In the development of Brain Machine Interfaces (BMIs), there is a great need to enable users to interact with changing environments during the activities of daily life. It is expected that the number ...and scope of the learning tasks encountered during interaction with the environment as well as the pattern of brain activity will vary over time. These conditions, in addition to neural reorganization, pose a challenge to decoding neural commands for BMIs. We have developed a new BMI framework in which a computational agent symbiotically decoded users' intended actions by utilizing both motor commands and goal information directly from the brain through a continuous Perception-Action-Reward Cycle (PARC).
The control architecture designed was based on Actor-Critic learning, which is a PARC-based reinforcement learning method. Our neurophysiology studies in rat models suggested that Nucleus Accumbens (NAcc) contained a rich representation of goal information in terms of predicting the probability of earning reward and it could be translated into an evaluative feedback for adaptation of the decoder with high precision. Simulated neural control experiments showed that the system was able to maintain high performance in decoding neural motor commands during novel tasks or in the presence of reorganization in the neural input. We then implanted a dual micro-wire array in the primary motor cortex (M1) and the NAcc of rat brain and implemented a full closed-loop system in which robot actions were decoded from the single unit activity in M1 based on an evaluative feedback that was estimated from NAcc.
Our results suggest that adapting the BMI decoder with an evaluative feedback that is directly extracted from the brain is a possible solution to the problem of operating BMIs in changing environments with dynamic neural signals. During closed-loop control, the agent was able to solve a reaching task by capturing the action and reward interdependency in the brain.
Brain-machine interface (BMI) systems give users direct neural control of robotic, communication, or functional electrical stimulation systems. As BMI systems begin transitioning from laboratory ...settings into activities of daily living, an important goal is to develop neural decoding algorithms that can be calibrated with a minimal burden on the user, provide stable control for long periods of time, and can be responsive to fluctuations in the decoder's neural input space (e.g. neurons appearing or being lost amongst electrode recordings). These are significant challenges for static neural decoding algorithms that assume stationary input/output relationships. Here we use an actor-critic reinforcement learning architecture to provide an adaptive BMI controller that can successfully adapt to dramatic neural reorganizations, can maintain its performance over long time periods, and which does not require the user to produce specific kinetic or kinematic activities to calibrate the BMI. Two marmoset monkeys used the Reinforcement Learning BMI (RLBMI) to successfully control a robotic arm during a two-target reaching task. The RLBMI was initialized using random initial conditions, and it quickly learned to control the robot from brain states using only a binary evaluative feedback regarding whether previously chosen robot actions were good or bad. The RLBMI was able to maintain control over the system throughout sessions spanning multiple weeks. Furthermore, the RLBMI was able to quickly adapt and maintain control of the robot despite dramatic perturbations to the neural inputs, including a series of tests in which the neuron input space was deliberately halved or doubled.
Long-term acquisition of high-quality neural recordings is a cornerstone of neuroprosthetic system design. Mitigating the experimental variability of chronically implanted arrays has been a ...formidable task because the sensor recording sites can be influenced by biotic and abiotic responses. Several studies have implicated changes in electrical interface impedance as a preliminary marker to infer electrode viability. Microelectrode impedance plays an important role in the monitoring of low amplitude and high-resolution extracellular neural signals. In this work, we seek to quantify long-term microelectrode array functionality and derive an impedance-based predictor for electrode functionality that correlates the recording site electrical properties with the functional neuronal recordings in vivo. High temporal resolution metrics of this type would allow one to assess, predict, and improve electrode performance in the future. In a large cohort of animals, we performed daily impedance measurements and neural signal recordings over long periods (up to 21 weeks) of time in rats using tungsten microwire arrays implanted into the somatosensory cortex. This study revealed that there was a time-varying trend in the modulation of impedance that was related to electrode performance. Single units were best detected from electrodes at time points when the electrode entered into the 40-150 KΩ impedance range. This impedance trend was modeled across the full cohort of animals to predict future electrode performance. The model was tested on data from all animals and was able to provide predictions of electrode performance chronically. Insight from this study can be combined with knowledge of electrode materials and histological analysis to provide a more comprehensive predictive model of electrode failure in the future.
Tourette syndrome (TS) is an idiopathic, childhood-onset neuropsychiatric disorder, which is marked by persistent multiple motor and phonic tics. The disorder is highly disruptive and in some cases ...completely debilitating. For those with severe, treatment-refractory TS, deep brain stimulation (DBS) has emerged as a possible option, although its mechanism of action is not fully understood. We performed a longitudinal study of the effects of DBS on TS symptomatology while concomitantly examining neurophysiological dynamics. We present the first report of the clinical correlation between the presence of gamma band activity and decreased tic severity. Local field potential recordings from five subjects implanted in the centromedian nucleus (CM) of the thalamus revealed a temporal correlation between the power of gamma band activity and the clinical metrics of symptomatology as measured by the Yale Global Tic Severity Scale and the Modified Rush Tic Rating Scale. Additional studies utilizing short-term stimulation also produced increases in gamma power. Our results suggest that modulation of gamma band activity in both long-term and short-term DBS of the CM is a key factor in mitigating the pathophysiology associated with TS.
