Paired vagus nerve stimulation drives precise remyelination and motor recovery after myelin loss.

Myelin loss in the central nervous system can cause permanent motor or cognitive deficits in patients with multiple sclerosis (MS). While current immunotherapy treatments decrease the frequency of demyelinating episodes, they do not promote myelin repair or functional recovery. Vagus nerve stimulation (VNS) is a neuromodulation therapy which enhances neuroplasticity and the recovery of motor function after stroke, but its effects on myelin repair are not known. To determine if VNS influences myelin repair, we applied VNS following a demyelinating injury and measured longitudinal myelin dynamics and functional recovery. We found that VNS promotes remyelination by increasing the generation of myelinating oligodendrocytes. Pairing VNS with a skilled reach task leads to the regeneration of myelin sheaths on previously myelinated axon segments, enhancing the restoration of the original pattern of myelination. Moreover, the magnitude of sheath pattern restoration correlates with long-term motor functional improvement. Together, these results suggest that recovery of the myelin sheath pattern is a key factor in the restoration of motor function following myelin loss and identify paired VNS as a potential remyelination therapy to treat demyelinating diseases.

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

MicroLED light source for optical sectioning structured illumination microscopy.

Optical sectioning structured illumination microscopy (OS-SIM) provides optical sectioning capability in wide-field microscopy. The required illumination patterns have traditionally been generated using spatial light modulators (SLM), laser interference patterns, or digital micromirror devices (DMDs) which are too complex to implement in miniscope systems. MicroLEDs have emerged as an alternative light source for patterned illumination due to their extreme brightness capability and small emitter sizes. This paper presents a directly addressable striped microLED microdisplay with 100 rows on a flexible cable (70 cm long) for use as an OS-SIM light source in a benchtop setup. The overall design of the microdisplay is described in detail with luminance-current-voltage characterization. OS-SIM implementation with a benchtop setup shows the optical sectioning capability of the system by imaging within a 500 µm thick fixed brain slice from a transgenic mouse where oligodendrocytes are labeled with a green fluorescent protein (GFP). Results show improved contrast in reconstructed optically sectioned images of 86.92% (OS-SIM) compared with 44.31% (pseudo-widefield). MicroLED based OS-SIM therefore offers a new capability for deep tissue widefield imaging.

Vagus nerve stimulation drives selective circuit modulation through cholinergic reinforcement.

Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and expanding set of neurologic conditions. However, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. VNS leads to widespread brain activation, but the effects on behavior are remarkably specific, indicating plasticity unique to behaviorally engaged neural circuits. To understand how VNS can lead to specific circuit modulation, we leveraged genetic tools including optogenetics and in vivo calcium imaging in mice learning a skilled reach task. We find that VNS enhances skilled motor learning in healthy animals via a cholinergic reinforcement mechanism, producing a rapid consolidation of an expert reach trajectory. In primary motor cortex (M1), VNS drives precise temporal modulation of neurons that respond to behavioral outcome. This suggests that VNS may accelerate motor refinement in M1 via cholinergic signaling, opening new avenues for optimizing VNS to target specific disease-relevant circuitry.

Miniature structured illumination microscope for in vivo 3D imaging of brain structures with optical sectioning.

We present a high-resolution miniature, light-weight fluorescence microscope with electrowetting lens and onboard CMOS for high resolution volumetric imaging and structured illumination for rejection of out-of-focus and scattered light. The miniature microscope (SIMscope3D) delivers structured light using a coherent fiber bundle to obtain optical sectioning with an axial resolution of 18 µm. Volumetric imaging of eGFP labeled cells in fixed mouse brain tissue at depths up to 260 µm is demonstrated. The functionality of SIMscope3D to provide background free 3D imaging is shown by recording time series of microglia dynamics in awake mice at depths up to 120 µm in the brain.

Motor learning promotes remyelination via new and surviving oligodendrocytes.

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here we report that, while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases oligodendrocyte precursor cell differentiation, oligodendrocyte generation and myelin sheath remodeling in the forelimb motor cortex. Immediately following demyelination, neurons exhibit hyperexcitability, learning is impaired and behavioral intervention provides no benefit to remyelination. However, partial remyelination restores neuronal and behavioral function, allowing learning to enhance oligodendrogenesis, remyelination of denuded axons and the ability of surviving oligodendrocytes to generate new myelin sheaths. Previously considered controversial, we show that sheath generation by mature oligodendrocytes is not only possible but also increases myelin pattern preservation following demyelination, thus presenting a new target for therapeutic interventions. Together, our findings demonstrate that precisely timed motor learning improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

Longitudinal neural and vascular structural dynamics produced by chronic microelectrode implantation.

