Brain-machine interface learning is facilitated by specific patterning of distributed cortical feedback.

Neuroprosthetics offer great hope for motor-impaired patients. One obstacle is that fine motor control requires near-instantaneous, rich somatosensory feedback. Such distributed feedback may be recreated in a brain-machine interface using distributed artificial stimulation across the cortical surface. Here, we hypothesized that neuronal stimulation must be contiguous in its spatiotemporal dynamics to be efficiently integrated by sensorimotor circuits. Using a closed-loop brain-machine interface, we trained head-fixed mice to control a virtual cursor by modulating the activity of motor cortex neurons. We provided artificial feedback in real time with distributed optogenetic stimulation patterns in the primary somatosensory cortex. Mice developed a specific motor strategy and succeeded to learn the task only when the optogenetic feedback pattern was spatially and temporally contiguous while it moved across the topography of the somatosensory cortex. These results reveal spatiotemporal properties of the sensorimotor cortical integration that set constraints on the design of neuroprosthetics.

Learning in a closed-loop brain-machine interface with distributed optogenetic cortical feedback.

Objective.Distributed microstimulations at the cortical surface can efficiently deliver feedback to a subject during the manipulation of a prosthesis through a brain-machine interface (BMI). Such feedback can convey vast amounts of information to the prosthesis user and may be key to obtain an accurate control and embodiment of the prosthesis. However, so far little is known of the physiological constraints on the decoding of such patterns. Here, we aimed to test a rotary optogenetic feedback that was designed to encode efficiently the 360° movements of the robotic actuators used in prosthetics. We sought to assess its use by mice that controlled a prosthesis joint through a closed-loop BMI.Approach.We tested the ability of mice to optimize the trajectory of a virtual prosthesis joint in order to solve a rewarded reaching task. They could control the speed of the joint by modulating the activity of individual neurons in the primary motor cortex. During the task, the patterned optogenetic stimulation projected on the primary somatosensory cortex continuously delivered information to the mouse about the position of the joint.Main results.We showed that mice are able to exploit the continuous, rotating cortical feedback in the active behaving context of the task. Mice achieved better control than in the absence of feedback by detecting reward opportunities more often, and also by moving the joint faster towards the reward angular zone, and by maintaining it longer in the reward zone. Mice controlling acceleration rather than speed of the joint failed to improve motor control.Significance.These findings suggest that in the context of a closed-loop BMI, distributed cortical feedback with optimized shapes and topology can be exploited to control movement. Our study has direct applications on the closed-loop control of rotary joints that are frequently encountered in robotic prostheses.

Continuity within the somatosensory cortical map facilitates learning.

The topographic organization is a prominent feature of sensory cortices, but its functional role remains controversial. Particularly, it is not well determined how integration of activity within a cortical area depends on its topography during sensory-guided behavior. Here, we train mice expressing channelrhodopsin in excitatory neurons to track a photostimulation bar that rotated smoothly over the topographic whisker representation of the primary somatosensory cortex. Mice learn to discriminate angular positions of the light bar to obtain a reward. They fail not only when the spatiotemporal continuity of the photostimulation is disrupted in this area but also when cortical areas displaying map discontinuities, such as the trunk and legs, or areas without topographic map, such as the posterior parietal cortex, are photostimulated. In contrast, when cortical topographic continuity enables to predict future sensory activation, mice demonstrate anticipation of reward availability. These findings could be helpful for optimizing feedback while designing cortical neuroprostheses.

Rich spatio-temporal stimulus dynamics unveil sensory specialization in cortical area S2.

