Cerebellar Modulation of Cortically Evoked Complex Movements in Rats.

Intracortical microstimulation (ICMS) delivered to the motor cortex (M1) via long- or short-train duration (long- or short-duration ICMS) can evoke coordinated complex movements or muscle twitches, respectively. The role of subcortical cerebellar input in M1 output, in terms of long- and short-duration ICMS-evoked movement and motor skill performance, was evaluated in rats with bilateral lesion of the deep cerebellar nuclei. After the lesion, distal forelimb movements were seldom observed, and almost 30% of proximal forelimb movements failed to match criteria defining the movement class observed under control conditions. The classifiable movements could be evoked in different cortical regions with respect to control and many kinematic variables were strongly affected. Furthermore, movement endpoints within the rat's workspace shrunk closer to the body, while performance in the reaching/grasping task worsened. Surprisingly, neither the threshold current values for evoking movements nor the overall size of forelimb movement representation changed with respect to controls in either long- or short-duration ICMS. We therefore conclude that cerebellar input via the motor thalamus is crucial for expressing the basic functional features of the motor cortex.

Whisker motor cortex reorganization after superior colliculus output suppression in adult rats.

The effect of unilateral superior colliculus (SC) output suppression on the ipsilateral whisker motor cortex (WMC) was studied at different time points after tetrodotoxin and quinolinic acid injections, in adult rats. The WMC output was assessed by mapping the movement evoked by intracortical microstimulation (ICMS) and by recording the ICMS-evoked electromyographic (EMG) responses from contralateral whisker muscles. At 1 h after SC injections, the WMC showed: (i) a strong decrease in contralateral whisker sites, (ii) a strong increase in ipsilateral whisker sites and in ineffective sites, and (iii) a strong increase in threshold current values. At 6 h after injections, the WMC size had shrunk to 60% of the control value and forelimb representation had expanded into the lateral part of the normal WMC. Thereafter, the size of the WMC recovered, returning to nearly normal 12 h later (94% of control) and persisted unchanged over time (1-3 weeks). The ICMS-evoked EMG response area decreased at 1 h after SC lesion and had recovered its baseline value 12 h later. Conversely, the latency of ICMS-evoked EMG responses had increased by 1 h and continued to increase for as long as 3 weeks following the lesion. These findings provide physiological evidence that SC output suppression persistently withdrew the direct excitatory drive from whisker motoneurons and induced changes in the WMC. We suggest that the changes in the WMC are a form of reversible short-term reorganization that is induced by SC lesion. The persistent latency increase in the ICMS-evoked EMG response suggested that the recovery of basic WMC excitability did not take place with the recovery of normal explorative behaviour.

Shaping the dynamics of a bidirectional neural interface.

Progress in decoding neural signals has enabled the development of interfaces that translate cortical brain activities into commands for operating robotic arms and other devices. The electrical stimulation of sensory areas provides a means to create artificial sensory information about the state of a device. Taken together, neural activity recording and microstimulation techniques allow us to embed a portion of the central nervous system within a closed-loop system, whose behavior emerges from the combined dynamical properties of its neural and artificial components. In this study we asked if it is possible to concurrently regulate this bidirectional brain-machine interaction so as to shape a desired dynamical behavior of the combined system. To this end, we followed a well-known biological pathway. In vertebrates, the communications between brain and limb mechanics are mediated by the spinal cord, which combines brain instructions with sensory information and organizes coordinated patterns of muscle forces driving the limbs along dynamically stable trajectories. We report the creation and testing of the first neural interface that emulates this sensory-motor interaction. The interface organizes a bidirectional communication between sensory and motor areas of the brain of anaesthetized rats and an external dynamical object with programmable properties. The system includes (a) a motor interface decoding signals from a motor cortical area, and (b) a sensory interface encoding the state of the external object into electrical stimuli to a somatosensory area. The interactions between brain activities and the state of the external object generate a family of trajectories converging upon a selected equilibrium point from arbitrary starting locations. Thus, the bidirectional interface establishes the possibility to specify not only a particular movement trajectory but an entire family of motions, which includes the prescribed reactions to unexpected perturbations.

