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Miniaturization of implantable neural recording systems to micron-scale volumes will enable minimally invasive implantation and alleviate cortical scarring, gliosis, and resulting signal degradation. Ultrasound (US) power transmission has been demonstrated to have high efficiency and low tissue attenuation for mm-scale implants at depth in tissue [1, 2, 3], but has not been demonstrated with precision recording circuitry. We present an US implantable wireless neural recording system scaled to 0.8mm3, verified to safely operate at 5cm depth with state of the art neural recording performance an average circuit power dissipation of 13μW, and 28.8μW including power conversion efficiency. Sub-mm scale is achieved through single-link power and communication on a single piezocrystal (Lead Zirconate Titanate, PZT) utilizing linear analog backscattering, small die area, and eliminating all other off-chip components.

We present a 6.5mm3, 10mg, wireless peripheral nerve stimulator. The stimulator is powered and controlled through ultrasound from an external transducer and utilizes a single 750×750×750μm3 piezocrystal for downlink communication, powering, and readout, reducing implant volume and mass. An IC with 0.06mm2 active circuit area, designed in TSMC 65nm LPCMOS process, converts harvested ultrasound to stimulation charge with a peak efficiency of 82%. A custom wireless protocol that does not require a clock or memory circuits reduces on-chip power to 4μW when not stimulating. The encapsulated stimulator was cuffed to the sciatic nerve of an anesthetized rodent and demonstrated full-scale nerve activation in vivo. We achieve a highly efficient and temporally precise wireless peripheral nerve stimulator that is the smallest and lightest to our knowledge.

We present an 180nm HV CMOS IC for concurrent neural stimulation and recording that combines 64 low-noise recording front-ends and 4 independent stimulators multiplexed to any of the 64 channels. The stimulators have 5mA peak current, 12V compliance and dynamic power management to maximize efficiency. Co-design of the stimulation and recording subsystems resulted in 100mV of recording linear range, 70nV/rtHz noise, and a rapid 1ms (single-sample) artifact recovery during stimulation.

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Emerging applications in brain-machine interface systems require high-resolution, chronic multisite cortical recordings, which cannot be obtained with existing technologies due to high power consumption, high invasiveness, or inability to transmit data wirelessly. In this paper, we describe a microsystem based on electrocorticography (ECoG) that overcomes these difficulties, enabling chronic recording and wireless transmission of neural signals from the surface of the cerebral cortex. The device is comprised of a highly flexible, high-density, polymer-based 64-channel electrode array and a flexible antenna, bonded to 2.4 mm × 2.4 mm CMOS integrated circuit (IC) that performs 64-channel acquisition, wireless power and data transmission. The IC digitizes the signal from each electrode at 1 kS/s with 1.2 μV input referred noise, and transmits the serialized data using a 1 Mb/s backscattering modulator. A dual-mode power-receiving rectifier reduces data-dependent supply ripple, enabling the integration of small decoupling capacitors on chip and eliminating the need for external components. Design techniques in the wireless and baseband circuits result in over 16× reduction in die area with a simultaneous 3× improvement in power efficiency over the state of the art. The IC consumes 225 μW and can be powered by an external reader transmitting 12 mW at 300 MHz, which is over 3× lower than IEEE and FCC regulations.

Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and

Although brain-machine interfaces (BMIs) are directly controlled by the modulation of a select local population of neurons, distributed networks consisting of cortical and subcortical areas have been implicated in learning and maintaining control. Previous work in rodents has demonstrated the involvement of the striatum in BMI learning. However, the prefrontal cortex has been largely ignored when studying motor BMI control despite its role in action planning, action selection, and learning abstract tasks. Here, we compare local field potentials simultaneously recorded from primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), and the caudate nucleus of the striatum (Cd) while nonhuman primates perform a two-dimensional, self-initiated, center-out task under BMI control and manual control. Our results demonstrate the presence of distinct neural representations for BMI and manual control in M1, DLPFC, and Cd. We find that neural activity from DLPFC and M1 best distinguishes control types at the go cue and target acquisition, respectively, while M1 best predicts target-direction at both task events. We also find effective connectivity from DLPFC → M1 throughout both control types and Cd → M1 during BMI control. These results suggest distributed network activity between M1, DLPFC, and Cd during BMI control that is similar yet distinct from manual control., (© 2023. Springer Nature Limited.)

It has been proposed that the nervous system has the capacity to generate a wide variety of movements because it reuses some invariant code. Previous work has identified that dynamics of neural population activity are similar during different movements, where dynamics refer to how the instantaneous spatial pattern of population activity changes in time. Here, we test whether invariant dynamics of neural populations are actually used to issue the commands that direct movement. Using a brain-machine interface (BMI) that transforms rhesus macaques' motor-cortex activity into commands for a neuroprosthetic cursor, we discovered that the same command is issued with different neural-activity patterns in different movements. However, these different patterns were predictable, as we found that the transitions between activity patterns are governed by the same dynamics across movements. These invariant dynamics are low dimensional, and critically, they align with the BMI, so that they predict the specific component of neural activity that actually issues the next command. We introduce a model of optimal feedback control (OFC) that shows that invariant dynamics can help transform movement feedback into commands, reducing the input that the neural population needs to control movement. Altogether our results demonstrate that invariant dynamics drive commands to control a variety of movements and show how feedback can be integrated with invariant dynamics to issue generalizable commands., Competing Interests: Declaration of interests We disclose that we have filed for a patent based on this work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brain-machine interfaces (BMIs) provide a framework for studying how cortical population dynamics evolve over learning in a task in which the mapping between neural activity and behavior is precisely defined. Learning to control a BMI is associated with the emergence of coordinated neural dynamics in populations of neurons whose activity serves as direct input to the BMI decoder (direct subpopulation). While previous work shows differential modification of firing rate modulation in this population relative to a population whose activity was not directly input to the BMI decoder (indirect subpopulation), little is known about how learning-related changes in cortical population dynamics within these groups compare.To investigate this, we monitored both direct and indirect subpopulations as two macaque monkeys learned to control a BMI. We found that while the combined population increased coordinated neural dynamics, this increase in coordination was primarily driven by changes in the direct subpopulation. These findings suggest that motor cortex refines cortical dynamics by increasing neural variance throughout the entire population during learning, with a more pronounced coordination of firing activity in subpopulations that are causally linked to behavior., (© 2022. The Author(s).)

