Visual responses in the dorsolateral frontal cortex of marmoset monkeys.

The marmoset monkey (Callithrix jacchus) has gained attention in neurophysiology research as a new primate model for visual processing and behavior. In particular, marmosets have a lissencephalic cortex, making multielectrode, optogenetic, and calcium-imaging techniques more accessible than other primate models. However, the degree of homology of brain circuits for visual behavior with those identified in macaques and humans is still being ascertained. For example, whereas the location of the frontal eye fields (FEF) within the dorsolateral frontal cortex has been proposed, it remains unclear whether neurons in the corresponding areas show visual responses-an important characteristic of FEF neurons in other species. Here, we provide the first description of receptive field properties and neural response latencies in the marmoset dorsolateral frontal cortex, based on recordings using Utah arrays in anesthetized animals. We find brisk visual responses in specific regions of the dorsolateral prefrontal cortex, particularly in areas 8aV, 8C, and 6DR. As in macaque FEF, the receptive fields were typically large (10°-30° in diameter) and the median responses latency was brisk (60 ms). These results constrain the possible interpretations about the location of the marmoset FEF and suggest that the marmoset model's significant advantages for the use of physiological techniques may be leveraged in the study of visuomotor cognition.NEW & NOTEWORTHY Behavior and cognition in humans and other primates rely on networks of brain areas guided by the frontal cortex. The marmoset offers exciting new opportunities to study links between brain physiology and behavior, but the functions of frontal cortex areas are still being identified in this species. Here, we provide the first evidence of visual receptive fields in the marmoset dorsolateral frontal cortex, an important step toward future studies of visual cognitive behavior.

Single-unit activity in marmoset posterior parietal cortex in a gap saccade task.

Abnormal saccadic eye movements can serve as biomarkers for patients with several neuropsychiatric disorders. The common marmoset (Callithrix jacchus) is becoming increasingly popular as a nonhuman primate model to investigate the cortical mechanisms of saccadic control. Recently, our group demonstrated that microstimulation in the posterior parietal cortex (PPC) of marmosets elicits contralateral saccades. Here we recorded single-unit activity in the PPC of the same two marmosets using chronic microelectrode arrays while the monkeys performed a saccadic task with gap trials (target onset lagged fixation point offset by 200 ms) interleaved with step trials (fixation point disappeared when the peripheral target appeared). Both marmosets showed a gap effect, shorter saccadic reaction times (SRTs) in gap vs. step trials. On average, stronger gap-period responses across the entire neuronal population preceded shorter SRTs on trials with contralateral targets although this correlation was stronger among the 15% "gap neurons," which responded significantly during the gap. We also found 39% "target neurons" with significant saccadic target-related responses, which were stronger in gap trials and correlated with the SRTs better than the remaining neurons. Compared with saccades with relatively long SRTs, short-SRT saccades were preceded by both stronger gap-related and target-related responses in all PPC neurons, regardless of whether such response reached significance. Our findings suggest that the PPC in the marmoset contains an area that is involved in the modulation of saccadic preparation.NEW & NOTEWORTHY As a primate model in systems neuroscience, the marmoset is a great complement to the macaque monkey because of its unique advantages. To identify oculomotor networks in the marmoset, we recorded from the marmoset posterior parietal cortex during a saccadic task and found single-unit activities consistent with a role in saccadic modulation. This finding supports the marmoset as a valuable model for studying oculomotor control.

Estimating Risk for Future Intracranial, Fully Implanted, Modular Neuroprosthetic Systems: A Systematic Review of Hardware Complications in Clinical Deep Brain Stimulation and Experimental Human Intracortical Arrays.