Origins of 1/f2 scaling in the power spectrum of intracortical local field potential.

It has been noted that the power spectrum of intracortical local field potential (LFP) often scales as 1/f(-2). It is thought that LFP mostly represents the spiking-related neuronal activity such as synaptic currents and spikes in the vicinity of the recording electrode, but no 1/f(2) scaling is detected in the spike power. Although tissue filtering or modulation of spiking activity by UP and DOWN states could account for the observed LFP scaling, there is no consensus as to how it arises. We addressed this question by recording simultaneously LFP and single neurons ("single units") from multiple sites in somatosensory cortex of anesthetized rats. Single-unit data revealed the presence of periods of high activity, presumably corresponding to the "UP" states when the neuronal membrane potential is depolarized, and periods of no activity, the putative "DOWN" states when the membrane potential is close to resting. As expected, the LFP power scaled as 1/f(2) but no such scaling was found in the power spectrum of spiking activity. Our analysis showed that 1/f(2) scaling in the LFP power spectrum was largely generated by the steplike transitions between UP and DOWN states. The shape of the LFP signal during these transitions, but not the transition timing, was crucial to obtain the observed scaling. These transitions were probably induced by synchronous changes in the membrane potential across neurons. We conclude that a 1/f(2) scaling in the LFP power indicates the presence of steplike transitions in the LFP trace and says little about the statistical properties of the associated neuronal firing.

Neurons of rat motor cortex become active during both grasping execution and grasping observation.

In non-human primates, a subset of frontoparietal neurons (mirror neurons) respond both when an individual executes an action and when it observes another individual performing a similar action.1-8 Mirror neurons constitute an observation and execution matching system likely involved in others' actions processing3,5,9 and in a large set of complex cognitive functions.10,11 Here, we show that the forelimb motor cortex of rats contains neurons presenting mirror properties analogous to those observed in macaques. We provide this evidence by event-related potentials acquired by microelectrocorticography and intracortical single-neuron activity, recorded from the same cortical region during grasping execution and observation. Mirror responses are highly specific, because grasping-related neurons do not respond to the observation of either grooming actions or graspable food alone. These results demonstrate that mirror neurons are present already in species phylogenetically distant from primates, suggesting for them a fundamental, albeit basic, role not necessarily related to higher cognitive functions. Moreover, because murine models have long been valued for their superior experimental accessibility and rapid life cycle, the present finding opens an avenue to new empirical studies tackling questions such as the innate or acquired origin of sensorimotor representations and the effects of social and environmental deprivation on sensorimotor development and recovery.

Suppression of activity in the forelimb motor cortex temporarily enlarges forelimb representation in the homotopic cortex in adult rats.

After forelimb motor cortex (FMC) damage, the unaffected homotopic motor cortex showed plastic changes. The present experiments were designed to clarify the electrophysiological nature of these interhemispheric effects. To this end, the output reorganization of the FMC was investigated after homotopic area activity was suppressed in adult rats. FMC output was compared after lidocaine-induced inactivation (L-group) or quinolinic acid-induced lesion (Q-group) of the contralateral homotopic cortex. In the Q-group of animals, FMC mapping was performed, respectively, 3 days (Q3D group) and 2 weeks (Q2W group) after cortical lesion. In each animal, FMC output was assessed by mapping movements induced by intracortical microstimulation (ICMS) in both hemispheres (hemisphere ipsilateral and contralateral to injections). The findings demonstrated that in the L-group, the size of forelimb representation was 42.2% higher than in the control group (P < 0.0001). The percentage of dual forelimb-vibrissa movement sites significantly increased over the controls (P < 0.0005). The dual-movement sites occupied a strip of the map along the rostrocaudal border between the forelimb and vibrissa representations. This form of interhemispheric diaschisis had completely reversed, with the recovery of the baseline map, 3 days after the lesion in the contralateral FMC. This restored forelimb map showed no ICMS-induced changes 2 weeks after the lesion in the contralateral FMC. The present results suggest that the FMCs in the two hemispheres interact continuously through predominantly inhibitory influences that preserve the forelimb representation and the border vs. vibrissa representation.

Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low-Noise Recording of Brain Activity.

We report on the superior electrochemical properties, in-vivo performance and long term stability under electrical stimulation of a new electrode material fabricated from lithographically patterned glassy carbon. For a direct comparison with conventional metal electrodes, similar ultra-flexible, micro-electrocorticography (µ-ECoG) arrays with platinum (Pt) or glassy carbon (GC) electrodes were manufactured. The GC microelectrodes have more than 70% wider electrochemical window and 70% higher CTC (charge transfer capacity) than Pt microelectrodes of similar geometry. Moreover, we demonstrate that the GC microelectrodes can withstand at least 5 million pulses at 0.45 mC/cm2 charge density with less than 7.5% impedance change, while the Pt microelectrodes delaminated after 1 million pulses. Additionally, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) was selectively electrodeposited on both sets of devices to specifically reduce their impedances for smaller diameters (<60 µm). We observed that PEDOT-PSS adhered significantly better to GC than Pt, and allowed drastic reduction of electrode size while maintaining same amount of delivered current. The electrode arrays biocompatibility was demonstrated through in-vitro cell viability experiments, while acute in vivo characterization was performed in rats and showed that GC microelectrode arrays recorded somatosensory evoked potentials (SEP) with an almost twice SNR (signal-to-noise ratio) when compared to the Pt ones.

pHEMA Encapsulated PEDOT-PSS-CNT Microsphere Microelectrodes for Recording Single Unit Activity in the Brain.

The long-term reliability of neural interfaces and stability of high-quality recordings are still unsolved issues in neuroscience research. High surface area PEDOT-PSS-CNT composites are able to greatly improve the performance of recording and stimulation for traditional intracortical metal microelectrodes by decreasing their impedance and increasing their charge transfer capability. This enhancement significantly reduces the size of the implantable device though preserving excellent electrical performances. On the other hand, the presence of nanomaterials often rises concerns regarding possible health hazards, especially when considering a clinical application of the devices. For this reason, we decided to explore the problem from a new perspective by designing and testing an innovative device based on nanostructured microspheres grown on a thin tether, integrating PEDOT-PSS-CNT nanocomposites with a soft synthetic permanent biocompatible hydrogel. The pHEMA hydrogel preserves the electrochemical performance and high quality recording ability of PEDOT-PSS-CNT coated devices, reduces the mechanical mismatch between soft brain tissue and stiff devices and also avoids direct contact between the neural tissue and the nanocomposite, by acting as a biocompatible protective barrier against potential nanomaterial detachment. Moreover, the spherical shape of the electrode together with the surface area increase provided by the nanocomposite deposited on it, maximize the electrical contact and may improve recording stability over time. These results have a good potential to contribute to fulfill the grand challenge of obtaining stable neural interfaces for long-term applications.

PEDOT-CNT-Coated Low-Impedance, Ultra-Flexible, and Brain-Conformable Micro-ECoG Arrays.

Electrocorticography (ECoG) is becoming a common tool for clinical applications, such as preparing patients for epilepsy surgery or localizing tumor boundaries, as it successfully balances invasiveness and information quality. Clinical ECoG arrays use millimeter-scale electrodes and centimeter-scale pitch and cannot precisely map neural activity. Higher-resolution electrodes are of interest for both current clinical applications, providing access to more precise neural activity localization and novel applications, such as neural prosthetics, where current information density and spatial resolution is insufficient to suitably decode signals for a chronic brain-machine interface. Developing such electrodes is not trivial because their small contact area increases the electrode impedance, which seriously affects the signal-to-noise ratio, and adhering such an electrode to the brain surface becomes critical. The most straightforward approach requires increasing the array conformability with flexible substrates while improving the electrode performance using materials with superior electrochemical properties. In this paper, we propose an ultra-flexible and conformable polyimide-based micro-ECoG array of submillimeter recording sites electrochemically coated with high surface area conductive polymer-carbon nanotube composites to improve their brain-electrical coupling capabilities. We characterized our devices both electrochemically and by recording from rat somatosensory cortex in vivo. The performance of the coated and uncoated electrodes was directly compared by simultaneously recording the same neuronal activity during multiwhisker deflection stimulation. Finally, we assessed the effect of electrode size on the extraction of somatosensory evoked potentials and found that in contrast to the normal high-impedance microelectrodes, the recording capabilities of our low-impedance microelectrodes improved upon reducing their size from 0.2 to 0.1 mm.

