Myomatrix arrays for high-definition muscle recording.

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.

Myomatrix arrays for high-definition muscle recording.

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

Highly Flexible Precisely Braided Multielectrode Probes and Combinatorics for Future Neuroprostheses.

The braided multielectrode probe (BMEP) is an ultrafine microwire bundle interwoven into a precise tubular braided structure, which is designed to be used as an invasive neural probe consisting of multiple microelectrodes for electrophysiological neural recording and stimulation. Significant advantages of BMEPs include highly flexible mechanical properties leading to decreased immune responses after chronic implantation in neural tissue and dense recording/stimulation sites (24 channels) within the 100-200 µm diameter. In addition, because BMEPs can be manufactured using various materials in any size and shape without length limitations, they could be expanded to applications in deep central nervous system (CNS) regions as well as peripheral nervous system (PNS) in larger animals and humans. Finally, the 3D topology of wires supports combinatoric rearrangements of wires within braids, and potential neural yield increases. With the newly developed next generation micro braiding machine, we can manufacture more precise and complex microbraid structures. In this article, we describe the new machine and methods, and tests of simulated combinatoric separation methods. We propose various promising BMEP designs and the potential modifications to these designs to create probes suitable for various applications for future neuroprostheses.

The interplay between cerebellum and basal ganglia in motor adaptation: A modeling study.

Motor adaptation to perturbations is provided by learning mechanisms operating in the cerebellum and basal ganglia. The cerebellum normally performs motor adaptation through supervised learning using information about movement error provided by visual feedback. However, if visual feedback is critically distorted, the system may disengage cerebellar error-based learning and switch to reinforcement learning mechanisms mediated by basal ganglia. Yet, the exact conditions and mechanisms of cerebellum and basal ganglia involvement in motor adaptation remain unknown. We use mathematical modeling to simulate control of planar reaching movements that relies on both error-based and non-error-based learning mechanisms. We show that for learning to be efficient only one of these mechanisms should be active at a time. We suggest that switching between the mechanisms is provided by a special circuit that effectively suppresses the learning process in one structure and enables it in the other. To do so, this circuit modulates learning rate in the cerebellum and dopamine release in basal ganglia depending on error-based learning efficiency. We use the model to explain and interpret experimental data on error- and non-error-based motor adaptation under different conditions.

Precise Tubular Braid Structures of Ultrafine Microwires as Neural Probes: Significantly Reduced Chronic Immune Response and Greater Local Neural Survival in Rat Cortex.

Braided multi-electrode probes (BMEPs) for neural interfaces comprise ultrafine microwire bundles interwoven into tubular braids. BMEPs provide highly flexible probes and tethers, and an open lattice structure with up to 24 recording/stimulating channels in precise geometries, currently all within a [Formula: see text] diameter footprint. This paper compares the long-term tissue effects of BMEPs ( [Formula: see text] wires) versus single conventional 50- [Formula: see text] wires, by testing nearby chronic immune response and neural survival in rat cortex. Four different types of electrodes were implanted in cortex in each of eight rats: 1) BMEP with tether; 2) tethered 50- [Formula: see text] wire; 3) BMEP without a tether; and 4) untethered 50- [Formula: see text] wire. Quantitative immunohistological statistical comparisons after eight weeks using GFAP, ED1, and NeuN staining clearly showed that both BMEP implants had significantly less tissue immune response and more neuronal survival than either of the 50- [Formula: see text] wires ( ) in each of the eight rats. Data strongly indicate that BMEP tissue responses are superior, and that BMEP designs partly alleviate chronic tissue inflammatory responses and neural losses. The flexible body, tether and open braid lattice, and finer wire diameters of BMEP designs may all contribute to reducing the biological long-term response.

The Functional Role of Striatal Cholinergic Interneurons in Reinforcement Learning From Computational Perspective.

In this study, we explore the functional role of striatal cholinergic interneurons, hereinafter referred to as tonically active neurons (TANs), via computational modeling; specifically, we investigate the mechanistic relationship between TAN activity and dopamine variations and how changes in this relationship affect reinforcement learning in the striatum. TANs pause their tonic firing activity after excitatory stimuli from thalamic and cortical neurons in response to a sensory event or reward information. During the pause striatal dopamine concentration excursions are observed. However, functional interactions between the TAN pause and striatal dopamine release are poorly understood. Here we propose a TAN activity-dopamine relationship model and demonstrate that the TAN pause is likely a time window to gate phasic dopamine release and dopamine variations reciprocally modulate the TAN pause duration. Furthermore, this model is integrated into our previously published model of reward-based motor adaptation to demonstrate how phasic dopamine release is gated by the TAN pause to deliver reward information for reinforcement learning in a timely manner. We also show how TAN-dopamine interactions are affected by striatal dopamine deficiency to produce poor performance of motor adaptation.

From the motor cortex to the movement and back again.

The motor cortex controls motor behaviors by generating movement-specific signals and transmitting them through spinal cord circuits and motoneurons to the muscles. Precise and well-coordinated muscle activation patterns are necessary for accurate movement execution. Therefore, the activity of cortical neurons should correlate with movement parameters. To investigate the specifics of such correlations among activities of the motor cortex, spinal cord network and muscles, we developed a model for neural control of goal-directed reaching movements that simulates the entire pathway from the motor cortex through spinal cord circuits to the muscles controlling arm movements. In this model, the arm consists of two joints (shoulder and elbow), whose movements are actuated by six muscles (4 single-joint and 2 double-joint flexors and extensors). The muscles provide afferent feedback to the spinal cord circuits. Cortical neurons are defined as cortical "controllers" that solve an inverse problem based on a proposed straight-line trajectory to a target position and a predefined bell-shaped velocity profile. Thus, the controller generates a motor program that produces a task-specific activation of low-level spinal circuits that in turn induce the muscle activation realizing the intended reaching movement. Using the model, we describe the mechanisms of correlation between cortical and motoneuronal activities and movement direction and other movement parameters. We show that the directional modulation of neuronal activity in the motor cortex and the spinal cord may result from direction-specific dynamics of muscle lengths. Our model suggests that directional modulation first emerges at the level of muscle forces, augments at the motoneuron level, and further increases at the level of the motor cortex due to the dependence of frictional forces in the joints, contractility of the muscles and afferent feedback on muscle lengths and/or velocities.

