Development of a multi-needle fiberoptic Raman spectroscopy technique for simultaneous multi-site deep tissue Raman measurements in the brain.

We report on the development of a multi-needle fiberoptic Raman spectroscopy (MNF-RS) technique for simultaneous multi-site deep Raman measurements in brain tissue. The multi-needle fiberoptic Raman probe is designed and fabricated using a number of 100 µm core diameter, aluminum-coated fibers under a coaxial laser excitation and Raman collection scheme, enabling simultaneous collection of deep tissue Raman spectra from a number of tissue sites. We have also developed a Raman retrieval algorithm based on the transformation matrix of each individual needle fiber probe projected to different pixels of a charge-coupled device (CCD) for recovering the tissue Raman spectra collected by each needle fiber probe, allowing simultaneous multi-channel detection by a single Raman spectrometer. High-quality tissue Raman spectra of different tissue types (e.g., muscle, fat, gray matter, and white matter in porcine brain) can be acquired in both the fingerprint (900-1800 cm-1) and high-wavenumber (2800-3300 cm-1) regions within sub-second times using the MNF-RS technique. We also demonstrate that by advancing the multi-needle fiberoptic Raman probe into deep porcine brain, tissue Raman spectra can be acquired simultaneously from different brain regions (e.g., cortex, thalamus, midbrain, and cerebellum). The significant biochemical differences across different brain tissues can also be distinguished, suggesting the promising potential of the MNF-RS technique for label-free neuroscience study at the molecular level.

Invasive Computational Psychiatry.

Computational psychiatry, a relatively new yet prolific field that aims to understand psychiatric disorders with formal theories about the brain, has seen tremendous growth in the past decade. Despite initial excitement, actual progress made by computational psychiatry seems stagnant. Meanwhile, understanding of the human brain has benefited tremendously from recent progress in intracranial neuroscience. Specifically, invasive techniques such as stereotactic electroencephalography, electrocorticography, and deep brain stimulation have provided a unique opportunity to precisely measure and causally modulate neurophysiological activity in the living human brain. In this review, we summarize progress and drawbacks in both computational psychiatry and invasive electrophysiology and propose that their combination presents a highly promising new direction-invasive computational psychiatry. The value of this approach is at least twofold. First, it advances our mechanistic understanding of the neural computations of mental states by providing a spatiotemporally precise depiction of neural activity that is traditionally unattainable using noninvasive techniques with human subjects. Second, it offers a direct and immediate way to modulate brain states through stimulation of algorithmically defined neural regions and circuits (i.e., algorithmic targeting), thus providing both causal and therapeutic insights. We then present depression as a use case where the combination of computational and invasive approaches has already shown initial success. We conclude by outlining future directions as a road map for this exciting new field as well as presenting cautions about issues such as ethical concerns and generalizability of findings.

Entre o medo e a esperança: um estudo sobre os usos e sentidos do treinamento cerebral no Brasil / Between fear and hope: a study on the uses and meanings of brain training in Brazil