► Corrosion of tungsten microwires used in intracortical microelectrode arrays was confirmed
in vitro by impedance spectroscopy, thermodynamic analysis, and optical microscopy. ► Corrosion rates of ...tungsten microwires
in vitro were limited by the rate of oxygen reduction. ► Corrosion rates of tungsten microwires were increased significantly in the presence of hydrogen peroxide, often associated with the immune response. ► Corrosion of tungsten microwires was observed
in vivo at a rate that was only slightly lower than that observed
in vitro. The difference was attributed to formation of biofilms on the implanted electrodes and to the reduced oxygen content of extracellular fluid as compared to air-saturated PBS.
In neuroprosthetic applications, long-term electrode viability is necessary for robust recording of the activity of neural populations used for generating communication and control signals. The corrosion of tungsten microwire electrodes used for intracortical recording applications was analyzed in a controlled bench-top study and compared to the corrosion of tungsten microwires used in an
in vivo study. Two electrolytes were investigated for the bench-top electrochemical analysis: 0.9% phosphate buffered saline (PBS) and 0.9% PBS containing 30
mM of hydrogen peroxide. The oxidation and reduction reactions responsible for corrosion were found by measurement of the open circuit potential and analysis of Pourbaix diagrams. Dissolution of tungsten to form the tungstic ion was found to be the corrosion mechanism. The corrosion rate was estimated from the polarization resistance, which was extrapolated from the electrochemical impedance spectroscopy data. The results show that tungsten microwires in an electrolyte of PBS have a corrosion rate of 300–700
μm/yr. The corrosion rate for tungsten microwires in an electrolyte containing PBS and 30
mM H
2O
2 is accelerated to 10,000–20,000
μm/yr. The corrosion rate was found to be controlled by the concentration of the reacting species in the cathodic reaction (e.g. O
2 and H
2O
2). The
in vivo corrosion rate, averaged over the duration of implantation, was estimated to be 100
μm/yr. The reduced
in vivo corrosion rate as compared to the bench-top rate is attributed to decreased rate of oxygen diffusion caused by the presence of a biological film and a reduced concentration of available oxygen in the brain.
Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, ...progression, and metastasis. Obesity‐associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro‐oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid‐derived suppressor cells and some subtypes of adipose‐tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.
For nearly 55 years, tungsten microwires have been widely used in neurophysiological experiments in animal models to chronically record neuronal activity. While tungsten microwires initially provide ...stable recordings, their inability to reliably record high-quality neural signals for tens of years has limited their efficacy for neuroprosthetic applications in humans. Comprehensive understanding of the mechanisms of electrode performance and failure is necessary for developing next generation neural interfaces for humans. In this study, we evaluated the abiotic (electrophysiology, impedance, electrode morphology) and biotic (microglial reactivity, blood-brain barrier disruption, biochemical markers of axonal injury) effects of 16-channel, 50 µm diameter, polyimide insulated tungsten microwires array for implant durations that ranged from acute to up to 9 months in 25 rats. Daily electrode impedance spectroscopy, electrophysiological recordings, blood and cerebrospinal fluid (CSF) withdrawals, and histopathological analysis were performed to study the time-varying effects of chronic electrode implantation. Structural changes at the electrode recording site were observed as early as within 2-3 h of electrode insertion. Abiotic analysis indicated the first 2-3 weeks following surgery was the most dynamic period in the chronic electrode lifetime as there were greater variations in the electrode impedance, functional electrode performance, and the structural changes occurring at the electrode recording tips. Electrode recording site deterioration continued for the long-term chronic animals as insulation damage occurred and recording surface became more recessed over time. In general, electrode impedance and functional performance had smaller daily variations combined with reduced electrode recording site changes during the chronic phase. Histopathological studies were focused largely on characterizing microglial cell responses to electrode implantation. We found that activated microglia were present near the electrode tracks in all non-acute animals studied, thus indicating presence of a neuroinflammatory response regardless of post-implantation survival times and electrode performance. Conversely, dystrophic microglia detectable as fragmented cells were found almost exclusively in acute animals surviving only few hours after implantation. While there was no consistent relationship between microglial cell responses and electrode performance, we noticed co-occurrence of high ferritin expression, intraparenchymal bleeding, and microglial degeneration suggesting presence of excessive oxidative stress via Fenton chemistry. Biochemical analysis indicated that these electrodes always caused a persistent release of axonal injury biomarkers even several months after implantation suggesting persistent tissue damage. Our study suggests that mechanisms of electrode failure are multi-factorial involving both abiotic and biotic parameters. Since these failure modes occur concurrently and cannot be isolated from one another, the lack of consistent relationship between electrode performance and microglial responses in our results suggest that one or more of the abiotic factors were equally responsible for degradation in electrode performance over long periods of time.