A compact and autoclavable system for acute extracellular neural recording and brain pressure monitoring for humans.

One of the most difficult tasks for the surgeon during the removal of low-grade gliomas is to identify as precisely as possible the borders between functional and non-functional brain tissue with the aim of obtaining the maximal possible resection which allows to the patient the longer survival. For this purpose, systems for acute extracellular recordings of single neuron and multi-unit activity are considered promising. Here we describe a system to be used with 16 microelectrodes arrays that consists of an autoclavable headstage, a built-in inserter for precise electrode positioning and a system that measures and controls the pressure exerted by the headstage on the brain with a twofold purpose: to increase recording stability and to avoid disturbance of local perfusion which would cause a degradation of the quality of the recording and, eventually, local ischemia. With respect to devices where only electrodes are autoclavable, our design permits the reduction of noise arising from long cable connections preserving at the same time the flexibility and avoiding long-lasting gas sterilization procedures. Finally, size is much smaller and set up time much shorter compared to commercial systems currently in use in surgery rooms, making it easy to consider our system very useful for intra-operatory mapping operations.

Smaller, softer, lower-impedance electrodes for human neuroprosthesis: a pragmatic approach.

Finding the most appropriate technology for building electrodes to be used for long term implants in humans is a challenging issue. What are the most appropriate technologies? How could one achieve robustness, stability, compatibility, efficacy, and versatility, for both recording and stimulation? There are no easy answers to these questions as even the most fundamental and apparently obvious factors to be taken into account, such as the necessary mechanical, electrical and biological properties, and their interplay, are under debate. We present here our approach along three fundamental parallel pathways: we reduced electrode invasiveness and size without impairing signal-to-noise ratio, we increased electrode active surface area by depositing nanostructured materials, and we protected the brain from direct contact with the electrode without compromising performance. Altogether, these results converge toward high-resolution ECoG arrays that are soft and adaptable to cortical folds, and have been proven to provide high spatial and temporal resolution. This method provides a piece of work which, in our view, makes several steps ahead in bringing such novel devices into clinical settings, opening new avenues in diagnostics of brain diseases, and neuroprosthetic applications.

Bio-inspired hybrid microelectrodes: a hybrid solution to improve long-term performance of chronic intracortical implants.

The use of implants that allow chronic electrical stimulation and recording in the brain of human patients is currently limited by a series of events that cause the deterioration over time of both the electrode surface and the surrounding tissue. The main reason of failure is the tissue inflammatory reaction that eventually causes neuronal loss and glial encapsulation, resulting in a progressive increase of the electrode-electrolyte impedance. Here, we describe a new method to create bio-inspired electrodes to mimic the mechanical properties and biological composition of the host tissue. This combination has a great potential to increase the implant lifetime by reducing tissue reaction and improving electrical coupling. Our method implies coating the electrode with reprogrammed neural or glial cells encapsulated within a hydrogel layer. We chose fibrin as a hydrogel and primary hippocampal neurons or astrocytes from rat brain as cellular layer. We demonstrate that fibrin coating is highly biocompatible, forms uniform coatings of controllable thickness, does not alter the electrochemical properties of the microelectrode and allows good quality recordings. Moreover, it reduces the amount of host reactive astrocytes - over time - compared to a bare wire and is fully reabsorbed by the surrounding tissue within 7 days after implantation, avoiding the common problem of hydrogels swelling. Both astrocytes and neurons could be successfully grown onto the electrode surface within the fibrin hydrogel without altering the electrochemical properties of the microelectrode. This bio-hybrid device has therefore a good potential to improve the electrical integration at the neuron-electrode interface and support the long-term success of neural prostheses.

