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.

Measuring fingerpad deformation during active object manipulation.

During active object manipulation, the finger-object interactions give rise to complex fingertip skin deformations. These deformations are in turn encoded by the local tactile afferents and provide rich and behaviorally relevant information to the central nervous system. Most of the work studying the mechanical response of the finger to dynamic loading has been performed under a passive setup, thereby precisely controlling the kinematics or the dynamics of the loading. However, to identify aspects of the deformations that are relevant to online control during object manipulation, it is desirable to measure the skin response in an active setup. To that end, we developed a device that allows us to monitor finger forces, skin deformations, and kinematics during fine manipulation. We describe the device in detail and test it to precisely describe how the fingertip skin in contact with the object deforms during a simple vertical oscillation task. We show that the level of grip force directly influences the fingerpad skin strains and that the strain rates are substantial during active manipulation (norm up to 100%/s). The developed setup will enable us to causally relate sensory information, i.e. skin deformation, to online control, i.e. grip force adjustment, in future studies.NEW & NOTEWORTHY We present a novel device, a manipulandum, that enables to image the contact between the finger and the contact surface during active manipulation of the device. The device is tested in a simple vertical oscillation task involving 18 participants. We demonstrate that substantial surface skin strains take place at the finger-object interface and argue that those deformations provide essential information for grasp stability during object manipulation.

EthoLoop: automated closed-loop neuroethology in naturalistic environments.

Accurate tracking and analysis of animal behavior is crucial for modern systems neuroscience. However, following freely moving animals in naturalistic, three-dimensional (3D) or nocturnal environments remains a major challenge. Here, we present EthoLoop, a framework for studying the neuroethology of freely roaming animals. Combining real-time optical tracking and behavioral analysis with remote-controlled stimulus-reward boxes, this system allows direct interactions with animals in their habitat. EthoLoop continuously provides close-up views of the tracked individuals and thus allows high-resolution behavioral analysis using deep-learning methods. The behaviors detected on the fly can be automatically reinforced either by classical conditioning or by optogenetic stimulation via wirelessly controlled portable devices. Finally, by combining 3D tracking with wireless neurophysiology we demonstrate the existence of place-cell-like activity in the hippocampus of freely moving primates. Taken together, we show that the EthoLoop framework enables interactive, well-controlled and reproducible neuroethological studies in large-field naturalistic settings.

Cellular-scale silicon probes for high-density, precisely localized neurophysiology.

Neural implants with large numbers of electrodes have become an important tool for examining brain functions. However, these devices typically displace a large intracranial volume compared with the neurons they record. This large size limits the density of implants, provokes tissue reactions that degrade chronic performance, and impedes the ability to accurately visualize recording sites within intact circuits. Here we report next-generation silicon-based neural probes at a cellular scale (5 × 10 µm cross section), with ultra-high-density packing (as little as 66 µm between shanks) and 64 or 256 closely spaced recording sites per probe. We show that these probes can be inserted into superficial or deep brain structures and record large spikes in freely behaving rats for many weeks. Finally, we demonstrate a slice-in-place approach for the precise registration of recording sites relative to nearby neurons and anatomical features, including striatal µ-opioid receptor patches. This scalable technology provides a valuable tool for examining information processing within neural circuits and potentially for human brain-machine interfaces.NEW & NOTEWORTHY Devices with many electrodes penetrating into the brain are an important tool for investigating neural information processing, but they are typically large compared with neurons. This results in substantial damage and makes it harder to reconstruct recording locations within brain circuits. This paper presents high-channel-count silicon probes with much smaller features and a method for slicing through probe, brain, and skull all together. This allows probe tips to be directly observed relative to immunohistochemical markers.

Microribbons composed of directionally self-assembled nanoflakes as highly stretchable ionic neural electrodes.

Many natural materials possess built-in structural variation, endowing them with superior performance. However, it is challenging to realize programmable structural variation in self-assembled synthetic materials since self-assembly processes usually generate uniform and ordered structures. Here, we report the formation of asymmetric microribbons composed of directionally self-assembled two-dimensional nanoflakes in a polymeric matrix during three-dimensional direct-ink printing. The printed ribbons with embedded structural variations show site-specific variance in their mechanical properties. Remarkably, the ribbons can spontaneously transform into ultrastretchable springs with controllable helical architecture upon stimulation. Such springs also exhibit superior nanoscale transport behavior as nanofluidic ionic conductors under even ultralarge tensile strains (>1,000%). Furthermore, to show possible real-world uses of such materials, we demonstrate in vivo neural recording and stimulation using such springs in a bullfrog animal model. Thus, such springs can be used as neural electrodes compatible with soft and dynamic biological tissues.

