Electrical Stimulation publications

Normally hearing humans can localize sound sources quite accurately, with minimum audible angles as small as 1°. To achieve this, these auditory pathways combine information from multiple acoustic cues, including interaural time and interaural level differences (ITDs and ILDs). Patients relying on cochlear implants (CIs) to hear the world do not match normal performance. These deficits are most pronounced in patients with little or no hearing experience early in life, and they appear to result from impaired sensitivity to ITDs, but not to ILDs. However, little is known about how ITD and ILD sensitivities develop and interact in an early deafened auditory system shortly after CI implantation. Neonatally deafened rats were fitted with bilateral CIs, and, providing informative ITDs and ILDs from stimulation onset, were trained to lateralize CI stimuli. These animals are exquisitely sensitive to both ILDs and ITDs of CI stimulus pulses, and combined information from both cues in a weighted sum. Importantly, ITDs are weighted heavily in the CI rats, such that only very modest ITDs pointing in one direction can confound quite large ILDs pointing in the opposite direction. This underlines the importance of informative ITDs for maximizing the potential for spatial hearing with CI devices.

As part of a deep brain stimulation (DBS) procedure, direct electrophysiological recordings from thalamic and basal ganglia circuits were obtained from a pediatric participant with secondary dystonia to examine the neural mechanisms of motor timing. The participant performed a two-phase repetitive timing task that began with synchronization to a series of externally presented auditory cues, followed by a continuation phase in which the participant maintained the movement rhythm without external guidance. Simultaneous recordings from stereoelectroencephalography (sEEG) leads implanted in the globus pallidus internus (GPi), subthalamic nucleus (STN), ventral oralis (Vo), centromedian nucleus (CM), and thalamic nuclei receiving projections from the cerebellum (ventral intermediate nucleus (VIM) and centrolateral nucleus (CL)) revealed behaviorally relevant neural dynamics. Local field potentials (LFPs) from recorded nuclei exhibited strong, time-locked responses during the synchronization phase, with reduced amplitudes during the continuation phase. Time-frequency analysis showed consistent power increases around the corresponding mean of the inter-response intervals (IRIs) in both behavioral output and neural signals, suggesting frequency-specific entrainment across circuits. These findings suggest of cerebellar-thalamic and basal ganglia contributions to temporal coordination.

Noise-induced hearing loss (NIHL) involves a biphasic pathophysiology. Intense noise exposure causes immediate cochlear vasoconstriction and ischemia, leading to transient hypoxia. Subsequent reperfusion triggers excess reactive oxygen species (ROS) production, resulting in oxidative stress and hair cell injury. This study therefore developed two oxygenated albumin microbubble (OMB) formulations-ionic-bond metformin-coated (iMet-OMBs) and covalent-bond metformin-encapsulated (cMet-OMBs)-and combined them with transcranial ultrasound (US) to enhance targeted delivery to the cochlea. This approach aims to provide transient oxygen supplementation while simultaneously reducing ROS-mediated injury. Microbubbles were characterized for morphology, oxygen loading, and metformin content. Based on their superior stability and drug-loading profile, cMet-OMBs were selected for in vivo evaluation. In a mouse NIHL model, animals were administered cMet-OMBs systemically via retro-orbital injection, followed by US triggering over the temporal bone. Auditory brainstem response (ABR) thresholds, cochlear oxygen tension, and outer hair cell (OHC) survival were assessed. US-mediated cMet-OMBs rupture transiently increased intracochlear oxygen tension, counteracting early hypoxia after noise exposure. Metformin released from cMet-OMBs attenuated ROS production through mitochondrial complex I inhibition and antioxidant pathway activation. Mice treated with cMet-OMBs + US showed significantly lower ABR threshold shifts and better OHC preservation compared with controls. This dual-action strategy combines transient oxygen supplementation from OMBs with sustained antioxidant protection from metformin. While oxygen delivery raises intracochlear oxygen tension, metformin suppresses ROS generation through mitochondrial complex I inhibition and AMPK/Nrf2 activation. This controlled, US-triggered release achieves net cochlear protection against NIHL without excessive oxidative burden.