During motor learning, 1 as well as during neuroprosthetic learning, 2-4 animals learn to control motor cortex activity in order to generate behavior. Two different populations of motor cortex neurons, intra-telencephalic (IT) and pyramidal tract (PT) neurons, convey the resulting cortical signals within and outside the telencephalon. Although a large amount of evidence demonstrates contrasting functional organization among both populations, 5 , 6 it is unclear whether the brain can equally learn to control the activity of either class of motor cortex neurons. To answer this question, we used a calcium-imaging-based brain-machine interface (CaBMI) 3 and trained different groups of mice to modulate the activity of either IT or PT neurons in order to receive a reward. We found that the animals learned to control PT neuron activity faster and better than IT neuron activity. Moreover, our findings show that the advantage of PT neurons is the result of characteristics inherent to this population as well as their local circuitry and cortical depth location. Taken together, our results suggest that the motor cortex is more efficient at controlling the activity of pyramidal tract neurons, which are embedded deep in the cortex, and relaying motor commands outside the telencephalon., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective. Brain-machine interfaces (BMIs) have the potential to augment human functions and restore independence in people with disabilities, yet a compromise between non-invasiveness and performance limits their relevance. Approach. Here, we hypothesized that a non-invasive neuromuscular-machine interface providing real-time neurofeedback of individual motor units within a muscle could enable independent motor unit control to an extent suitable for high-performance BMI applications. Main results. Over 6 days of training, eight participants progressively learned to skillfully and independently control three biceps brachii motor units to complete a 2D center-out task. We show that neurofeedback enabled motor unit activity that largely violated recruitment constraints observed during ramp-and-hold isometric contractions thought to limit individual motor unit controllability. Finally, participants demonstrated the suitability of individual motor units for powering general applications through a spelling task. Significance. These results illustrate the flexibility of the sensorimotor system and highlight individual motor units as a promising source of control for BMI applications., (Creative Commons Attribution license.)

Pronounced activity is observed in both hemispheres of the motor cortex during preparation and execution of unimanual movements. The organizational principles of bi-hemispheric signals and the functions they serve throughout motor planning remain unclear. Using an instructed-delay reaching task in monkeys, we identified two components in population responses spanning PMd and M1. A "dedicated" component, which segregated activity at the level of individual units, emerged in PMd during preparation. It was most prominent following movement when M1 became strongly engaged, and principally involved the contralateral hemisphere. In contrast to recent reports, these dedicated signals solely accounted for divergence of arm-specific neural subspaces. The other "distributed" component mixed signals for each arm within units, and the subspace containing it did not discriminate between arms at any stage. The statistics of the population response suggest two functional aspects of the cortical network: one that spans both hemispheres for supporting preparatory and ongoing processes, and another that is predominantly housed in the contralateral hemisphere and specifies unilateral output., Competing Interests: The authors have declared that no competing interests exist.

Calcium imaging has great potential to be applied to online brain-machine interfaces (BMIs). As opposed to two-photon imaging settings, a one-photon microendoscopic imaging device can be chronically implanted and is subject to little motion artifacts. Traditionally, one-photon microendoscopic calcium imaging data are processed using the constrained nonnegative matrix factorization (CNMFe) algorithm, but this batched processing algorithm cannot be applied in real-time. An online analysis of calcium imaging data algorithm (or OnACIDe) has been proposed, but OnACIDe updates the neural components by repeatedly performing neuron identification frame-by-frame, which may decelerate the update speed if applying to online BMIs. For BMI applications, the ability to track a stable population of neurons in real-time has a higher priority over accurately identifying all the neurons in the field of view. By leveraging the fact that 1) microendoscopic recordings are rather stable with little motion artifacts and 2) the number of neurons identified in a short training period is sufficient for potential online BMI tasks such as cursor movements, we proposed the short-training CNMFe algorithm (stCNMFe) that skips motion correction and neuron identification processes to enable a more efficient BMI training program in a one-photon microendoscopic setting.

Microendoscopic calcium imaging with one-photon miniature microscopes enables unprecedented readout of neural circuit dynamics during active behavior in rodents. In this study, we describe successful application of this technology in the rhesus macaque, demonstrating plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from large populations of neurons simultaneously in bilateral dorsal premotor cortices during performance of a naturalistic motor reach task. Imaging is stable over several months, allowing us to longitudinally track individual neurons and monitor their relationship to motor behavior over time. We observe neuronal calcium dynamics selective for reach direction, which we could use to decode the animal's trial-by-trial motor behavior. This work establishes head-mounted microendoscopic calcium imaging in macaques as a powerful approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and it promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease., Competing Interests: Declaration of interests A.B., P.S.X., and J.J.N. are paid employees of Inscopix, Inc. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Advancements in novel neurotechnologies, such as brain computer interfaces (BCI) and neuromodulatory devices such as deep brain stimulators (DBS), will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose (1) democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, (2) new measures, including "Neurorights," for data privacy, security, and consent to empower neurotechnology users' control over their data, (3) new methods of identifying and preventing bias, and (4) the adoption of public guidelines for safe and equitable distribution of neurotechnological devices., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

