A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation.

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.

Biomechanical and Cortical Control of Tongue Movements During Chewing and Swallowing.

Tongue function is vital for chewing and swallowing and lingual dysfunction is often associated with dysphagia. Better treatment of dysphagia depends on a better understanding of hyolingual morphology, biomechanics, and neural control in humans and animal models. Recent research has revealed significant variation among animal models in morphology of the hyoid chain and suprahyoid muscles which may be associated with variation in swallowing mechanisms. The recent deployment of XROMM (X-ray Reconstruction of Moving Morphology) to quantify 3D hyolingual kinematics has revealed new details on flexion and roll of the tongue during chewing in animal models, movements similar to those used by humans. XROMM-based studies of swallowing in macaques have falsified traditional hypotheses of mechanisms of tongue base retraction during swallowing, and literature review suggests that other animal models may employ a diversity of mechanisms of tongue base retraction. There is variation among animal models in distribution of hyolingual proprioceptors but how that might be related to lingual mechanics is unknown. In macaque monkeys, tongue kinematics-shape and movement-are strongly encoded in neural activity in orofacial primary motor cortex, giving optimism for development of brain-machine interfaces for assisting recovery of lingual function after stroke. However, more research on hyolingual biomechanics and control is needed for technologies interfacing the nervous system with the hyolingual apparatus to become a reality.

Microstimulation of human somatosensory cortex evokes task-dependent, spatially patterned responses in motor cortex.

The primary motor (M1) and somatosensory (S1) cortices play critical roles in motor control but the signaling between these structures is poorly understood. To fill this gap, we recorded - in three participants in an ongoing human clinical trial (NCT01894802) for people with paralyzed hands - the responses evoked in the hand and arm representations of M1 during intracortical microstimulation (ICMS) in the hand representation of S1. We found that ICMS of S1 activated some M1 neurons at short, fixed latencies consistent with monosynaptic activation. Additionally, most of the ICMS-evoked responses in M1 were more variable in time, suggesting indirect effects of stimulation. The spatial pattern of M1 activation varied systematically: S1 electrodes that elicited percepts in a finger preferentially activated M1 neurons excited during that finger's movement. Moreover, the indirect effects of S1 ICMS on M1 were context dependent, such that the magnitude and even sign relative to baseline varied across tasks. We tested the implications of these effects for brain-control of a virtual hand, in which ICMS conveyed tactile feedback. While ICMS-evoked activation of M1 disrupted decoder performance, this disruption was minimized using biomimetic stimulation, which emphasizes contact transients at the onset and offset of grasp, and reduces sustained stimulation.

Multiple regions of sensorimotor cortex encode bite force and gape.

The precise control of bite force and gape is vital for safe and effective breakdown and manipulation of food inside the oral cavity during feeding. Yet, the role of the orofacial sensorimotor cortex (OSMcx) in the control of bite force and gape is still largely unknown. The aim of this study was to elucidate how individual neurons and populations of neurons in multiple regions of OSMcx differentially encode bite force and static gape when subjects (Macaca mulatta) generated different levels of bite force at varying gapes. We examined neuronal activity recorded simultaneously from three microelectrode arrays implanted chronically in the primary motor (MIo), primary somatosensory (SIo), and cortical masticatory (CMA) areas of OSMcx. We used generalized linear models to evaluate encoding properties of individual neurons and utilized dimensionality reduction techniques to decompose population activity into components related to specific task parameters. Individual neurons encoded bite force more strongly than gape in all three OSMCx areas although bite force was a better predictor of spiking activity in MIo vs. SIo. Population activity differentiated between levels of bite force and gape while preserving task-independent temporal modulation across the behavioral trial. While activation patterns of neuronal populations were comparable across OSMCx areas, the total variance explained by task parameters was context-dependent and differed across areas. These findings suggest that the cortical control of static gape during biting may rely on computations at the population level whereas the strong encoding of bite force at the individual neuron level allows for the precise and rapid control of bite force.

Dynamic structure of motor cortical neuron coactivity carries behaviorally relevant information.