Bilateral cochlear implants (BiCIs) improve spatial-hearing outcomes relative to a single cochlear implant (CI), but the extent varies across patients. One limiting factor may be interaurally asymmetric spectro-temporal representations of sounds. The present study simulated interaural spectro-temporal asymmetries to explore how they affect binaural processing in listeners with normal hearing. We simulated CI stimulation using high-rate (500 pps) band limited acoustic pulse trains with a 3 mm bandwidth and 4 or 6.5 kHz center frequency. Second-order amplitude modulation (AM) was applied at a 100 Hz modulation rate, 20% or 50% modulation depth, and sinusoidal or sawtooth shape. Intracranial lateralization was used to assess utility of whole-waveform interaural time differences (ITDs). Results demonstrated that lateralization of envelope ITDs was limited by the ear with smaller AM depth. This effect depended upon the sharpness of temporal onsets and the extent to which frequencies overlapped in each ear. These results suggest that interaural asymmetry in spectro-temporal representations may limit binaural outcomes of patients with BiCIs. Two well-established models of binaural processing that assume interaural symmetry and rely on coincidence-detection were used to predict performance. Models were mostly predictive of performance, but made consistent errors, suggesting that models of BiCI stimulation using coincidence-detection should be improved to account for asymmetries.

Objective Transcranial current stimulation (tCS) is a promising technique to non-invasively modulate human brain activity. However, stimulation artifacts in EEG and MEG recordings severely hinder the study of its online effects. Approach Here, we introduce a new approach to account for these artifacts. The approach rests on two key ideas. First, we focus on interactions of tCS with intrinsic brain activity, which are absent for tCS artifacts. Second, rather than removing artifacts, we compare composite signals that share similar artifacts but potentially differ in the interaction of tCS with intrinsic brain activity. We follow a simple logic: if tCS does not interact with intrinsic brain activity, then neural activity during simultaneous sensory stimulation and tCS should equal the linear superposition of the neural effects of each applied alone. Any deviation from this prediction provides evidence for a neural interaction. Main results We tested this approach in a proof-of-principle MEG study, applying 10 Hz transcranial alternating current stimulation (tACS) during rest and during a 10 Hz visual flicker. We compared neural activity during simultaneous stimulation with that predicted by the linear superposition of flicker and tACS alone and found a phase-dependent interaction between tACS and flicker-evoked brain activity. Significance Our work establishes a novel approach to investigate online effects of tCS and suggests a state-dependent interaction of tACS with human brain activity.

Background: Optimizing deep brain stimulation (DBS) parameter settings requires postoperative adjustments through a time-consuming trial-and-error process. As such, researchers have been developing computational models to guide DBS programming. Despite growing interest in image-guided DBS technology, and recent adoption into clinical practice, the direct validation of the prediction accuracy remains limited. Objective: The objective of this study was to establish a comparative framework for validating the accuracy of various DBS computational modeling methodologies in predicting the activation of clinically relevant pathways using in vivo measurements from PD patients undergoing subthalamic (STN) DBS surgery. Methods: In this study, we compared the accuracy of six computational modeling variations for predicting the activation of the corticospinal/bulbar tract (CSBT) and cortico-subthalamic hyperdirect pathway (HDP) using very short- (<2 ms) and short-latency (2-4 ms) cortical evoked potentials (cEPs). We constructed the variations using three key factors: modeling method (Driving Force [DF] vs. Volume of Tissue Activated [VTA]), imaging space (native vs. normative), and anatomical representation (pathway vs. structure). The model performances were quantified using the coefficient of determination (R2) between the cEP amplitudes and percent pathway or structure activation. Results: We compared model accuracy for 11 PD patients. The DF-Native-Pathway model was the most accurate method for quantitatively predicting experimental subcortical pathway activations. Additionally, our analysis showed that using normative brain space significantly diminished the accuracy of model predictions. Conclusion: The choice of methodology should depend on the specific application and the required level of precision for the intended analysis. However, model parameters should be optimized to accurately predict known experimental activation measures.

