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Intracortical recordings can be used to voluntarily control external devices via brain-machine interfaces (BMI). Multiple factors, including the foreign body response (FBR), limit the stability of these neural signals over time. Current clinically approved devices consist of multi-electrode arrays with a single electrode site at the tip of each shank, confining the recording interface to a single layer of the cortex. Advancements in manufacturing technology have led to the development of high-density electrodes that can record from multiple layers. However, the long-term stability of neural recordings and the extent of neuronal cell loss around the electrode across different cortical depths have yet to be explored. To answer these questions, we recorded neural signals from rats chronically implanted with a silicon-substrate microelectrode array spanning the layers of the cortex. Our results show the long-term stability of intracortical recordings varies across cortical depth, with electrode sites around L4-L5 having the highest stability. Using machine learning guided segmentation, our novel histological technique, DeepHisto, revealed that the extent of neuronal cell loss varies across cortical layers, with L2/3 and L4 electrodes having the largest area of neuronal cell loss. These findings suggest that interfacing depth plays a major role in the FBR and long-term performance of intracortical neuroprostheses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MD declared a shared affiliation with the author SF to the handling editor at the time of review., (Copyright © 2023 Urdaneta, Kunigk, Peñaloza-Aponte, Currlin, Malone, Fried and Otto.)

Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain's foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kunigk, Urdaneta, Malone, Delgado and Otto.)

Intracortical microstimulation (ICMS) of the somatosensory cortex (S1) can restore sensory function in patients with paralysis. Studies assessing the stability of ICMS have reported heterogeneous responses across electrodes and over time, potentially hindering the implementation and translatability of these technologies. The foreign body response (FBR) and the encapsulating glial scar have been associated with a decay in chronic performance of implanted electrodes. Moreover, the morphology, intrinsic properties, and function of cells vary across cortical layers, each potentially affecting the sensitivity to ICMS as well as the degree of the FBR across cortical depth. However, layer-by-layer comparisons of the long-term stability of ICMS as well as the extent of the astrocytic glial scar change across cortical layers have not been well explored. Here, we implanted silicon microelectrodes with electrode sites spanning all the layers of S1 in rats. Using a behavioral paradigm, we obtained ICMS detection thresholds from all cortical layers for up to 40 weeks. Our results showed that the sensitivity and long-term performance of ICMS is indeed layer dependent. Overall, detection thresholds decreased during the first 7 weeks post-implantation (WPI). This was followed by a period in which thresholds remained stable or increased depending on the interfacing layer: thresholds in L1 and L6 exhibited the most consistent increases over time, while those in L4 and L5 remained the most stable. Furthermore, histological investigation of the tissue surrounding the electrode showed a biological response of microglia and macrophages which peaked at L1, while the area of the astrocytic glial scar peaked at L2/3. Interestingly, the biological response of these FBR markers is less exacerbated at L4 and L5, suggesting a potential link between the FBR and the long-term stability of ICMS. These findings suggest that interfacing depth can play an important role in the design of chronically stable implantable microelectrodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Urdaneta, Kunigk, Currlin, Delgado, Fried and Otto.)

Intracortical microelectrodes are neuroprosthetic devices used in brain-machine interfaces to both record and stimulate neural activity in the brain. These technologies have been improved by advances in microfabrication, which have led to the creation of subcellular and high-density microelectrodes. The greater number of independent stimulation channels in these devices allows for improved neuromodulation selectivity, compared to single-site microelectrodes. Elements of electrode design such as electrode-site placement can influence the long-term performance of neuroprostheses. Previous studies have shown that electrode-sites placed on the edge of a planar microelectrode have greater chronic recording functionality than sites placed in the center. However, the effect of electrode-site placement on long-term intracortical microstimulation (ICMS) is still unknown. Here, we show that, in rats chronically implanted with custom-made planar silicon microelectrodes, electrode-sites on the tip of the device outperformed those on both the edge and center in terms of the effect per charge delivered, though there is still a slight advantage to using edge sites over center sites for ICMS. Longitudinal analysis of ICMS detection thresholds over a 16-week period revealed that while all sites followed a similar trend over time, the tip and edge sites consistently elicited the behavioral response with less charge compared to center sites. Furthermore, we quantified channel activity over time and found that edge sites remained more active than center sites over time, though the rate of decay of active sites for center and edge sites was comparable. Our results demonstrate that electrode-site placement plays an important role in the long-term stability of intracortical microstimulation and could be a potential factor to consider in the design of future intracortical electrodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saldanha, Urdaneta and Otto.)