Skillful, voluntary movements are underpinned by computations performed by networks of interconnected neurons in the primary motor cortex (M1). Computations are reflected by patterns of coactivity between neurons. Using pairwise spike time statistics, coactivity can be summarized as a functional network (FN). Here, we show that the structure of FNs constructed from an instructed-delay reach task in nonhuman primates is behaviorally specific: Low-dimensional embedding and graph alignment scores show that FNs constructed from closer target reach directions are also closer in network space. Using short intervals across a trial, we constructed temporal FNs and found that temporal FNs traverse a low-dimensional subspace in a reach-specific trajectory. Alignment scores show that FNs become separable and correspondingly decodable shortly after the Instruction cue. Finally, we observe that reciprocal connections in FNs transiently decrease following the Instruction cue, consistent with the hypothesis that information external to the recorded population temporarily alters the structure of the network at this moment.

Tessellation of artificial touch via microstimulation of human somatosensory cortex.

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participant's hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multichannel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

Interplay between external inputs and recurrent dynamics during movement preparation and execution in a network model of motor cortex.

The primary motor cortex has been shown to coordinate movement preparation and execution through computations in approximately orthogonal subspaces. The underlying network mechanisms, and the roles played by external and recurrent connectivity, are central open questions that need to be answered to understand the neural substrates of motor control. We develop a recurrent neural network model that recapitulates the temporal evolution of neuronal activity recorded from the primary motor cortex of a macaque monkey during an instructed delayed-reach task. In particular, it reproduces the observed dynamic patterns of covariation between neural activity and the direction of motion. We explore the hypothesis that the observed dynamics emerges from a synaptic connectivity structure that depends on the preferred directions of neurons in both preparatory and movement-related epochs, and we constrain the strength of both synaptic connectivity and external input parameters from data. While the model can reproduce neural activity for multiple combinations of the feedforward and recurrent connections, the solution that requires minimum external inputs is one where the observed patterns of covariance are shaped by external inputs during movement preparation, while they are dominated by strong direction-specific recurrent connectivity during movement execution. Our model also demonstrates that the way in which single-neuron tuning properties change over time can explain the level of orthogonality of preparatory and movement-related subspaces.

Robust cortical encoding of 3D tongue shape during feeding in macaques.

Dexterous tongue deformation underlies eating, drinking, and speaking. The orofacial sensorimotor cortex has been implicated in the control of coordinated tongue kinematics, but little is known about how the brain encodes-and ultimately drives-the tongue's 3D, soft-body deformation. Here we combine a biplanar x-ray video technology, multi-electrode cortical recordings, and machine-learning-based decoding to explore the cortical representation of lingual deformation. We trained long short-term memory (LSTM) neural networks to decode various aspects of intraoral tongue deformation from cortical activity during feeding in male Rhesus monkeys. We show that both lingual movements and complex lingual shapes across a range of feeding behaviors could be decoded with high accuracy, and that the distribution of deformation-related information across cortical regions was consistent with previous studies of the arm and hand.

Propagating motor cortical patterns of excitability are ubiquitous across human and non-human primate movement initiation.

A spatiotemporal pattern of excitability propagates across the primary motor cortex prior to the onset of a reaching movement in non-human primates. If this pattern is a necessary component of voluntary movement initiation, it should be present across a variety of motor tasks, end-effectors, and even species. Here, we show that propagating patterns of excitability occur during the initiation of precision grip force and tongue protrusion in non-human primates, and even isometric wrist extension in a human participant. In all tasks, the directions of propagation across the cortical sheet were bimodally distributed across trials with modes oriented roughly opposite to one another. Propagation speed was unimodally distributed with similar mean speeds across tasks and species. Additionally, propagation direction and speed did not vary systematically with any behavioral measures except response times indicating that this propagating pattern is invariant to kinematic or kinetic details and may be a generic movement initiation signal.

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands.

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant's ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

Propagating spatiotemporal activity patterns across macaque motor cortex carry kinematic information.

Propagating spatiotemporal neural patterns are widely evident across sensory, motor, and association cortical areas. However, it remains unclear whether any characteristics of neural propagation carry information about specific behavioral details. Here, we provide the first evidence for a link between the direction of cortical propagation and specific behavioral features of an upcoming movement on a trial-by-trial basis. We recorded local field potentials (LFPs) from multielectrode arrays implanted in the primary motor cortex of two rhesus macaque monkeys while they performed a 2D reach task. Propagating patterns were extracted from the information-rich high-gamma band (200 to 400 Hz) envelopes in the LFP amplitude. We found that the exact direction of propagating patterns varied systematically according to initial movement direction, enabling kinematic predictions. Furthermore, characteristics of these propagation patterns provided additional predictive capability beyond the LFP amplitude themselves, which suggests the value of including mesoscopic spatiotemporal characteristics in refining brain-machine interfaces.

