Biology subjects

Borton, D. A.

Publications and source records attributed to Borton, D. A..

14 recordsLinked to original sources

bioRxiv2026

A modular, high-bandwidth, bidirectional implantable device for neural interrogation

Modern neuroelectronic interfaces have shown great potential to diagnose conditions, address neurological dysfunction, and advance neuroscientific knowledge. However, neural interface systems today require tethered connections that restrict mobility, prevent testing across ecological contexts, and inhibit clinical translation to at-home use. Fully implantable commercial systems have previously been developed, but exhibit significant constraints, including a bulky design, limited modularity, low bandwidth, or unidirectional communication (e.g. deep brain stimulation systems, DBS; spinal cord stimulation systems, SCS). Here, we have developed the Modular Bionic Interface (MBI), a system composed of a fully implantable device and a worn unit for high-bandwidth, bidirectional interfacing with the nervous system. The MBI can record high fidelity electrophysiological signals and deliver spatiotemporally modulated electrical stimulation for clinical and research purposes through flexible interaction with third party implantable devices. We performed benchtop evaluation to validate the recording and stimulation capabilities of the MBI across a diverse range of inputs and outputs. We then evaluated the MBI system in vivo through chronic implantation within a sheep, where results were stable for the length of evaluation, over three months. While connected to an actively powered, third-party high-resolution spinal cord stimulation electrode array, the MBI system was able to deliver stimulation to evoke lower extremity motor responses and record spinal compound action potentials evoked by peripheral nerve and spinal stimulation. Through rigorous evaluation, we demonstrate a fully implantable system with a small footprint capable of high-resolution, bi-directional communication with the nervous system via modular connections to third-party devices. We expect that modular devices will further our ability to treat complex neurological disease and injury.

neuroscience↗

bioRxiv2024

An active electronic bidirectional interface for high resolution interrogation of the spinal cord

ObjectiveEpidural electrical stimulation (EES) has shown promise as both a clinical therapy and research tool for studying nervous system function. However, available clinical EES paddles are limited to using a small number of contacts due to the burden of wires necessary to connect each contact to the therapeutic delivery device, limiting the treatment area or density of epidural electrode arrays. We aimed to eliminate this burden using advanced on-paddle electronics. ApproachWe developed a smart EES paddle with a 60-electrode programmable array, addressable using an active electronic multiplexer embedded within the electrode paddle body. The electronics are sealed in novel, ultra-low profile hermetic packaging. We conducted extensive reliability testing on the novel array, including a battery of ISO 10993-1 biocompatibility tests and determination of the hermetic package leak rate. We then evaluated the EES device in vivo, placed on the epidural surface of the ovine lumbosacral spinal cord for 15 months. Main resultsThe active paddle array performed nominally when implanted in sheep for over 15 months and no device-related malfunctions were observed. The onboard multiplexer enabled bespoke electrode arrangements across, and within, experimental sessions. We identified stereotyped responses to stimulation in lower extremity musculature, and examined local field potential responses to EES using high-density recording bipoles. Finally, spatial electrode encoding enabled machine learning models to accurately perform EES parameter inference for unseen stimulation electrodes, reducing the need for extensive training data in future deep models. SignificanceWe report the development and chronic large animal in vivo evaluation of a high-density EES paddle array containing active electronics. Our results provide a foundation for more advanced computation and processing to be integrated directly into devices implanted at the neural interface, opening new avenues for the study of nervous system function and new therapies to treat neural injury and dysfunction.

bioengineering↗

bioRxiv2023

Towards a Brighter Constellation: Multi-Organ Neuroimaging of Neural and Vascular Dynamics in the Spinal Cord and Brain

