Outcome measures in pediatric chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Objective outcome measures in children undergoing treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are lacking. The aim of the study was to record serial grip strength and motor nerve conduction studies to assess interval change. METHODS: This was a retrospective review of 16 children (8 females and 8 males; median age, 9.7 years; interquartile range, 6-13 years) with CIDP followed at a tertiary children's hospital from 2013 to 2021. Subjects were treated with intravenous immunoglobulin (IVIG). Right and left grip strength measurements were obtained at each clinic visit using a handheld dynamometer. Annual right median motor nerve conduction study data were recorded during the study period. RESULTS: Mean duration of follow-up was 2.9 years. Grip strength (right: 0.19 kg/month, p < 0.001; left 0.23 kg/month, p < 0.001) and median F-wave latencies (-0.23/month, p = 0.015) showed significant improvement over time. Akaike information criterion showed time + IVIG frequency <21 days as best fit for grip strength and distal compound muscle action potential amplitude. DISCUSSION: Our study results indicate serial grip strength measurements are a feasible and objective way to assess motor strength improvement in children with CIDP receiving immunotherapy.

Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Strain-tunable Berry curvature in quasi-two-dimensional chromium telluride.

Magnetic transition metal chalcogenides form an emerging platform for exploring spin-orbit driven Berry phase phenomena owing to the nontrivial interplay between topology and magnetism. Here we show that the anomalous Hall effect in pristine Cr2Te3 thin films manifests a unique temperature-dependent sign reversal at nonzero magnetization, resulting from the momentum-space Berry curvature as established by first-principles simulations. The sign change is strain tunable, enabled by the sharp and well-defined substrate/film interface in the quasi-two-dimensional Cr2Te3 epitaxial films, revealed by scanning transmission electron microscopy and depth-sensitive polarized neutron reflectometry. This Berry phase effect further introduces hump-shaped Hall peaks in pristine Cr2Te3 near the coercive field during the magnetization switching process, owing to the presence of strain-modulated magnetic layers/domains. The versatile interface tunability of Berry curvature in Cr2Te3 thin films offers new opportunities for topological electronics.

Mitigating Mismatch Compression in Differential Local Field Potentials.

Deep brain stimulation (DBS) devices capable of measuring differential local field potentials ( ∂ LFP) enable neural recordings alongside clinical therapy. Efforts to identify oscillatory correlates of various brain disorders, or disease readouts, are growing but must proceed carefully to ensure readouts are not distorted by brain environment. In this report we identified, characterized, and mitigated a major source of distortion in ∂ LFP that we introduce as mismatch compression (MC). Using in vivo, in silico, and in vitro models of MC, we showed that impedance mismatches in the two recording electrodes can yield incomplete rejection of stimulation artifact and subsequent gain compression that distorts oscillatory power. We then developed and validated an opensource mitigation pipeline that mitigates the distortions arising from MC. This work enables more reliable oscillatory readouts for adaptive DBS applications.

DeepLabCut increases markerless tracking efficiency in X-ray video analysis of rodent locomotion.

Despite the prevalence of rat models to study human disease and injury, existing methods for quantifying behavior through skeletal movements are problematic owing to skin movement inaccuracies associated with optical video analysis, or require invasive implanted markers or time-consuming manual rotoscoping for X-ray video approaches. We examined the use of a machine learning tool, DeepLabCut, to perform automated, markerless tracking in bi-planar X-ray videos of locomoting rats. Models were trained on 590 pairs of video frames to identify 19 unique skeletal landmarks of the pelvic limb. Accuracy, precision and time savings were assessed. Machine-identified landmarks deviated from manually labeled counterparts by 2.4±0.2 mm (n=1710 landmarks). DeepLabCut decreased analysis time by over three orders of magnitude (1627×) compared with manual labeling. Distribution of these models may enable the processing of a large volume of accurate X-ray kinematics locomotion data in a fraction of the time without requiring surgically implanted markers.

