Restoration of grasp following paralysis through brain-controlled stimulation of muscles

Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.     

Neuronal ensemble control of prosthetic devices by a human with tetraplegia

Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a 'neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.     

Real-time prediction of hand trajectory by ensembles of cortical neurons in primates

Signals derived from the rat motor cortex can be used for controlling one-dimensional movements of a robot arm. It remains unknown, however, whether real-time processing of cortical signals can be employed to reproduce, in a robotic device, the kind of complex arm movements used by primates to reach objects in space. Here we recorded the simultaneous activity of large populations of neurons, distributed in the premotor, primary motor and posterior parietal cortical areas, as non-human primates performed two distinct motor tasks. Accurate real-time predictions of one- and three-dimensional arm movement trajectories were obtained by applying both linear and nonlinear algorithms to cortical neuronal ensemble activity recorded from each animal. In addition, cortically derived signals were successfully used for real-time control of robotic devices, both locally and through the Internet. These results suggest that long-term control of complex prosthetic robot arm movements can be achieved by simple real-time transformations of neuronal population signals derived from multiple cortical areas in primates.     

Reach and grasp by people with tetraplegia using a neurally controlled robotic arm

Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control physical devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5?years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.     

Long-term motor cortex plasticity induced by an electronic neural implant

It has been proposed that the efficacy of neuronal connections is strengthened when there is a persistent causal relationship between presynaptic and postsynaptic activity. Such activity-dependent plasticity may underlie the reorganization of cortical representations during learning, although direct in vivo evidence is lacking. Here we show that stable reorganization of motor output can be induced by an artificial connection between two sites in the motor cortex of freely behaving primates. An autonomously operating electronic implant used action potentials recorded on one electrode to trigger electrical stimuli delivered at another location. Over one or more days of continuous operation, the output evoked from the recording site shifted to resemble the output from the corresponding stimulation site, in a manner consistent with the potentiation of synaptic connections between the artificially synchronized populations of neurons. Changes persisted in some cases for more than one week, whereas the output from sites not incorporated in the connection was unaffected. This method for inducing functional reorganization in vivo by using physiologically derived stimulus trains may have practical application in neurorehabilitation after injury.     

Cortical control of a prosthetic arm for self-feeding

Arm movement is well represented in populations of neurons recorded from the motor cortex. Cortical activity patterns have been used in the new field of brain-machine interfaces to show how cursors on computer displays can be moved in two- and three-dimensional space. Although the ability to move a cursor can be useful in its own right, this technology could be applied to restore arm and hand function for amputees and paralysed persons. However, the use of cortical signals to control a multi-jointed prosthetic device for direct real-time interaction with the physical environment ('embodiment') has not been demonstrated. Here we describe a system that permits embodied prosthetic control; we show how monkeys (Macaca mulatta) use their motor cortical activity to control a mechanized arm replica in a self-feeding task. In addition to the three dimensions of movement, the subjects' cortical signals also proportionally controlled a gripper on the end of the arm. Owing to the physical interaction between the monkey, the robotic arm and objects in the workspace, this new task presented a higher level of difficulty than previous virtual (cursor-control) experiments. Apart from an example of simple one-dimensional control, previous experiments have lacked physical interaction even in cases where a robotic arm or hand was included in the control loop, because the subjects did not use it to interact with physical objects-an interaction that cannot be fully simulated. This demonstration of multi-degree-of-freedom embodied prosthetic control paves the way towards the development of dexterous prosthetic devices that could ultimately achieve arm and hand function at a near-natural level.     

Instant neural control of a movement signal

The activity of motor cortex (MI) neurons conveys movement intent sufficiently well to be used as a control signal to operate artificial devices, but until now this has called for extensive training or has been confined to a limited movement repertoire. Here we show how activity from a few (7-30) MI neurons can be decoded into a signal that a monkey is able to use immediately to move a computer cursor to any new position in its workspace (14 degrees x 14 degrees visual angle). Our results, which are based on recordings made by an electrode array that is suitable for human use, indicate that neurally based control of movement may eventually be feasible in paralysed humans.     