Biologically compatible neural interface to safely couple nanocoated electrodes to the surface of the brain.

The ongoing interest in densely packed miniaturized electrode arrays for high-resolution epicortical recordings has induced many researchers to explore the use of nanomaterial coatings to reduce electrode impedance while increasing signal-to-noise ratio and charge injection capability. Although these materials are very effective, their use in clinical practice is strongly inhibited by concerns about the potential risks derived from the use of nanomaterials in direct contact with the human brain. In this work we propose a novel approach to safely couple nanocoated electrodes to the brain surface by encapsulating them with a biocompatible hydrogel. We prove that fibrin hydrogel coating over nanocoated high-density arrays of epicortical microelectrodes is electrically transparent and allows avoiding direct exposure of the brain tissue to the nanocoatings while maintaining all the advantages derived from the nanostructured electrode surface. This method may make available acute and sub-acute neural recordings with nanocoated high-resolution arrays for clinical applications.

Superior electrochemical performance of carbon nanotubes directly grown on sharp microelectrodes.

We report for the first time how coatings made by directly growing carbon nanotubes (CNTs) on the tip of neural microelectrodes outperform others made by electrodeposited CNT composites. Not only do they reduce microelectrode impedance but they also are able to inject high currents without degradation and are stable in time. These results suggest that they are excellent candidates for chronic applications especially when both neural recording and stimulation have to be performed by the same microelectrode.

Carbon nanotube composite coating of neural microelectrodes preferentially improves the multiunit signal-to-noise ratio.

Extracellular metal microelectrodes are widely used to record single neuron activity in vivo. However, their signal-to-noise ratio (SNR) is often far from optimal due to their high impedance value. It has been recently reported that carbon nanotube (CNT) coatings may decrease microelectrode impedance, thus improving their performance. To tease out the different contributions to SNR of CNT-coated microelectrodes we carried out impedance and noise spectroscopy measurements of platinum/tungsten microelectrodes coated with a polypyrrole-CNT composite. Neuronal signals were recorded in vivo from rat cortex by employing tetrodes with two recording sites coated with polypyrrole-CNT and the remaining two left untreated. We found that polypyrrole-CNT coating significantly reduced the microelectrode impedance at all neuronal signal frequencies (from 1 to 10 000 Hz) and induced a significant improvement of the SNR, up to fourfold on average, in the 150-1500 Hz frequency range, largely corresponding to the multiunit frequency band. An equivalent circuit, previously proposed for porous conducting polymer coatings, reproduced the impedance spectra of our coated electrodes but could not explain the frequency dependence of SNR improvement following polypyrrole-CNT coating. This implies that neither the neural signal amplitude, as recorded by a CNT-coated metal microelectrode, nor noise can be fully described by the equivalent circuit model we used here and suggests that a more detailed approach may be needed to better understand the signal propagation at the electrode-solution interface. Finally, the presence of significant noise components that are neither thermal nor electronic makes it difficult to establish a direct relationship between the actual electrode noise and the impedance spectra.

New Perspectives on the Dialogue between Brains and Machines.

Brain-machine interfaces (BMIs) are mostly investigated as a means to provide paralyzed people with new communication channels with the external world. However, the communication between brain and artificial devices also offers a unique opportunity to study the dynamical properties of neural systems. This review focuses on bidirectional interfaces, which operate in two ways by translating neural signals into input commands for the device and the output of the device into neural stimuli. We discuss how bidirectional BMIs help investigating neural information processing and how neural dynamics may participate in the control of external devices. In this respect, a bidirectional BMI can be regarded as a fancy combination of neural recording and stimulation apparatus, connected via an artificial body. The artificial body can be designed in virtually infinite ways in order to observe different aspects of neural dynamics and to approximate desired control policies.

Plastic changes in the vibrissa motor cortex in adult rats after output suppression in the homotopic cortex.

