A next-generation subdural spinal cord stimulator based on an array of wireless micro-implants is proposed to achieve unprecedented electrode count and stimulation focality. A 433 MHz three-layer inductive coupling system is designed to energize $\mathbf{8 4}$ micro-stimulators of $\mathbf{1} \times \mathbf{1} \mathbf{~ m m}^{\mathbf{2}}$ size. Electromagnetic simulation confirms that at least 2 mW of RF power is delivered to each node, while the peak specific absorption rate (SAR) is 20.1 W/kg. This shows that patterned stimulation up to 50% duty cycle can be achieved within the safety limit.

In a major step toward clinical translation, transplanting stem cells into the injured spinal cords of rhesus monkeys improves hand function.

Deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy for treatment resistant obsessive-compulsive disorder (trOCD). DBS initiation often produces acute improvements in mood and energy. These acute behavioral changes, which we refer to as “approach behaviors”, include increased social engagement and talkativeness. We investigated the relationship between stimulation amplitude, spectral power in the ventrolateral prefrontal cortex (vlPFC), and speech rate in one male patient with trOCD implanted with bilateral VC/VS DBS leads and subdural electrodes adjacent to orbitofrontal cortex (OFC) and vlPFC. Several times over the first 17 weeks of therapy, we conducted experiments where we recorded data during epochs of high amplitude or zero/low amplitude stimulation. We found that both speech rate and vlPFC power in a high beta frequency band (31±1.5Hz, 1/f activity removed) increased during high amplitude as compared to low amplitude periods. Speech rate correlated with vlPFC high beta power. These effects were more consistent across time points in the left hemisphere than the right. At week 17, we performed an experiment where stimulation was held constant while the patient was asked to speak or remain silent. We showed that the presence or absence of speech was not sufficient to increase the vlPFC high beta power, suggesting stimulation is a key driver of the observed neurobehavioral phenomenon. Our results suggest vlPFC high beta power is a biomarker for approach behaviors associated with VC/VS DBS. Significance Statement In one patient receiving DBS of the ventral capsule and ventral striatum (VC/VS) for OCD, we leveraged a unique clinical opportunity to study the neurophysiological basis of approach behaviors using chronic intracranial recordings from prefrontal cortical regions. VC/VS DBS initiation often produces acute improvements in mood and energy associated with increased social engagement and talkativeness (approach behaviors). Our results suggest that vlPFC high beta activity (particularly in the left hemisphere) may index approach behaviors (quantified here by speech features). This neural signal is consistent with our previous non-invasive studies identifying predictors of mania in patients with bipolar disorder, and we hope to gather further evidence that it indexes a continuum from adaptive approach behavior to maladaptive manic symptoms.

Objective.Advances in electronics and materials science have led to the development of sophisticated components for clinical and research neurotechnology systems. However, instrumentation to easily evaluate how these components function in a complete system does not yet exist. In this work, we set out to design and validate a software-defined mixed-signal routing fabric, 'xDev', that enables neurotechnology system designers to rapidly iterate, evaluate, and deploy advanced multi-component systems.Approach.We developed a set of system requirements for xDev, and implemented a design based on a 16 × 16 analog crosspoint multiplexer. We then tested the impedance and switching characteristics of the design, assessed signal gain and crosstalk attenuation across biological and high-speed digital signaling frequencies, and evaluated the ability of xDev to flexibly reroute microvolt-scale amplitude and high-speed signals. Finally, we conducted an intraoperativein vivodeployment of xDev to rapidly conduct neuromodulation experiments using diverse neurotechnology submodules.Main results.The xDev system impedance matching, crosstalk attenuation, and frequency response characteristics accurately transmitted signals over a broad range of frequencies, encapsulating features typical of biosignals and extending into high-speed digital ranges. Microvolt-scale biosignals and 600 Mbps Ethernet connections were accurately routed through the fabric. These performance characteristics culminated in anin vivodemonstration of the flexibility of the system via implanted spinal electrode arrays in an ovine model.Significance.xDev represents a first-of-its-kind, low-cost, software-defined neurotechnology development accelerator platform. Through the public, open-source distribution of our designs, we lower the obstacles facing the development of future neurotechnology systems.

Objective: Epidural 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. Approach: We 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 results: The 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. Significance: We 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.

Significance:Pain comprises 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. Aim:We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. Approach:We 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 BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). Results:We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. Conclusions:The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

BACKGROUND AND OBJECTIVES: Recent advances in stereotactic and functional neurosurgery have brought forth the stereo-electroencephalography approach which allows deeper interrogation and characterization of the contributions of deep structures to neural and affective functioning. We argue that this approach can and should be brought to bear on the notoriously intractable issue of defining the pathophysiology of refractory psychiatric disorders and developing patient-specific optimized stimulation therapies. METHODS: We have developed a suite of methods for maximally leveraging the stereo-electroencephalography approach for an innovative application to understand affective disorders, with high translatability across the broader range of refractory neuropsychiatric conditions. RESULTS: This article provides a roadmap for determining desired electrode coverage, tracking high-resolution research recordings across a large number of electrodes, synchronizing intracranial signals with ongoing research tasks and other data streams, applying intracranial stimulation during recording, and design choices for patient comfort and safety. CONCLUSION: These methods can be implemented across other neuropsychiatric conditions needing intensive electrophysiological characterization to define biomarkers and more effectively guide therapeutic decision-making in cases of severe and treatment-refractory disease.

Neuromodulation and brain–computer interfaces are rapidly evolving fields with distinct origins but with the shared goal of improving the lives of people with neurological and psychiatric disorders or injuries. Their increasing technological overlap provides new opportunities for collaborative work and rapid progress in neurotechnology.

Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically relevant tools that have long been used to measure electromagnetic fields in the somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in the 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 upward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by downward-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 directed downward 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 (S. R. 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 downward current flow of the MN P1. Model results further predicted that the initial ~170 ms downward 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.

Prefrontal 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. Here, 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). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

Adaptive deep brain stimulation (aDBS) has emerged as a potential strategy for improving the efficacy of DBS therapy for both movement and psychiatric disorders. Until recently, opportunities for intracranial electrophysiological recordings in individuals with psychiatric disorders have been limited to in-hospital settings, which are not conducive to capturing the wide variety of symptom states necessary to develop robust classifiers to inform therapy changes.

A reliable physiological biomarker for Major Depressive Disorder (MDD) is necessary to improve treatment success rates by shoring up variability in outcome measures. In this study, we establish a passive biomarker that tracks with changes in mood on the order of minutes to hours. We record from intracranial electrodes implanted deep in the brain - a surgical setting providing exquisite temporal and spatial sensitivity to detect this relationship in a difficult-to-measure brain area, the ventromedial prefrontal cortex (VMPFC). The aperiodic slope of the power spectral density captures the balance of activity across all frequency bands and is construed as a putative proxy for excitatory/inhibitory balance in the brain. This study demonstrates how shifts in aperiodic slope correlate with depression severity in a clinical trial of deep brain stimulation for treatment-resistant depression (TRD). The correlation between depression severity scores and aperiodic slope is significant in N=5 subjects, indicating that flatter (less negative) slopes correspond to reduced depression severity, especially in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient response to MDD treatment, facilitating individualized therapies in both intracranial and non-invasive monitoring scenarios.

In vitro cell culture models can offer high-resolution and high-throughput experimentation of cellular behaviors. However, in vitro culture approaches often fail to fully recapitulate complex cell processes involving synergistic interactions between heterogeneous neural cell populations and the surrounding neural microenvironment. Here, we describe the formation of a three-dimensional primary cortical cell culture system compatible with live confocal microscopy.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

BACKGROUND:Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE:/Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS:We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS:Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION:This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.

Despite the success of deep brain stimulation (DBS) for treatment of refractory obsessive-compulsive disorder (OCD), there are currently no robust neural signatures for obsessive-compulsive (OC) symptoms or initial mood and energy improvements often associated with DBS. This may be due to limited opportunities available for conducting intracranial electrophysiological recordings in natural environments where fluctuations in symptoms take place.

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.

INTRODUCTION: Deficits in cognitive control, defined as the ability to adjust response or attention in the face of competing or changing demands, are thought to be responsible for inflexible behaviors in neuropsychiatric diseases. Here, we seek to understand frontotemporal networks underlying dysfunctional cognitive function using sEEG recordings and deep brain stimulation (DBS) in human subjects with treatment-resistant depression (TRD). METHODS: We employed a forced two-choice cognitive control task where the strength in the target and the distractor interference of a visual stimulus was parametrically and independently varied, resulting in granular variation in response congruence. This task was performed in 13 total subjects, 10 of whom underwent sEEG implants for epilepsy monitoring, whereas 3 subjects were participating in a clinical trial of DBS for TRD and were additionally implanted with DBS leads in the ventral capsule/ventral striatum and subcallosal cingulate. RESULTS: Reaction time (RT) and accuracy worsened with increasing levels of conflict across all subjects (Cohen’s d-accuracy = 0.7, Cohen’s d-RT = 0.2) prior to stimulation. Single-trial regression analyses revealed a parametric effect of task conflict with theta-band (4-7 Hz) power across the dorsolateral PFC (dlPFC), dorsal anterior cingulate cortex, orbitofrontal cortex (OFC) as well as the insula. DBS significantly improved behavioral performance, demonstrated by reduced RT (1080 土 10 ms to 840 土 50 ms), and improved accuracy(70 土 9.8% to 90 土 5%). While we observed an overall increase in theta power across the PFC and ACC in TRD participants following DBS, the effect of conflict in theta power was reversed (theta power decreased with increasing conflict in dlPFC and OFC). CONCLUSIONS: Leveraging this unique behavioral paradigm with concurrent distributed intracranial recordings and causal manipulation broadens our understanding of neural substrates of decision-making as well as the mechanisms of therapeutic action of DBS for TRD and other psychiatric disorders.

Deep brain stimulation (DBS) therapies have shown clinical success in the treatment of a number of neurological illnesses, including obsessive-compulsive disorder, depression, and Parkinson’s 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.

Objective.The recording instability of neural implants due to neuroinflammation at the device-tissue interface 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. We aimed to understand and mitigate the isolated the innate neuroinflammatory response to devices.Approach.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-dimensionalin vitromodel of the device-tissue interface by seeding primary cortical cells around microwires. Live imaging of both dye and Adeno-Associated Virus (AAV) - mediated functional, structural, and lipid peroxidation fluorescence was employed to characterize the neuroinflammatory response.Main results.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 thein vivoblood 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.Significance.Our three-dimensionalin vitromodel of the device-tissue interface exhibited symptoms of OS-mediated innate neuroinflammation, indicating a significant local immune response to devices. The dysregulation of functional connectivity of microcircuits surround implants suggests the presence of an observer effect, in which the process of recording neural activity may fundamentally change the neural signal. Finally, the demonstration of antioxidant ceria nanoparticle treatment exhibited substantial promise as a neuroprotective and anti-inflammatory treatment strategy.