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.     

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.     

Direct control of paralysed muscles by cortical neurons

A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.     

Morphological and electrophysiological evidence for regeneration of transected spinal cord fibers and restoration of motor functions in adult rats

The evoked potentials are regarded as an efficientindex to evaluate the functional status of a nervoussystem[1]. When stimulating the motor area of cerebralcortex with transcranial magnetic stimulation, elec-tronic signals can be obtained at the spinal co…     

Activity in motor-sensory projections reveals distributed coding in somatosensation

Cortical-feedback projections to primary sensory areas terminate most heavily in layer 1 (L1) of the neocortex, where they make synapses with tuft dendrites of pyramidal neurons. L1 input is thought to provide ‘contextual’ information, but the signals transmitted by L1 feedback remain uncharacterized. In the rodent somatosensory system, the spatially diffuse feedback projection from vibrissal motor cortex (vM1) to vibrissal somatosensory cortex (vS1, also known as the barrel cortex) may allow whisker touch to be interpreted in the context of whisker position to compute object location. When mice palpate objects with their whiskers to localize object features, whisker touch excites vS1 and later vM1 in a somatotopic manner. Here we use axonal calcium imaging to track activity in vM1-->vS1 afferents in L1 of the barrel cortex while mice performed whisker-dependent object localization. Spatially intermingled individual axons represent whisker movements, touch and other behavioural features. In a subpopulation of axons, activity depends on object location and persists for seconds after touch. Neurons in the barrel cortex thus have information to integrate movements and touches of multiple whiskers over time, key components of object identification and navigation by active touch.     

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.     

Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice

Electrical microstimulation can establish causal links between the activity of groups of neurons and perceptual and cognitive functions. However, the number and identities of neurons microstimulated, as well as the number of action potentials evoked, are difficult to ascertain. To address these issues we introduced the light-gated algal channel channelrhodopsin-2 (ChR2) specifically into a small fraction of layer 2/3 neurons of the mouse primary somatosensory cortex. ChR2 photostimulation in vivo reliably generated stimulus-locked action potentials at frequencies up to 50 Hz. Here we show that naive mice readily learned to detect brief trains of action potentials (five light pulses, 1 ms, 20 Hz). After training, mice could detect a photostimulus firing a single action potential in approximately 300 neurons. Even fewer neurons (approximately 60) were required for longer stimuli (five action potentials, 250 ms). Our results show that perceptual decisions and learning can be driven by extremely brief epochs of cortical activity in a sparse subset of supragranular cortical pyramidal neurons.     

Imaging cortical correlates of illusion in early visual cortex

Exploring visual illusions reveals fundamental principles of cortical processing. Illusory motion perception of non-moving stimuli was described almost a century ago by Gestalt psychologists. However, the underlying neuronal mechanisms remain unknown. To explore cortical mechanisms underlying the 'line-motion' illusion, we used real-time optical imaging, which is highly sensitive to subthreshold activity. We examined, in the visual cortex of the anaesthetized cat, responses to five stimuli: a stationary small square and a long bar; a moving square; a drawn-out bar; and the well-known line-motion illusion, a stationary square briefly preceding a long stationary bar presentation. Whereas flashing the bar alone evoked the expected localized, short latency and high amplitude activity patterns, presenting a square 60-100 ms before a bar induced the dynamic activity patterns resembling that of fast movement. The preceding square, even though physically non-moving, created gradually propagating subthreshold cortical activity that must contribute to illusory motion, because it was indistinguishable from cortical representations of real motion in this area. These findings demonstrate the effect of spatio-temporal patterns of subthreshold synaptic potentials on cortical processing and the shaping of perception.     

A new cellular mechanism for coupling inputs arriving at different cortical layers

Pyramidal neurons in layer 5 of the neocortex of the brain extend their axons and dendrites into all layers. They are also unusual in having both an axonal and a dendritic zone for the initiation of action potentials. Distal dendritic inputs, which normally appear greatly attenuated at the axon, must cross a high threshold at the dendritic initiation zone to evoke calcium action potentials but can then generate bursts of axonal action potentials. Here we show that a single back-propagating sodium action potential generated in the axon facilitates the initiation of these calcium action potentials when it coincides with distal dendritic input within a time window of several milliseconds. Inhibitory dendritic input can selectively block the initiation of dendritic calcium action potentials, preventing bursts of axonal action potentials. Thus, excitatory and inhibitory postsynaptic potentials arising in the distal dendrites can exert significantly greater control over action potential initiation in the axon than would be expected from their electrotonically isolated locations. The coincidence of a single back-propagating action potential with a subthreshold distal excitatory postsynaptic potential to evoke a burst of axonal action potentials represents a new mechanism by which the main cortical output neurons can associate inputs arriving at different cortical layers.     

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.     

Neural population dynamics during reaching

Most theories of motor cortex have assumed that neural activity represents movement parameters. This view derives from what is known about primary visual cortex, where neural activity represents patterns of light. Yet it is unclear how well the analogy between motor and visual cortex holds. Single-neuron responses in motor cortex are complex, and there is marked disagreement regarding which movement parameters are represented. A better analogy might be with other motor systems, where a common principle is rhythmic neural activity. Here we find that motor cortex responses during reaching contain a brief but strong oscillatory component, something quite unexpected for a non-periodic behaviour. Oscillation amplitude and phase followed naturally from the preparatory state, suggesting a mechanistic role for preparatory neural activity. These results demonstrate an unexpected yet surprisingly simple structure in the population response. This underlying structure explains many of the confusing features of individual neural responses.     