Imbalance of oxidants is a universal contributor to the failure of implanted devices and tissues. A sustained oxidative environment leads to cytotoxicity, prolonged inflammation, and ultimately host rejection of implanted devices/grafts. The incorporation of antioxidant materials can inhibit this redox/inflammatory cycle and enhance implant efficacy. Cerium oxide nanoparticles (CONP) is a highly promising agent that exhibits potent, ubiquitous, and self-renewable antioxidant properties. Integrating CONP as surface coatings provides ease in translating antioxidant properties to various implants/grafts. Herein, we describe the formation of CONP coatings, generated via the sequential deposition of CONP and alginate, and the impact of coating properties, pH, and polymer molecular weight, on their resulting redox profile. Investigation of CONP deposition, layer formation, and coating uniformity/thickness on their resulting oxidant scavenging activity identified key parameters for customizing global antioxidant properties. Results found lower molecular weight alginates and physiological pH shift CONP activity to a higher H 2 O 2 to O 2 - -scavenging capability. The antioxidant properties measured for these various coatings translated to distinct antioxidant protection to the underlying encapsulated cells. Information gained from this work can be leveraged to tailor coatings towards specific oxidant-scavenging applications and prolong the function of medical devices and cellular implants.

Objective . Intracortical microstimulation of the primary somatosensory cortex (S1) has shown great progress in restoring touch sensations to patients with paralysis. Stimulation parameters such as amplitude, phase duration, and frequency can influence the quality of the evoked percept as well as the amount of charge necessary to elicit a response. Previous studies in V1 and auditory cortices have shown that the behavioral responses to stimulation amplitude and phase duration change across cortical depth. However, this depth-dependent response has yet to be investigated in S1. Similarly, to our knowledge, the response to microstimulation frequency across cortical depth remains unexplored. Approach . To assess these questions, we implanted rats in S1 with a microelectrode with electrode-sites spanning all layers of the cortex. A conditioned avoidance behavioral paradigm was used to measure detection thresholds and responses to phase duration and frequency across cortical depth. Main results . Analogous to other cortical areas, the sensitivity to charge and strength-duration chronaxies in S1 varied across cortical layers. Likewise, the sensitivity to microstimulation frequency was layer dependent. Significance . These findings suggest that cortical depth can play an important role in the fine-tuning of stimulation parameters and in the design of intracortical neuroprostheses for clinical applications., (© 2021 IOP Publishing Ltd.)

Advances in neural engineering have brought about a number of implantable devices for improved brain stimulation and recording. Unfortunately, many of these micro-implants have not been adopted due to issues of signal loss, deterioration, and host response to the device. While glial scar characterization is critical to better understand the mechanisms that affect device functionality or tissue viability, analysis is frequently hindered by immunohistochemical tissue processing methods that result in device shattering and tissue tearing artifacts. Devices are commonly removed prior to sectioning, which can itself disturb the quality of the study. In this methods implementation study, we use the label free, optical sectioning method of second harmonic generation (SHG) to examine brain slices of various implanted intracortical electrodes and demonstrate collagen fiber distribution not found in normal brain tissue. SHG can easily be used in conjunction with multiphoton microscopy to allow direct intrinsic visualization of collagen-containing glial scars on the surface of cortically implanted electrode probes without imposing the physical strain of tissue sectioning methods required for other high resolution light microscopy modalities. Identification and future measurements of these collagen fibers may be useful in predicting host immune response and device signal fidelity., (Copyright © 2020 Esquibel, Wendt, Lee, Gaire, Shoffstall, Urdaneta, Chacko, Brodnick, Otto, Capadona, Williams and Eliceiri.)

The pancreas is a visceral organ with exocrine functions for digestion and endocrine functions for maintenance of blood glucose homeostasis. In pancreatic diseases such as Type 1 diabetes, islets of the endocrine pancreas become dysfunctional and normal regulation of blood glucose concentration ceases. In healthy individuals, parasympathetic signaling to islets via the vagus nerve, triggers release of insulin from pancreatic β-cells and glucagon from α-cells. Using electrical stimulation to augment parasympathetic signaling may provide a way to control pancreatic endocrine functions and ultimately control blood glucose. Historical data suggest that cervical vagus nerve stimulation recruits many visceral organ systems. Simultaneous modulation of liver and digestive function along with pancreatic function provides differential signals that work to both raise and lower blood glucose. Targeted pancreatic vagus nerve stimulation may provide a solution to minimizing off-target effects through careful electrode placement just prior to pancreatic insertion., Competing Interests: Financial & competing interests disclosure This work was sponsored by the Defense Advanced Research Projects Agency (DARPA) BTO under the auspices of D Weber and EV Gieson through the DARPA Contracts Management Office (Grant No. HR0011-17-2-0019) and by a National Institute of Diabetes and Digestive and Kidney Diseases T32 training grant (5T32DK108736-03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Future Medicine Ltd.)