O presente trabalho tem como objeto de análise os usos e sentidos das práticas de treinamento cerebral na realidade brasileira. Este tipo de treinamento, também chamado de treinamento cognitivo e ginástica cerebral, diz respeito à prática guiada de determinados exercícios e jogos com o objetivo de preservar ou melhorar as habilidades cognitivas e/ou a cognição como um todo. O objetivo central deste trabalho é mapear e analisar os sentidos atribuídos pelas empresas de treinamento cerebral e seus clientes às próprias atividades de treinamento cerebral. Para atingir tal objetivo realizamos a análise de conteúdo de dois conjuntos de dados: a) informações textuais dos sites oficiais das três franquias de treinamento cerebral existentes no Brasil (Supera, Super Cérebro e Ginástica do Cérebro) assim como das principais plataformas virtuais brasileiras (Supera Online, NeuroForma, Afinando o Cérebro e Mente Turbinada); b) transcrições de entrevistas semiestruturadas com dez clientes destas empresas, com idades entre 22 e 87 anos, e que praticavam regulamente tais atividades. Após analisarmos o conteúdo dos sites e das entrevistas pudemos observar que os sentidos do treinamento cerebral se relacionam, para os clientes, a uma série de medos e esperanças ­ e também à busca por diversão e sociabilidade. Dentre os medos destaca-se aquele relacionado à possibilidade de desenvolver a doença de Alzheimer ou algum outro quadro demencial que prejudique suas funções cognitivas e os levem a perder a autonomia e se tornarem dependentes de outras pessoas. Por outro lado, a busca por atividades de treinamento cerebral se relaciona também à esperança de reverter ou interromper o "declínio cognitivo" e de evitar, assim, o desenvolvimento de uma demência. As empresas, por sua vez, fomentam em seus clientes e potenciais clientes, através dos seus sites publicitários, diferentes formas de esperança, em especial a esperança de um futuro com capacidade cognitiva nas diversas etapas da vida. É possível dizer que o que há em comum entre aquilo que é vendido pelas empresas e aquilo que é comprado por seus clientes é a esperança. Apontamos, por fim, para as técnicas de treinamento cerebral como tecnologias da esperança, devido ao fato de serem utilizadas pelas empresas do ramo para fomentarem em seus clientes e potenciais clientes a crença de que é possível agir no presente de forma a preservar e aprimorar as habilidades cognitivas, a prevenir doenças como o Alzheimer e a prolongar o tempo de vida com saúde, autonomia e independência... (AU)

The main goal of the present doctoral thesis is to analyze the uses and meanings of the practices of cerebral training in Brazil. This type of training, also known as cognitive training and cerebral gymnastics, is related to the guided practice of specific exercises and games to preserve or improve cognitive skills and/or cognition in general. The main objective of this work is to map and analyze the definitions attributed to cerebral training companies and their clients to their brain training activities. To achieve this goal, we analyzed two groups of data: a) textual information available on the official websites of three Brazilian franchises focused on brain training (Super, Super Cérebro e Ginástica do Cérebro), as well the leading Brazilian virtual platforms (Supera Online, NeuroForma, Afinando o Cérebro e Mente Turbinada); b) transcriptions of semi-structured interviews with ten regular consumers of these companies, ages from 22 to 87 years. After analyzing the contents available on the websites and interviews, we could observe that the aims of brain training are connected. Besides the search for fun and sociability on the client's side, there are a series of fears and hopes. Among fears, we could stand out as the ones connected to the possibility of developing a future Alzheimer's disease or any other type of dementia state that could harm their cognitive functions and, consequently, lead them to lose their autonomy and become dependent on others. On the other hand, the search for brain gymnastic activities is related to the hope to revert or interrupt the "cognitive decline" and avoid the development of dementia. However, on their side, the companies encourage their clients and potential clients, through their advertising websites, different ways to trigger their hopes, especially the hope of a future when they develop cognitive capacities in different parts of their lives. We could claim that what connects the message released and these types of products, bought and sold, is hope. We finally point out that the techniques of brain training are technologies of hope since the companies of the field use them to foment their clients and potential clients the belief that it is possible to achieve, in the present, some preservation and improvement of cognitive skills, to prevent some diseases as Alzheimer and to lengthen their life expectancy healthily, enjoying autonomy and independence...(AU)

The significance of neural inter-frequency power correlations.

It is of great interest in neuroscience to determine what frequency bands in the brain have covarying power. This would help us robustly identify the frequency signatures of neural processes. However to date, to the best of the author's knowledge, a comprehensive statistical approach to this question that accounts for intra-frequency autocorrelation, frequency-domain oversampling, and multiple testing under dependency has not been undertaken. As such, this work presents a novel statistical significance test for correlated power across frequency bands for a broad class of non-stationary time series. It is validated on synthetic data. It is then used to test all of the inter-frequency power correlations between 0.2 and 8500 Hz in continuous intracortical extracellular neural recordings in Macaque M1, using a very large, publicly available dataset. The recordings were Current Source Density referenced and were recorded with a Utah array. The results support previous results in the literature that show that neural processes in M1 have power signatures across a very broad range of frequency bands. In particular, the power in LFP frequency bands as low as 20 Hz was found to almost always be statistically significantly correlated to the power in kHz frequency ranges. It is proposed that this test can also be used to discover the superimposed frequency domain signatures of all the neural processes in a neural signal, allowing us to identify every interesting neural frequency band.