Purpose: We aim to develop a robust method to improve the estimation accuracy of motor-evoked potential (MEP) recruitment curves (RCs), including motor threshold, in small-sample settings which typically involve fewer than 40 stimuli. Methods: We present a hierarchical Bayesian (HB) method to model MEP size as a rectified-logistic function of stimulation intensity. This method is designed to account for small samples, handle outliers without discarding data, quantify estimation uncertainty, and simulate synthetic data that closely matches real observations, useful for optimizing experimental design. We validate its performance on transcranial magnetic stimulation (TMS), epidural spinal cord stimulation (SCS), and synthetic TMS datasets, and provide an open-source library for Python, called hbMEP, for diverse applications. Results: The rectified-logistic outperformed sigmoidal functions in predictive accuracy on TMS and SCS datasets, as demonstrated through cross-validation. A mixture extension of the HB model improved robustness to outliers by further increasing its predictive accuracy. The HB model reduced threshold estimation error by up to 70% on sparse synthetic TMS data compared to non-hierarchical models. Bayesian estimation with the HB model reduced the required number of participants by at least 23% to detect a shift in threshold with 80% power, compared to frequentist testing. Empirical results on human SCS data further validated its applicability to real data. Conclusion: By improving accuracy on sparse data, our method minimizes the number of stimuli needed to probe each individual's neuromuscular parameters across multiple muscles simultaneously, thereby reducing session duration and the risk of inadvertent neuromodulation. Our approach provides a more statistically powerful and conclusive framework for inferring changes in threshold, and therefore corticospinal excitability. The hbMEP library streamlines and unifies the analysis of RCs across stimulation modalities and experimental paradigms.

Introduction Bilateral cochlear implants (BiCIs) do not restore sound localization abilities to the full extent exhibited by typical hearing (TH) listeners, partly due to poor encoding of interaural time differences (ITDs). ITD cues have been provided and investigated using synchronized research processors that ensure the precise delivery of ITD cues. These studies have been conducted in a direct stimulation setting, which bypasses the processor microphones and, in most cases, removes interaural level difference cues (ILDs). To our knowledge, this is the first study that evaluated the efficacy of synchronized stimulation in restoring sensitivity to ITDs in a free field localization experiment. This was made possible by the CCi-MOBILE, a portable and real-time processing research platform that allows for synchronizing microphone inputs. Methods Fourteen BiCI listeners were tested with experimental real-time coding strategies in comparison to unsynchronized clinical processors. We calculated the binaural cues from the acoustic stimuli at the level of microphone input. Results The recordings show that the experimental coding strategies in this study deliver ITDs with greater precision than the clinical strategy. However, psychophysical testing did not show the benefit of an ITD-encoding strategy in improving localization in a free field. The ITD encoding strategies preserved ITDs, which better differentiated unique loudspeaker locations than interaural level differences (ILDs), suggesting that listeners could achieve improved performance if they accessed these cues. As expected, ILDs were similar across all strategies, including the ITD encoding strategies. The lack of improvement in localization performance is likely because ILDs remained to be the dominant cue in acute localization testing, even when ITD cues were available. Discussion Providing BiCI listeners with adequate experiences with ITD cues may be necessary to shift their reliance from ILD dominance to a combined reliance on ILD and ITD cues in free-field conditions. The CCi-MOBILE could enable take-home practice with novel stimulation strategies for extended experiences and long-term evaluation in real-world listening environments.