Implanted microelectrode arrays sense local neuronal activity, signals which are used as control commands for brain computer interface (BCI) technology. Patients with tetraplegia have used BCI technology to achieve an extraordinary degree of interaction with their local environment. However, current microelectrode arrays for BCIs lose the ability to record high-quality neural signals in the months-to-years following implantation. Very little is known regarding the dynamic response of neurons and vasculature in the months following electrode array implantation, but loss of structural integrity near the electrode may contribute to the degradation of recording signals. Here, we use in-vivo dual-modality imaging to characterize neuronal and vasculature structures in the same animal for 3 months following electrode insertion. We find ongoing neuronal atrophy, but relative vascular stability, in close proximity to the electrode, along with evidence suggesting links between rare, abrupt hypoxic events and neuronal process atrophy.

Neural engineering: the process, applications, and its role in the future of medicine.

OBJECTIVE: Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits. APPROACH: This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate. MAIN RESULTS: Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products. SIGNIFICANCE: This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

Phantom-based evaluation of near-infrared intracranial hematoma detector performance.

Near-infrared spectroscopy (NIRS) is emerging as a rapid, low-cost approach for point-of-care triage of hematomas resulting from traumatic brain injury. However, there remains a lack of standardized test methods for benchtop performance assessment of these devices and incomplete understanding of relevant light-tissue interactions. We propose a phantom-based test method for systems operating near the 800-nm oxy-/deoxy-hemoglobin isosbestic point and implement it to evaluate a clinical system. Semi-idealized phantom geometries are designed to represent epidural/subdural, subarachnoid, and intracerebral hemorrhages. Measurements of these phantoms are made with a commercial NIRS-based hematoma detector to quantify the effect of hematoma type, depth, and size, as well as measurement repeatability and detector positioning relative to the hematoma. Results indicated high sensitivity to epidural/subdural and subarachnoid hematomas. Intracerebral hematomas are detectable to a maximum depth of ∼2.5 cm, depending on thickness and diameter. The maximum lateral detection area for the single-emitter/single-collector device studied here appears elliptical and decreases strongly with inclusion depth. Overall, this study provides unique insights into hematoma detector function and indicates the utility of modular polymer tissue phantoms in performance tests for emerging NIRS-based cerebral diagnostic technology.

Automated reactive accelerated aging for rapid in vitro evaluation of neural implant performance.

Novel therapeutic applications for neural implants require miniaturized devices. Miniaturization imposes stricter requirements for reliability of materials. Pilot clinical studies suggest that rapid failure of the miniaturized neural implants in the body presents a major challenge for this type of technology. Traditional evaluations of neural implant performance over clinically relevant durations present time- and resource-intensive experiments in animals. Reactive accelerated aging (RAA) is an in vitro test platform that was developed to expedite durability testing of neural implants, as a screening technique designed to simulate the aggressive physiological environment experienced by the implants. This approach employs hydrogen peroxide, which mimics reactive oxygen species, and a high temperature to accelerate chemical reactions that lead to device degradation similar to that found with devices implanted in vivo. The original RAA system required daily manual maintenance and was prone to variability in performance. To address these limitations, this work introduces automated reactive accelerated aging (aRAA) with closed-loop monitoring components that make the system simple, robust, and scalable. The core novel technology in the aRAA is electrochemical detection for feedback control of hydrogen peroxide concentration, implemented with simple off-the-shelf components. The aRAA can run multiple parallel experiments for high-throughput device testing and optimization. For this reason, the aRAA provides a simple tool for rapid in vitro evaluation of the durability of neural implants, ultimately expediting the development of a new generation of miniaturized devices with a long functional lifespan.

Advancing Science: How Bias Holds Us Back.

As scientists and engineers, we must recognize the overwhelming evidence that we each harbor bias that influences our professional decisions. Yet, solving today's increasingly complex public health challenges requires diverse perspectives from multidisciplinary teams. We all have the opportunity to actively promote a more representative scientific community; let's harness the power of collective action to build diverse teams that deliver the most innovative science.