Expansion microscopy: A powerful nanoscale imaging tool for neuroscientists.

One of the biggest unsolved questions in neuroscience is how molecules and neuronal circuitry create behaviors, and how their misregulation or dysfunction results in neurological disease. Light microscopy is a vital tool for the study of neural molecules and circuits. However, the fundamental optical diffraction limit precludes the use of conventional light microscopy for sufficient characterization of critical signaling compartments and nanoscopic organizations of synapse-associated molecules. We have witnessed rapid development of super-resolution microscopy methods that circumvent the resolution limit by controlling the number of emitting molecules in specific imaging volumes and allow highly resolved imaging in the 10-100 nm range. Most recently, Expansion Microscopy (ExM) emerged as an alternative solution to overcome the diffraction limit by physically magnifying biological specimens, including nervous systems. Here, we discuss how ExM works in general and currently available ExM methods. We then review ExM imaging in a wide range of nervous systems, including Caenorhabditis elegans, Drosophila, zebrafish, mouse, and human, and their applications to synaptic imaging, neuronal tracing, and the study of neurological disease. Finally, we provide our prospects for expansion microscopy as a powerful nanoscale imaging tool in the neurosciences.

A parsimonious laboratory system for the evaluation of rat reaching task: recovery from the massive destruction of motor areas.

The rat reaching task is one of the best paradigms from behavioral study of upper limb movements. Rats are trained to reach and grab a pellet by extending their hand through a vertical slit. A few conventional imaging systems specific for the rat reaching task are commercially available with a high installation cost. Based on image analysis of video recordings obtained during the reaching task, we, herewith, developed a new, low-cost laboratory system that can be used for the quantitative analysis of ten basic forearm movements, in contrast to subjective assessments used in previous studies. We quantified images of the pronated and supinated palm and the accuracy and speed of reaching the target. Applying this newly developed method, we compared the forearm movements during the reaching task before and after a massive anatomical lesion of the sensorimotor cortex performed by tissue aspiration. We also wanted to investigate the recovery of upper limb function possibly induced by repeating the task for a relatively short term of a few weeks. In the experiment, 7 injured groups and 3 control groups were used. We found characteristic abnormalities of the forearm movements and a significant recovery in the success rate of grasping the target pellet. The present results demonstrate that our method is straightforward for the quantitative evaluation of forearm movements during the reaching task primarily controlled by the sensorimotor cortex.

Neuroengineering challenges of fusing robotics and neuroscience.

Advances in neuroscience are inspiring developments in robotics and vice versa.

Guidelines to Study and Develop Soft Electrode Systems for Neural Stimulation.

Electrical stimulation of nervous structures is a widely used experimental and clinical method to probe neural circuits, perform diagnostics, or treat neurological disorders. The recent introduction of soft materials to design electrodes that conform to and mimic neural tissue led to neural interfaces with improved functionality and biointegration. The shift from stiff to soft electrode materials requires adaptation of the models and characterization methods to understand and predict electrode performance. This guideline aims at providing (1) an overview of the most common techniques to test soft electrodes in vitro and in vivo; (2) a step-by-step design of a complete study protocol, from the lab bench to in vivo experiments; (3) a case study illustrating the characterization of soft spinal electrodes in rodents; and (4) examples of how interpreting characterization data can inform experimental decisions. Comprehensive characterization is paramount to advancing soft neurotechnology that meets the requisites for long-term functionality in vivo.

Challenges for Large-Scale Cortical Interfaces.