Dynamic Oscillations Evoked by Subcallosal Cingulate Deep Brain Stimulation.

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCCwm) alleviates symptoms of depression, but its mechanistic effects on brain dynamics remain unclear. In this study we used novel intracranial recordings (LFP) in n = 6 depressed patients stimulated with DBS around the SCCwm target, observing a novel dynamic oscillation (DOs). We confirm that DOs in the LFP are of neural origin and consistently evoked within certain patients. We then characterize the frequency and dynamics of DOs, observing significant variability in DO behavior across patients. Under the hypothesis that LFP-DOs reflect network engagement, we characterize the white matter tracts associated with LFP-DO observations and report a preliminary observation of DO-like activity measured in a single patient's electroencephalography (dEEG). These results support further study of DOs as an objective signal for mechanistic study and connectomics guided DBS.

B-Doped δ-Layers and Nanowires from Area-Selective Deposition of BCl3 on Si(100).

Atomically precise, δ-doped structures forming electronic devices in Si have been routinely fabricated in recent years by using depassivation lithography in a scanning tunneling microscope (STM). While H-based precursor/monatomic resist chemistries for incorporation of donor atoms have dominated these efforts, the use of halogen-based chemistries offers a promising path toward atomic-scale manufacturing of acceptor-based devices. Here, B-doped δ-layers were fabricated in Si(100) by using BCl3 as an acceptor dopant precursor in ultrahigh vacuum. Additionally, we demonstrate compatibility of BCl3 with both H and Cl monatomic resists to achieve area-selective deposition on Si. In comparison to bare Si, BCl3 adsorption selectivity ratios for H- and Cl-passivated Si were determined by secondary ion mass spectrometry depth profiling (SIMS) to be 310(10):1 and 1529(5):1, respectively. STM imaging revealed that BCl3 adsorbed readily on bare Si at room temperature, with SIMS measurements indicating a peak B concentration greater than 1.2(1) × 1021 cm-3 with a total areal dose of 1.85(1) × 1014 cm-2 resulting from a 30 langmuir BCl3 dose at 150 °C. In addition, SIMS showed a δ-layer thickness of ∼0.5 nm. Hall bar measurements of a similar sample were performed at 3.0 K, revealing a sheet resistance of ρ□ = 1.9099(4) kΩ â–¡-1, a hole carrier concentration of p = 1.90(2) × 1014 cm-2, and a hole mobility of µ = 38.0(4) cm2 V-1 s-1 without performing an incorporation anneal. Finally, 15 nm wide B δ-doped nanowires were fabricated from BCl3 and were found to exhibit ohmic conduction. This validates the use of BCl3 as a dopant precursor for atomic-precision fabrication of acceptor-doped devices in Si and enables development of simultaneous n- and p-type doped bipolar devices.

Solution Chemistry to Control Boron-Containing Monolayers on Silicon: Reactions of Boric Acid and 4-Fluorophenylboronic Acid with H- and Cl-terminated Si(100).

The reactions of boric acid and 4-fluorophenylboronic acid with H- and Cl-terminated Si(100) surfaces in solution were investigated. X-ray photoelectron spectroscopy (XPS) studies reveal that both molecules react preferentially with Cl-Si(100) and not with H-Si(100) at identical conditions. On Cl-Si(100), the reactions introduce boron onto the surface, forming a Si-O-B structure. The quantification of boron surface coverage demonstrates that the 4-fluorophenylboronic acid leads to ∼2.8 times higher boron coverage compared to that of boric acid on Cl-Si(100). Consistent with these observations, density functional theory studies show that the reaction of boric acid and 4-fluorophenylboronic acid is more favorable with the Cl- versus H-terminated surface and that on Cl-Si(100) the reaction with 4-fluorophenylboronic acid is ∼55.3 kJ/mol more thermodynamically favorable than the reaction with boric acid. The computational studies were also used to demonstrate the propensity of the overall approach to form high-coverage monolayers on these surfaces, with implications for selective-area boron-based monolayer doping.