Intracortical microstimulation has proven to be effective in a variety of sensory applications, such as returning touch percepts to paralyzed patients. The parameters of microstimulation play an important role in the perception quality of the stimulus. Eliciting naturalistic percepts is essential for the adaptability and functionality of this technology. Compared to the typical biphasic symmetric waveforms, asymmetric waveforms enhance activation selectivity by preferentially activating cell bodies. Behavioral studies have shown that asymmetric waveforms can elicit behavioral responses, but these require higher charges than typical symmetric waveforms. Here, we investigated the effects of phase duration and waveform asymmetry for somatosensory cortex intracortical microstimulation of freely-behaving rats. Detection thresholds were obtained using a conditioned avoidance behavioral paradigm. Our results indicate that phase duration has significant effects on threshold regardless of symmetry, polarity, and phase order of the waveform. Specifically, shorter phase durations tend to elicit lower behavioral thresholds. Analogous to studies in the auditory cortex, asymmetric waveforms in which the short pulse was cathodic were more effective than those with short-anodic pulses. With short phase durations, these short-cathodic waveforms are capable of evoking behavioral responses at low charges (<; 5 nC/Phase). Altogether, these results suggest the possibility of cell body selective microstimulation at safe thresholds, as well as the potential translatability of neuromodulation parameters across distinct sensory cortical areas.

Although the basal ganglia have been implicated in a growing list of human behaviors, they include some of the least understood nuclei in the brain. For several decades studies have employed numerous methodologies to uncover evidence pointing to the basal ganglia as a hub of both motor and non-motor function. Recently, new electrophysiological characterization of the basal ganglia in humans has become possible through direct access to these deep structures as part of routine neurosurgery. Electrophysiological approaches for identifying non-motor function have the potential to unlock a deeper understanding of pathways that may inform clinical interventions and particularly neuromodulation. Various electrophysiological modalities can also be combined to reveal functional connections between the basal ganglia and traditional structures throughout the neocortex that have been linked to non-motor behavior. Several reviews have previously summarized evidence for non-motor function in the basal ganglia stemming from behavioral, clinical, computational, imaging, and non-primate animal studies; in this review, instead we turn to electrophysiological studies of non-human primates and humans. We begin by introducing common electrophysiological methodologies for basal ganglia investigation, and then we discuss studies across numerous non-motor domains-emotion, response inhibition, conflict, decision-making, error-detection and surprise, reward processing, language, and time processing. We discuss the limitations of current approaches and highlight the current state of the information.

Objective: To determine costs of drug and nondrug treatment of HIV-infected patients during introduction of protease inhibitors and combination therapy., Study Design: Longitudinal, observational study of insurance claims data., Patients and Methods: Data from managed care organizations in Texas and California contracting with an HIV case management group were reviewed for all non-Medicaid/non-MediCal adults infected with HIV for costs of drugs and nondrug treatment per HIV-infected member per month from January 1995 to December 1997. Costs of care for patients with and without undetectable viral loads (< 400 copies/mL) were quantified., Results: Per HIV-infected member, average monthly drug costs increased, nondrug costs decreased, and total costs remained stable. Quarterly mortality rates decreased from 4.8% to 0.25%. From the first quarter of 1996 to the last quarter of 1997, the proportion of patients with undetectable viral loads increased from 6% to 56%. Increasing drug costs and decreasing nondrug costs were observed in patients with and without undetectable viral loads, but costs were higher for the latter: after the second quarter of 1996, drug costs were $67 to $277 higher for patients without undetectable viral loads, nondrug costs were $185 to $741 higher, and total costs were $333 to $808 higher., Conclusions: Reduced mortality rates and increased viral suppression to undetectable levels were observed during introduction of protease inhibitors and combination therapy in this MCO setting. Increased average monthly drug costs per HIV-infected patient were offset by decreased average monthly nondrug costs, and both costs were lower when patients achieved undetectable viral loads.

HIV-infected persons receiving methadone maintenance must often seek their medical care at a separate site. However, little data is available on the receipt of antiretroviral therapy (ART), beliefs about ART, and influences on the decision to initiate ART among those referred off-site. HIV-infected injection drug users (n = 72) were interviewed at three methadone maintenance programs; 83% with CD4 cell counts under 500 reported that they had received ART. Of these persons, 56% had used three drug combination therapy. Beliefs about the benefits of ART included: increased survival, 96%; decreased viral load 87%; decreased HIV-related infections 87%; could cure HIV, 29%. For those receiving ART, physician input, CD4 count, and possible side effects were more important than friends, family or mass media in deciding to start ART. We conclude that the model of referral for HIV care off-site does not appear to impede access to ART for HIV-infected IDUs in methadone maintenance.

This study investigated the extent to which mental illness and substance use hospitalization rates were related to the supply of psychiatric treatment services. Supply variables, notably the per capita rate of psychiatrists, primary care physicians, and specialty units, were strongly related to mental illness and substance use hospitalization rates to acute care hospitals across 114 small geographic areas in Iowa. The supply of outpatient services was not related to hospitalization rates. The need to study the reliability of patient assessment processes, refine guidelines and admissions criteria, and understand the contributions of supply variables to hospitalization rates are indicated by these results. A conceptual model is offered within which the dynamic cycle from patient functioning to service delivery may be framed.