This Perspective examines the status of large-scale cortical interfaces through the lens of potential applications to active implants for brain-machine interfaces. Examples of research and development in a still embryonic field are discussed from a neuroengineer's perspective, touching on the design of scalable electrophysiological sensors with the ambition to access thousands of cortical points at near-cellular-level resolution. Important issues include microscale geometry of neural probes, design of implantable ultra-low-power electronics, implementation of high-data-rate wireless telemetry, and compatible device packaging-all requiring advanced solutions along a translational path for chronic human use.

Emerging Frontier of Peripheral Nerve and Organ Interfaces.

The development of new tools to interface with the nervous system, empowered by advances in electronics and materials science, has transformed neuroscience and is informing therapies for neurological and mental conditions. Although the vast majority of neural engineering research has focused on advancing tools to study the brain, understanding the peripheral nervous system and other organs can similarly benefit from these technologies. To realize this vision, the neural interface technologies need to address the biophysical, mechanical, and chemical challenges posed by the peripheral nerves and organs. In this Perspective, we discuss design considerations and recent technological advances to modulate electrical signaling outside the central nervous system. The innovations in bioelectronics borne out of interdisciplinary collaborations between biologists and physical scientists may not only advance fundamental study of peripheral (neuro)physiology but also empower clinical interventions for conditions including neurological, gastrointestinal, and immune dysfunction.

Developing Collaborative Platforms to Advance Neurotechnology and Its Translation.

Neurotechnological devices are failing to deliver on their therapeutic promise because of the time it takes to translate them from bench to clinic. In this Perspective, we reflect on lessons learned from medical device successes and failures and consider how such lessons might shape a strategic vision for translating neurotechnologies in the future. We articulate how the intentional design and deployment of "scientific platforms," from the technology stack of hardware and software through the supporting ecosystem, could catalyze a new wave of innovation, discovery, and therapy. We also identify specific actions that could promote future neurotechnology roadmaps and industrial-academic-government collaborative activities. We believe that community-supported neurotechnology platforms will prove to be transformational in accelerating ideas from bench to bedside, maximizing scientific discovery and improving patient care.

Recent Advances in Electrical Neural Interface Engineering: Minimal Invasiveness, Longevity, and Scalability.

Electrical neural interfaces serve as direct communication pathways that connect the nervous system with the external world. Technological advances in this domain are providing increasingly more powerful tools to study, restore, and augment neural functions. Yet, the complexities of the nervous system give rise to substantial challenges in the design, fabrication, and system-level integration of these functional devices. In this review, we present snapshots of the latest progresses in electrical neural interfaces, with an emphasis on advances that expand the spatiotemporal resolution and extent of mapping and manipulating brain circuits. We include discussions of large-scale, long-lasting neural recording; wireless, miniaturized implants; signal transmission, amplification, and processing; as well as the integration of interfaces with optical modalities. We outline the background and rationale of these developments and share insights into the future directions and new opportunities they enable.

A Modular Setup to Run a Large Line of Behavioral Testing in Mice in a Single Space.

Elucidating the complex neural mechanisms that underlie cognition is contingent upon our ability to measure behavioral outputs reliably in animal models. While the development of open-source software has made behavioral science more accessible, behavioral research remains underappreciated and underutilized. One reason is the large real estate necessitated by traditional behavioral setups. Space must be specifically allocated for a controlled testing environment, accommodate the large footprint of mazes used in behavioral research, and allow a contiguous computerized area for data acquisition. Additionally, to achieve the distinct and sometimes incompatible environmental conditions required by different tasks, a suite of testing rooms may be necessary. Because space is a limited resource, this makes behavioral testing impractical for some labs or leads to implementation of suboptimal solutions that compromise the ergonomics of the working space, prevent the adequate control of environmental parameters around the testing setup, and jeopardize experimental reproducibility. Here, we describe a modular, space-saving, self-sufficient, functional, customizable, and cost-efficient setup to allow a large line of behavioral tests in mice within a single, compact room (<8 m2 ). Because it is modular by design, this setup requires no compromises on ergonomics, environmental control, or complexity of the visual landscape. It is inherently effective at streamlining behavioral experiments by eliminating the need to redefine tracking parameters, and makes swapping between configurations fast (∼1 min) and effortless. Presently, this design allows one to run eight major behavioral tasks, permitting a detailed and comprehensive analysis of mouse behavior within the footprint of a small office. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Constructing the support table Support Protocol 1: Constructing the open-field maze Support Protocol 2: Constructing IR-permissive inserts for light-dark assays Support Protocol 3: Constructing the three-chamber maze Support Protocol 4: Constructing the Y maze Support Protocol 5: Constructing the elevated plus maze Support Protocol 6: Constructing the Barnes maze Basic Protocol 2: Setting up the behavior room: flange and pulley systems Basic Protocol 3: Setting up the behavior room: environmental and storage systems Basic Protocol 4: Assembling and switching between configurations.