Tactile perception in rodents depends on simultaneous, multi-whisker contacts with objects. Although it is known that neurons in secondary somatosensory cortex (wS2) respond to individual deflections of many whiskers, wS2's precise function remains unknown. The convergence of information from multiple whiskers into wS2 neurons suggests that they are good candidates for integrating multi-whisker information. Here, we apply stimulation patterns with rich dynamics simultaneously to 24 macro-vibrissae of rats while recording large populations of single neurons. Varying inter-whisker correlations without changing single whisker statistics, we observe pronounced supra-linear multi-whisker integration. Using novel analysis methods, we show that continuous multi-whisker movements contribute to the firing of wS2 neurons over long temporal windows, facilitating spatio-temporal integration. In contrast, primary cortex (wS1) neurons encode fine features of whisker movements on precise temporal scales. These results provide the first description of wS2's representation during multi-whisker stimulation and outline its specialized role in parallel to wS1 tactile processing.

A fast intracortical brain-machine interface with patterned optogenetic feedback.

OBJECTIVE: The development of brain-machine interfaces (BMIs) brings new prospects to patients with a loss of autonomy. By combining online recordings of brain activity with a decoding algorithm, patients can learn to control a robotic arm in order to perform simple actions. However, in contrast to the vast amounts of somatosensory information channeled by limbs to the brain, current BMIs are devoid of touch and force sensors. Patients must therefore rely solely on vision and audition, which are maladapted to the control of a prosthesis. In contrast, in a healthy limb, somatosensory inputs alone can efficiently guide the handling of a fragile object, or ensure a smooth trajectory. We have developed a BMI in the mouse that includes a rich artificial somatosensory-like cortical feedback. APPROACH: Our setup includes online recordings of the activity of multiple neurons in the whisker primary motor cortex (vM1) and delivers feedback simultaneously via a low-latency, high-refresh-rate, spatially structured photo-stimulation of the whisker primary somatosensory cortex (vS1), based on a mapping obtained by intrinsic imaging. MAIN RESULTS: We demonstrate the operation of the loop and show that mice can detect the neuronal spiking in vS1 triggered by the photo-stimulations. Finally, we show that the mice can learn a behavioral task relying solely on the artificial inputs and outputs of the closed-loop BMI. SIGNIFICANCE: This is the first motor BMI that includes a short-latency, intracortical, somatosensory-like feedback. It will be a useful platform to discover efficient cortical feedback schemes towards future human BMI applications.

Supra-barrel Distribution of Directional Tuning for Global Motion in the Mouse Somatosensory Cortex.

Rodents explore their environment with an array of whiskers, inducing complex patterns of whisker deflections. Cortical neuronal networks can extract global properties of tactile scenes. In the primary somatosensory cortex, the information relative to the global direction of a spatiotemporal sequence of whisker deflections can be extracted at the single neuron level. To further understand how the cortical network integrates multi-whisker inputs, we imaged and recorded the mouse barrel cortex activity evoked by sequences of multi-whisker deflections generating global motions in different directions. A majority of barrel-related cortical columns show a direction preference for global motions with an overall preference for caudo-ventral directions. Responses to global motions being highly sublinear, the identity of the first deflected whiskers is highly salient but does not seem to determine the global direction preference. Our results further demonstrate that the global direction preference is spatially organized throughout the barrel cortex at a supra-columnar scale.

Representation of tactile scenes in the rodent barrel cortex.

After half a century of research, the sensory features coded by neurons of the rodent barrel cortex remain poorly understood. Still, views of the sensory representation of whisker information are increasingly shifting from a labeled line representation of single-whisker deflections to a selectivity for specific elements of the complex statistics of the multi-whisker deflection patterns that take place during spontaneous rodent behavior - so called natural tactile scenes. Here we review the current knowledge regarding the coding of patterns of whisker stimuli by barrel cortex neurons, from responses to single-whisker deflections to the representation of complex tactile scenes. A number of multi-whisker tunings have already been identified, including center-surround feature extraction, angular tuning during edge-like multi-whisker deflections, and even tuning to specific statistical properties of the tactile scene such as the level of correlation across whiskers. However, a more general model of the representation of multi-whisker information in the barrel cortex is still missing. This is in part because of the lack of a human intuition regarding the perception emerging from a whisker system, but also because in contrast to other primary sensory cortices such as the visual cortex, the spatial feature selectivity of barrel cortex neurons rests on highly nonlinear interactions that remained hidden to classical receptive field approaches.