A dynamic subset of network interactions underlies tuning to natural movements in marmoset sensorimotor cortex.

Mechanisms of computation in sensorimotor cortex must be flexible and robust to support skilled motor behavior. Patterns of neuronal coactivity emerge as a result of computational processes. Pairwise spike-time statistical relationships, across the population, can be summarized as a functional network (FN) which retains single-unit properties. We record populations of single-unit neural activity in forelimb sensorimotor cortex during prey-capture and spontaneous behavior and use an encoding model incorporating kinematic trajectories and network features to predict single-unit activity during forelimb movements. The contribution of network features depends on structured connectivity within strongly connected functional groups. We identify a context-specific functional group that is highly tuned to kinematics and reorganizes its connectivity between spontaneous and prey-capture movements. In the remaining context-invariant group, interactions are comparatively stable across behaviors and units are less tuned to kinematics. This suggests different roles in producing natural forelimb movements and contextualizes single-unit tuning properties within population dynamics.

Loss of oral sensation impairs feeding performance and consistency of tongue-jaw coordination.

BACKGROUND: Individuals with impaired oral sensation report difficulty chewing, but little is known about the underlying changes to tongue and jaw kinematics. Methodological challenges impede the measurement of 3D tongue movement and its relationship to the gape cycle. OBJECTIVE: The aim of this study was to quantify the impact of loss of oral somatosensation on feeding performance, 3D tongue kinematics and tongue-jaw coordination. METHODOLOGY: XROMM (X-ray Reconstruction of Moving Morphology) was used to quantify 3D tongue and jaw kinematics during feeding in three rhesus macaques (Macaca mulatta) before and after an oral tactile nerve block. Feeding performance was measured using feeding sequence duration, number of manipulation cycles and swallow frequency. Coordination was measured using event- and correlation-based metrics of jaw pitch, anterior tongue length, width and roll. RESULTS: In the absence of tactile sensation to the tongue and other oral structures, feeding performance decreased, and the fast open phase of the gape cycle became significantly longer, relative to the other phases (p < .05). The tongue made similar shapes in both the control and nerve block conditions, but the pattern of tongue-jaw coordination became significantly more variable after the block (p < .05). CONCLUSION: Disruption of oral somatosensation impacts feeding performance by introducing variability into the typically tight pattern of tongue-jaw coordination.

Validating markerless pose estimation with 3D X-ray radiography.

To reveal the neurophysiological underpinnings of natural movement, neural recordings must be paired with accurate tracking of limbs and postures. Here, we evaluated the accuracy of DeepLabCut (DLC), a deep learning markerless motion capture approach, by comparing it with a 3D X-ray video radiography system that tracks markers placed under the skin (XROMM). We recorded behavioral data simultaneously with XROMM and RGB video as marmosets foraged and reconstructed 3D kinematics in a common coordinate system. We used the toolkit Anipose to filter and triangulate DLC trajectories of 11 markers on the forelimb and torso and found a low median error (0.228 cm) between the two modalities corresponding to 2.0% of the range of motion. For studies allowing this relatively small error, DLC and similar markerless pose estimation tools enable the study of increasingly naturalistic behaviors in many fields including non-human primate motor control.

Longevity and reliability of chronic unit recordings using the Utah, intracortical multi-electrode arrays.

Objective.Microelectrode arrays are standard tools for conducting chronic electrophysiological experiments, allowing researchers to simultaneously record from large numbers of neurons. Specifically, Utah electrode arrays (UEAs) have been utilized by scientists in many species, including rodents, rhesus macaques, marmosets, and human participants. The field of clinical human brain-computer interfaces currently relies on the UEA as a number of research groups have clearance from the United States Federal Drug Administration (FDA) for this device through the investigational device exemption pathway. Despite its widespread usage in systems neuroscience, few studies have comprehensively evaluated the reliability and signal quality of the Utah array over long periods of time in a large dataset.Approach.We collected and analyzed over 6000 recorded datasets from various cortical areas spanning almost nine years of experiments, totaling 17 rhesus macaques (Macaca mulatta) and 2 human subjects, and 55 separate microelectrode Utah arrays. The scale of this dataset allowed us to evaluate the average life of these arrays, based primarily on the signal-to-noise ratio of each electrode over time.Main results.Using implants in primary motor, premotor, prefrontal, and somatosensory cortices, we found that the average lifespan of available recordings from UEAs was 622 days, although we provide several examples of these UEAs lasting over 1000 days and one up to 9 years; human implants were also shown to last longer than non-human primate implants. We also found that electrode length did not affect longevity and quality, but iridium oxide metallization on the electrode tip exhibited superior yield as compared to platinum metallization.Significance.Understanding longevity and reliability of microelectrode array recordings allows researchers to set expectations and plan experiments accordingly and maximize the amount of high-quality data gathered. Our results suggest that one can expect chronic unit recordings to last at least two years, with the possibility for arrays to last the better part of a decade.