Measurement of axonal excitability: Consensus guidelines.

Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.

Characterization of in vitro neural functional connectivity on a neurofluidic device.

Understanding the mechanism of functional connectivity in neural system is of great benefit to lot of researches and applications. Microfluidics and microelectrode arrays (MEAs) have been frequently utilized for in vitro neural cultures study. However, there are few studies on the functional connectivity of neural cultures grown on a microfluidic chip. It is intriguing to unveil the influences of microfluidic structures on in vitro neuronal networks from the perspective of functional connectivity. Hence, in the present study, a device was established, which comprised a microfluidic chamber for cell growth and a MEA substrate for recording the electrophysiological response of the neuronal networks. The network topology, neural firing rate, neural bursting rate and network burst frequency were adopted as representative characteristics for neuronal networks analysis. Functional connectivity was estimated by means of cross-covariance analysis and graph theory. The results demonstrated that the functional connectivity of the in vitro neuronal networks formed in the microchannel has been apparently reinforced, corresponding to improve neuronal network density and increased small-worldness.

A passive, camera-based head-tracking system for real-time, three-dimensional estimation of head position and orientation in rodents.

Tracking head position and orientation in small mammals is crucial for many applications in the field of behavioral neurophysiology, from the study of spatial navigation to the investigation of active sensing and perceptual representations. Many approaches to head tracking exist, but most of them only estimate the 2D coordinates of the head over the plane where the animal navigates. Full reconstruction of the pose of the head in 3D is much more more challenging and has been achieved only in handful of studies, which employed headsets made of multiple LEDs or inertial units. However, these assemblies are rather bulky and need to be powered to operate, which prevents their application in wireless experiments and in the small enclosures often used in perceptual studies. Here we propose an alternative approach, based on passively imaging a lightweight, compact, 3D structure, painted with a pattern of black dots over a white background. By applying a cascade of feature extraction algorithms that progressively refine the detection of the dots and reconstruct their geometry, we developed a tracking method that is highly precise and accurate, as assessed through a battery of validation measurements. We show that this method can be used to study how a rat samples sensory stimuli during a perceptual discrimination task and how a hippocampal place cell represents head position over extremely small spatial scales. Given its minimal encumbrance and wireless nature, our method could be ideal for high-throughput applications, where tens of animals need to be simultaneously and continuously tracked.NEW & NOTEWORTHY Head tracking is crucial in many behavioral neurophysiology studies. Yet reconstruction of the head's pose in 3D is challenging and typically requires implanting bulky, electrically powered headsets that prevent wireless experiments and are hard to employ in operant boxes. Here we propose an alternative approach, based on passively imaging a compact, 3D dot pattern that, once implanted over the head of a rodent, allows estimating the pose of its head with high precision and accuracy.

Chronically implanted Neuropixels probes enable high-yield recordings in freely moving mice.

The advent of high-yield electrophysiology using Neuropixels probes is now enabling researchers to simultaneously record hundreds of neurons with remarkably high signal to noise. However, these probes have not been well-suited to use in freely moving mice. It is critical to study neural activity in unrestricted animals for many reasons, such as leveraging ethological approaches to study neural circuits. We designed and implemented a novel device that allows Neuropixels probes to be customized for chronically implanted experiments in freely moving mice. We demonstrate the ease and utility of this approach in recording hundreds of neurons during an ethological behavior across weeks of experiments. We provide the technical drawings and procedures for other researchers to do the same. Importantly, our approach enables researchers to explant and reuse these valuable probes, a transformative step which has not been established for recordings with any type of chronically-implanted probe.

NIMH MonkeyLogic: Behavioral control and data acquisition in MATLAB.