Whisker movements evoked by stimulation of single pyramidal cells in rat motor cortex

Neuronal activity in the motor cortex is understood to be correlated with movements, but the impact of action potentials (APs) in single cortical neurons on the generation of movement has not been fully determined. Here we show that trains of APs in single pyramidal cells of rat motor cortex can evoke long sequences of small whisker movements. For layer-5 pyramids, we find that evoked rhythmic movements have a constant phase relative to the AP train, indicating that single layer-5 pyramids can reset the rhythm of whisker movements. Action potentials evoked in layer-6 pyramids can generate bursts of rhythmic whisking, with a variable phase of movements relative to the AP train. An increasing number of APs decreases the latency to onset of movement, whereas AP frequency determines movement direction and amplitude. We find that the efficacy of cortical APs in evoking whisker movements is not dependent on background cortical activity and is greatly enhanced in waking rats. We conclude that in vibrissae motor cortex sparse AP activity can evoke movements.     

Horizontal and vertical components of head movement are controlled by distinct neural circuits in the barn owl

To generate behaviour, the brain must transform sensory information into signals that are appropriate to control movement. Sensory and motor coordinate frames are fundamentally different, however: sensory coordinates are based on the spatiotemporal patterns of activity arising from the various sense organs, whereas motor coordinates are based on the pulling directions of muscles or groups of muscles. Results from psychophysical experiments suggest that in the process of transforming sensory information into motor control signals, the brain encodes movements in abstract or extrinsic coordinate frames, that is ones not closely related to the geometry of the sensory apparatus or of the skeletomusculature. Here we show that an abstract code underlies movements of the head by the barn owl. Specifically, the data show that subsequent to the retinotopic code for space in the optic tectum yet before the motor neuron code for muscle tensions there exists a code for head movement in which upward, downward, leftward and rightward components of movement are controlled by four functionally distinct neural circuits. Such independent coding of orthogonal components of movement may be a common intermediate step in the transformation of sensation into behaviour.     

Early motor activity drives spindle bursts in the developing somatosensory cortex

Sensorimotor coordination emerges early in development. The maturation period is characterized by the establishment of somatotopic cortical maps, the emergence of long-range cortical connections, heightened experience-dependent plasticity and spontaneous uncoordinated skeletal movement. How these various processes cooperate to allow the somatosensory system to form a three-dimensional representation of the body is not known. In the visual system, interactions between spontaneous network patterns and afferent activity have been suggested to be vital for normal development. Although several intrinsic cortical patterns of correlated neuronal activity have been described in developing somatosensory cortex in vitro, the in vivo patterns in the critical developmental period and the influence of physiological sensory inputs on these patterns remain unknown. We report here that in the intact somatosensory cortex of the newborn rat in vivo, spatially confined spindle bursts represent the first and only organized network pattern. The localized spindles are selectively triggered in a somatotopic manner by spontaneous muscle twitches, motor patterns analogous to human fetal movements. We suggest that the interaction between movement-triggered sensory feedback signals and self-organized spindle oscillations shapes the formation of cortical connections required for sensorimotor coordination.     

Relation of neurons in the nonprimary motor cortex to bilateral hand movement

In the primate cerebral cortex there are at least two somatotopically organized, nonprimary motor fields rostral to the primary motor area. To understand the functions of these multiple motor representations we have compared the neuronal activity in each of these fields while monkeys performed a trained motor task, using right, left or both hands. In the nonprimary motor cortex, activity in a number of neurons was related to the movement the animal chose and performed, whereas in the primary motor cortex, changes in the firing of most neurons were simply related to activity in the contralateral muscles. This result indicates that the nonprimary motor cortex is involved in higher-order coding of the laterality of the motor response, implying that it exerts its motor control function at a higher hierarchical level than its counterpart in the primary motor cortex.     