Innovations in electrical stimulation harness neural plasticity to restore motor function.

Novel technology and innovative stimulation paradigms allow for unprecedented spatiotemporal precision and closed-loop implementation of neurostimulation systems. In turn, precise, closed-loop neurostimulation appears to preferentially drive neural plasticity in motor networks, promoting neural repair. Recent clinical studies demonstrate that electrical stimulation can drive neural plasticity in damaged motor circuits, leading to meaningful improvement in users. Future advances in these areas hold promise for the treatment of a wide range of motor systems disorders.

Epidermal Electrode Technology for Detecting Ultrasonic Perturbation of Sensory Brain Activity.

OBJECTIVE: We aim to demonstrate the in vivo capability of a wearable sensor technology to detect localized perturbations of sensory-evoked brain activity. METHODS: Cortical somatosensory evoked potentials (SSEPs) were recorded in mice via wearable, flexible epidermal electrode arrays. We then utilized the sensors to explore the effects of transcranial focused ultrasound, which noninvasively induced neural perturbation. SSEPs recorded with flexible epidermal sensors were quantified and benchmarked against those recorded with invasive epidural electrodes. RESULTS: We found that cortical SSEPs recorded by flexible epidermal sensors were stimulus frequency dependent. Immediately following controlled, focal ultrasound perturbation, the sensors detected significant SSEP modulation, which consisted of dynamic amplitude decreases and altered stimulus-frequency dependence. These modifications were also dependent on the ultrasound perturbation dosage. The effects were consistent with those recorded with invasive electrodes, albeit with roughly one order of magnitude lower signal-to-noise ratio. CONCLUSION: We found that flexible epidermal sensors reported multiple SSEP parameters that were sensitive to focused ultrasound. This work therefore 1) establishes that epidermal electrodes are appropriate for monitoring the integrity of major CNS functionalities through SSEP; and 2) leveraged this technology to explore ultrasound-induced neuromodulation. The sensor technology is well suited for this application because the sensor electrical properties are uninfluenced by direct exposure to ultrasound irradiation. SIGNIFICANCE: The sensors and experimental paradigm we present involve standard, safe clinical neurological assessment methods and are thus applicable to a wide range of future translational studies in humans with any manner of health condition.

New Light on Gamma Oscillations.

Two papers in this issue of Neuron by Saleem et al. (2017) and Storchi et al. (2017) show that increases in background light intensity trigger proportional increases in narrowband gamma oscillations with a peak at 60 Hz in retina, lateral geniculate, and primary visual cortex of the mouse visual system.

Alterations in neurovascular coupling following acute traumatic brain injury.

Following acute traumatic brain injury (TBI), timely transport to a hospital can significantly improve the prognosis for recovery. There is, however, a dearth of quantitative biomarkers for brain injury that can be rapidly acquired and interpreted in active, field environments in which TBIs are frequently incurred. We explored potential functional indicators for TBI that can be noninvasively obtained through portable detection modalities, namely optical and electrophysiological approaches. By combining diffuse correlation spectroscopy with colocalized electrophysiological measurements in a mouse model of TBI, we observed concomitant alterations in sensory-evoked cerebral blood flow (CBF) and electrical potentials following controlled cortical impact. Injury acutely reduced the peak amplitude of both electrophysiological and CBF responses, which mostly recovered to baseline values within 30 min, and intertrial variability for these parameters was also acutely altered. Notably, the postinjury dynamics of the CBF overshoot and undershoot amplitudes differed significantly; whereas the amplitude of the initial peak of stimulus-evoked CBF recovered relatively rapidly, the ensuing undershoot did not appear to recover within 30 min of injury. Additionally, acute injury induced apparent low-frequency oscillatory behavior in CBF ([Formula: see text]). Histological assessment indicated that these physiological alterations were not associated with any major, persisting anatomical changes. Several time-domain features of the blood flow and electrophysiological responses showed strong correlations in recovery kinetics. Overall, our results reveal an array of stereotyped, injury-induced alterations in electrophysiological and hemodynamic responses that can be rapidly obtained using a combination of portable detection techniques.

Real-Time Detection and Monitoring of Acute Brain Injury Utilizing Evoked Electroencephalographic Potentials.