BACKGROUND: Computerized control of behavioral paradigms is an essential element of neurobehavioral studies, especially physiological recording studies that require sub-millisecond precision. Few software solutions provide a simple, flexible environment to create and run these applications. MonkeyLogic, a MATLAB-based package, was developed to meet these needs, but faces a performance crisis and obsolescence due to changes in MATLAB itself. NEW METHOD: Here we report a complete redesign and rewrite of MonkeyLogic, now NIMH MonkeyLogic, that natively supports the latest 64-bit MATLAB on the Windows platform. Major layers of the underlying real-time hardware control were removed and replaced by custom toolboxes: NIMH DAQ Toolbox and MonkeyLogic Graphics Library. The redesign resolves undesirable delays in data transfers and limitations in graphics capabilities. RESULTS: NIMH MonkeyLogic is essentially a new product. It provides a powerful new scripting framework, has dramatic speed enhancements and provides major new graphics abilities. COMPARISON WITH EXISTING METHOD: NIMH MonkeyLogic is fully backward compatible with earlier task scripts, but with better temporal precision. It provides more input device options, superior graphics and a new real-time closed-loop programming model. Because NIMH MonkeyLogic requires no commercial toolbox and has a reduced hardware requirement, implementation costs are substantially reduced. CONCLUSION: NIMH MonkeyLogic is a versatile, powerful, up-to-date tool for controlling a wide range of experiments. It is freely available from https://monkeylogic.nimh.nih.gov/.

The laryngoscope and nineteenth-century British understanding of laryngeal movements.

The source of the human voice is obscured from view. The development of the laryngoscope in the late 1850s provided the potential to see the action of the vocal folds during speaking for the first time. This new instrument materially contributed to the understanding of vocal fold neuroanatomy, neurophysiology, and neuropathology. The laryngoscope led to elaborated understanding of disorders that previously were determined by changes in sound. The objective of this paper is to detail the consequences of this novel visualization of the larynx, and to trace how it aided in the development of understanding of the movements of the vocal folds. This is demonstrated through an examination of the activities and practices of a group of London clinicians in the second half of the nineteenth century.

Elastocapillary self-assembled neurotassels for stable neural activity recordings.

Implantable neural probes that are mechanically compliant with brain tissue offer important opportunities for stable neural interfaces in both basic neuroscience and clinical applications. Here, we developed a Neurotassel consisting of an array of flexible and high-aspect ratio microelectrode filaments. A Neurotassel can spontaneously assemble into a thin and implantable fiber through elastocapillary interactions when withdrawn from a molten, tissue-dissolvable polymer. Chronically implanted Neurotassels elicited minimal neuronal cell loss in the brain and enabled stable activity recordings of the same population of neurons in mice learning to perform a task. Moreover, Neurotassels can be readily scaled up to 1024 microelectrode filaments, each with a neurite-scale cross-sectional footprint of 3 × 1.5 µm2, to form implantable fibers with a total diameter of ~100 µm. With their ultrasmall sizes, high flexibility, and scalability, Neurotassels offer a new approach for stable neural activity recording and neuroprosthetics.

An Actuated Neural Probe Architecture for Reducing Gliosis-Induced Recording Degradation.

Glial encapsulation of chronically implanted neural probes inhibits recording and stimulation, and this signal loss is a significant factor limiting the clinical viability of most neural implant topologies for decades-long implantation. We demonstrate a mechanical proof of concept for silicon shank-style neural probes intended to minimize gliosis near the recording sites. Compliant whiskers on the edges of the probe fold inward to minimize tissue damage during insertion. Once implanted to the target depth and retracted slightly, these whiskers splay outward. The splayed tips, on which recording sites could be patterned, extend beyond the typical 50-100 [Formula: see text] radius of a glial scar. The whiskers are micrometer-scale to minimize or avoid glial scarring. Electrically inactive devices with whiskers of varying widths and curvature were designed and monolithically fabricated from a 5- [Formula: see text] silicon-on-insulator (SOI) wafer, and their mechanical functionality was demonstrated in a 0.6% agar brain phantom. Deflection was plotted versus deflection speed, and those that were most compliant actuated successfully. This probe requires no preparation for use beyond what is typical for a shank-style silicon probe.

Recording of Neural Activity With Modulation of Photolysis of Caged Compounds Using Microelectrode Arrays in Rats With Seizures.