Bioelectronic implants for neurostimulation aim to steer disordered neurophysiological processes back towards a healthy state. However, physiology is subject to biological rhythms, including the circadian rhythm and the sleep-wake cycle. These predictable rhythms affect disease symptomatology, biomarkers used in closed-loop therapies, and a physiological system’s expected response to stimulation. Therefore, therapeutic devices should incorporate feedforward elements to align algorithm parameters with predictable changes in physiological state, as a parallel of physiological rheostatic control. Here we introduce the DyNeuMo-2c, the first clinical-grade implant capable of delivering closed-loop neurostimulation while flexibly changing its functional configuration according to time of day. The device can chronically measure brain activity and motion state to track potential biomarker patterns in natural, out-of-clinic settings, allowing identification and targeting of patient-specific chronotypes. The system implements a hierarchical control flow, with baseline therapy set by a circadian scheduler, and adaptive policies layered to take effect based on specific biomarkers indicating patient and disease state. Using a benchtop validation setup, we demonstrate that the system has the required capabilities for delivering time-contingent closed-loop therapy in two established clinical use cases: Parkinson’s disease and epilepsy. Next, we deploy the system in vivo to deliver closed-loop deep brain stimulation in a healthy non-human primate model of vigilance, highlighting the importance of synchronisation between device operation and physiological state in various conditions (task performance, unconstrained behaviour, and sleep). Time-of-day-dependent adaptation of closed-loop stimulation enabled modulation of both vigilance and behaviour. Overall, the novel device architecture provides a proof-of-concept for delivering time-contingent therapy in chronic therapeutic settings where biological rhythms are of key importance.

Sympathetic hyperactivity is a common feature observed in both primary and secondary hypertension, and neuromodulation-based therapies targeting this overactivity are under active investigation. The intermediolateral nucleus (IML) in the spinal cord plays a central role in sympathetic regulation, and its direct stimulation induces a transient, frequency-dependent reduction in blood pressure. However, this effect gradually diminishes as the baroreflex restores blood pressure to baseline. Therefore, this study aims to develop a closed-loop (CL) stimulation system that adjusts parameters in real-time based on neural activity recorded from the IML and to enhance and prolong the transient antihypertensive effect. This strategy was evaluated in normotensive and angiotensin II-induced hypertensive rat models and compared to open-loop (OL) stimulation of equal intensity. In both models, CL stimulation produced a more sustained blood pressure reduction than that of OL stimulation. These findings suggest that CL spinal cord stimulation offers a more effective and durable therapeutic option for treating hypertension.

Most spinal cord injuries (SCI) spare descending and sublesional circuits that can be targeted through motor cortex and spinal cord stimulation to mitigate locomotor deficits. However, the potential synergy between cortical and spinal stimulation remains unknown. Here, we first investigated the phase-locked electrical stimulation of the motor cortex and lumbar spinal cord at 40 Hz in a rat model of unilateral SCI. Combining cortical and lumbar stimulation around the anticipated lift synergistically enhanced leg movements. When integrated into rehabilitation training, cortical stimulation proved essential for the recovery of skilled locomotion. We next investigated the effects of high-frequency (330 Hz) lumbar and sacral stimulation combined with cortical stimulation. Timely integration during the swing phase showed that cortical and lumbar stimulations enhance the initial and mid-swing phases, while sacral stimulation improves extension velocity in the late swing. These findings indicate that supraspinal and sublesional neuromodulation offer complementary neuroprosthetic effects in targeted SCI gait rehabilitation.

Although clinical and experimental evidence highlight the role of the thalamus in voluntary movement production, the involvement of the thalamus in complex motor tasks such as speech production remains to be elucidated. The present study examined neural activity within the bilateral thalamus in 13 participants (seven females) with essential tremor undergoing awake deep brain stimulation implantation surgery, using three speech tasks of varied complexity [vowel vocalization, a diadochokinetic task (DDK), and sentence repetition]. Low-frequency neural activity (delta/theta band) activity was significantly increased during sentence and DDK compared with vowel vocalization in the bilateral motor thalamus and, to a lesser extent, increased for sentence repetition compared with DDK. Moreover, there was prominent prespeech beta band activity, with a greater decrease in the power of beta activity for sentence compared with DDK and vowel vocalization. The greater low-frequency activity in more complex speech tasks may reflect the allocation of additional cognitive resources to monitor the execution of speech motor plans through cortico–thalamo–cortical pathways in a temporally precise manner. The greater decrease in the power of beta activity prior to the onset of sentence repetition may imply greater involvement of the bilateral thalamus in the planning of complex speech tasks. These findings provide new insights into the role of the bilateral thalamus in speech production and may have clinical implications for neurological disorders that affect speech production.