OBJECTIVE: A new age of neuromodulation is emerging: one of restorative neuroengineering and neuroprosthetics. As novel device systems move toward regulatory evaluation and clinical trials, a critical need arises for evidence-based identification of potential sources of hardware-related complications to assist in clinical trial design and mitigation of potential risk. MATERIALS AND METHODS: The objective of this systematic review is to provide a detailed safety analysis for future intracranial, fully implanted, modular neuroprosthetic systems. To achieve this aim, we conducted an evidence-based analysis of hardware complications for the most established clinical intracranial modular system, deep brain stimulation (DBS), as well as the most widely used intracranial human experimental system, the silicon-based (Utah) array. RESULTS: Of 2328 publications identified, 240 articles met the inclusion criteria and were reviewed for DBS hardware complications. The most reported adverse events were infection (4.57%), internal pulse generator malfunction (3.25%), hemorrhage (2.86%), lead migration (2.58%), lead fracture (2.56%), skin erosion (2.22%), and extension cable malfunction (1.63%). Of 433 publications identified, 76 articles met the inclusion criteria and were reviewed for Utah array complications. Of 48 human subjects implanted with the Utah array, 18 have chronic implants. Few specific complications are described in the literature; hence, implant duration served as a lower bound for complication-free operation. The longest reported duration of a person with a Utah array implant is 1975 days (~5.4 years). CONCLUSIONS: Through systematic review of the clinical and human-trial literature, our study provides the most comprehensive safety review to date of DBS hardware and human neuroprosthetic research using the Utah array. The evidence-based analysis serves as an important reference for investigators seeking to identify hardware-related safety data, a necessity to meet regulatory requirements and to design clinical trials for future intracranial, fully implanted, modular neuroprosthetic systems.

Utah array characterization and histological analysis of a multi-year implant in non-human primate motor and sensory cortices.

Objective.The Utah array is widely used in both clinical studies and neuroscience. It has a strong track record of safety. However, it is also known that implanted electrodes promote the formation of scar tissue in the immediate vicinity of the electrodes, which may negatively impact the ability to record neural waveforms. This scarring response has been primarily studied in rodents, which may have a very different response than primate brain.Approach.Here, we present a rare nonhuman primate histological dataset (n= 1 rhesus macaque) obtained 848 and 590 d after implantation in two brain hemispheres. For 2 of 4 arrays that remained within the cortex, NeuN was used to stain for neuron somata at three different depths along the shanks. Images were filtered and denoised, with neurons then counted in the vicinity of the arrays as well as a nearby section of control tissue. Additionally, 3 of 4 arrays were imaged with a scanning electrode microscope to evaluate any materials damage that might be present.Main results.Overall, we found a 63% percent reduction in the number of neurons surrounding the electrode shanks compared to control areas. In terms of materials, the arrays remained largely intact with metal and Parylene C present, though tip breakage and cracks were observed on many electrodes.Significance.Overall, these results suggest that the tissue response in the nonhuman primate brain shows similar neuron loss to previous studies using rodents. Electrode improvements, for example using smaller or softer probes, may therefore substantially improve the tissue response and potentially improve the neuronal recording yield in primate cortex.

Understanding charge transfer on the clinically used conical Utah electrode array: charge storage capacity, electrochemical impedance spectroscopy and effective electrode area.

Objective. The Utah electrode is used for pre/clinical studies on neural recording and stimulation. Anecdotal and empirical reports on their performance have been made, resulting in variable testing methods. An in depth investigation was performed to understand the electrochemical behaviour and charge transfer mechanisms occurring on these clinically important electrodes. The impact of electrode geometry and material on performance was determined.Approach. Platinum and iridium electrodes were assessed by cyclic voltammetry and electrochemical impedance spectroscopy. The effective electrode area was measured by reduction of Ru(NH3)63+.Main results. Pristine Utah electrodes have little to no oxide present and the surface roughness is less than the diffusion length of Ru(NH3)63+during voltammetry, which was ∼30µm. Pristine iridium electrodes pass charge through capacitance and oxide formation. Hydride and anion adsorption occurs on the platinum electrode. Anodic current oxidises both metal surfaces, altering the charge transfer mechanisms at the electrode-solution interface. Charge storage capacity depends on measurement technique and electrode structure, this simplified number ignores more detailed information on charge transfer mechanisms that can be obtained from cyclic voltammetry. Electrode oxidation increases pseudocapacitance, reducing impedance. Charge transfer was non-homogeneous, most likely due to the electrode geometry enhancing charge density at the electrode tip and base. Oxidation of the electrode surface enhanced charge transfer inhomogeneity. The effective electrode area could be measured by reduction of Ru(NH3)63+and calculated with a finite cone geometry.Significance. Increasing electrode pseudocapacitance, demonstrated by metal oxidation, reduces impedance. Increasing electrode capacitance offers a potential route to reducing thermal noise and increasing signal-to-noise ratio of neural recording. The effective electrode area of conical electrodes can be measured. The charge density of the conical electrode was greater than expected compared to a planar disc electrode, indicating modification of electrode geometry can increase an electrodes safe charge injection capacity.in vivoelectrochemical measurements often do not include sufficient details to understand the electrode behaviour. Electrode oxidation most likely accounts for a significant amount of variation in previously published Utah electrode impedance data.