OBJECTIVE: In this paper, a new method was established to monitor multichannel neural activity with microelectrode arrays (MEAs) under modulation of caged compounds in a rat model of seizures. METHODS: The 16-channel MEAs were fabricated and implanted into the hippocampus of normal rats and epileptic rats for neural spike and local field potential (LFP) recording. Using optical fibers with drug delivery tubing, two different caged compounds [ruthenium-bipyridine-trimethylphosphine glutamate (RuBi-Glu) and ruthenium-bipyridine-trimethylphosphine gamma aminobutyric acid (RuBi-GABA)] were applied, and blue light (465 nm) was used to modulate neural activity. RESULTS: In normal rats, RuBi-Glu excited neural activity, and RuBi-GABA inhibited neural activity. The amplitude of spikes increased 26% from 154 to 194 µV with RuBi-Glu modulation. During RuBi-GABA modulation, spikes recovered to 142 µV. The firing rate increased from 1.4 to 4.5 Hz with RuBi-Glu modulation and decreased to 0.8 Hz after RuBi-GABA modulation. The power of LFPs increased from 566 to 1128 µW with RuBi-Glu modulation and recovered to 710 µW with RuBi-GABA modulation. In epileptic rats, the neural activity during seizures was significantly inhibited by RuBi-GABA modulation. The amplitude of spikes was 242 µV during seizures and decreased to 112 µV with RuBi-GABA modulation. The firing rate decreased from 20.29 to 1.33 Hz with RuBi-GABA modulation. CONCLUSION: Using MEAs, the modulation of neural activity with caged compound photolysis was observed with high temporal-spatial resolution in normal and epileptic rats. SIGNIFICANCE: This new method is important for monitoring neural activity with photo-switchable modulation.

A low-cost open-architecture taste delivery system for gustatory fMRI and BCI experiments.

BACKGROUND: Tasting is a complex process involving chemosensory perception and cognitive evaluation. Different experimental designs and solution delivery approaches may in part explain the variability reported in literature. These technical aspects certainly limit the development of taste-related brain computer interface devices. NEW METHOD: We propose a novel modular, scalable and low-cost device for rapid injection of small volumes of taste solutions during fMRI experiments that gathers the possibility to flexibly increase the number of channels, allowing complex multi-dimensional taste experiments. We provide the full description of the hardware and software architecture and illustrate the application of the working prototype in single-subject event-related fMRI experiments by showing the BOLD responses to basic taste qualities and to five intensities of tastes during the course of perception. RESULTS: The device is shown to be effective in activating multiple clusters within the gustatory pathway and a precise time-resolved event-related analysis is shown to be possible by the impulsive nature of the induced perception. COMPARISON WITH EXISTING METHOD(S): This gustometer represents the first implementation of a low-cost, easily replicable and portable device that is suitable for all kinds of fMRI taste experiments. Its scalability will boost the experimental design of more complex multi-dimensional fMRI studies of the human taste pathway. CONCLUSIONS: The gustometer represents a valid open-architecture alternative to other available devices and its spread and development may contribute to an increased standardization of experimental designs in human fMRI studies of taste perception and pave the way to the development of novel taste-related BCIs.

Semi-chronic laminar recordings in the brainstem of behaving marmoset monkeys.

BACKGROUND: Chronic recordings with multi-electrode arrays are widely used to study neural networks underlying complex primate behaviors. Most of these systems are designed for studying neural activity in the cortical hemispheres resulting in a lack of devices being capable of simultaneously recording from ensembles of neurons in deep brainstem structures. However, to fully understand complex behavior, it is fundamental to also decipher the intrinsic mechanisms of the underlying motor pattern generating circuits in the brainstem. NEW METHOD: We report a light-weight system that simultaneously measures single-unit activity from a large number of recording sites in the brainstem of marmoset monkeys. It includes a base chamber fixed to the animal's skull and a removable upper chamber that can be semi-chronically mounted to the base chamber to flexibly position an embedded micro-drive containing a 32-channel laminar probe to record from various positions within the brainstem for several weeks. RESULTS: The current system is capable of simultaneously recording stable single-unit activity from a large number of recording sites in the brainstem of vocalizing marmoset monkeys. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, chronic systems to record from deep brainstem structures with multi-site laminar probes in awake, behaving monkeys do not yet exist. CONCLUSIONS: The semi-chronic implantation of laminar electrodes into the brainstem of behaving marmoset monkeys opens new research possibilities in fully understanding the neural mechanisms underlying complex behaviors in marmoset monkeys.

A novel simplistic fabrication technique for cranial epidural electrodes for chronic recording and stimulation in rats.