Introduction The posterior tail of the striatum receives dense inputs from sensory regions of cortex and thalamus, as well as midbrain dopaminergic innervation, providing a neural substrate for associative sensory learning. Previously, we have demonstrated that developmental hearing loss is associated with aberrant physiological states in striatal medium spiny neurons (MSNs). Methods Here we directly investigated auditory associative learning impairments in the striatum of adult Mongolian gerbils that underwent transient developmental hearing loss or sham hearing loss during the critical period of auditory development. We used electrophysiology to reveal significant changes to neuronal population responses in vivo and intrinsic and synaptic properties to medium spiny neurons in vitro as animals learned an appetitive “Go/No-Go” auditory discrimination task. For in vivo experiments a 64-channel electrode was implanted in the auditory region of the posterior tail of the striatum and neuronal recordings were carried out as animals learned the task. For in vitro experiments, corticostriatal slice preparations were made from animals on each day of training. Results In naïve animals from both groups there was limited to no phase locking to either auditory stimulus in vivo , and long term depression resulted from theta burst stimulation in vitro . Furthermore, intrinsic and synaptic properties in normal hearing animals were unaffected; however, the hearing loss group continued to show lowered synaptic inhibition, synaptic hyperexcitation, and suppressed intrinsic excitability in the hearing loss group. Starting around day 3–4 in both groups, the emergence of striatal medium spiny neuron phase locking to the auditory conditioning stimuli was observed in vivo . This occurred contemporaneous to an increased probability of theta burst induced LTP during MSN whole cell recording in vitro , and acquisition of the task as the correct rejection response significantly increased in the behaving animals. During the acquisition phase MSNs in the normal hearing group showed a significant decrease in synaptic inhibition and increase in synaptic excitation with no change to intrinsic excitability, while the MSNs in the hearing loss group showed a significant increase in synaptic inhibition, reduction of synaptic hyper excitability, and compensatory changes to intrinsic excitability that supported normal action potential generation. In both groups, synaptic properties were resolved to similar level of E/I balance that could be part of a conserved learning state. Discussion These changes to the intrinsic and synaptic properties likely support LTP induction in vivo and the strengthening of synapses between auditory inputs and MSNs that facilitate neuronal phase locking. These findings have significant implications for our understanding of striatal resilience to sensory impairments in early life, in addition to establishing a granular understanding of the striatal circuit changes that support reward driven stimulus–response learning.