Rapid detection and diagnosis of a traumatic brain injury (TBI) can significantly improve the prognosis for recovery. Helmet-mounted sensors that detect impact severity based on measurements of acceleration or pressure show promise for aiding triage and transport decisions in active, field environments such as professional sports or military combat. The detected signals, however, report on the mechanics of an impact rather than directly indicating the presence and severity of an injury. We explored the use of cortical somatosensory evoked electroencephalographic potentials (SSEPs) to detect and track, in real-time, neural electrophysiological abnormalities within the first hour following head injury in an animal model. To study the immediate electrophysiological effects of injury in vivo, we developed an experimental paradigm involving focused ultrasound that permits continuous, real-time measurements and minimizes mechanical artifact. Injury was associated with a dramatic reduction of amplitude over the damaged hemisphere directly after the injury. The amplitude systematically improved over time but remained significantly decreased at one hour, compared with baseline. In contrast, at one hour there was a concomitant enhancement of the cortical SSEP amplitude evoked from the uninjured hemisphere. Analysis of the inter-trial electroencephalogram (EEG) also revealed significant changes in low-frequency components and an increase in EEG entropy up to 30 minutes after injury, likely reflecting altered EEG reactivity to somatosensory stimuli. Injury-induced alterations in SSEPs were also observed using noninvasive epidermal electrodes, demonstrating viability of practical implementation. These results suggest cortical SSEPs recorded at just a few locations by head-mounted sensors and associated multiparametric analyses could potentially be used to rapidly detect and monitor brain injury in settings that normally present significant levels of mechanical and electrical noise.

Tissue damage thresholds during therapeutic electrical stimulation.

OBJECTIVE: Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. APPROACH: In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. MAIN RESULTS: For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. SIGNIFICANCE: It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device safety.

Sensory-driven and spontaneous gamma oscillations engage distinct cortical circuitry.

Gamma oscillations are a robust component of sensory responses but are also part of the background spontaneous activity of the brain. To determine whether the properties of gamma oscillations in cortex are specific to their mechanism of generation, we compared in mouse visual cortex in vivo the laminar geometry and single-neuron rhythmicity of oscillations produced during sensory representation with those occurring spontaneously in the absence of stimulation. In mouse visual cortex under anesthesia (isoflurane and xylazine), visual stimulation triggered oscillations mainly between 20 and 50 Hz, which, because of their similar functional significance to gamma oscillations in higher mammals, we define here as gamma range. Sensory representation in visual cortex specifically increased gamma oscillation amplitude in the supragranular (L2/3) and granular (L4) layers and strongly entrained putative excitatory and inhibitory neurons in infragranular layers, while spontaneous gamma oscillations were distributed evenly through the cortical depth and primarily entrained putative inhibitory neurons in the infragranular (L5/6) cortical layers. The difference in laminar distribution of gamma oscillations during the two different conditions may result from differences in the source of excitatory input to the cortex. In addition, modulation of superficial gamma oscillation amplitude did not result in a corresponding change in deep-layer oscillations, suggesting that superficial and deep layers of cortex may utilize independent but related networks for gamma generation. These results demonstrate that stimulus-driven gamma oscillations engage cortical circuitry in a manner distinct from spontaneous oscillations and suggest multiple networks for the generation of gamma oscillations in cortex.

Acute insertion effects of penetrating cortical microelectrodes imaged with quantitative optical coherence angiography.

The vascular response during cortical microelectrode insertion was measured with amplitude decorrelation-based quantitative optical coherence angiography (OCA). Four different shank-style microelectrode configurations were inserted in murine motor cortex beneath a surgically implanted window in discrete steps while OCA images were collected and processed for angiography and flowmetry. Quantitative measurements included tissue displacement (measured by optical flow), perfused capillary density, and capillary flow velocity. The primary effect of insertion was mechanical perturbation, the effects of which included tissue displacement, arteriolar rupture, and compression of a branch of the anterior cerebral artery causing a global decrease in flow. Other effects observed included local flow drop-out in the region immediately surrounding the microelectrode. The mean basal capillary network velocity for all animals was 0.23 ( ± 0.05 SD ) and 0.18 ( ± 0.07 SD ) mm / s for capillaries from 100 to 300 µ m and 300 to 500 µ m , respectively. Upon insertion, the 2-shank electrode arrays caused a decrease in capillary flow density and velocity, while the results from other configurations were not different from controls. The proximity to large vessels appears to play a larger role than the array configuration. These results can guide neurosurgeons and electrode designers to minimize trauma and ischemia during microelectrode insertion.