Multiple dynamic representations in the motor cortex during sensorimotor learning

The mechanisms linking sensation and action during learning are poorly understood. Layer 2/3 neurons in the motor cortex might participate in sensorimotor integration and learning; they receive input from sensory cortex and excite deep layer neurons, which control movement. Here we imaged activity in the same set of layer 2/3 neurons in the motor cortex over weeks, while mice learned to detect objects with their whiskers and report detection with licking. Spatially intermingled neurons represented sensory (touch) and motor behaviours (whisker movements and licking). With learning, the population-level representation of task-related licking strengthened. In trained mice, population-level representations were redundant and stable, despite dynamism of single-neuron representations. The activity of a subpopulation of neurons was consistent with touch driving licking behaviour. Our results suggest that ensembles of motor cortex neurons couple sensory input to multiple, related motor programs during learning.     

Cortical ensemble activity increasingly predicts behaviour outcomes during learning of a motor task

When an animal learns to make movements in response to different stimuli, changes in activity in the motor cortex seem to accompany and underlie this learning. The precise nature of modifications in cortical motor areas during the initial stages of motor learning, however, is largely unknown. Here we address this issue by chronically recording from neuronal ensembles located in the rat motor cortex, throughout the period required for rats to learn a reaction-time task. Motor learning was demonstrated by a decrease in the variance of the rats' reaction times and an increase in the time the animals were able to wait for a trigger stimulus. These behavioural changes were correlated with a significant increase in our ability to predict the correct or incorrect outcome of single trials based on three measures of neuronal ensemble activity: average firing rate, temporal patterns of firing, and correlated firing. This increase in prediction indicates that an association between sensory cues and movement emerged in the motor cortex as the task was learned. Such modifications in cortical ensemble activity may be critical for the initial learning of motor tasks.     

Numerical representation for action in the parietal cortex of the monkey

The anterior part of the parietal association area in the cerebral cortex of primates has been implicated in the integration of somatosensory signals, which generate neural images of body parts and apposed objects and provide signals for sensorial guidance of movements. Here we show that this area is active in primates performing numerically based behavioural tasks. We required monkeys to select and perform movement A five times, switch to movement B for five repetitions, and return to movement A, in a cyclical fashion. Cellular activity in the superior parietal lobule reflected the number of self-movement executions. For the most part, the number-selective activity was also specific for the type of movement. This type of numerical representation of self-action was seen less often in the inferior parietal lobule, and rarely in the primary somatosensory cortex. Such activity in the superior parietal lobule is useful for processing numerical information, which is necessary to provide a foundation for the forthcoming motor selection.     

Dynamic coding of behaviourally relevant stimuli in parietal cortex.

A general function of cerebral cortex is to allow the flexible association of sensory stimuli with specific behaviours. Many neurons in parietal, prefrontal and motor cortical areas are activated both by particular movements and by sensory cues that trigger these movements, suggesting a role in linking sensation to action. For example, neurons in the lateral intraparietal area (LIP) encode both the location of visual stimuli and the direction of saccadic eye movements. LIP is not believed to encode non-spatial stimulus attributes such as colour. Here we investigated whether LIP would encode colour if colour was behaviourally linked to the eye movement. We trained monkeys to make an eye movement in one of two directions based alternately on the colour or location of a visual cue. When cue colour was relevant for directing eye movement, we found a substantial fraction of LIP neurons selective for cue colour. However, when cue location was relevant, colour selectivity was virtually absent in LIP. These results demonstrate that selectivity of cortical neurons can change as a function of the required behaviour.     

Performance monitoring by the supplementary eye field

Intelligent behaviour requires self-control based on the consequences of actions. The countermanding task is designed to study self-control; it requires subjects to withhold planned movements in response to an imperative stop signal, which they can do with varying success. In humans, the medial frontal cortex has been implicated in the supervisory control of action. In monkeys, the supplementary eye field in the dorsomedial frontal cortex is involved in producing eye movements, but its precise function has not been clarified. To investigate the role of the supplementary eye field in the control of eye movements, we recorded neural activity in macaque monkeys trained to perform an eye movement countermanding task. Distinct groups of neurons were active after errors, after successful withholding of a partially prepared movement, or in association with reinforcement. These three forms of activation could not be explained by sensory or motor factors. Our results lead us to put forward the hypothesis that the supplementary eye field contributes to monitoring the context and consequences of eye movements.     

