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Noninvasive electrical stimulation of the vestibular system in humans has become an increasingly popular tool with a broad range of research and clinical applications. However, common assumptions regarding the neural mechanisms that underlie the activation of central vestibular pathways through such stimulation, known as galvanic vestibular stimulation (GVS), have not been directly tested. Here, we show that GVS is encoded by VIIIth nerve vestibular afferents with nonlinear dynamics that differ markedly from those predicted by current models. GVS produced asymmetric activation of both semicircular canal and otolith afferents to the onset versus offset and cathode versus anode of applied current, that in turn produced asymmetric eye movement responses in three awake-behaving male monkeys. Additionally, using computational methods, we demonstrate that the experimentally observed nonlinear neural response dynamics lead to an unexpected directional bias in the net population response when the information from both vestibular nerves is centrally integrated. Together our findings reveal the neural basis by which GVS activates the vestibular system, establish that neural response dynamics differ markedly from current predictions, and advance our mechanistic understanding of how asymmetric activation of the peripheral vestibular system alters vestibular function. We suggest that such nonlinear encoding is a general feature of neural processing that will be common across different noninvasive electrical stimulation approaches.SIGNIFICANCE STATEMENTHere, we show that the application of noninvasive electrical currents to the vestibular system (GVS) induces more complex responses than commonly assumed. We recorded vestibular afferent activity in macaque monkeys exposed to GVS using a setup analogous to human studies. GVS evoked notable asymmetries in irregular afferent responses to cathodal versus anodal currents. We developed a nonlinear model explaining these GVS-evoked afferent responses. Our model predicts that GVS induces directional biases in centrally integrated head motion signals and establishes electrical stimuli that recreate physiologically plausible sensations of motion. Altogether, our findings provide new insights into how GVS activates the vestibular system, which will be vital to advancing new clinical and biomedical applications.

The vestibulocollic reflex is a compensatory response that stabilizes the head in space. During everyday activities, this stabilizing response is evoked by head movements that typically span frequencies from 0 to 30 Hz. Transient head impacts, however, can elicit head movements with frequency content up to 300–400 Hz, raising the question whether vestibular pathways contribute to head stabilization at such high frequencies. Here, we first established that electrical vestibular stimulation modulates human neck motor unit (MU) activity at sinusoidal frequencies up to 300 Hz, but that sensitivity increases with frequency up to a low-pass cutoff of ∼70–80 Hz. To examine the neural substrates underlying the low-pass dynamics of vestibulocollic reflexes, we then recorded vestibular afferent responses to the same electrical stimuli in monkeys. Vestibular afferents also responded to electrical stimuli up to 300 Hz, but in contrast to MUs their sensitivity increased with frequency up to the afferent resting firing rate (∼100–150 Hz) and at higher frequencies afferents tended to phase-lock to the vestibular stimulus. This latter nonlinearity, however, was not transmitted to neck motoneurons, which instead showed minimal phase-locking that decreased at frequencies >75 Hz. Similar to human data, we validated that monkey muscle activity also exhibited low-pass filtered vestibulocollic reflex dynamics. Together, our results show that neck MUs are activated by high-frequency signals encoded by primary vestibular afferents, but undergo low-pass filtering at intermediate stages in the vestibulocollic reflex. These high-frequency contributions to vestibular-evoked neck muscle responses could stabilize the head during unexpected head transients.SIGNIFICANCE STATEMENTVestibular-evoked neck muscle responses rely on accurate encoding and transmission of head movement information to stabilize the head in space. Unexpected transient events, such as head impacts, are likely to push the limits of these neural pathways since their high-frequency features (0–300 Hz) extend beyond the frequency bandwidth of head movements experienced during everyday activities (0–30 Hz). Here, we demonstrate that vestibular primary afferents encode high-frequency stimuli through frequency-dependent increases in sensitivity and phase-locking. When transmitted to neck motoneurons, these signals undergo low-pass filtering that limits neck motoneuron phase-locking in response to stimuli >75 Hz. This study provides insight into the neural dynamics producing vestibulocollic reflexes, which may respond to high-frequency transient events to stabilize the head.