After motor cortex damage, the unaffected homotopic cortex shows changes in motor output. The present experiments were designed to clarify the nature of these interhemispheric effects. We investigate the vibrissa motor cortex (VMC) output after activity suppression of the homotopic area in adult rats. Comparison was made of VMC output after lidocaine inactivation (L-group) or quinolinic acid lesion (Q-group) of the homotopic cortex. In the Q-group, VMC mapping was performed 3 days (Q3Ds group), 2 weeks (Q2Ws group) and 4 weeks (Q4Ws group) after cortical lesion. In each animal, VMC output was assessed by mapping movements induced by intracortical microstimulation (ICMS) in both hemispheres (hemisphere ipsilateral and contralateral to injections). Findings demonstrated that, in the L-group, the size of vibrissal representation was 39.5% smaller and thresholds required to evoke vibrissa movement were 46.3% higher than those in the Control group. There was an increase in the percentage of ineffective sites within the medial part of the VMC and an increase in the percentage of forelimb sites within the lateral part. Both the Q3Ds group and the L-group led to a similar VMC reorganization (Q3Ds vs. L-group, P > 0.05). In the Q2Ws group the VMC representation showed improvement in size (83.4% recovery compared with controls). The VMC showed recovery to normal output at 4 weeks after lesion (Control vs. Q4Ws group, P > 0.05). These results suggest that the VMC of the two hemispheres continuously interact through excitatory influences, preserving the normal output and inhibitory influences defining the border with the forelimb representation.

Postnatal development of vibrissae motor output following neonatal infraorbital nerve manipulation.

Using the model of infraorbital nerve (IoN) injury, we have studied the role IoN signals have on the developing vibrissal motor system. To this end, in ten rats, the IoN was severed on the day of birth: in five rats, the IoN was repaired to promote axon regeneration (Reinnervated group) while axon regeneration was prevented in the remaining five rats (Deafferented group). In another five rats, the isolated IoN was left intact (Sham group) and still another group of five rats was left untouched (Control group). After these rats had reached adulthood, the compound muscle action potential (MAP) was recorded from the vibrissa muscle and intracortical microstimulation (ICMS)-evoked movements were mapped in the frontal cortex contralateral to the operated side. We found: (i) no difference between Control, Sham and Reinnervated groups in the integrated MAPs and in the size and excitability of the M1 vibrissal representation. (ii) the Deafferented group showed a 42.9% decrease in the integrated MAP plus a 47.2% and 36.9% reduction, respectively, in the size and excitability of the M1 vibrissae representation. We conclude that, during perinatal life, IoN signals regulate the development of both the peripheral and central vibrissal motor system and that IoN reinnervation restores sensory signals able to stabilize normal development of the vibrissal motor system.

The vibrissal motor output following severing and repair of the facial nerve in the newborn rat reorganises less than in the adult.

This study examined the ability of facial motoneurons and motor cortex to reorganise their relationship with the somatic musculature following the severing and repair of the facial nerve in rats at birth. In each adult rat, the organisation of the facial nucleus and the cortical motor output corresponding to the normal side were compared with those corresponding to the reinnervated side. Labelling was used to reveal reinnervation-induced long-term changes in the motoneuron pool supplying vibrissal muscles. Cortical motor output was assessed by mapping the vibrissal movement area extension and thresholds evoked by intracortical microstimulation. After facial nerve reinnervation: (i) the proportion of labelled cell profiles decreased by 85.2% of that in the control side and cortical representation of vibrissal movement decreased by 66.3% of that in control hemispheres; (ii) the reorganised vibrissal representation was shrunken to the medialmost portion of the normal vibrissal representation and there was a medial extension of the forelimb representation, and a more modest lateral extension of eye representation, into the vibrissal territory; (iii) the normal pattern of contralateral vibrissal movement was observed in only 10% of the vibrissal sites, whereas ipsilateral vibrissal movement was found in 53% of the vibrissal sites; (iv) there was an increase in the mean threshold required to evoke contralateral vibrissal movement (32.5+/-11.1 vs. 20.5+/-6.9 microA). Thresholds to evoke other types of movement were similar to normal. These changes indicate that an incomplete motor axon regeneration at birth does not restore normal innervation and normal cortical control over the vibrissal muscles.