Explant Analysis of Utah Electrode Arrays Implanted in Human Cortex for Brain-Computer-Interfaces.

Brain-computer interfaces are being developed to restore movement for people living with paralysis due to injury or disease. Although the therapeutic potential is great, long-term stability of the interface is critical for widespread clinical implementation. While many factors can affect recording and stimulation performance including electrode material stability and host tissue reaction, these factors have not been investigated in human implants. In this clinical study, we sought to characterize the material integrity and biological tissue encapsulation via explant analysis in an effort to identify factors that influence electrophysiological performance. We examined a total of six Utah arrays explanted from two human participants involved in intracortical BCI studies. Two platinum (Pt) arrays were implanted for 980 days in one participant (P1) and two Pt and two iridium oxide (IrOx) arrays were implanted for 182 days in the second participant (P2). We observed that the recording quality followed a similar trend in all six arrays with an initial increase in peak-to-peak voltage during the first 30-40 days and gradual decline thereafter in P1. Using optical and two-photon microscopy we observed a higher degree of tissue encapsulation on both arrays implanted for longer durations in participant P1. We then used scanning electron microscopy and energy dispersive X-ray spectroscopy to assess material degradation. All measures of material degradation for the Pt arrays were found to be more prominent in the participant with a longer implantation time. Two IrOx arrays were subjected to brief survey stimulations, and one of these arrays showed loss of iridium from most of the stimulated sites. Recording performance appeared to be unaffected by this loss of iridium, suggesting that the adhesion of IrOx coating may have been compromised by the stimulation, but the metal layer did not detach until or after array removal. In summary, both tissue encapsulation and material degradation were more pronounced in the arrays that were implanted for a longer duration. Additionally, these arrays also had lower signal amplitude and impedance. New biomaterial strategies that minimize fibrotic encapsulation and enhance material stability should be developed to achieve high quality recording and stimulation for longer implantation periods.

Intuitive neuromyoelectric control of a dexterous bionic arm using a modified Kalman filter.

BACKGROUND: Multi-articulate prostheses are capable of performing dexterous hand movements. However, clinically available control strategies fail to provide users with intuitive, independent and proportional control over multiple degrees of freedom (DOFs) in real-time. NEW METHOD: We detail the use of a modified Kalman filter (MKF) to provide intuitive, independent and proportional control over six-DOF prostheses such as the DEKA "LUKE" arm. Input features include neural firing rates recorded from Utah Slanted Electrode Arrays and mean absolute value of intramuscular electromyographic (EMG) recordings. Ad-hoc modifications include thresholds and non-unity gains on the output of a Kalman filter. RESULTS: We demonstrate that both neural and EMG data can be combined effectively. We also highlight that modifications can be optimized to significantly improve performance relative to an unmodified Kalman filter. Thresholds significantly reduced unintended movement and promoted more independent control of the different DOFs. Gains were significantly greater than one and served to ease movement initiation. Optimal modifications can be determined quickly offline and translate to functional improvements online. Using a portable take-home system, participants performed various activities of daily living. COMPARISON WITH EXISTING METHODS: In contrast to pattern recognition, the MKF allows users to continuously modulate their force output, which is critical for fine dexterity. The MKF is also computationally efficient and can be trained in less than five minutes. CONCLUSIONS: The MKF can be used to explore the functional and psychological benefits associated with long-term, at-home control of dexterous prosthetic hands.