How do organisms learn to do again, on-demand, a behavior that led to a desirable outcome? Dopamine-dependent cortico-striatal plasticity provides a framework for learning behavior's value, but it is less clear how it enables the brain to re-enter desired behaviors and refine them over time. Reinforcing behavior is achieved by re-entering and refining the neural patterns that produce it. We review studies using brain-machine interfaces which reveal that reinforcing cortical population activity requires cortico-basal ganglia circuits. Then, we propose a formal framework for how reinforcement in cortico-basal ganglia circuits acts on the neural dynamics of cortical populations. We propose two parallel mechanisms: i) fast reinforcement which selects the inputs that permit the re-entrance of the particular cortical population dynamics which naturally produced the desired behavior, and ii) slower reinforcement which leads to refinement of cortical population dynamics and more reliable production of neural trajectories driving skillful behavior on-demand., (Copyright © 2019. Published by Elsevier Ltd.)

Clinically approved neural stimulators are limited by battery requirements, as well as by their large size compared with the stimulation targets. Here, we describe a wireless, leadless and battery-free implantable neural stimulator that is 1.7 mm 3 and that incorporates a piezoceramic transducer, an energy-storage capacitor and an integrated circuit. An ultrasonic link and a hand-held external transceiver provide the stimulator with power and bidirectional communication. The stimulation protocols were wirelessly encoded on the fly, reducing power consumption and on-chip memory, and enabling protocol complexity with a high temporal resolution and low-latency feedback. Uplink data indicating whether stimulation occurs are encoded by the stimulator through backscatter modulation and are demodulated at the external transceiver. When embedded in ex vivo porcine tissue, the integrated circuit efficiently harvested ultrasonic power, decoded downlink data for the stimulation parameters and generated current-controlled stimulation pulses. When cuff-mounted and acutely implanted onto the sciatic nerve of anaesthetized rats, the device conferred repeatable stimulation across a range of physiological responses. The miniaturized neural stimulator may facilitate closed-loop neurostimulation for therapeutic interventions.

Objective: Microwire and Utah-style neural recording arrays are the predominant devices used for cortical neural recording, but the implanted electrodes cause a significant adverse biological response and suffer from well-studied performance degradation. Recent work has demonstrated that carbon fiber electrodes do not elicit this same adverse response, but these existing designs are not practically scalable to hundreds or thousands of recording sites. We present technology that overcomes these issues while additionally providing fine electrode pitch for spatial oversampling., Approach: We present a 32-channel carbon fiber monofilament-based intracortical neural recording array fabricated through a combination of bulk silicon microfabrication processing and microassembly. This device represents the first truly two-dimensional carbon fiber neural recording array. The density, channel count, and size scale of this array are enabled by an out-of-plane microassembly technique in which individual fibers are inserted through metallized and isotropically conductive adhesive-filled holes in an oxide-passivated microfabricated silicon substrate., Main Results: Five-micron diameter fibers are spaced at a pitch of 38 microns, four times denser than state of the art one-dimensional arrays. The fine diameter of the carbon fibers affords both minimal cross-section and nearly three orders of magnitude greater lateral compliance than standard tungsten microwires. Typical [Formula: see text] impedances are on the order of hundreds of kiloohms, and successful in vivo recording is demonstrated in the motor cortex of a rat. 22 total units are recorded on 20 channels, with unit SNR ranging from 1.4 to 8.0., Significance: This is the highest density microwire-style electrode array to date, and this fabrication technique is scalable to a larger number of electrodes and allows for the potential future integration of microelectronics. Large-scale carbon fiber neural recording arrays are a promising technology for reducing the inflammatory response and increasing the information density, particularly in neural recording applications where microwire arrays are already used.

Closed-loop neuromodulation systems aim to treat a variety of neurological conditions by delivering and adjusting therapeutic electrical stimulation in response to a patient's neural state, recorded in real time. Existing systems are limited by low channel counts, lack of algorithmic flexibility, and the distortion of recorded signals by large and persistent stimulation artefacts. Here, we describe an artefact-free wireless neuromodulation device that enables research applications requiring high-throughput data streaming, low-latency biosignal processing, and simultaneous sensing and stimulation. The device is a miniaturized neural interface capable of closed-loop recording and stimulation on 128 channels, with on-board processing to fully cancel stimulation artefacts. In addition, it can detect neural biomarkers and automatically adjust stimulation parameters in closed-loop mode. In a behaving non-human primate, the device enabled long-term recordings of local field potentials and the real-time cancellation of stimulation artefacts, as well as closed-loop stimulation to disrupt movement preparatory activity during a delayed-reach task. The neuromodulation device may help advance neuroscientific discovery and preclinical investigations of stimulation-based therapeutic interventions.

The neural dust platform uses ultrasonic power and communication to enable a scalable, wireless, and batteryless system for interfacing with the nervous system. Ultrasound offers several advantages over alternative wireless approaches, including a safe method for powering and communicating with sub mm-sized devices implanted deep in tissue. Early studies demonstrated that neural dust motes could wirelessly transmit high-fidelity electrophysiological data in vivo, and that theoretically, this system could be miniaturized well below the mm-scale. Future developments are focused on further minimization of the platform, better encapsulation methods as a path towards truly chronic neural interfaces, improved delivery mechanisms, stimulation capabilities, and finally refinements to enable deployment of neural dust in the central nervous system., (Copyright © 2017. Published by Elsevier Ltd.)

