Publications using TDT

Intracortical microelectrodes (IMEs) can be used to restore motor and sensory function as a part of brain–computer interfaces in individuals with neuromusculoskeletal disorders. However, the neuroinflammatory response to IMEs can result in their premature failure, leading to reduced therapeutic efficacy. Mechanically-adaptive, resveratrol-eluting (MARE) neural probes target two mechanisms believed to contribute to the neuroinflammatory response by reducing the mechanical mismatch between the brain tissue and device, as well as locally delivering an antioxidant therapeutic. To create the mechanically-adaptive substrate, a dispersion, casting, and evaporation method is used, followed by a microfabrication process to integrate functional recording electrodes on the material. Resveratrol release experiments were completed to generate a resveratrol release profile and demonstrated that the MARE probes are capable of long-term controlled release. Additionally, our results showed that resveratrol can be degraded by laser-micromachining, an important consideration for future device fabrication. Finally, the electrodes were shown to have a suitable impedance for single-unit neural recording and could record single units in vivo .

Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1β and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n = 6) or smooth control (n = 6) probes, and their recording performance was evaluated over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated an increased impedance and noise floor compared to controls. However, the recording performances of the nanopatterned and smooth probes were similar, with active electrode yields for control probes and nanopatterned probes being approximately 50% and 45%, respectively, by 4 weeks post-implantation. Gene expression analysis showed one gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: this study provides a foundation for investigating novel nanoscale topographies on neural probes.

Compound nerve action potentials (CNAPs) were used as a metric to assess the stimulation performance of a novel high-density, transverse, intrafascicular electrode in rat models. We show characteristic CNAPs recorded from distally implanted cuff electrodes. Evaluation of the CNAPs as a function of stimulus current and calculation of recruitment plots were used to obtain a qualitative approximation of the neural interface’s placement and orientation inside the nerve. This method avoids elaborate surgeries required for the implantation of EMG electrodes and thus minimizes surgical complications and may accelerate the healing process of the implanted subject.

Neural representations of perceptual decision formation that are abstracted from specific motor requirements have previously been identified in humans using non-invasive electrophysiology; however, it is currently unclear where these originate in the brain. Here we capitalized on the high spatiotemporal precision of intracranial EEG to localize such abstract decision signals. Participants undergoing invasive electrophysiological monitoring for epilepsy were asked to judge the direction of random-dot stimuli and respond either with a speeded button press (N = 24), or vocally, after a randomized delay (N = 12). We found a widely distributed motor-independent network of regions where high-frequency activity exhibited key characteristics consistent with evidence accumulation, including a gradual buildup that was modulated by the strength of the sensory evidence, and an amplitude that predicted participants' choice accuracy and response time. Our findings offer a new view on the brain networks governing human decision-making.

Melody is a core component of music in which discrete pitches are serially arranged to convey emotion and meaning. Perception varies along several pitch-based dimensions: (i) the absolute pitch of notes, (ii) the difference in pitch between successive notes, and (iii) the statistical expectation of each note given prior context. How the brain represents these dimensions and whether their encoding is specialized for music remains unknown. We recorded high-density neurophysiological activity directly from the human auditory cortex while participants listened to Western musical phrases. Pitch, pitch-change, and expectation were selectively encoded at different cortical sites, indicating a spatial map for representing distinct melodic dimensions. The same participants listened to spoken English, and we compared responses to music and speech. Cortical sites selective for music encoded expectation, while sites that encoded pitch and pitch-change in music used the same neural code to represent equivalent properties of speech. Findings reveal how the perception of melody recruits both music-specific and general-purpose sound representations.