Neural electrode resilience against dielectric damage may be improved by use of highly doped silicon as a conductive material.

BACKGROUND: Dielectric damage occurring in vivo to neural electrodes, leading to conductive material exposure and impedance reduction over time, limits the functional lifetime and clinical viability of neuroprosthetics. We used silicon micromachined Utah Electrode Arrays (UEAs) with iridium oxide (IrOx) tip metallization and parylene C dielectric encapsulation to understand the factors affecting device resilience and drive improvements. NEW METHOD: In vitro impedance measurements and finite element analyses were conducted to evaluate how exposed surface area of silicon and IrOx affect UEA properties. Through an aggressive in vitro reactive accelerated aging (RAA) protocol, in vivo parylene degradation was simulated on UEAs to explore agreement with our models. Electrochemical properties of silicon and other common electrode materials were compared to help inform material choice in future neural electrode designs. RESULTS: Exposure of silicon on UEAs was found to primarily affect impedance at frequencies >1kHz, while characteristics at 1 kHz and below were largely unchanged. Post-RAA impedance reduction of UEAs was mitigated in cases where dielectric damage was more likely to expose silicon instead of IrOx. Silicon was found to have a per-area electrochemical impedance >10×higher than many common electrode materials regardless of doping level and resistivity, making it best suited for use as a low-shunting conductor. COMPARISON WITH EXISTING METHODS: Non-semiconductor electrode materials commonly used in neural electrode design are more susceptible to shunting neural interface signals through dielectric defects, compared to highly doped silicon. CONCLUSION: Strategic use of silicon and similar materials may increase neural electrode robustness against encapsulation failures.

Microelectrode array stimulation combined with intrinsic optical imaging: A novel tool for functional brain mapping.

BACKGROUND: Functional brain mapping via cortical microstimulation is a widely used clinical and experimental tool. However, data are traditionally collected point by point, making the technique very time consuming. Moreover, even in skilled hands, consistent penetration depths are difficult to achieve. Finally, the effects of microstimulation are assessed behaviorally, with no attempt to capture the activity of the local cortical circuits being stimulated. NEW METHOD: We propose a novel method for functional brain mapping, which combines the use of a microelectrode array with intrinsic optical imaging. The precise spacing of electrodes allows for fast, accurate mapping of the area of interest in a regular grid. At the same time, the optical window allows for visualization of local neural connections when stimulation is combined with intrinsic optical imaging. RESULTS: We demonstrate the efficacy of our technique using the primate motor cortex as a sample application, using a combination of microstimulation, imaging and electrophysiological recordings during wakefulness and under anesthesia. Comparison with current method: We find the data collected with our method is consistent with previous data published by others. We believe that our approach enables data to be collected faster and in a more consistent fashion and makes possible a number of studies that would be difficult to carry out with the traditional approach. CONCLUSIONS: Our technique allows for simultaneous modulation and imaging of cortical sensorimotor networks in wakeful subjects over multiple sessions which is highly desirable for both the study of cortical organization and the design of brain machine interfaces.

Mechanical and Biological Interactions of Implants with the Brain and Their Impact on Implant Design.

Neural prostheses have already a long history and yet the cochlear implant remains the only success story about a longterm sensory function restoration. On the other hand, neural implants for deep brain stimulation are gaining acceptance for variety of disorders including Parkinsons disease and obsessive-compulsive disorder. It is anticipated that the progress in the field has been hampered by a combination of technological and biological factors, such as the limited understanding of the longterm behavior of implants, unreliability of devices, biocompatibility of the implants among others. While the field's understanding of the cell biology of interactions at the biotic-abiotic interface has improved, relatively little attention has been paid on the mechanical factors (stress, strain), and hence on the geometry that can modulate it. This focused review summarizes the recent progress in the understanding of the mechanisms of mechanical interaction between the implants and the brain. The review gives an overview of the factors by which the implants interact acutely and chronically with the tissue: blood-brain barrier (BBB) breach, vascular damage, micromotions, diffusion etc. We propose some design constraints to be considered in future studies. Aspects of the chronic cell-implant interaction will be discussed in view of the chronic local inflammation and the ways of modulating it.