Spontaneous and evoked activity of fetal primary afferents in vivo

The first movements of the fetus are apparently random and spontaneous. Their onset coincides with the growth of dorsal root afferents into the spinal cord and it is possible that they are not simply a result of spontaneous motoneuron activity but are reflex responses to sensory stimulation. It is not clear what stimuli could normally evoke such reflexes because nothing is known of the properties of primary afferent neurons in the fetus. I have investigated this by making recordings from single dorsal root ganglion cells in fetal rats in vivo. The afferents have small, defined receptive fields and respond to mechanical stimulation of skin or muscle at intensities that might occur in utero. Many of them are also chemosensitive. Unlike postnatal afferents they display background activity which peaks at the same age as fetal movements. Repeated stimulation causes long-lasting increases of both background and evoked activity. Such sensory input is likely to have a considerable influence on fetal movements and on the development of spinal cord connections.     

Dissociation between hand motion and population vectors from neural activity in motor cortex

The population vector hypothesis was introduced almost twenty years ago to illustrate that a population vector constructed from neural activity in primary motor cortex (MI) of non-human primates could predict the direction of hand movement during reaching. Alternative explanations for this population signal have been suggested but could not be tested experimentally owing to movement complexity in the standard reaching model. We re-examined this issue by recording the activity of neurons in contralateral MI of monkeys while they made reaching movements with their right arms oriented in the horizontal plane-where the mechanics of limb motion are measurable and anisotropic. Here we found systematic biases between the population vector and the direction of hand movement. These errors were attributed to a non-uniform distribution of preferred directions of neurons and the non-uniformity covaried with peak joint power at the shoulder and elbow. These observations contradict the population vector hypothesis and show that non-human primates are capable of generating reaching movements to spatial targets even though population vectors based on MI activity do not point in the direction of hand motion.     

Bold claims for optogenetics

In a recent Letter to Nature, Lee and colleagues combined optogenetic stimulation with functional magnetic resonance imaging (ofMRI) to examine the relationship between pyramidal-cell spiking and the blood oxygenation level dependent (BOLD) signal. To do so, they injected an adeno-associated viral vector into the primary motor cortex (M1) of adult rats to drive the expression of channelrhodopsin (ChR2) in cortical projection neurons, thus making them sensitive to light. The authors then used combined light stimulation and functional magnetic resonance imaging (fMRI) to examine the effects of selective activation of the light-sensitive pyramidal cells on the BOLD signal, as well as to probe the value of this methodology for mapping brain connectivity. They found that excitation of these neurons induced positive BOLD signals both in the injected M1 region and in remote target thalamic nuclei receiving direct projections from that region, and concluded that ofMRI reliably links positive BOLD signals with increased local neuronal excitation. However, their analysis neglects the almost immediate activation of other circuits that could lead to the generation of BOLD signals through local perisynaptic rather than spiking activity. Their experiments therefore do not pin down the identity of the specific neuronal signals that give rise to the BOLD signal.     

Cortical representations of olfactory input by trans-synaptic tracing

In the mouse, each class of olfactory receptor neurons expressing a given odorant receptor has convergent axonal projections to two specific glomeruli in the olfactory bulb, thereby creating an odour map. However, it is unclear how this map is represented in the olfactory cortex. Here we combine rabies-virus-dependent retrograde mono-trans-synaptic labelling with genetics to control the location, number and type of 'starter' cortical neurons, from which we trace their presynaptic neurons. We find that individual cortical neurons receive input from multiple mitral cells representing broadly distributed glomeruli. Different cortical areas represent the olfactory bulb input differently. For example, the cortical amygdala preferentially receives dorsal olfactory bulb input, whereas the piriform cortex samples the whole olfactory bulb without obvious bias. These differences probably reflect different functions of these cortical areas in mediating innate odour preference or associative memory. The trans-synaptic labelling method described here should be widely applicable to mapping connections throughout the mouse nervous system.