To treat neurological and psychiatric diseases with deep brain stimulation, a trained clinician must select parameters for each patient by monitoring their symptoms and side-effects in a months-long trial-and-error process, delaying optimal clinical outcomes. Bayesian optimization has been proposed as an efficient method to quickly and automatically search for optimal parameters. However, conventional Bayesian optimization does not account for patient safety and could trigger unwanted or dangerous side-effects. In this study we develop SAFE-OPT, a Bayesian optimization algorithm designed to learn subject-specific safety constraints to avoid potentially harmful stimulation settings during optimization. We prototype and validate SAFE-OPT using a rodent multielectrode stimulation paradigm which causes subject-specific performance deficits in a spatial memory task. We first use data from an initial cohort of subjects to build a simulation where we design the best SAFE-OPT configuration for safe and accurate searching in silico . We then deploy both SAFE-OPT and conventional Bayesian optimization in new subjects in vivo , showing that SAFE-OPT can find an optimally high stimulation amplitude that does not harm task performance with comparable sample efficiency to Bayesian optimization and without selecting amplitude values that exceed the subject’s safety threshold. The incorporation of safety constraints will provide a key step for adopting Bayesian optimization in real-world applications of deep brain stimulation.

Neural responses to sensory inputs can scale with the likelihood of encountering the input. This is consistent with the predictive coding framework, in that the human brain is expected to be less responsive to predicted inputs. Typically, however, prediction is not explicitly measured. It is inferred from the probability of encountering an event. When an input is explicitly predicted, responses to predicted inputs can be enhanced. Here, we ask if this effect can be ascribed to a generic priming effect, from pre-cogitating about one of two possible inputs. Consistent with this, we find that P300s (a relatively late event-related potential measured with electroencephalography) are greater for explicitly predicted audio and visual inputs, and that this effect cannot be distinguished from a priming effect from pre-imagining audio or visual presentations. Evidence indicates that participants engaged in pre-imagining presentations, as we were able to decode online what type of presentation (audio or visual) they were imagining with a high success rate (approx. 73%), and we encouraged compliance with neuro-feedback regarding this success rate. Our data confirm that human cortex can be more responsive to inputs that have been subject to pre-cogitation—including explicit predictions. This highlights that while anticipatory processes can reduce responding to likely inputs, they can also enhance responding to explicitly predicted inputs.

In order to investigate the involvement of the primary visual cortex (V1) in working memory (WM), parallel, multisite recordings of multi-unit activity were obtained from monkey V1 while the animals performed a delayed match-to-sample (DMS) task. During the delay period, V1 population firing rate vectors maintained a lingering trace of the sample stimulus that could be reactivated by intervening impulse stimuli that enhanced neuronal firing. This fading trace of the sample did not require active engagement of the monkeys in the DMS task and likely reflects the intrinsic dynamics of recurrent cortical networks in lower visual areas. This renders an active, attention-dependent involvement of V1 in the maintenance of WM contents unlikely. By contrast, population responses to the test stimulus depended on the probabilistic contingencies between sample and test stimuli. Responses to tests that matched expectations were reduced which agrees with concepts of predictive coding.

Background Cuff electrodes target various nerves throughout the body, providing neuromodulation therapies for motor, sensory, or autonomic disorders. However, when using standard, thick silicone cuffs, fabricated in discrete circular sizes, complications may arise, namely cuff displacement or nerve compression, due to a poor adaptability to variable nerve shapes and sizes encountered in vivo. Improvements in cuff design, materials, closing mechanism and surgical approach are necessary to overcome these issues. Methods In this work, we propose a microfabricated multi-channel silicone-based soft cuff electrode with a novel easy-to-implant and size-adaptable design and evaluate a number of essential features such as nerve-cuff contact, nerve compression, cuff locking stability, long-term integration and stimulation selectivity. We also compared performance to that of standard fixed-size cuffs. Results The belt-like cuff made of 150 μm thick silicone membranes provides a stable and pressure-free conformal contact, independently of nerve size variability, combined with a straightforward implantation procedure. The adaptable design and use of soft materials lead to limited scarring and demyelination after 6-week implantation. In addition, multi-contact designs, ranging from 6 to 16 electrodes, allow for selective stimulation in models of rat and pig sciatic nerve, achieving targeted activation of up to 5 hindlimb muscles. Conclusion These results suggest a promising alternative to classic fixed-diameter cuffs and may facilitate the adoption of soft, adaptable cuffs in clinical settings.