A 340 nW/Channel 110 dB PSRR Neural Recording Analog Front-End Using Replica-Biasing LNA, Level-Shifter Assisted PGA, and Averaged LFP Servo Loop in 65 nm CMOS.

This paper presents an 8-channel energy-efficient analog front-end (AFE) for neural recording, with improvements in power supply rejection ratio (PSRR) and dynamic range. The input stage in the low noise amplifier (LNA) adopts low voltage supply (0.35 V) and current-reusing to achieve ultralow power. To maintain a high PSRR performance while using such a low-voltage supply, a replica-biasing scheme is proposed to generate a stable bias current for the input stage of the LNA despite large supply interference. By exploiting the signal characteristics in the tetrode recording, an averaged local field potential (A-LFP) servo loop is introduced to extend the dynamic range without consuming too much extra power and chip area. The A-LFP signal is generated by integrating the four-channel PGA outputs from the same tetrode. Furthermore, the outputs of the programmable gain amplifier (PGA) are level shifted to bias the input nodes of the amplifier through large pseudo resistors, thus increase the maximum output range without distortion under the low-voltage supply. The proof-of-concept prototype is fabricated in a 65 nm CMOS process. Each recording channel including an LNA and a PGA occupies 0.04 mm 2 and consumes 340 nW from the 0.35 V and 0.7 V supply. Each A-LFP servo loop, which is shared by four recording channels, occupies 0.04 mm 2 and consumes 190 nW. The maximum gain of the AFE is 54 dB, and the input-referred noise is 6.7 µV over the passband from 0.5 Hz to 6.5 kHz. Measurement also shows that the 0.35 V replica-biasing input stage can tolerate a large interferer up to 200 mVpp with a PSRR of 74 dB, which has been improved to 110 dB with a silicon respin that shields critical wires in the layout.

Ex Vivo Whole Nerve Electrophysiology Setup, Action Potential Recording, and Data Analyses in a Rodent Model.

Ex vivo rodent whole nerves provide a model for assessing the effects of interventions on nerve impulse transmission and consequent sensory and/or motor function. Nerve impulse transmission can be measured through sciatic nerve compound action potential (CAP) recordings. However, de novo development and implementation of an ex vivo whole nerve resection protocol and an electrophysiology setup that retains nerve viability, that produces low noise CAP signals, and that allows for data analysis is challenging. Additionally, some of the existing literature lacks detail and accuracy and may be out of date. This article describes detailed protocols for rodent ex vivo sciatic nerve dissection and handling; importance of an optimal physiologic solution; computer-aided designs for 3D printing of readily adaptable ex vivo rodent whole nerve electrophysiology chambers; construction of low-cost, effective suction electrodes; setup and use of nerve stimulators and amplifiers; acquisition of low noise, small voltage CAP data and digital conversion; use of software for data analyses of CAP components; and tips for troubleshooting. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Electrophysiology wiring and hardware setup Support Protocol 1: 3D printing an electrophysiology chamber Support Protocol 2: Building suction electrodes Basic Protocol 2: Sciatic nerve dissection and compound action potential recording Basic Protocol 3: Data export and analysis Support Protocol 3: Preparation of HEPES-buffered physiologic solution.