Purpose Descriptions of large series of accessory atrioventricular pathway (AP) ablations in adults and adolescents have been limited to referral centers and published over 20 years ago. We aimed to characterize contemporary accessory AP distribution and features in a large community-based population that influence ablation outcomes. Methods Retrospective analysis of 289 patients (age 14–81) who underwent AP ablation from 2015–2019 was performed. Pathways were categorized into anteroseptal (AS), left freewall (LFW), posteroseptal (PS), and right freewall (RFW) locations. We analyzed patient and pathway features to identify factors associated with prolonged procedure time parameters. Results Initial ablation success rate was 94.7% with long-term success rate of 93.4% and median follow-up of 931 days. APs were in LFW (61.6%), PS (24.6%), RFW (9.6%), and AS (4.3%) locations. Procedure outcome was dependent on pathway location. Acute success was highest for LFW pathways (97.1%) with lowest case times (144 ± 68 minutes) and fluoroscopy times (15 ± 19 minutes). Longest procedure time parameters were seen with AS, left anterolateral, epicardial-coronary sinus, and right anterolateral pathway ablations. A novel ECG algorithm was developed to predicts AP locations and further guide procedure planning. Conclusion In this community-based population, majority of APs are located in the left freewall and posteroseptal region, with only retrograde conduction, and can be ablated using traditional approaches with short time parameters and high success. Using a novel ECG algorithm for pathway localization, we can predict cases with longer procedure times, higher fluoroscopy exposure, and lower acute and long-term success for manifest pathways.

It is commonly assumed that the brain’s neural coding strategies are adapted to the statistics of natural stimuli. Specifically, to maximize information transmission, a sensory neuron’s tuning function should effectively oppose the decaying stimulus spectral power, such that the neural response is temporally decorrelated (i.e. ‘whitened’). However, theory predicts that the structure of neuronal variability also plays an essential role in determining how coding is optimized. Here, we provide experimental evidence supporting this view by recording from neurons in early vestibular pathways during naturalistic self-motion. We found that central vestibular neurons displayed temporally whitened responses that could not be explained by their tuning alone. Rather, computational modeling and analysis revealed that neuronal variability and tuning were matched to effectively complement natural stimulus statistics, thereby achieving temporal decorrelation and optimizing information transmission. Taken together, our findings reveal a novel strategy by which neural variability contributes to optimized processing of naturalistic stimuli.

A simple, fast, and reproducible method for the fabrication of disk ultramicroelectrodes (UMEs) with controlled geometry is reported. The use of prepulled soda-lime glass capillaries allows one to bypass the irreproducible torch-sealing and experimentally challenging tip-sharpening steps used in conventional fabrication protocols. A micron-sized electroactive wire is sealed inside this capillary producing UMEs with a highly reproducible geometry. Total fabrication time (1 h) and experimental difficulty are significantly reduced. Disk UMEs with various diameters and cores were fabricated, including carbon fiber (7 and 11 μm), gold (10 and 25 μm), platinum (10 and 25 μm), silver (25 μm), and mercury (25 μm). The ratio of the insulating sheath to the electroactive core of the UMEs was 2.5-3.6. Silver UMEs were also used to produce a Ag/AgCl microreference electrode. This general fabrication method can readily be applied to other electroactive cores and could allow any research group to produce high quality disk UMEs, which are a prerequisite for quantitative scanning electrochemical microscopy.

At the synapse, D-serine is an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR). It plays an important role in synaptic transmission and plasticity and has also been linked to several pathological diseases such as schizophrenia and Huntington's. The quantification of local changes in D-serine concentration is essential to further understanding these processes. We report herein the development of a disk-shaped amperometric enzymatic biosensor for detection of D-serine based on a 25 μm diameter platinum disk microelectrode with an electrodeposited poly-m-phenylenediamine (PPD) layer and an R. gracilis D-amino acid oxidase (RgDAAO) layer. The disk-shaped D-serine biosensor is 1-5 orders of magnitude smaller than previously reported probes and exhibits a sensitivity of 276 μA cm(-2) mM(-1) with an in vitro detection limit of 0.6 μM. We demonstrate its usefulness for in vivo applications by measuring the release of endogenous D-serine in the brain of Xenopus laevis tadpoles.