscience

ABSTRACTThe promise of educational neuroscience lies in its potential to uncover mechanistic insights into the science of learning. However, to realize that promise, the field must overcome a fundamental difference between the constituent disciplines: neuroscience is primarily concerned with understanding how the brain works; whereas education attempts to change the brain regardless of its workings. Learning is one domain where these orientations align: it is a deep feature of nervous systems and a target outcome of education. This article proposes coupling training studies with neuroimaging to assess the impact of real‐world learning on brain activity patterns, and simultaneously ask fundamental questions about the causal role of specific patterns of brain activity in academic skill acquisition. Finally, planning and implementing these studies requires multiple forms of expertise and collaborating across disciplines, which will contribute to a more cohesive educational neuroscience research community.

Chapter 2 - Brain donation procedures in the Sudden Death Brain Bank in Edinburgh

Brain banks typically receive donations through premortem consent procedures, often through disease-specific patient cohorts, such as dementia. While some control cases can be obtained through this route, access to age-matched control tissues, and some chronic neurologic conditions, particularly psychiatric disorders, can be challenging. The Edinburgh Sudden Death Brain Bank was established to try and increase access to control cases across all ages, and also access to psychiatric disorders through suicides. This chapter outlines the processes for establishing donations through medicolegal postmortems, which, although often with a prolonged postmortem interval, can provide high-quality well-characterized postmortem brain tissue to the neuroscience research community.

(Invited) Next Generation Strategy for Reproducible, Compliant Microelectrode Arrays

Implantable MEAs are an essential tool for the elucidation of the functional circuitry of the brain. These devices offer a means of simultaneously recording from neurons to elucidate modular and hierarchical processing, as well as neural circuitry involved in adaptation. In addition, MEAs have the potential to serve as a clinical neuroprostheses. MEAs implanted in cortex record from motor regions to enable control of devices, systems, and can restore control of the patients own paralyzed limbs when combined with functional electrical stimulation systems. The majority of MEAs, and especially those that are available commercially, are fabricated from silicon and leverage techniques associated with integrated circuit microfabrication and packaging. Using industry standard approaches, the features of MEAs can be reproducibly created and the resulting devices can be manufactured and disseminated. Two well-known approaches are MEAs initially developed at the University of Utah and at the University of Michigan now available to the neuroscience research community through Blackrock Microsystems and Neuronexus, respectively. It is now widely understood that these devices exhibit limited long term viability where recordings fail after 6 months – 1 year after implantation. One of the causes for this failure is believed to originate from the chronic foreign body response from microglia and astrocytes which extends well beyond the normal acute inflammatory response following initial implantation. This foreign body response has often been attributed, in large part, to the mechanical mismatch that exists between the MEAs and the surrounding brain tissue as well as the feature size of the MEAs. In this presentation, we will discuss a novel type of MEA that achieves compliance by material properties, specifically MEAs created from shape memory polymers (SMPs) where formulations allow tunable and dynamic mechanical properties. SMPs can be fabricated which are stiff at room temperature, but soften by 1-2 degrees of magnitude once inserted in the brain. This strategy, which leverages conventional photolithography, can be utilized to create devices customized for recording and stimulation within cortical and deep brain regions. An important aspect of this strategy is that it provides a pathway for translation and dissemination of novel, manufacturable neurotechnology. This presentation will provide an overview of work to date to create and demonstrate compliant and flexible MEAs and the electrochemical characterization of these devices both in vitro and in vivo.

Marmoset vocal communication: Behavior and neurobiology.

There has been recent increasing interest in the use of marmosets, a New World primate species, as a model in biomedical research. One of the principal advantages of marmosets as a research model is their rich vocal repertoire and communicative vocal behaviors displayed both in the wild and in captivity. Studies of this species' vocal communication system have the potential to reveal the evolutionary underpinnings of human speech, and therefore are of interest to the neuroscience and biology research communities. Here a recent research into the behavioral and neurobiological basis of marmoset vocal communication was reviewed and they argued for their broader value as a neuroscientific model. They discuss potential avenues for future research including developmental neurobiology and the application of modern molecular tools to the study of primate communication. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 286-299, 2017.

Leaky Integrate-and-Fire Neuron Circuit Based on Floating-Gate Integrator.

The artificial spiking neural network (SNN) is promising and has been brought to the notice of the theoretical neuroscience and neuromorphic engineering research communities. In this light, we propose a new type of artificial spiking neuron based on leaky integrate-and-fire (LIF) behavior. A distinctive feature of the proposed FG-LIF neuron is the use of a floating-gate (FG) integrator rather than a capacitor-based one. The relaxation time of the charge on the FG relies mainly on the tunnel barrier profile, e.g., barrier height and thickness (rather than the area). This opens up the possibility of large-scale integration of neurons. The circuit simulation results offered biologically plausible spiking activity (<100 Hz) with a capacitor of merely 6 fF, which is hosted in an FG metal-oxide-semiconductor field-effect transistor. The FG-LIF neuron also has the advantage of low operation power (<30 pW/spike). Finally, the proposed circuit was subject to possible types of noise, e.g., thermal noise and burst noise. The simulation results indicated remarkable distributional features of interspike intervals that are fitted to Gamma distribution functions, similar to biological neurons in the neocortex.

The NSW brain tissue resource centre: Banking for alcohol and major neuropsychiatric disorders research.

The New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney (Australia) is an established human brain bank providing tissue to the neuroscience research community for investigations on alcohol-related brain damage and major psychiatric illnesses such as schizophrenia. The NSWBTRC relies on wide community engagement to encourage those with and without neuropsychiatric illness to consent to donation through its allied research programs. The subsequent provision of high-quality samples relies on standardized operational protocols, associated clinical data, quality control measures, integrated information systems, robust infrastructure, and governance. These processes are continually augmented to complement the changes in internal and external governance as well as the complexity and diversity of advanced investigation techniques. This report provides an overview of the dynamic process of brain banking and discusses the challenges of meeting the future needs of researchers, including synchronicity with other disease-focus collections.

Perspectives on decision-making: implications for understanding psychopathology in psychiatric and psychoanalytic practice

Research on decision-making from the perspectives of economics, game theory, and neuroscience has been expanding rapidly over the last three decades [Kable, J. W., & Glimcher, P. W. (2009). The neurobiology of decision: Consensus and Controversy. Neuron, 63, 733–745]. However, there is relatively little exploration of impairment of decision-making, as a symptom of psychic dysfunction, in clinical psychiatric or psychoanalytic literature. As a result there is a widening gap between the understanding of psychopathology among clinically oriented psychiatrists and psychoanalysts, and the evolving importance of decision-making as presented by the neuroscience research community. “Decision-making” as a psychic function is not currently considered an important criteria for defining, classifying, understanding or treating psychopathology. This paper is an attempt by a clinician to point to the significance of decision-making as a clinical phenomenon, and to explore the various components of decision-making that are relevant to clinicians and can serve as guideposts for further neurobiological research.