Neuroética: bases para la introducción de la neuroimagen en el proceso judicial penal / Neuroethics: Basis for the introduction of neuroimaging in the criminal process / Neuroètica: bases per a la introducció de la neuroimatge al procés judicial penal

En el presente trabajo se efectúa una aproximación general a los reparos éticos que la investigación neurocientífica plantea, especialmente respecto de sus usos extralimitados en el proceso penal. Así pues, con el objetivo de regular un uso adecuado, respetuoso con los principios generalmente aceptados en el ámbito biomédico, se desarrolla una propuesta de regulación ética de esta materia que preceda a su uso probatorio en el ámbito forense

The present paper makes a general approach to the ethical concerns that neuroscientific research suggests, especially evaluating its overreaching uses in the criminal process. Therefore, with the objective of regulating an adequate use, a proposal of ethical regulation of this matter is made, which should precede its probative use in the forensic field

En el present treball es fa una aproximació general a les objeccions ètiques que la investigació neurocientífica planteja, especialment respecte al seus usos extralimitats en el procés penal. Així doncs, amb l'objectiu de regular un ús adequat, respectuós amb els principis generalment acceptats en l'àmbit biomèdic, es desenvolupa una proposta de regulació ètica d'aquesta matèria que precedeixi al seu ús probatori en l'àmbit forense

Adaptable Angled Stereotactic Approach for Versatile Neuroscience Techniques.

Stereotactic surgery is an essential tool in the modern neuroscience lab. However, the ability to precisely and accurately target difficult-to-reach brain regions still presents a challenge, particularly when targeting brain structures along the midline. These challenges include avoiding of the superior sagittal sinus and third ventricle and the ability to consistently target selective and discrete brain nuclei. In addition, more advanced neuroscience techniques (e.g., optogenetics, fiber photometry, and two-photon imaging) rely on targeted implantation of significant hardware to the brain, and spatial limitations are a common hindrance. Presented here is a modifiable protocol for stereotactic targeting of rodent brain structures using an angled coronal approach. It can be adapted to 1) mouse or rat models, 2) various neuroscience techniques, and 3) multiple brain regions. As a representative example, it includes the calculation of stereotactic coordinates for targeting of the mouse hypothalamic ventromedial nucleus (VMN) for an optogenetic inhibition experiment. This procedure begins with the bilateral microinjection of an adeno-associated virus (AAV) encoding a light-sensitive chloride channel (SwiChR++) to a Cre-dependent mouse model, followed by the angled bilateral implantation of fiberoptic cannulae. Using this approach, findings show that activation of a subset of VMN neurons is required for intact glucose counterregulatory responses to insulin-induced hypoglycemia.

Accuracy and precision of stimulus timing and reaction times with Unreal Engine and SteamVR.

The increasing interest in Virtual Reality (VR) as a tool for neuroscientific research contrasts with the current lack of established toolboxes and standards. In several recent studies, game engines like Unity or Unreal Engine were used. It remains to be tested whether these software packages provide sufficiently precise and accurate stimulus timing and time measurements that allow inferring ongoing mental and neural processes. We here investigated the precision and accuracy of the timing mechanisms of Unreal Engine 4 and SteamVR in combination with the HTC Vive VR system. In a first experiment, objective external measures revealed that stimulus durations were highly accurate. In contrast, in a second experiment, the assessment of the precision of built-in timing procedures revealed highly variable reaction time measurements and inaccurate determination of stimulus onsets. Hence, we developed a new software-based method that allows precise and accurate reaction time measurements with Unreal Engine and SteamVR. Instead of using the standard timing procedures implemented within Unreal Engine, time acquisition was outsourced to a background application. Timing benchmarks revealed that the newly developed method allows reaction time measurements with a precision and accuracy in the millisecond range. Overall, the present results indicate that the HTC Vive together with Unreal Engine and SteamVR can achieve high levels of precision and accuracy both concerning stimulus duration and critical time measurements. The latter can be achieved using a newly developed routine that allows not only accurate reaction time measures but also provides precise timing parameters that can be used in combination with time-sensitive functional measures such as electroencephalography (EEG) or transcranial magnetic stimulation (TMS).