Chronic wireless neural population recordings with common marmosets.

Marmosets are an increasingly important model system for neuroscience in part due to genetic tractability and enhanced cortical accessibility, due to a lissencephalic neocortex. However, many of the techniques generally employed to record neural activity in primates inhibit the expression of natural behaviors in marmosets precluding neurophysiological insights. To address this challenge, we have developed methods for recording neural population activity in unrestrained marmosets across multiple ethological behaviors, multiple brain states, and over multiple years. Notably, our flexible methodological design allows for replacing electrode arrays and removal of implants providing alternative experimental endpoints. We validate the method by recording sensorimotor cortical population activity in freely moving marmosets across their natural behavioral repertoire and during sleep.

Neural population dynamics in motor cortex are different for reach and grasp.

Low-dimensional linear dynamics are observed in neuronal population activity in primary motor cortex (M1) when monkeys make reaching movements. This population-level behavior is consistent with a role for M1 as an autonomous pattern generator that drives muscles to give rise to movement. In the present study, we examine whether similar dynamics are also observed during grasping movements, which involve fundamentally different patterns of kinematics and muscle activations. Using a variety of analytical approaches, we show that M1 does not exhibit such dynamics during grasping movements. Rather, the grasp-related neuronal dynamics in M1 are similar to their counterparts in somatosensory cortex, whose activity is driven primarily by afferent inputs rather than by intrinsic dynamics. The basic structure of the neuronal activity underlying hand control is thus fundamentally different from that underlying arm control.

Integrating XMALab and DeepLabCut for high-throughput XROMM.

Marker tracking is a major bottleneck in studies involving X-ray reconstruction of moving morphology (XROMM). Here, we tested whether DeepLabCut, a new deep learning package built for markerless tracking, could be applied to videoradiographic data to improve data processing throughput. Our novel workflow integrates XMALab, the existing XROMM marker tracking software, and DeepLabCut while retaining each program's utility. XMALab is used for generating training datasets, error correction and 3D reconstruction, whereas the majority of marker tracking is transferred to DeepLabCut for automatic batch processing. In the two case studies that involved an in vivo behavior, our workflow achieved a 6 to 13-fold increase in data throughput. In the third case study, which involved an acyclic, post-mortem manipulation, DeepLabCut struggled to generalize to the range of novel poses and did not surpass the throughput of XMALab alone. Deployed in the proper context, this new workflow facilitates large scale XROMM studies that were previously precluded by software constraints.

Decoding hand kinematics from population responses in sensorimotor cortex during grasping.

OBJECTIVE: The hand-a complex effector comprising dozens of degrees of freedom of movement-endows us with the ability to flexibly, precisely, and effortlessly interact with objects. The neural signals associated with dexterous hand movements in primary motor cortex (M1) and somatosensory cortex (SC) have received comparatively less attention than have those associated with proximal upper limb control. APPROACH: To fill this gap, we trained two monkeys to grasp objects varying in size and shape while tracking their hand postures and recording single-unit activity from M1 and SC. We then decoded their hand kinematics across tens of joints from population activity in these areas. MAIN RESULTS: We found that we could accurately decode kinematics with a small number of neural signals and that different cortical fields carry different amounts of information about hand kinematics. In particular, neural signals in rostral M1 led to better performance than did signals in caudal M1, whereas Brodmann's area 3a outperformed areas 1 and 2 in SC. Moreover, decoding performance was higher for joint angles than joint angular velocities, in contrast to what has been found with proximal limb decoders. SIGNIFICANCE: We conclude that cortical signals can be used for dexterous hand control in brain machine interface applications and that postural representations in SC may be exploited via intracortical stimulation to close the sensorimotor loop.