Deep Brain Stimulation (DBS) of the superolateral medial forebrain bundle has shown promising long-term anti-depressant effects in treatment-resistant depression patients, although the mechanisms are not clear. The study explored medial forebrain bundle DBS mediated modulation of central noradrenaline transmission in a rodent depression model, the Flinders Sensitive Line (FSL), and in controls, Sprague Dawley (SD) rats. In vivo noradrenergic signaling in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and ultrasonic vocalization were monitored during unilateral mfb-DBS across diverse stimulation parameters. The fiber amount, myelination status, and the activation of ascending projected noradrenergic cell groups (A1, A2, A6) were quantified. Moreover, stimulation induced changes in the parvalbumin-mediated feedforward microcircuitry and neuron activation at PFC and NAc were assessed. FSL rats showed decrease in NA fibers in mfb. Stimulation increased PFC noradrenergic signaling similarly across both groups compared to baseline, but in the NAc, the FSLs had notably higher signaling compared with SDs. FSLs demonstrated more positive affective ultrasonic vocalizations post-DBS than SDs. Brainstem nuclei A1 and A2 had similar noradrenergic neuron density across the experimental groups, and mfb DBS increased neuronal activation in both groups. FSLs had fewer noradrenergic neurons in the A6 nuclei, fewer unmyelinated noradrenergic fibers traversing the mfb, and decreased parvalbumin interneuron activity in both PFC and NAc. DBS normalized parvalbumin interneuron activity in the FSL rats. The study proposes that mfb DBS, via the modulation of the central NA system and the GABAergic inhibitory control of neural excitability, likely contributes to the anti-depressant therapeutic mechanisms reported in both clinical and experimental studies.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established treatment for dystonia, yet the neurophysiological mechanisms underlying frequency-dependent effects remain poorly understood. In this study, we investigate how different GPi-DBS frequencies modulate evoked potential (EP) characteristics within the basal ganglia-thalamo-cortical network in pediatric dystonia patients. We evaluated how increasing stimulation frequency alters EP morphology, focusing on peak-to-peak amplitude (PPa), peak-to-peak duration (PPd), and time to peak (TP). This analysis was motivated by clinical observations that higher DBS frequencies often produce distinct therapeutic effects, suggesting underlying differences in how neural circuits respond to varying stimulation rates. We analyzed intracranial electrophysiological recordings from 13 pediatric and young adult dystonia patients undergoing staged DBS implantation. EPs were recorded from the GPi and subthalamic nucleus (STN) of basal ganglia, and ventral oralis (VO) nucleus of the thalamus during unilateral GPi stimulation at 55, 85, 185, and 250 Hz. EP detection and characterization were performed using an automated algorithm, and group-level analyses were conducted using linear mixed effects models to assess frequency-dependent changes across regions. Increasing stimulation frequency significantly decreased PPa and increased PPd and TP, with a clear threshold effect: 55 Hz and 85 Hz produced similar responses, while 185 Hz and 250 Hz elicited significantly greater changes. These frequency-dependent effects were most pronounced in GPi recordings, followed by STN and VO, suggesting that local circuit dynamics are more sensitive to frequency modulation. Our findings highlight the distinct neurophysiological effects of DBS frequency on EP characteristics, emphasizing the need for personalized DBS programming. The pronounced frequency-dependent modulation observed in GPi suggests that optimal stimulation parameters should be tailored to the target region rather than applying uniform settings across patients. Future studies should investigate the clinical relevance of these EP dynamics and explore their potential as biomarkers for DBS optimization in dystonia.

We developed an extended reciprocity theorem approach to model neuron signals which handles heterogeneous dielectric environments and arbitrary electrode shapes, and use it to study analytically the single fiber action potential. We then established a semi-analytic model that also uses hybrid electromagnetic-electrophysiological simulations to model evoked compound action potential (eCAP) signals from multi-fascicular nerves populated with heterogeneous fiber populations. For validation, model predictions were compared with cuff electrode recordings of activity induced by vagus nerve stimulation in in vivo porcine experiments. The semi-analytic model produces signals that approximate the shape and amplitude of in vivo measurements. It can account for the important variation in the recorded eCAP due to changes in the shape and placement of the stimulus and recording electrodes. We find that partially activated fascicles contribute particularly to the signal, as eCAP contributions from smoothly varying fiber calibers in fully activated ones partially cancel. As a result, eCAP magnitude does not depend monotonically on the stimulation current and recruitment level. Our method can be used to rapidly assess new stimulation and recording setups involving complex nerves and neurovascular bundles, e.g., to maximize signal information content, for closed-loop control in bioelectronic medicine applications, and potentially to non-destructively reconstruct structural and functional nerve topologies through inverse problem solving. In a proof-of-concept study, we demonstrate that parameter optimization can recover the ground-truth distribution of fiber diameters in a simplifed variant of our model.