Animals acquire behaviors through instrumental conditioning. Brain-machine interfaces have used instrumental conditioning to reinforce patterns of neural activity directly, especially in frontal and motor cortices, which are a rich source of signals for voluntary action. However, evidence suggests that activity in primary sensory cortices may also reflect internally driven processes, instead of purely encoding antecedent stimuli. Here, we show that rats and mice can learn to produce arbitrary patterns of neural activity in their primary visual cortex to control an auditory cursor and obtain reward. Furthermore, learning was prevented when neurons in the dorsomedial striatum (DMS), which receives input from visual cortex, were optogenetically inhibited, but not during inhibition of nearby neurons in the dorsolateral striatum. After learning, DMS inhibition did not affect production of the rewarded patterns. These data demonstrate that cortico-basal ganglia circuits play a general role in learning to produce cortical activity that leads to desirable outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Thorndike's law of effect states that actions that lead to reinforcements tend to be repeated more often. Accordingly, neural activity patterns leading to reinforcement are also reentered more frequently. Reinforcement relies on dopaminergic activity in the ventral tegmental area (VTA), and animals shape their behavior to receive dopaminergic stimulation. Seeking evidence for a neural law of effect, we found that mice learn to reenter more frequently motor cortical activity patterns that trigger optogenetic VTA self-stimulation. Learning was accompanied by gradual shaping of these patterns, with participating neurons progressively increasing and aligning their covariance to that of the target pattern. Motor cortex patterns that lead to phasic dopaminergic VTA activity are progressively reinforced and shaped, suggesting a mechanism by which animals select and shape actions to reliably achieve reinforcement., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Value-based decision-making involves an assessment of the value of items available and the actions required to obtain them. The basal ganglia are highly implicated in action selection and goal-directed behavior [1-4], and the striatum in particular plays a critical role in arbitrating between competing choices [5-9]. Previous work has demonstrated that neural activity in the caudate nucleus is modulated by task-relevant action values [6, 8]. Nonetheless, how value is represented and maintained in the striatum remains unclear since decision-making in these tasks relied on spatially lateralized responses, confounding the ability to generalize to a more abstract choice task [6, 8, 9]. Here, we investigate striatal value representations by applying caudate electrical stimulation in macaque monkeys (n = 3) to bias decision-making in a task that divorces the value of a stimulus from motor action. Electrical microstimulation is known to induce neural plasticity [10, 11], and caudate microstimulation in primates has been shown to accelerate associative learning [12, 13]. Our results indicate that stimulation paired with a particular stimulus increases selection of that stimulus, and this effect was stimulus dependent and action independent. The modulation of choice behavior using microstimulation was best modeled as resulting from changes in stimulus value. Caudate neural recordings (n = 1) show that changes in value-coding neuron activity are stimulus value dependent. We argue that caudate microstimulation can differentially increase stimulus values independent of action, and unilateral manipulations of value are sufficient to mediate choice behavior. These results support potential future applications of microstimulation to correct maladaptive plasticity underlying dysfunctional decision-making related to neuropsychiatric conditions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is characterized by motor symptoms such as rigidity and bradykinesia that prevent normal movement. Beta band oscillations (13-30 Hz) in neural local field potentials (LFPs) have been associated with these motor symptoms. Here, three PD patients implanted with a therapeutic deep brain neural stimulator that can also record and wirelessly stream neural data played a neurofeedback game where they modulated their beta band power from sensorimotor cortical areas. Patients' beta band power was streamed in real-time to update the position of a cursor that they tried to drive into a cued target. After playing the game for 1-2 hours each, all three patients exhibited above chance-level performance regardless of subcortical stimulation levels. This study, for the first time, demonstrates using an invasive neural recording system for at-home neurofeedback training. Future work will investigate chronic neurofeedback training as a potentially therapeutic tool for patients with neurological disorders.

Objective: Current neural probes have a limited device lifetime of a few years. Their common failure mode is the degradation of insulating films and/or the delamination of the conductor-insulator interfaces. We sought to develop a technology that does not suffer from such limitations and would be suitable for chronic applications with very long device lifetimes., Approach: We developed a fabrication method that integrates polycrystalline conductive silicon carbide with insulating silicon carbide. The technology employs amorphous silicon carbide as the insulator and conductive silicon carbide at the recording sites, resulting in a seamless transition between doped and amorphous regions of the same material, eliminating heterogeneous interfaces prone to delamination. Silicon carbide has outstanding chemical stability, is biocompatible, is an excellent molecular barrier and is compatible with standard microfabrication processes., Main Results: We have fabricated silicon carbide electrode arrays using our novel fabrication method. We conducted in vivo experiments in which electrocorticography recordings from the primary visual cortex of a rat were obtained and were of similar quality to those of polymer based electrocorticography arrays. The silicon carbide electrode arrays were also used as a cuff electrode wrapped around the sciatic nerve of a rat to record the nerve response to electrical stimulation. Finally, we demonstrated the outstanding long term stability of our insulating silicon carbide films through accelerated aging tests., Significance: Clinical translation in neural engineering has been slowed in part due to the poor long term performance of current probes. Silicon carbide devices are a promising technology that may accelerate this transition by enabling truly chronic applications.

Brain-machine interface (BMI) systems use signals acquired from the brain to directly control the movement of an actuator, such as a computer cursor or a robotic arm, with the goal of restoring motor function lost due to injury or disease of the nervous system. In BMIs with kinematically redundant actuators, the combination of the task goals and the system under neural control can allow for many equally optimal task solutions. The extent to which kinematically redundant degrees of freedom (DOFs) in a BMI system may be under direct neural control is unknown. To address this question, a Kalman filter was used to decode single- and multi-unit cortical neural activity of two macaque monkeys into the joint velocities of a virtual four-link kinematic chain. Subjects completed movements of the chain's endpoint to instructed target locations within a two-dimensional plane. This system was kinematically redundant for an endpoint movement task, as four DOFs were used to manipulate the 2-D endpoint position. Both subjects successfully performed the task and improved with practice by producing faster endpoint velocity control signals. Kinematic redundancy allowed null movements whereby the individual links of the chain could move in a way that cancels out and does not result in endpoint movement. As the subjects became more proficient at controlling the chain, the amount of null movement also increased. Task performance suffered when the links of the kinematic chain were hidden and only the endpoint was visible. Furthermore, all four DOFs of the joint-velocity control space exhibited task-relevant modulation. The relative usage of each DOF depended on the configuration of the chain, and trials in which the less-prominent DOFs were utilized also had better task performance. Overall, these results indicate that the subjects incorporated the redundant components of the control space into their control strategy. Future BMI systems with kinematic redundancy, such as exoskeletal systems or anthropomorphic robotic arms, may benefit from allowing neural control over redundant configuration dimensions as well as the end-effector.