Parvalbumin-Expressing GABAergic Neurons in Primary Motor Cortex Signal Reaching.

The control of targeted reaching is thought to be shaped by distinct subtypes of local GABAergic inhibitory neurons in primary forelimb motor cortex (M1). However, little is known about their action potential firing dynamics during reaching. To address this, we recorded the activity of parvalbumin-expressing (PV+) GABAergic neurons identified from a larger population of fast-spiking units and putative excitatory regular-spiking units in layer 5 of the mouse forelimb M1 during an M1-dependent, sensory-triggered reaching task. PV+ neurons showed short latency responses to the acoustic cue and vibrotactile trigger stimulus and an increase in firing at reaching onset that scaled with the amplitude of reaching. Unexpectedly, PV+ neurons fired before regular-spiking units at reach onset and showed high overall firing rates during both sensory-triggered and spontaneous reaches. Our data suggest that increasing M1 PV+ neuron firing rates may play a role in the initiation of voluntary reaching.

Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity.

The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors in vivo. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.

A radial map of multi-whisker correlation selectivity in the rat barrel cortex.

In the barrel cortex, several features of single-whisker stimuli are organized in functional maps. The barrel cortex also encodes spatio-temporal correlation patterns of multi-whisker inputs, but so far the cortical mapping of neurons tuned to such input statistics is unknown. Here we report that layer 2/3 of the rat barrel cortex contains an additional functional map based on neuronal tuning to correlated versus uncorrelated multi-whisker stimuli: neuron responses to uncorrelated multi-whisker stimulation are strongest above barrel centres, whereas neuron responses to correlated and anti-correlated multi-whisker stimulation peak above the barrel-septal borders, forming rings of multi-whisker synchrony-preferring cells.

Matching Cell Type to Function in Cortical Circuits.

In this issue of Neuron, Pinto and Dan (2015) performed single-cell calcium imaging in the mouse dorsomedial prefrontal cortex to reveal correlated, cell-type-specific responses in three major GABA-ergic interneuron subtypes during a goal-directed sensory discrimination task.

Cortical fosGFP expression reveals broad receptive field excitatory neurons targeted by POm.

Neighboring cortical excitatory neurons show considerable heterogeneity in their responses to sensory stimulation. We hypothesized that a subset of layer 2 excitatory neurons in the juvenile (P18 to 27) mouse whisker somatosensory cortex, distinguished by expression of the activity-dependent fosGFP reporter gene, would be preferentially activated by whisker stimulation. In fact, two-photon targeted, dual whole-cell recordings showed that principal whisker stimulation elicits similar amplitude synaptic responses in fosGFP-expressing and fosGFP(-) neurons. FosGFP(+) neurons instead displayed shorter latency and larger amplitude subthreshold responses to surround whisker stimulation. Using optogenetic stimulation, we determined that these neurons are targeted by axons from the posteromedial nucleus (POm), a paralemniscal thalamic nucleus associated with broad receptive fields and widespread cortical projections. We conclude that fosGFP expression discriminates between single- and multi-whisker receptive field layer 2 pyramidal neurons.

[What the whiskers tell the tactile brain]. / Ce que les vibrisses disent au cerveau tactile.

The rodent whisker system became one of the main system models for the study of the functional properties of sensory neurons. This is due on one hand to the detailed knowledge that we have on the afferent pathways linking the mechanoreceptors in the follicles to the primary somatosensory cortex and on the other hand to the possibility of controlling the sensory input at a micrometer and millisecond scale. The observation of the natural use of the whiskers by rodents indicates that exploration of objects and textures imply multiple contacts with tens of whiskers simultaneously. We have studied the neural code in the barrel cortex, which receives tactile information from the whiskers. By combining multi-electrode recordings and controlled multiwhisker tactile stimulation with theoretical analysis, we have observed a dependence of neural responses on the statistics of the sensory input. Several classes of neuronal responses, similar to those described in a number of cortical visual areas, were observed in the same cortical volume, indicating that various coding schemes are implemented in the same cortical network and can be put into play differentially to cope with the changing statistics of the peripheral stimuli.