SignificancePain is comprised of a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. AimHere, we aimed to develop and validate new tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations were targeted to developing novel imaging hardware that addresses the many challenges of multi-site imaging. The second key set of innovations were targeted to enabling bioluminescent imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity and decreased resolution due to scattering of excitation signals. ApproachWe designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one-or two-photon microscopy or optogenetic stimulation). We also tested the viability for bioluminescent imaging, and developed a novel modified miniscope optimized for these signals (BLmini). ResultsHere, we describe novel universal implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of bioluminescent signals in both foci, and a new miniscope, the BLmini, which has reduced weight, cost and form-factor relative to standard wearable miniscopes. ConclusionsThe combination of 3D printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a new coalition of methods for understanding spinal cord-brain interactions. This work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

bioengineering↗

bioRxiv2023

Transient gamma events delineate somatosensory modality in S1

Gamma band activity localized to the primary somatosensory cortex (S1) in humans and animals is implicated in the higher order neural processing of painful and tactile stimuli. However, it is unclear if gamma band activity differs between these distinct somatosensory modalities. Here, we coupled a novel behavioral approach with chronic extracellular electrophysiology to investigate differences in S1 gamma band activity elicited by noxious and innocuous hind paw stimulation in transgenic mice. Like prior studies, we found that trial-averaged gamma power in S1 increased following both noxious and innocuous stimuli. However, on individual trials, we noticed that evoked gamma band activity was not a continuous oscillatory signal but a series of transient spectral events. Upon further analysis we found that there was a significantly higher incidence of these gamma band events following noxious stimulation than innocuous stimulation. These findings suggest that somatosensory stimuli may be represented by specific features of gamma band activity at the single trial level, which may provide insight to mechanisms underlying acute pain.

neuroscience↗

bioRxiv2022

Frontotemporal network engagement by human intracranial stimulation in limbic hubs

BackgroundPrefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. MethodsHere, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). ResultsWe demonstrate a shared frontotemporal circuit consisting of the ventromedial PFC, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found subject-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. ConclusionsOur findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS DBS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

neuroscience↗

bioRxiv2022

Estimation of Periodic Signals with Applications to Deep Brain Stimulation

Deep brain stimulation (DBS) therapies have shown clinical success in the treatment of a number of neurological illnesses, including obsessive-compulsive disorder, depression, and Parkinsons disease. An emerging strategy for increasing the efficacy of DBS therapies is to develop closed-loop, adaptive DBS systems that can sense biomarkers associated with particular symptoms and in response, adjust DBS parameters in realtime. The development of such systems requires extensive analysis of the underlying neural signals while DBS is on, so that candidate biomarkers can be identified and the effects of varying the DBS parameters can be better understood. However, DBS creates high amplitude, high frequency stimulation artifacts that prevent the underlying neural signals and thus the biological mechanisms underlying DBS from being analyzed. Additionally, DBS devices often require low sampling rates, which alias the artifact frequency, and rely on wireless data transmission methods that can create signal recordings with missing data of unknown length. Thus, traditional artifact removal methods cannot be applied to this setting. We present a novel periodic artifact removal algorithm for DBS applications that can accurately remove stimulation artifacts in the presence of missing data and in some cases where the stimulation frequency exceeds the Nyquist frequency. The numerical examples suggest that, if implemented on dedicated hardware, this algorithm has the potential to be used in embedded closed-loop DBS therapies to remove DBS stimulation artifacts and hence, to aid in the discovery of candidate biomarkers in real-time. Code for our proposed algorithm is publicly available on Github.

neuroscience↗

bioRxiv2022

Emergence of distinct neural subspaces in motor cortical dynamics during volitional adjustments of ongoing locomotion