Motor cortical beta oscillations have been reported for decades, yet their behavioral correlates remain unresolved. Some studies link beta oscillations to changes in underlying neural activity, but the specific behavioral manifestations of these reported changes remain elusive. To investigate how changes in population neural activity, beta oscillations, and behavior are linked, we recorded multi-scale neural activity from motor cortex while three macaques performed a novel neurofeedback task. Subjects volitionally brought their beta oscillatory power to an instructed state and subsequently executed an arm reach. Reaches preceded by a reduction in beta power exhibited significantly faster movement onset times than reaches preceded by an increase in beta power. Further, population neural activity was found to shift farther from a movement onset state during beta oscillations that were neurofeedback-induced or naturally occurring during reaching tasks. This finding establishes a population neural basis for slowed movement onset following periods of beta oscillatory activity.

During motor learning, movements and underlying neural activity initially exhibit large trial-to-trial variability that decreases over learning. However, it is unclear how task-relevant neural populations coordinate to explore and consolidate activity patterns. Exploration and consolidation could happen for each neuron independently, across the population jointly, or both. We disambiguated among these possibilities by investigating how subjects learned de novo to control a brain-machine interface using neurons from motor cortex. We decomposed population activity into the sum of private and shared signals, which produce uncorrelated and correlated neural variance, respectively, and examined how these signals' evolution causally shapes behavior. We found that initially large trial-to-trial movement and private neural variability reduce over learning. Concomitantly, task-relevant shared variance increases, consolidating a manifold containing consistent neural trajectories that generate refined control. These results suggest that motor cortex acquires skillful control by leveraging both independent and coordinated variance to explore and consolidate neural patterns., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Brain-machine interfaces (BMI) create novel sensorimotor pathways for action. Much as the sensorimotor apparatus shapes natural motor control, the BMI pathway characteristics may also influence neuroprosthetic control. Here, we explore the influence of control and feedback rates, where control rate indicates how often motor commands are sent from the brain to the prosthetic, and feedback rate indicates how often visual feedback of the prosthetic is provided to the subject. We developed a new BMI that allows arbitrarily fast control and feedback rates, and used it to dissociate the effects of each rate in two monkeys. Increasing the control rate significantly improved control even when feedback rate was unchanged. Increasing the feedback rate further facilitated control. We also show that our high-rate BMI significantly outperformed state-of-the-art methods due to higher control and feedback rates, combined with a different point process mathematical encoding model. Our BMI paradigm can dissect the contribution of different elements in the sensorimotor pathway, providing a unique tool for studying neuroprosthetic control mechanisms.

The emerging field of bioelectronic medicine seeks methods for deciphering and modulating electrophysiological activity in the body to attain therapeutic effects at target organs. Current approaches to interfacing with peripheral nerves and muscles rely heavily on wires, creating problems for chronic use, while emerging wireless approaches lack the size scalability necessary to interrogate small-diameter nerves. Furthermore, conventional electrode-based technologies lack the capability to record from nerves with high spatial resolution or to record independently from many discrete sites within a nerve bundle. Here, we demonstrate neural dust, a wireless and scalable ultrasonic backscatter system for powering and communicating with implanted bioelectronics. We show that ultrasound is effective at delivering power to mm-scale devices in tissue; likewise, passive, battery-less communication using backscatter enables high-fidelity transmission of electromyogram (EMG) and electroneurogram (ENG) signals from anesthetized rats. These results highlight the potential for an ultrasound-based neural interface system for advancing future bioelectronics-based therapies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Many closed-loop, continuous-control brain-machine interface (BMI) architectures rely on decoding via a linear readout of noisy population neural activity. However, recent work has found that decomposing neural population activity into correlated and uncorrelated variability reveals that improvements in cursor control coincide with the emergence of correlated neural variability. In order to address how correlated and uncorrelated neural variability arises and contributes to BMI cursor control, we simulate a neural population receiving combinations of shared inputs affecting all cells and private inputs affecting only individual cells. When simulating BMI cursor-control with different populations, we find that correlated activity generates faster, straighter cursor trajectories, yet sometimes at the cost of inaccuracies. We also find that correlated variability can be generated from either shared inputs or quickly updated private inputs. Overall, our results suggest a role for both correlated and uncorrelated neural activity in cursor control, and potential mechanisms by which correlated activity may emerge.