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.     

Behavioural report of single neuron stimulation in somatosensory cortex

Understanding how neural activity in sensory cortices relates to perception is a central theme of neuroscience. Action potentials of sensory cortical neurons can be strongly correlated to properties of sensory stimuli and reflect the subjective judgements of an individual about stimuli. Microstimulation experiments have established a direct link from sensory activity to behaviour, suggesting that small neuronal populations can influence sensory decisions. However, microstimulation does not allow identification and quantification of the stimulated cellular elements. The sensory impact of individual cortical neurons therefore remains unknown. Here we show that stimulation of single neurons in somatosensory cortex affects behavioural responses in a detection task. We trained rats to respond to microstimulation of barrel cortex at low current intensities. We then initiated short trains of action potentials in single neurons by juxtacellular stimulation. Animals responded significantly more often in single-cell stimulation trials than in catch trials without stimulation. Stimulation effects varied greatly between cells, and on average in 5% of trials a response was induced. Whereas stimulation of putative excitatory neurons led to weak biases towards responding, stimulation of putative inhibitory neurons led to more variable and stronger sensory effects. Reaction times for single-cell stimulation were long and variable. Our results demonstrate that single neuron activity can cause a change in the animal's detection behaviour, suggesting a much sparser cortical code for sensations than previously anticipated.     

Naturalistic experience transforms sensory maps in the adult cortex of caged animals

Much of what is known about the functional organization and plasticity of adult sensory cortex is derived from animals housed in standard laboratory cages. Here we report that the transfer of adult rats reared in standard laboratory cages to a naturalistic habitat modifies the functional and morphological organization of the facial whisker representation in the somatosensory 'barrel' cortex. Cortical whisker representations, visualized with repeated intrinsic signal optical imaging in the same animals, contracted by 46% after four to six weeks of exposure to the naturalistic habitat. Acute, multi-site extracellular recordings demonstrated suppressed evoked neuronal responses and smaller, sharper constituent receptive fields in the upper cortical layers (II/III), but not in the thalamic recipient layer (IV), of rats with naturalistic experience. Morphological plasticity of the layer IV barrel field was observed, but on a substantially smaller scale than the functional plasticity. Thus, transferring animals to an environment that promotes the expression of natural, innate behaviours induces a large-scale functional refinement of cortical sensory maps.     

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.     

Receptive field dynamics in adult primary visual cortex.

The adult brain has a remarkable ability to adjust to changes in sensory input. Removal of afferent input to the somatosensory, auditory, motor or visual cortex results in a marked change of cortical topography. Changes in sensory activity can, over a period of months, alter receptive field size and cortical topography. Here we remove visual input by focal binocular retinal lesions and record from the same cortical sites before and within minutes after making the lesion and find immediate striking increases in receptive field size for cortical cells with receptive fields near the edge of the retinal scotoma. After a few months even the cortical areas that were initially silenced by the lesion recover visual activity, representing retinotopic loci surrounding the lesion. At the level of the lateral geniculate nucleus, which provides the visual input to the striate cortex, a large silent region remains. Furthermore, anatomical studies show that the spread of geniculocortical afferents is insufficient to account for the cortical recovery. The results indicate that the topographic reorganization within the cortex was largely due to synaptic changes intrinsic to the cortex, perhaps through the plexus of long-range horizontal connections.     

Involvement of secondary motor areas in externally-triggered single-finger movements of dominant and non-dominant hands

Abstract Whether the secondary motor areas are involved in simple voluntary movements remains controversial. Differences in the neural substrates of movements with the dominant and the non-dominant hands have not been well documented. In the present study, functional magnetic resonance imaging (fMRI) was used to investigate the hemodynamic response in the primary motor cortex (M1), supple-mentary motor area (SMA) and premotor cortex (PMC) in six healthy right-handed subjects while performing a visually-guided finger-tapping task with their dominant or non-dominant hands. Significant activation was observed in M1, SMA and PMC during this externally triggered simple voluntary movement task. While dominant hand movements only activated contralateral motor areas, non-domi-nant hand movements also activated ipsilateral SMA and PMC. The results provide strong evidence for the involvement of the secondary motor areas in simple voluntarymovements, and also suggest that movements of the dominant hand primarily engage the contralateral secondary motor areas, whereas movements of the non-dominant hand engage bilateral secondary motor areas.     

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.     

Free choice activates a decision circuit between frontal and parietal cortex

We often face alternatives that we are free to choose between. Planning movements to select an alternative involves several areas in frontal and parietal cortex that are anatomically connected into long-range circuits. These areas must coordinate their activity to select a common movement goal, but how neural circuits make decisions remains poorly understood. Here we simultaneously record from the dorsal premotor area (PMd) in frontal cortex and the parietal reach region (PRR) in parietal cortex to investigate neural circuit mechanisms for decision making. We find that correlations in spike and local field potential (LFP) activity between these areas are greater when monkeys are freely making choices than when they are following instructions. We propose that a decision circuit featuring a sub-population of cells in frontal and parietal cortex may exchange information to coordinate activity between these areas. Cells participating in this decision circuit may influence movement choices by providing a common bias to the selection of movement goals.