Social behaviors often consist of a motivational phase followed by action. Here we show that neurons in the ventromedial hypothalamus ventrolateral area (VMHvl) of mice encode the temporal sequence of aggressive motivation to action. The VMHvl receives local inhibitory input (VMHvl shell) and long-range input from the medial preoptic area (MPO) with functional coupling to neurons with specific temporal profiles. Encoding models reveal that during aggression, VMHvl shellvgat+ activity peaks at the start of an attack, whereas activity from the MPO-VMHvlvgat+ input peaks at specific interaction endpoints. Activation of the MPO-VMHvlvgat+ input promotes and prolongs a low motivation state, whereas activation of VMHvl shellvgat+ results in action-related deficits, acutely terminating attack. Moreover, stimulation of MPO-VMHvlvgat+ input is positively valenced and anxiolytic. Together, these data demonstrate how distinct inhibitory inputs to the hypothalamus can independently gate the motivational and action phases of aggression through a single locus of control.

The basal ganglia are essential for executing motor actions. How the basal ganglia engage spinal motor networks has remained elusive. Medullary Chx10 gigantocellular (Gi) neurons are required for turning gait programs, suggesting that turning gaits organized by the basal ganglia are executed via this descending pathway. Performing deep brainstem recordings of Chx10 Gi Ca 2+ activity in adult mice, we show that striatal projection neurons initiate turning gaits via a dominant crossed pathway to Chx10 Gi neurons on the contralateral side. Using intersectional viral tracing and cell-type-specific modulation, we uncover the principal basal ganglia–spinal cord pathway for locomotor asymmetries in mice: basal ganglia → pontine reticular nucleus, oral part (PnO) → Chx10 Gi → spinal cord. Modulating the restricted PnO → Chx10 Gi pathway restores turning competence upon striatal damage, suggesting that dysfunction of this pathway may contribute to debilitating turning deficits observed in Parkinson’s disease. Our results reveal the stratified circuit architecture underlying a critical motor program.

Background The avoidance of aversive stimuli due to negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITC d ) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making. Methods We investigated the impact of ITC d function on negative reinforcement and extinction by applying fiber photometry measurement of GCamp6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of OCD-like behavior: the Sapap3 -null mouse. Results We find impaired neural activity in the ITC d of male and female Sapap3 -null mice to the encoding of negative stimuli during platform-mediated avoidance. Sapap3 -null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITC d neural activity. Conclusions Sapap3 -null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITC d activity. This deficit can be rescued by optogenetically inhibiting ITC d during extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITC d in responding to negative stimuli in complex environments.

The cortex integrates sound- and movement-related signals to predict the acoustic consequences of behavior and detect violations from expectations. Although expectation- and prediction-related activity has been observed in the auditory cortex of humans, monkeys, and mice during vocal and non-vocal acoustic behaviors, the specific cortical circuitry required for forming memories, recalling expectations, and making predictions remains unknown. By combining closed-loop behavior, electrophysiological recordings, longitudinal pharmacology, and targeted optogenetic circuit activation, we identify a cortical locus for the emergence of expectation and error signals. Movement-related expectation signals and sound-related error signals emerge in parallel in the auditory cortex and are concentrated in largely distinct neurons, consistent with a compartmentalization of different prediction-related computations. On a trial-by-trial basis, expectation and error signals are correlated in auditory cortex, consistent with a local circuit implementation of an internal model. Silencing the auditory cortex during motor-sensory learning prevents the emergence of expectation signals and error signals, revealing the auditory cortex as a necessary node for learning to make predictions. Prediction-like signals can be experimentally induced in the auditory cortex, even in the absence of behavioral experience, by pairing optogenetic motor cortical activation with sound playback, indicating that cortical circuits are sufficient for movement-like predictive processing. Finally, motor-sensory experience realigns the manifold dimensions in which auditory cortical populations encode movement and sound, consistent with predictive processing. These findings show that prediction-related signals reshape auditory cortex dynamics during behavior and reveal a cortical locus for the emergence of expectation and error.