BACKGROUND: The demand for neuromodulatory and recording tools has resulted in a surge of publications describing techniques for fabricating devices and accessories in-house suitable for neurological recordings. However, many of these fabrication protocols use equipment which are not common to biological laboratories, thus limiting researchers to the use of commercial alternatives. New method:We have developed a simple yet robust implantable stimulating surface electrode which can be fabricated in all wet-bench laboratories. RESULTS: Female Sprague-Dawley rats received epidural implantation of the electrodes over the fore and hind limb areas of their motor cortex. Stimulation of the motor cortex successfully evoked fore- and hind limb motor outputs. The device was also able to record surface potentials of the motor cortex following epidural stimulation of the spinal cord. Comparisons with existing methods:For stimulation of the motor cortex, often stiff stainless or copper wires are roughly tucked underneath the skull, with little accuracy of localization. While, commercially available devices utilize burr holes and screw electrodes. Our new electrode design provides us stereotaxic accuracy that was not previously available. CONCLUSION: We developed a chronic implantable electrode capable of being fabricated in all wet-labs, are robust, versatile and electrically sensitive enough for long-term chronic use. The simple and versatile electrode design provides scientific, economical and ethical benefits.

Customizable cap implants for neurophysiological experimentation.

BACKGROUND: Several primate neurophysiology laboratories have adopted acrylic-free, custom-fit cranial implants. These implants are often comprised of titanium or plastic polymers, such as polyether ether ketone (PEEK). Titanium is favored for its mechanical strength and osseointegrative properties whereas PEEK is notable for its lightweight, machinability, and MRI compatibility. Recent titanium/PEEK implants have proven to be effective in minimizing infection and implant failure, thereby prolonging experiments and optimizing the scientific contribution of a single primate. NEW METHOD: We created novel, customizable PEEK 'cap' implants that contour to the primate's skull. The implants were created using MRI and/or CT data, SolidWorks software and CNC-machining. RESULTS: Three rhesus macaques were implanted with a PEEK cap implant. Head fixation and chronic recordings were successfully performed. Improvements in design and surgical technique solved issues of granulation tissue formation and headpost screw breakage. COMPARISON WITH EXISTING METHODS: Primate cranial implants have traditionally been fastened to the skull using acrylic and anchor screws. This technique is prone to skin recession, infection, and implant failure. More recent methods have used imaging data to create custom-fit titanium/PEEK implants with radially extending feet or vertical columns. Compared to our design, these implants are more surgically invasive over time, have less force distribution, and/or do not optimize the utilizable surface area of the skull. CONCLUSIONS: Our PEEK cap implants served as an effective and affordable means to perform electrophysiological experimentation while reducing surgical invasiveness, providing increased strength, and optimizing useful surface area.

A Low-Power Current-Reuse Analog Front-End for High-Density Neural Recording Implants.

Studying brain activity in vivo requires collecting bioelectrical signals from several microelectrodes simultaneously in order to capture neuron interactions. In this work, we present a new current-reuse analog front-end (AFE), which is scalable to very large numbers of recording channels, thanks to its small implementation silicon area and its low-power consumption. This current-reuse AFE, which is including a low-noise amplifier (LNA) and a programmable gain amplifier (PGA), employs a new fully differential current-mirror topology using fewer transistors, and improving several design parameters, such as power consumption and noise, over previous current-reuse amplifier circuit implementations. We show that the proposed current-reuse amplifier can provide a theoretical noise efficiency factor (NEF) as low as 1.01, which is the lowest reported theoretical NEF provided by an LNA topology. A foue-channel current-reuse AFE implemented in a CMOS 0.18-µm technology is presented as a proof-of-concept. T-network capacitive circuits are used to decrease the size of input capacitors and to increase the gain accuracy in the AFE. The measured performance of the whole AFE is presented. The total power consumption per channel, including the LNA and the PGA stage, is 9 µW (4.5 µW for LNA and 4.5 µW for PGA), for an input referred noise of 3.2 µVrms, achieving a measured NEF of 1.94. The entire AFE presents three selectable gains of 35.04, 43.1, and 49.5 dB, and occupies a die area of 0.072 mm2 per channel. The implemented circuit has a measured inter-channel rejection ratio of 54 dB. In vivo recording results obtained with the proposed AFE are reported. It successfully allows collecting low-amplitude extracellular action potential signals from a tungsten wire microelectrode implanted in the hippocampus of a laboratory mouse.