3The brain is capable of simultaneously carrying out multiple functions, such as making different types of movements at the same time. One example is how we are able to both carry out stereotyped walking or running movements, while concurrently performing precise, target-directed movements such as kicking a ball in a soccer match. Recently, research has shown that different computations within the same population of neurons can be carried out without disrupting each other by confining the processes into separate subspaces. Whether this strategy is used to precisely control our limbs while maintaining locomotion is still an open question. Here, we recorded the activity of primary motor cortex in nonhuman primates during obstacle avoidance on a treadmill. We found that the same neural population was active during both basic unobstructed locomotion and volitional obstacle avoidance movements. Additionally, we identified the neural modes spanning the subspace of the low-dimensional dynamics in M1 using both supervised and unsupervised techniques. We found that motor cortex employs a subspace that consistently maintains the same cyclic activity throughout obstacle stepping, despite large changes in the movement itself. All the variance corresponding to the large change in movement during the obstacle avoidance is confined to its own distinct subspace. Our findings suggest that M1 utilizes different activity subspaces to coordinate the maintenance of ongoing locomotor-related neural dynamics and fast volitional gait adjustments during complex locomotion. 4 Significance StatementOur ability to modulate our ongoing walking gait with precise, voluntary adjustments is what allows us to navigate complex terrains. Locomotion and precise, goal-directed movements, such as reaching are two distinct movement modalities and have been shown to have differing requirements of motor cortical input. It is unknown how these two movements are represented in M1 low dimensional dynamics when both are carried out at the same time, such as during obstacle avoidance. We developed a novel obstacle avoidance paradigm in freely-moving non-human primates and discovered that the strategy employed by motor cortex is to confine the rhythmic locomotion-related dynamics and the voluntary, gait-adjustment movement into separate subspaces.

neuroscience↗

bioRxiv2022

PELP: accounting for missing data in neural time series by Periodic Estimation of Lost Packets

ObjectiveImplanted electrical stimulators with sensing capabilities have enabled the development of closed-loop neuromodulation therapies capable of responding to patient needs in real-time. Through a combination of rechargeable technologies and wireless data transmission, it is now possible for researchers to acquire extensive neural recordings from human participants in naturalistic settings using these bidirectional devices. However, data losses during wireless transmission hamper processing and the identification of neural signals of interest, driving the need for methodologies to properly estimate the impact of data loss. ApproachTo accurately reconstruct the timing of data containing losses, we have developed a method called Periodic Estimation of Lost Packets (PELP) to precisely determine the number of samples lost from implanted recordings during active stimulation. PELP leverages a data-driven procedure for determining the period of stimulation and the knowledge that stimulation continues identically during periods where data are missing to accurately account for the number of samples lost. Main resultsUsing simulated stimulation added to collected human EEG data, we show that PELP is robust to a range of stimulation waveforms and noise characteristics. Lastly, we successfully applied PELP to local field potential (LFP) recordings from an implanted, bidirectional device using data recorded in the clinic and the patients own home. SignificanceBy effectively accounting for the timing of missing data, PELP enables the analysis of complex, naturalistic neural time series data from bidirectional implanted devices aiding in the development of novel therapeutic approaches. NCT04806516 (ClinicalTrials.gov).

neuroscience↗

bioRxiv2021

Three-dimensional in vitro model of the device-tissue interface reveals innate neuroinflammation can be mitigated by antioxidant ceria nanoparticles

The recording instability of neural implants due to neuroinflammation at the device-tissue interface (DTI) is a primary roadblock to broad adoption of brain-machine interfaces. While a multiphasic immune response, marked by glial scaring, oxidative stress (OS), and neurodegeneration, is well-characterized, the independent contributions of systemic and local "innate" immune responses are not well-understood. Three-dimensional primary neural cultures provide a unique environment for studying the drivers of neuroinflammation by decoupling the innate and systemic immune systems, while conserving an endogenous extracellular matrix and structural and functional network complexity. We created a three-dimensional in vitro model of the DTI by seeding primary cortical cells around microwires. Live imaging of microtissues over time revealed independent innate neuroinflammation, marked by increased OS, decreased neuronal density, and increased functional connectivity. We demonstrated the use of this model for therapeutic screening by directly applying drugs to neural tissue, bypassing low bioavailability through the in vivo blood brain barrier. As there is growing interest in long-acting antioxidant therapies, we tested efficacy of "perpetual" antioxidant ceria nanoparticles, which reduced OS, increased neuronal density, and protected functional connectivity. Overall, our avascular in vitro model of the DTI exhibited symptoms of OS-mediated innate neuroinflammation which were mitigated by antioxidant intervention.

bioengineering↗

bioRxiv2021

Distinct neocortical mechanisms underlie human SI responses to median nerve and laser evoked peripheral activation

Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically-relevant tools that have long been used to measure electromagnetic fields in somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at [~]20 ms post-stimulus (i.e., MN N1) corresponds to outward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by inward-directed current at [~]30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at [~]170 ms (i.e., LE N1) and is oriented inward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at [~]30 ms is an essential mechanism contributing to the inward current flow of the MN P1. Model results further predicted that the initial [~]170 ms inward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency ([~]40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.

neuroscience↗

bioRxiv2021

Lipopolysaccharide-induced neuroinflammation disrupts functional connectivity and community structure in primary cortical microtissues

Three-dimensional (3D) neural microtissues are a powerful in vitro paradigm for studying brain development and disease under controlled conditions, while maintaining many key attributes of the in vivo environment. Here, we used primary cortical microtissues to study the effects of neuroinflammation on neural microcircuits. We demonstrated the use of a genetically encoded calcium indicator combined with a novel live-imaging platform to record spontaneous calcium transients in microtissues from day 14-34 in vitro. We implemented graph theory analysis of calcium activity to characterize underlying functional connectivity and community structure of microcircuits, which are capable of capturing subtle changes in network dynamics during early diseases states. We found that microtissues cultured for 34 days displayed functional remodeling of microcircuits and that community structure strengthened over time. Lipopolysaccharide, a neuroinflammatory agent, significantly increased functional connectivity and disrupted community structure 5-9 days after exposure. These microcircuit-level changes have broad implications for the role of neuroinflammation in functional dysregulation of neural networks.

neuroscience↗

bioRxiv2021

How do packet losses affect measures of averaged neural signals?

Recent advances in implanted device development have enabled chronic streaming of neural data to external devices allowing for long timescale, naturalistic recordings. However, characteristic data losses occur during wireless transmission. Estimates for the duration of these losses are typically uncertain reducing signal quality and impeding analyses. To characterize the effect of these losses on recovery of averaged neural signals, we simulated neural time series data for a typical event-related potential (ERP) experiment. We investigated how the signal duration and the degree of timing uncertainty affected the offset of the ERP, its duration in time, its amplitude, and the ability to resolve small differences corresponding to different task conditions. Simulations showed that long timescale signals were generally robust to the effects of packet losses apart from timing offsets while short timescale signals were significantly delocalized and attenuated. These results provide clarity on the types of signals that can be resolved using these datasets and provide clarity on the restrictions imposed by data losses on typical analyses.

bioengineering↗

bioRxiv2020

Uncovering biomarkers during therapeutic neuromodulation with PARRM: Period-based Artifact Reconstruction and Removal Method

Advances in device development have enabled concurrent stimulation and recording at adjacent locations in the central nervous system. However, stimulation artifacts obscure the sensed underlying neural activity. Here, we developed a novel method, termed Period-based Artifact Reconstruction and Removal Method (PARRM), to remove stimulation artifacts from neural recordings by leveraging the exact period of stimulation to construct and subtract a high-fidelity template of the artifact. Benchtop saline experiments, computational simulations, five unique in vivo paradigms across animal and human studies, and an obscured movement biomarker were used for validation. Performance was found to exceed that of state-of-the-art filters in recovering complex signals without introducing contamination. PARRM has several advantages: it is 1) superior in signal recovery; 2) easily adaptable to several neurostimulation paradigms; and 3) low-complexity for future on-device implementation. Real-time artifact removal via PARRM will enable unbiased exploration and detection of neural biomarkers to enhance efficacy of closed-loop therapies. SummaryOnline, real-time artifact removal via PARRM will enable unbiased exploration of neural biomarkers previously obscured by stimulation artifact.

neuroscience↗

bioRxiv2019

Automated and rapid self-report of nociception in transgenic mice.

A time-resolved, conscious report of detected nociceptive stimuli in mice offers an opportunity to examine the relationship between higher order neural circuits and pain perception. We have developed a detection behavior in transgenic mice that leverages temporally precise and cell-specific stimulation to elicit self-reports of nociception. Conscious reporting of peripheral nociceptive input may help identify neural mechanisms that generate pain perception.

animal behavior and cognition↗