•DARPA's programs foster multi-disciplinary collaborations.•DARPA's BCI programs span four major challenges: detect, emulate, restore, & improve.•Aims: restore function after injury; improve ...performance of healthy individuals.
The Defense Advanced Research Projects Agency (DARPA) has funded innovative scientific research and technology developments in the field of brain–computer interfaces (BCI) since the 1970s. This review highlights some of DARPA's major advances in the field of BCI, particularly those made in recent years. Two broad categories of DARPA programs are presented with respect to the ultimate goals of supporting the nation's warfighters: (1) BCI efforts aimed at restoring neural and/or behavioral function, and (2) BCI efforts aimed at improving human training and performance. The programs discussed are synergistic and complementary to one another, and, moreover, promote interdisciplinary collaborations among researchers, engineers, and clinicians. Finally, this review includes a summary of some of the remaining challenges for the field of BCI, as well as the goals of new DARPA efforts in this domain.
Oocyte cryopreservation is extremely beneficial for assisted reproductive technologies, the treatment of infertility and biotechnology and offers a viable alternative to embryo freezing and ovarian ...grafting approaches for the generation of embryonic stem cells and live offspring. It also offers the potential to store oocytes to rescue endangered species by somatic cell nuclear transfer and for the generation of embryonic stem cells to study development in these species. We vitrified mouse oocytes using a range of concentrations of trehalose (0 to 0.3 M) and demonstrated that 0.1 and 0.3 M trehalose had similar developmental rates, which were significantly different to the 0.2 M cohort (P<0.05). As mitochondria are important for fertilisation outcome, we observed that the clustering and distribution of mitochondria of the 0.2 M cohort were more affected by vitifrication than the other groups. Nevertheless, all 3 cohorts were able to develop to blastocyst, following in vitro fertilisation, although developmental rates were better for the 0.1 and 0.3 M cohorts than the 0.2 M cohort (P<0.05). Whilst blastocysts gave rise to embryonic stem-like cells, it was apparent from immunocytochemistry and RT-PCR that these cells did not demonstrate true pluripotency and exhibited abnormal karyotypes. However, they gave rise to teratomas following injection into SCID mice and differentiated into cells of each of the germinal layers following in vitro differentiation. The transfer of 2-cell embryos from the 0.1 and 0.3 M cohorts resulted in the birth of live offspring that had normal karyotypes (9/10). When 2-cell embryos from vitrified oocytes underwent vitrification, and were thawed and transferred, live offspring were obtained that exhibited normal karyotypes, with the exception of one offspring who was larger and died at 7 months. We conclude that these studies highlight the importance of the endometrial environment for the maintenance of genetic stability and thus the propagation of specific genetic traits.
•Marmosets are a good bridge between rodent and larger primate models.•Husbandry, handling and acclimation to laboratory environments are presented here.•Marmosets were trained for reaching tasks and ...a touch screen task.•Neurosurgical techniques in marmosets are discussed in detail.
The common marmoset (Callithrix jacchus) has been proposed as a suitable bridge between rodents and larger primates. They have been used in several types of research including auditory, vocal, visual, pharmacological and genetics studies. However, marmosets have not been used as much for behavioral studies.
Here we present data from training 12 adult marmosets for behavioral neuroscience studies. We discuss the husbandry, food preferences, handling, acclimation to laboratory environments and neurosurgical techniques. In this paper, we also present a custom built “scoop” and a monkey chair suitable for training of these animals.
The animals were trained for three tasks: 4 target center-out reaching task, reaching tasks that involved controlling robot actions, and touch screen task. All animals learned the center-out reaching task within 1–2 weeks whereas learning reaching tasks controlling robot actions task took several months of behavioral training where the monkeys learned to associate robot actions with food rewards.
We propose the marmoset as a novel model for behavioral neuroscience research as an alternate for larger primate models. This is due to the ease of handling, quick reproduction, available neuroanatomy, sensorimotor system similar to larger primates and humans, and a lissencephalic brain that can enable implantation of microelectrode arrays relatively easier at various cortical locations compared to larger primates.
All animals were able to learn behavioral tasks well and we present the marmosets as an alternate model for simple behavioral neuroscience tasks.
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