Target engagement determines therapeutic efficacy. In spinal cord stimulation (SCS), efficacy depends on the attributes of the electrodes used to deliver stimulation, particularly their position, interelectrode distance, size, and current orientation. We tested the effects of these electrode parameters using cervical stimulation to elicit forelimb muscle responses in the rat. We implanted devices over the C6 dorsal root entry zone (DREZ) in eight rats and measured responses in six forelimb muscles. We used custom designed electrode arrays to systematically vary position, distance, and size with linear arrays, and current orientation with circular arrays. Stimulation consisted of biphasic and pseudomonophasic pulse shapes with bipolar or distant return, and a high-definition montage with four returns surrounding a central contact to increase local current density. Efficacy was calculated from the motor thresholds of recruitment curves, and parameters were compared using linear mixed models. For position, stimulation over the DREZ was most effective, reducing thresholds by 25.9% ( p = 0.0002) relative to the midline; efficacy decreased as the electrode was positioned medial or lateral to the DREZ. For distance, placing the electrodes farther apart significantly improved efficacy ( p = 0.0022). For size, large electrodes increased SCS efficacy, reducing thresholds by 21.5% ( p = 0.0026) relative to small electrodes. After accounting for position and distance, current orientation did not affect SCS efficacy. Lastly, the high-definition montage decreased efficacy, increasing thresholds by 16.7% ( p = 0.003) relative to monopolar stimulation with a distant return. In conclusion, electrode position, distance, and size had the greatest effect on SCS efficacy, with the optimal parameters combining large electrodes at the DREZ position with a distant return. These results have the potential to lower the current needed to engage cervical spinal circuitry and to inform the design of SCS systems to improve dexterity in people with neurological injury or disease.

Purpose Present-day cochlear implants (CIs) can deliver usable speech reception in quiet surroundings. Most CI users, however, show impaired sensitivity to temporal fine structure, which hampers their use of pitch contours and spatial cues to segregate competing talkers. In previous short-term animal studies, we used intraneural (IN) electrodes to stimulate pathways originating from various cochlear turns. Neurons in the inferior colliculus synchronized to apical stimulation at higher rates than to stimulation of the middle-to-basal pathways that are stimulated primarily by today’s CIs. Here, we use non-invasive recordings to test the safety and efficacy of up to 6 months of IN implantation and stimulation in cats. Methods Deafened cats (ten female, two male) were implanted with IN and/or conventional CI electrodes. The IN electrodes were single activated-iridium shanks that targeted apical-turn fibers. Scalp recordings were made from sedated animals at 2–3-week intervals. Auditory brainstem responses to single electrical pulses (eABR) tracked sensitivity and growth of responses. Frequency following responses to electrical pulse trains (eFFR) assessed brainstem temporal transmission at varying pulse rates. Results Thresholds for eABR were lower for IN than for CI stimulation, dynamic ranges were wider, and (by inference) spread of activation was more restricted. The eFFR evaluated at latencies comparable to those of inferior-colliculus spikes synchronized at maximum pulse rates averaging > 360 pulses/s for IN compared to ~ 240 pulses/s for CI stimulation. The eABR thresholds and eFFR cutoff rates were stable out to 6 months after implantation. Conclusions The results demonstrate the safety and efficacy of chronic IN stimulation in an animal model. In a future clinical device, an IN electrode could augment cochlear-implant performance by enhancing temporal acuity, thereby improving speech reception amid competing sounds.

Gastrointestinal (GI) dysmotility and associated conditions affect over 20% of population, yet pharmacological, behavioural, and surgical interventions offer limited therapeutic efficacy. Targeted electrical stimulation addressing underlying neuromuscular pathology stands to transform our ability to treat dysmotility. Here, we developed a closed-loop GI neuroprosthesis which activates or relaxes GI tract musculature through electrochemical stimulation in response to sensed food stimuli. We additionally describe a tool supporting minimally invasive endoscopically guided implantation that can penetrate the mucosa, accurately localize the submucosa, and safely deploy this device to directly interface with the enteric nervous system. The neuroprosthesis enables generation of coordinated peristaltic waves, significantly increasing the motility rate in a swine model of oesophageal and stomach dysmotility (p < 0.05, student's t-test). Further, by directly modulating the myenteric plexus and thus mimicking meal ingestion, we induce peristalsis in a fasted state and achieve a metabolic response commensurate with a fed or satiated state. This neuroprosthesis and implantation platform expand opportunities in fundamental studies and treatments of metabolic and neuromuscular pathologies affecting the GI tract.

Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.