Self-control is the capacity to inhibit self-defeating behavior in the face of temptation. The neural basis of self-control remains elusive, due to the difficulty of disentangling self-control from value-based economic choice. To overcome this problem, we designed a novel task for monkeys that allows to identify states of high and low self-control. We found that neurons in the Supplementary Eye Field encode self-control and predict whether and when monkeys give in to temptation. This neuronal activity was present early in the trial, even preceding presentation of choice options. Our findings suggest that Supplementary Eye Field is part of a neuronal circuit exerting proactive self-control, which is crucial for selecting and maintaining the pursuit of costly goals that are beneficial in the long run. One-Sentence Summary Supplementary eye field encodes proactive self-control signals independent from cost-benefit estimation.

The stria vascularis (SV) is a stratified epithelium in the lateral wall of the mammalian cochlea, responsible for both endolymphatic ion homeostasis and generation of the endocochlear potential (EP) critical for normal hearing. The SV has three layers consisting predominantly of basal, intermediate, and marginal cells. Intermediate and marginal cells form an intricate interdigitated network of cell projections making discrimination of the cells challenging. To enable intermediate cell visualization, we engineered by BAC transgenesis, reporter mouse lines expressing ZsGreen fluorescent protein under the control of Kcnj10 promoter and regulatory sequences. Kcnj10 encodes KCNJ10 protein (also known as Kir4.1 or Kir1.2), an ATP-sensitive inwardly-rectifying potassium channel critical to EP generation, highly expressed in SV intermediate cells. In these transgenic mice, ZsGreen fluorescence mimics Kcnj10 endogenous expression in the cochlea and was detected in the intermediate cells of the SV, in the inner phalangeal cells, Hensen’s, Deiters’ and pillar cells, in a subset of spiral ganglion neurons, and in glial cells. We show that expression of the transgene in hemizygous mice does not alter auditory function, nor EP. These transgenic Tg( Kcnj10 -ZsGreen) mice allow live and fixed tissue visualization of ZsGreen-expressing intermediate cells and will facilitate future studies of stria vascularis cell function.

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstem responses. These positive results motivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients.

The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations and increases DA transporter (DAT) activity and trafficking to the membrane. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6 mice. First, we established that the rise and fall of spontaneous DA signals were due to DA release and reuptake, respectively. Then mice were systemically administered the KOR agonist U50,488H (U50), with or without pretreatment with the KOR antagonist aticaprant (ATIC). U50 reduced both the amplitude and width of spontaneous signals in males, but only reduced width in females. Further, the slope of the correlation between amplitude and width was increased in both sexes, suggesting that DA uptake rates were increased. U50 also reduced the frequency of signals in both males and females. All effects of KOR activation were stronger in males. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DAT-mediated uptake, and reducing the frequency of signals.

Cochlear Implants (CI) are an effective neuroprosthesis for humans with profound hearing loss, enabling deaf adults to have phone calls without lipreading and babies to have successful language development. However, CIs have significant limitations in complex hearing situations, motivating the need for further research, including studies in animal models. Here, we demonstrate the usefulness of wide field Ca++ imaging in assessing different CI stimulation strategies. One major challenge in electrophysiology in CI animals lies in excluding the CI electric artifacts from the recording, since they are orders of magnitude larger than the amplitude of action potentials. Also, electrophysiology can rarely sample large areas of neuropil at high spatial resolution. To circumvent these problems, we have set up an imaging system allowing us to monitor neural activity in the auditory cortex (AC) of CI supplied rats using the Ca++ sensitive dye OGB. Here we describe an initial experiment with this setup, in which we recorded cortical responses to 4 different stimulation patterns which were delivered across 3 CI channels to the contralateral ear. We then investigated two parameters that have been shown to affect intelligibility in CI users: pulse rate and relative pulse timing across CI channels. While pulse rate had only a very modest effect on the discriminability of the neural responses, the stimulation mode had a major effect, with simultaneous pulse timing, perhaps surprisingly, allowing much better pattern discrimination than interleaved sampling. The result suggests that allowing collisions of pulses on neighboring channels may not always be detrimental, at least if partial overlaps of pulses, in which anodic and cathodic pulse phases might cancel, are avoided.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.