Reaction of BCl3 with H- and Cl-terminated Si(1 0 0) as a pathway for selective, monolayer doping through wet chemistry.

The reaction of boron trichloride with the H and Cl-terminated Si(100) surfaces was investigated to understand the interaction of this molecule with the surface for designing wet-chemistry based silicon surface doping processes using a carbon- and oxygen-free precursor. The process was followed with X-ray photoelectron spectroscopy (XPS). Within the reaction conditions investigated, the reaction is highly effective on Cl-Si(100) for temperatures below 70°C, at which point both surfaces react with BCl3. The XPS investigation followed the formation of a B 1s peak at 193.5 eV corresponding to (B-O)x species. Even the briefest exposure to ambient conditions lead to hydroxylation of surface borochloride species. However, the Si 2p signature at 102 eV allowed for a confirmation of the formation of a direct Si-B bond. Density functional theory was utilized to supplement the analysis and identify possible major surface species resulting from these reactions. This work provides a new pathway to obtain a functionalized silicon surface with a direct Si-B bond that can potentially be exploited as a means of selective, ultra-shallow, and supersaturated doping.

Reaction of Hydrazine with Solution- and Vacuum-Prepared Selectively Terminated Si(100) Surfaces: Pathways to the Formation of Direct Si-N Bonds.

The reactivity of liquid hydrazine (N2H4) with respect to H-, Cl-, and Br-terminated Si(100) surfaces was investigated to uncover the principles of nitrogen incorporation into the interface. This process has important implications in a wide variety of applications, including semiconductor surface passivation and functionalization, nitride growth, and many others. The use of hydrazine as a precursor allows for reactions that exclude carbon and oxygen, the primary sources of contamination in processing. In this work, the reactivity of N2H4 with H- and Cl-terminated surfaces prepared by traditional solvent-based methods and with a Br-terminated Si(100) prepared in ultrahigh vacuum was compared. The reactions were studied with X-ray photoelectron spectroscopy, atomic force microscopy, and scanning tunneling microscopy, and the observations were supported by computational investigations. The H-terminated surface led to the highest level of nitrogen incorporation; however, the process proceeds with increasing surface roughness, suggesting possible etching or replacement reactions. In the case of Cl-terminated (predominantly dichloride) and Br-terminated (monobromide) surfaces, the amount of nitrogen incorporation on both surfaces after the reaction with hydrazine was very similar despite the differences in preparation, initial structure, and chemical composition. Density functional theory was used to propose the possible surface structures and to analyze surface reactivity.

Core Competencies for Undergraduates in Bioengineering and Biomedical Engineering: Findings, Consequences, and Recommendations.

This paper provides a synopsis of discussions related to biomedical engineering core curricula that occurred at the Fourth BME Education Summit held at Case Western Reserve University in Cleveland, Ohio in May 2019. This summit was organized by the Council of Chairs of Bioengineering and Biomedical Engineering, and participants included over 300 faculty members from 100+ accredited undergraduate programs. This discussion focused on six key questions: QI: Is there a core curriculum, and if so, what are its components? QII: How does our purported core curriculum prepare students for careers, particularly in industry? QIII: How does design distinguish BME/BIOE graduates from other engineers? QIV: What is the state of engineering analysis and systems-level modeling in BME/BIOE curricula? QV: What is the role of data science in BME/BIOE undergraduate education? QVI: What core experimental skills are required for BME/BIOE undergrads? s. Indeed, BME/BIOI core curricula exists and has matured to emphasize interdisciplinary topics such as physiology, instrumentation, mechanics, computer programming, and mathematical modeling. Departments demonstrate their own identities by highlighting discipline-specific sub-specialties. In addition to technical competence, Industry partners most highly value our students' capacity for problem solving and communication. As such, BME/BIOE curricula includes open-ended projects that address unmet patient and clinician needs as primary methods to prepare graduates for careers in industry. Culminating senior design experiences distinguish BME/BIOE graduates through their development of client-centered engineering solutions to healthcare problems. Finally, the overall BME/BIOE curriculum is not stagnant-it is clear that data science will become an ever-important element of our students' training and that new methods to enhance student engagement will be of pedagogical importance as we embark on the next decade.