Much progress has been made in brain-machine interfaces (BMI) using decoders such as Kalman filters and finding their parameters with closed-loop decoder adaptation (CLDA). However, current decoders do not model the spikes directly, and hence may limit the processing time-scale of BMI control and adaptation. Moreover, while specialized CLDA techniques for intention estimation and assisted training exist, a unified and systematic CLDA framework that generalizes across different setups is lacking. Here we develop a novel closed-loop BMI training architecture that allows for processing, control, and adaptation using spike events, enables robust control and extends to various tasks. Moreover, we develop a unified control-theoretic CLDA framework within which intention estimation, assisted training, and adaptation are performed. The architecture incorporates an infinite-horizon optimal feedback-control (OFC) model of the brain's behavior in closed-loop BMI control, and a point process model of spikes. The OFC model infers the user's motor intention during CLDA-a process termed intention estimation. OFC is also used to design an autonomous and dynamic assisted training technique. The point process model allows for neural processing, control and decoder adaptation with every spike event and at a faster time-scale than current decoders; it also enables dynamic spike-event-based parameter adaptation unlike current CLDA methods that use batch-based adaptation on much slower adaptation time-scales. We conducted closed-loop experiments in a non-human primate over tens of days to dissociate the effects of these novel CLDA components. The OFC intention estimation improved BMI performance compared with current intention estimation techniques. OFC assisted training allowed the subject to consistently achieve proficient control. Spike-event-based adaptation resulted in faster and more consistent performance convergence compared with batch-based methods, and was robust to parameter initialization. Finally, the architecture extended control to tasks beyond those used for CLDA training. These results have significant implications towards the development of clinically-viable neuroprosthetics.

Objective: Movements made by healthy individuals can be characterized as superpositions of smooth bell-shaped velocity curves. Decomposing complex movements into these simpler "submovement" building blocks is useful for studying the neural control of movement as well as measuring motor impairment due to neurological injury., Approach: One prevalent strategy to submovement decomposition is to formulate it as an optimization problem. This optimization problem is nonconvex and finding an exact solution is computationally burdensome. We build on previous literature that generated approximate solutions to the submovement optimization problem., Results: First, we demonstrate broad conditions on the submovement building block functions that enable the optimization variables to be partitioned into disjoint subsets, allowing for a faster alternating minimization solution. Specifically, the amplitude parameters of a submovement can typically be fit independently of its shape parameters. Second, we develop a method to concentrate the search in regions of high error to make more efficient use of optimization routine iterations., Conclusion: Both innovations result in substantial reductions in computation time across multiple nonhuman primate subjects and diverse task conditions., Significance: These innovations may accelerate analysis of submovements for basic neuroscience and enable real-time applications of submovement decomposition.

Evidence suggests that the CNS uses motor primitives to simplify movement control, but whether it actually stores primitives instead of computing solutions on the fly to satisfy task demands is a controversial and still-unanswered possibility. Also in contention is whether these primitives take the form of time-invariant muscle coactivations ("spatial" synergies) or time-varying muscle commands ("spatiotemporal" synergies). Here, we examined forelimb muscle patterns and motor cortical spiking data in rhesus macaques (Macaca mulatta) handling objects of variable shape and size. From these data, we extracted both spatiotemporal and spatial synergies using non-negative decomposition. Each spatiotemporal synergy represents a sequence of muscular or neural activations that appeared to recur frequently during the animals' behavior. Key features of the spatiotemporal synergies (including their dimensionality, timing, and amplitude modulation) were independently observed in the muscular and neural data. In addition, both at the muscular and neural levels, these spatiotemporal synergies could be readily reconstructed as sequential activations of spatial synergies (a subset of those extracted independently from the task data), suggestive of a hierarchical relationship between the two levels of synergies. The possibility that motor cortex may execute even complex skill using spatiotemporal synergies has novel implications for the design of neuroprosthetic devices, which could gain computational efficiency by adopting the discrete and low-dimensional control that these primitives imply., Significance Statement: We studied the motor cortical and forearm muscular activity of rhesus macaques (Macaca mulatta) as they reached, grasped, and carried objects of varied shape and size. We applied non-negative matrix factorization separately to the cortical and muscular data to reduce their dimensionality to a smaller set of time-varying "spatiotemporal" synergies. Each synergy represents a sequence of cortical or muscular activity that recurred frequently during the animals' behavior. Salient features of the synergies (including their dimensionality, timing, and amplitude modulation) were observed at both the cortical and muscular levels. The possibility that the brain may execute even complex behaviors using spatiotemporal synergies has implications for neuroprosthetic algorithm design, which could become more computationally efficient by adopting the discrete and low-dimensional control that they afford., (Copyright © 2015 the authors 0270-6474/15/3512615-10$15.00/0.)

In this paper, we present an ultrasonic beamforming system capable of interrogating individual implantable sensors via backscatter in a distributed, ultrasound-based recording platform known as Neural Dust [1]. A custom ASIC drives a 7 × 2 PZT transducer array with 3 cycles of 32V square wave with a specific programmable time delay to focus the beam at the 800mm neural dust mote placed 50mm away. The measured acoustic-to-electrical conversion efficiency of the receive mote in water is 0.12% and the overall system delivers 26.3% of the power from the 1.8V power supply to the transducer drive output, consumes 0.75μJ in each transmit phase, and has a 0.5% change in the backscatter per volt applied to the input of the backscatter circuit. Further miniaturization of both the transmit array and the receive mote can pave the way for a wearable, chronic sensing and neuromodulation system.

Local field potential (LFP) activity in motor cortical and basal ganglia regions exhibits prominent beta (15-40Hz) oscillations during reaching and grasping, muscular contraction, and attention tasks. While in vitro and computational work has revealed specific mechanisms that may give rise to the frequency and duration of this oscillation, there is still controversy about what behavioral processes ultimately drive it. Here, simultaneous behavioral and large-scale neural recording experiments from non-human primate and human subjects are reviewed in the context of specific hypotheses about how beta band activity is generated. Finally, a new experimental paradigm utilizing operant conditioning combined with motor tasks is proposed as a way to further investigate this oscillation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

With the advent of high-throughput measurement techniques, scientists and engineers are starting to grapple with massive data sets and encountering challenges with how to organize, process and extract information into meaningful structures. Multidimensional spatio-temporal biological data sets such as time series gene expression with various perturbations over different cell lines, or neural spike trains across many experimental trials, have the potential to acquire insight about the dynamic behavior of the system. For this potential to be realized, we need a suitable representation to understand the data. A general question is how to organize the observed data into meaningful structures and how to find an appropriate similarity measure. A natural way of viewing these complex high dimensional data sets is to examine and analyze the large-scale features and then to focus on the interesting details. Since the wide range of experiments and unknown complexity of the underlying system contribute to the heterogeneity of biological data, we develop a new method by proposing an extension of Robust Principal Component Analysis (RPCA), which models common variations across multiple experiments as the lowrank component and anomalies across these experiments as the sparse component. We show that the proposed method is able to find distinct subtypes and classify data sets in a robust way without any prior knowledge by separating these common responses and abnormal responses. Thus, the proposed method provides us a new representation of these data sets which has the potential to help users acquire new insight from data.