Correlated input reveals coexisting coding schemes in a sensory cortex.

As in other sensory modalities, one function of the somatosensory system is to detect coherence and contrast in the environment. To investigate the neural bases of these computations, we applied different spatiotemporal patterns of stimuli to rat whiskers while recording multiple neurons in the barrel cortex. Model-based analysis of the responses revealed different coding schemes according to the level of input correlation. With uncorrelated stimuli on 24 whiskers, we identified two distinct functional categories of neurons, analogous in the temporal domain to simple and complex cells of the primary visual cortex. With correlated stimuli, however, a complementary coding scheme emerged: two distinct cell populations, similar to reinforcing and antagonist neurons described in the higher visual area MT, responded specifically to correlations. We suggest that similar context-dependent coexisting coding strategies may be present in other sensory systems to adapt sensory integration to specific stimulus statistics.

An interdisciplinary learning experience in neuro-optics.

How can a Ph.D. student initially trained as a biologist take part in the development of a multineuronal recording method that requires cross interaction between physics, neurobiology and mathematics? Beyond student training in the laboratory, interdisciplinary research calls for a new style of academic training of young researchers. Here we present an innovative approach to graduate student academic training that fills the need for multidisciplinary knowledge and provides students, in addition, with a deeper understanding of the interdisciplinary approach to scientific research.

Spatial structure of multiwhisker receptive fields in the barrel cortex is stimulus dependent.

The tactile sensations mediated by the whisker-trigeminal system allow rodents to efficiently detect and discriminate objects. These capabilities rely strongly on the temporal and spatial structure of whisker deflections. Subthreshold but also spiking receptive fields in the barrel cortex encompass a large number of vibrissae, and it seems likely that the functional properties of these multiwhisker receptive fields reflect the multiple-whisker interactions encountered by the animal during exploration of its environment. The aim of this study was to examine the dependence of the spatial structure of cortical receptive fields on stimulus parameters. Using a newly developed 24-whisker stimulation matrix, we applied a forward correlation analysis of spiking activity to randomized whisker deflections (sparse noise) to characterize the receptive fields that result from caudal and rostral directions of whisker deflection. We observed that the functionally determined principal whisker, the whisker eliciting the strongest response with the shortest latency, differed according to the direction of whisker deflection. Thus, for a given neuron, maximal responses to opposite directions of whisker deflections could be spatially separated. This spatial separation resulted in a displacement of the center of mass between the rostral and caudal subfields and was accompanied by differences between response latencies in rostral and caudal directions of whisker deflection. Such direction-dependent receptive field organization was observed in every cortical layer. We conclude that the spatial structure of receptive fields in the barrel cortex is not an intrinsic property of the neuron but depends on the properties of sensory input.

The Matrix: a new tool for probing the whisker-to-barrel system with natural stimuli.

The whisker to barrel system in rodents has become one of the major models for the study of sensory processing. Several tens of whiskers (or vibrissae) are distributed in a regular manner on both sides of the snout. Many tactile discrimination tasks using this system need multiple contacts with more than one whisker to be solved. With the aim of mimicking those multi-whisker stimuli during electrophysiological recordings, we developed a novel mechanical stimulator composed of 24 independent multi-directional piezoelectric benders adapted to the five rows and the five caudal arcs of the rat whisker pad. The most widely used technology for producing mechanical deflections of the whiskers is based on piezoelectric benders that display a non-linear behavior when driven with high frequency input commands and, if not compensated, show high unwanted ringing at particular resonance frequencies. If not corrected, this non-linear behavior precludes the application of high frequency deflections and the study of cortical responses to behaviorally relevant stimuli. To cope with the ringing problem, a mechanical and a software based solutions have been developed. With these corrections, the upper bound of the linear range of the bender is increased to 1 kHz. This new device allows the controlled delivery of large scale natural patterns of whisker deflections characterized by rapid high frequency vibrations of multiple whiskers.