Reward Based Motor Adaptation Mediated by Basal Ganglia.

It is widely accepted that the basal ganglia (BG) play a key role in action selection and reinforcement learning. However, despite considerable number of studies, the BG architecture and function are not completely understood. Action selection and reinforcement learning are facilitated by the activity of dopaminergic neurons, which encode reward prediction errors when reward outcomes are higher or lower than expected. The BG are thought to select proper motor responses by gating appropriate actions, and suppressing inappropriate ones. The direct striato-nigral (GO) and the indirect striato-pallidal (NOGO) pathways have been suggested to provide the functions of BG in the two-pathway concept. Previous models confirmed the idea that these two pathways can mediate the behavioral choice, but only for a relatively small number of potential behaviors. Recent studies have provided new evidence of BG involvement in motor adaptation tasks, in which adaptation occurs in a non-error-based manner. In such tasks, there is a continuum of possible actions, each represented by a complex neuronal activity pattern. We extended the classical concept of the two-pathway BG by creating a model of BG interacting with a movement execution system, which allows for an arbitrary number of possible actions. The model includes sensory and premotor cortices, BG, a spinal cord network, and a virtual mechanical arm performing 2D reaching movements. The arm is composed of 2 joints (shoulder and elbow) controlled by 6 muscles (4 mono-articular and 2 bi-articular). The spinal cord network contains motoneurons, controlling the muscles, and sensory interneurons that receive afferent feedback and mediate basic reflexes. Given a specific goal-oriented motor task, the BG network through reinforcement learning constructs a behavior from an arbitrary number of basic actions represented by cortical activity patterns. Our study confirms that, with slight modifications, the classical two-pathway BG concept is consistent with results of previous studies, including non-error based motor adaptation experiments, pharmacological manipulations with BG nuclei, and functional deficits observed in BG-related motor disorders.

Local delivery of minocycline from metal ion-assisted self-assembled complexes promotes neuroprotection and functional recovery after spinal cord injury.

Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations. The inability to translate the high doses of MH used in experimental animals to tolerable doses in human patients limits its clinical efficacy. In addition, the duration of MH treatment is limited because long-term systemic administration of high doses of MH has been shown to cause liver toxicity and even death. We have developed a drug delivery system in the form of hydrogel loaded with polysaccharide-MH complexes self-assembled by metal ions for controlled release of MH. This drug delivery system can be injected into the intrathecal space for local delivery of MH with sufficient dose and duration, without causing any additional tissue damage. We show that local delivery of MH at a dose that is lower than the standard human dose (3 mg/kg) was more effective in reducing secondary injury and promoting locomotor functional recovery than systemic injection of MH with the highest dose and duration reported in experimental animal SCI (90-135 mg/kg).

Mixed-mode oscillations and population bursting in the pre-Bötzinger complex.

This study focuses on computational and theoretical investigations of neuronal activity arising in the pre-Bötzinger complex (pre-BötC), a medullary region generating the inspiratory phase of breathing in mammals. A progressive increase of neuronal excitability in medullary slices containing the pre-BötC produces mixed-mode oscillations (MMOs) characterized by large amplitude population bursts alternating with a series of small amplitude bursts. Using two different computational models, we demonstrate that MMOs emerge within a heterogeneous excitatory neural network because of progressive neuronal recruitment and synchronization. The MMO pattern depends on the distributed neuronal excitability, the density and weights of network interconnections, and the cellular properties underlying endogenous bursting. Critically, the latter should provide a reduction of spiking frequency within neuronal bursts with increasing burst frequency and a dependence of the after-burst recovery period on burst amplitude. Our study highlights a novel mechanism by which heterogeneity naturally leads to complex dynamics in rhythmic neuronal populations.

Braided multi-electrode probes: mechanical compliance characteristics and recordings from spinal cords.

OBJECTIVE: To test a novel braided multi-electrode probe design with compliance exceeding that of a 50 µm microwire, thus reducing micromotion- and macromotion-induced tissue stress. APPROACH: We use up to 24 ultra-fine wires interwoven into a tubular braid to obtain a highly flexible multi-electrode probe. The tether-portion wires are simply non-braided extensions of the braid structure, allowing the microprobe to follow gross neural tissue movements. Mechanical calculation and direct measurements evaluated bending stiffness and axial compression forces in the probe and tether system. These were compared to 50 µm nichrome microwire standards. Recording tests were performed in decerebrate animals. MAIN RESULTS: Mechanical bending tests on braids comprising 9.6 or 12.7 µm nichrome wires showed that implants (braided portions) had 4 to 21 times better mechanical compliance than a single 50 µm wire and non-braided tethers were 6 to 96 times better. Braided microprobes yielded robust neural recordings from animals' spinal cords throughout cord motions. SIGNIFICANCE: Microwire electrode arrays that can record and withstand tissue micro- and macromotion of spinal cord tissues are demonstrated. This technology may provide a stable chronic neural interface into spinal cords of freely moving animals, is extensible to various applications, and may reduce mechanical tissue stress.