A major hurdle in brain-machine interfaces (BMI) is the lack of an implantable neural interface system that remains viable for a substantial fraction of the user's lifetime. Recently, sub-mm implantable, wireless electromagnetic (EM) neural interfaces have been demonstrated in an effort to extend system longevity. However, EM systems do not scale down in size well due to the severe inefficiency of coupling radio-waves at those scales within tissue. This paper explores fundamental system design trade-offs as well as size, power, and bandwidth scaling limits of neural recording systems built from low-power electronics coupled with ultrasonic power delivery and backscatter communication. Such systems will require two fundamental technology innovations: (1) 10-100 μm scale, free-floating, independent sensor nodes, or neural dust, that detect and report local extracellular electrophysiological data via ultrasonic backscattering and (2) a sub-cranial ultrasonic interrogator that establishes power and communication links with the neural dust. We provide experimental verification that the predicted scaling effects follow theory; (127 μm)(3) neural dust motes immersed in water 3 cm from the interrogator couple with 0.002064% power transfer efficiency and 0.04246 ppm backscatter, resulting in a maximum received power of ∼0.5 μW with ∼1 nW of change in backscatter power with neural activity. The high efficiency of ultrasonic transmission can enable the scaling of the sensing nodes down to 10s of micrometer. We conclude with a brief discussion of the application of neural dust for both central and peripheral nervous system recordings, and perspectives on future research directions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Brain-machine interfaces (BMIs) aim to help people with paralysis by decoding movement-related neural signals into control signals for guiding computer cursors, prosthetic arms, and other assistive devices. Despite compelling laboratory experiments and ongoing FDA pilot clinical trials, system performance, robustness, and generalization remain challenges. We provide a perspective on how two complementary lines of investigation, that have focused on decoder design and neural adaptation largely separately, could be brought together to advance BMIs. This BMI paradigm should also yield new scientific insights into the function and dysfunction of the nervous system., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Brain-machine interfaces (BMIs) are dynamical systems whose properties ultimately influence performance. For instance, a 2-D BMI in which cursor position is controlled using a Kalman filter will, by default, create an attractor point that "pulls" the cursor to particular points in the workspace. If created unintentionally, such effects may not be beneficial for BMI performance. However, there have been few empirical studies exploring how various dynamical effects of closed-loop BMIs ultimately influence performance. In this work, we utilize experimental data from two macaque monkeys operating a closed-loop BMI to reach to 2-D targets and show that certain dynamical properties correlate with performance loss. We also show that other dynamical properties represent tradeoffs between naturally competing objectives, such as speed versus accuracy. These findings highlight the importance of fine-tuning the dynamical properties of closed-loop BMIs to optimize task-specific performance.

Closed-loop decoder adaptation (CLDA) is an emerging paradigm for both improving and maintaining online performance in brain-machine interfaces (BMIs). The time required for initial decoder training and any subsequent decoder recalibrations could be potentially reduced by performing continuous adaptation, in which decoder parameters are updated at every time step during these procedures, rather than waiting to update the decoder at periodic intervals in a more batch-based process. Here, we present recursive maximum likelihood (RML), a CLDA algorithm that performs continuous adaptation of a Kalman filter decoder's parameters. We demonstrate that RML possesses a variety of useful properties and practical algorithmic advantages. First, we show how RML leverages the accuracy of updates based on a batch of data while still adapting parameters on every time step. Second, we illustrate how the RML algorithm is parameterized by a single, intuitive half-life parameter that can be used to adjust the rate of adaptation in real time. Third, we show how even when the number of neural features is very large, RML's memory-efficient recursive update rules can be reformulated to also be computationally fast so that continuous adaptation is still feasible. To test the algorithm in closed-loop experiments, we trained three macaque monkeys to perform a center-out reaching task by using either spiking activity or local field potentials to control a 2D computer cursor. RML achieved higher levels of performance more rapidly in comparison to a previous CLDA algorithm that adapts parameters on a more intermediate timescale. Overall, our results indicate that RML is an effective CLDA algorithm for achieving rapid performance acquisition using continuous adaptation.

Neuroplasticity may play a critical role in developing robust, naturally controlled neuroprostheses. This learning, however, is sensitive to system changes such as the neural activity used for control. The ultimate utility of neuroplasticity in real-world neuroprostheses is thus unclear. Adaptive decoding methods hold promise for improving neuroprosthetic performance in nonstationary systems. Here, we explore the use of decoder adaptation to shape neuroplasticity in two scenarios relevant for real-world neuroprostheses: nonstationary recordings of neural activity and changes in control context. Nonhuman primates learned to control a cursor to perform a reaching task using semistationary neural activity in two contexts: with and without simultaneous arm movements. Decoder adaptation was used to improve initial performance and compensate for changes in neural recordings. We show that beneficial neuroplasticity can occur alongside decoder adaptation, yielding performance improvements, skill retention, and resistance to interference from native motor networks. These results highlight the utility of neuroplasticity for real-world neuroprostheses., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Brain-machine interfaces are not only promising for neurological applications, but also powerful for investigating neuronal ensemble dynamics during learning. We trained mice to operantly control an auditory cursor using spike-related calcium signals recorded with two-photon imaging in motor and somatosensory cortex. Mice rapidly learned to modulate activity in layer 2/3 neurons, evident both across and within sessions. Learning was accompanied by modifications of firing correlations in spatially localized networks at fine scales.