Challenges associated with nerve conduction block using kilohertz electrical stimulation.

Neuromodulation therapies, which electrically stimulate parts of the nervous system, have traditionally attempted to activate neurons or axons to restore function or alleviate disease symptoms. In stark contrast to this approach is inhibiting neural activity to relieve disease symptoms and/or restore homeostasis. One potential approach is kilohertz electrical stimulation (KES) of peripheral nerves-which enables a rapid, reversible, and localized block of conduction. This review highlights the existing scientific and clinical utility of KES and discusses the technical and physiological challenges that must be addressed for successful translation of KES nerve conduction block therapies.

Kilohertz Electrical Stimulation Nerve Conduction Block: Effects of Electrode Material.

Kilohertz electrical stimulation (KES) has enabled a novel new paradigm for spinal cord and peripheral nerve stimulation to treat a variety of neurological diseases. KES can excite or inhibit nerve activity and is used in many clinical devices today. However, the impact of different electrode materials on the efficacy of KES is unknown. We investigated the effect of different electrode materials and their respective charge injection mechanisms on KES nerve block thresholds using 20- and 40-kHz current-controlled sinusoidal KES waveforms. We evaluated the nerve block threshold and the power requirements for achieving an effective KES nerve block. In addition, we evaluated potential effects on the onset duration and recovery of normal conduction after delivery of KES. We found that thresholds and the onset and recovery of KES nerve block are not a function of the electrode material. In contrast, the power dissipation varies among electrode materials and is a function of the materials' properties at high frequencies. We conclude that materials with a proven track record of chronic stability, both for the tissue and electrode, are suitable for developing KES nerve block therapies.

Corrigendum: Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

This corrects the article DOI: 10.1038/srep39810.

Hard real-time closed-loop electrophysiology with the Real-Time eXperiment Interface (RTXI).

The ability to experimentally perturb biological systems has traditionally been limited to static pre-programmed or operator-controlled protocols. In contrast, real-time control allows dynamic probing of biological systems with perturbations that are computed on-the-fly during experimentation. Real-time control applications for biological research are available; however, these systems are costly and often restrict the flexibility and customization of experimental protocols. The Real-Time eXperiment Interface (RTXI) is an open source software platform for achieving hard real-time data acquisition and closed-loop control in biological experiments while retaining the flexibility needed for experimental settings. RTXI has enabled users to implement complex custom closed-loop protocols in single cell, cell network, animal, and human electrophysiology studies. RTXI is also used as a free and open source, customizable electrophysiology platform in open-loop studies requiring online data acquisition, processing, and visualization. RTXI is easy to install, can be used with an extensive range of external experimentation and data acquisition hardware, and includes standard modules for implementing common electrophysiology protocols.

Kilohertz Electrical Stimulation Nerve Conduction Block: Effects of Electrode Surface Area.

Kilohertz electrical stimulation (KES) induces repeatable and reversible conduction block of nerve activity and is a potential therapeutic option for various diseases and disorders resulting from pathological or undesired neurological activity. However, successful translation of KES nerve block to clinical applications is stymied by many unknowns, such as the relevance of the onset response, acceptable levels of waveform contamination, and optimal electrode characteristics. We investigated the role of electrode geometric surface area on the KES nerve block threshold using 20- and 40-kHz current-controlled sinusoidal KES. Electrodes were electrochemically characterized and used to characterize typical KES waveforms and electrode charge characteristics. KES nerve block amplitudes, onset duration, and recovery of normal conduction after delivery of the KES were evaluated along with power requirements for effective KES nerve block. Results from this investigation demonstrate that increasing electrode geometric surface area provides for a more power-efficient KES nerve block. Reductions in block threshold by increased electrode surface area were found to be KES-frequency-dependent, with block thresholds and average power consumption reduced by greater than two times with 20-kHz KES waveforms and greater than three times for 40-kHz KES waveforms.

Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.

Stochastic slowly adapting ionic currents may provide a decorrelation mechanism for neural oscillators by causing wander in the intrinsic period.

Oscillatory neurons integrate their synaptic inputs in fundamentally different ways than normally quiescent neurons. We show that the oscillation period of invertebrate endogenous pacemaker neurons wanders, producing random fluctuations in the interspike intervals (ISI) on a time scale of seconds to minutes, which decorrelates pairs of neurons in hybrid circuits constructed using the dynamic clamp. The autocorrelation of the ISI sequence remained high for many ISIs, but the autocorrelation of the ΔISI series had on average a single nonzero value, which was negative at a lag of one interval. We reproduced these results using a simple integrate and fire (IF) model with a stochastic population of channels carrying an adaptation current with a stochastic component that was integrated with a slow time scale, suggesting that a similar population of channels underlies the observed wander in the period. Using autoregressive integrated moving average (ARIMA) models, we found that a single integrator and a single moving average with a negative coefficient could simulate both the experimental data and the IF model. Feeding white noise into an integrator with a slow time constant is sufficient to produce the autocorrelation structure of the ISI series. Moreover, the moving average clearly accounted for the autocorrelation structure of the ΔISI series and is biophysically implemented in the IF model using slow stochastic adaptation. The observed autocorrelation structure may be a neural signature of slow stochastic adaptation, and wander generated in this manner may be a general mechanism for limiting episodes of synchronized activity in the nervous system.

Microneedle cuff electrodes for extrafascicular peripheral nerve interfacing.

OBJECTIVE: The work presented here describes a new tool for peripheral nerve interfacing, called the microneedle cuff (µN-cuff) electrode. APPROACH: µN arrays are designed and integrated into cuff electrodes for penetrating superficial tissues while remaining non-invasive to delicate axonal tracts. MAIN RESULTS: In acute testing, the presence of 75 µm height µNs decreased the electrode-tissue interface impedance by 0.34 kΩ, resulting in a 0.9 mA reduction in functional stimulation thresholds and increased the signal-to-noise ratio by 9.1 dB compared to standard (needle-less) nerve cuff electrodes. Preliminary acute characterization suggests that µN-cuff electrodes provide the stability and ease of use of standard cuff electrodes while enhancing electrical interfacing characteristics. SIGNIFICANCE: The ability to stimulate, block, and record peripheral nerve activity with greater specificity, resolution, and fidelity can enable more precise spatiotemporal control and measurement of neural circuits.

Differential fiber-specific block of nerve conduction in mammalian peripheral nerves using kilohertz electrical stimulation.

Kilohertz electrical stimulation (KES) has been shown to induce repeatable and reversible nerve conduction block in animal models. In this study, we characterized the ability of KES stimuli to selectively block specific components of stimulated nerve activity using in vivo preparations of the rat sciatic and vagus nerves. KES stimuli in the frequency range of 5-70 kHz and amplitudes of 0.1-3.0 mA were applied. Compound action potentials were evoked using either electrical or sensory stimulation, and block of components was assessed through direct nerve recordings and muscle force measurements. Distinct observable components of the compound action potential had unique conduction block thresholds as a function of frequency of KES. The fast component, which includes motor activity, had a monotonically increasing block threshold as a function of the KES frequency. The slow component, which includes sensory activity, showed a nonmonotonic block threshold relationship with increasing KES frequency. The distinct trends with frequency of the two components enabled selective block of one component with an appropriate choice of frequency and amplitude. These trends in threshold of the two components were similar when studying electrical stimulation and responses of the sciatic nerve, electrical stimulation and responses of the vagus nerve, and sensorimotor stimulation and responses of the sciatic nerve. This differential blocking effect of KES on specific fibers can extend the applications of KES conduction block to selective block and stimulation of neural signals for neuromodulation as well as selective control of neural circuits underlying sensorimotor function.