Objective: Intracortical brain-machine interfaces (BMIs) have predominantly utilized spike activity as the control signal. However, an increasing number of studies have shown the utility of local field potentials (LFPs) for decoding motor related signals. Currently, it is unclear how well different LFP frequencies can serve as features for continuous, closed-loop BMI control., Approach: We demonstrate 2D continuous LFP-based BMI control using closed-loop decoder adaptation, which adapts decoder parameters to subject-specific LFP feature modulations during BMI control. We trained two macaque monkeys to control a 2D cursor in a center-out task by modulating LFP power in the 0-150 Hz range., Main Results: While both monkeys attained control, they used different strategies involving different frequency bands. One monkey primarily utilized the low-frequency spectrum (0-80 Hz), which was highly correlated between channels, and obtained proficient performance even with a single channel. In contrast, the other monkey relied more on higher frequencies (80-150 Hz), which were less correlated between channels, and had greater difficulty with control as the number of channels decreased. We then restricted the monkeys to use only various sub-ranges (0-40, 40-80, and 80-150 Hz) of the 0-150 Hz band. Interestingly, although both monkeys performed better with some sub-ranges than others, they were able to achieve BMI control with all sub-ranges after decoder adaptation, demonstrating broad flexibility in the frequencies that could potentially be used for LFP-based BMI control., Significance: Overall, our results demonstrate proficient, continuous BMI control using LFPs and provide insight into the subject-specific spectral patterns of LFP activity modulated during control.

Electrical microstimulation studies provide some of the most direct evidence for the neural representation of muscle synergies. These synergies, i.e., coordinated activations of groups of muscles, have been proposed as building blocks for the construction of motor behaviors by the nervous system. Intraspinal or intracortical microstimulation (ICMS) has been shown to evoke muscle patterns that can be resolved into a small set of synergies similar to those seen in natural behavior. However, questions remain about the validity of microstimulation as a probe of neural function, particularly given the relatively long trains of supratheshold stimuli used in these studies. Here, we examined whether muscle synergies evoked during ICMS in two rhesus macaques were similarly encoded by nearby motor cortical units during a purely voluntary behavior involving object reach, grasp, and carry movements. At each microstimulation site we identified the synergy most strongly evoked among those extracted from muscle patterns evoked over all microstimulation sites. For each cortical unit recorded at the same microstimulation site, we then identified the synergy most strongly encoded among those extracted from muscle patterns recorded during the voluntary behavior. We found that the synergy most strongly evoked at an ICMS site matched the synergy most strongly encoded by proximal units more often than expected by chance. These results suggest a common neural substrate for microstimulation-evoked motor responses and for the generation of muscle patterns during natural behaviors.

In this paper, we examine the use of beamforming techniques to interrogate a multitude of neural implants in a distributed, ultrasound-based intra-cortical recording platform known as Neural Dust. We propose a general framework to analyze system design tradeoffs in the ultrasonic beamformer that extracts neural signals from modulated ultrasound waves that are backscattered by free-floating neural dust (ND) motes. Simulations indicate that high-resolution linearly-constrained minimum variance beamforming sufficiently suppresses interference from unselected ND motes and can be incorporated into the ND-based cortical recording system.

Brain-machine interface (BMI) performance has been improved using Kalman filters (KF) combined with closed-loop decoder adaptation (CLDA). CLDA fits the decoder parameters during closed-loop BMI operation based on the neural activity and inferred user velocity intention. These advances have resulted in the recent ReFIT-KF and SmoothBatch-KF decoders. Here we demonstrate high-performance and robust BMI control using a novel closed-loop BMI architecture termed adaptive optimal feedback-controlled (OFC) point process filter (PPF). Adaptive OFC-PPF allows subjects to issue neural commands and receive feedback with every spike event and hence at a faster rate than the KF. Moreover, it adapts the decoder parameters with every spike event in contrast to current CLDA techniques that do so on the time-scale of minutes. Finally, unlike current methods that rotate the decoded velocity vector, adaptive OFC-PPF constructs an infinite-horizon OFC model of the brain to infer velocity intention during adaptation. Preliminary data collected in a monkey suggests that adaptive OFC-PPF improves BMI control. OFC-PPF outperformed SmoothBatch-KF in a self-paced center-out movement task with 8 targets. This improvement was due to both the PPF's increased rate of control and feedback compared with the KF, and to the OFC model suggesting that the OFC better approximates the user's strategy. Also, the spike-by-spike adaptation resulted in faster performance convergence compared to current techniques. Thus adaptive OFC-PPF enabled proficient BMI control in this monkey.

Brain-machine interfaces (BMIs) are an emerging technology with great promise for developing restorative therapies for those with disabilities. BMIs also create novel, well-defined functional circuits for action that are distinct from the natural sensorimotor apparatus. Closed-loop control of BMI systems can also actively engage learning and adaptation. These properties make BMIs uniquely suited to study learning of motor and non-physical, abstract skills. Recent work used motor BMIs to shed light on the neural representations of skill formation and motor adaptation. Emerging work in sensory BMIs, and other novel interface systems, also highlight the promise of using BMI systems to study fundamental questions in learning and sensorimotor control. This paper outlines the interpretation of BMIs as novel closed-loop systems and the benefits of these systems for studying learning. We review BMI learning studies, their relation to motor control, and propose future directions for this nascent field. Understanding learning in BMIs may both elucidate mechanisms of natural motor and abstract skill learning, and aid in developing the next generation of neuroprostheses.