Immobilization of cell-binding peptides on poly-ε-caprolactone film surface to biomimic the peripheral nervous system.

Cell-material interactions are crucial for cell adhesion and proliferation on biomaterial surfaces. Immobilization of biomolecules leads to the formation of biomimetic substrates, improving cell response. We introduced RGD (Arg-Gly-Asp) sequences on poly-ε-caprolactone (PCL) film surfaces using thiol chemistry to enhance Schwann cell (SC) response. XPS elemental analysis indicated an estimate of 2-3% peptide functionalization on the PCL surface, comparable with carbodiimide chemistry. Contact angle was not remarkably reduced; hence, cell response was only affected by chemical cues on the film surface. Adhesion and proliferation of Schwann cells were enhanced after PCL modification. Particularly, RGD immobilization increased cell attachment up to 40% after 6 h of culture. It was demonstrated that SC morphology changed from round to very elongated shape when surface modification was carried out, with an increase in the length of cellular processes up to 50% after 5 days of culture. Finally RGD immobilization triggered the formation of focal adhesion related to higher cell spreading. In summary, this study provides a method for immobilization of biomolecules on PCL films to be used in peripheral nerve repair, as demonstrated by the enhanced response of Schwann cells.

Representations of uncertainty in sensorimotor control.

Uncertainty is ubiquitous in our sensorimotor interactions, arising from factors such as sensory and motor noise and ambiguity about the environment. Setting it apart from previous theories, a quintessential property of the Bayesian framework for making inference about the state of world so as to select actions, is the requirement to represent the uncertainty associated with inferences in the form of probability distributions. In the context of sensorimotor control and learning, the Bayesian framework suggests that to respond optimally to environmental stimuli the central nervous system needs to construct estimates of the sensorimotor transformations, in the form of internal models, as well as represent the structure of the uncertainty in the inputs, outputs and in the transformations themselves. Here we review Bayesian inference and learning models that have been successful in demonstrating the sensitivity of the sensorimotor system to different forms of uncertainty as well as recent studies aimed at characterizing the representation of the uncertainty at different computational levels.

Adaptive control of stiffness to stabilize hand position with large loads.

The goal of this work was to investigate stability in relation to the magnitude and direction of forces applied by the hand. The endpoint stiffness and joint stiffness of the arm were measured during a postural task in which subjects exerted up to 30% maximum voluntary force in each of four directions while controlling the position of the hand. All four coefficients of the joint stiffness matrix were found to vary linearly with both elbow and shoulder torque. This contrasts with the results of a previous study, which employed a force control task and concluded that the joint stiffness coefficients varied linearly with either shoulder or elbow torque but not both. Joint stiffness was transformed into endpoint stiffness to compare the effect on stability as endpoint force increased. When the joint stiffness coefficients were modeled as varying with the net torque at only one joint, as in the previous study, we found that hand position became unstable if endpoint force exceeded about 22 N in a specific direction. This did not occur when the joint stiffness coefficients were modeled as varying with the net torque at both joints, as in the present study. Rather, hand position became increasingly more stable as endpoint force increased for all directions of applied force. Our analysis suggests that co-contraction of biarticular muscles was primarily responsible for the increased stability. This clearly demonstrates how the central nervous system can selectively adapt the impedance of the arm in a specific direction to stabilize hand position when the force applied by the hand has a destabilizing effect in that direction.

Impedance control and internal model use during the initial stage of adaptation to novel dynamics in humans.

This study investigated the neuromuscular mechanisms underlying the initial stage of adaptation to novel dynamics. A destabilizing velocity-dependent force field (VF) was introduced for sets of three consecutive trials. Between sets a random number of 4-8 null field trials were interposed, where the VF was inactivated. This prevented subjects from learning the novel dynamics, making it possible to repeatedly recreate the initial adaptive response. We were able to investigate detailed changes in neural control between the first, second and third VF trials. We identified two feedforward control mechanisms, which were initiated on the second VF trial and resulted in a 50% reduction in the hand path error. Responses to disturbances encountered on the first VF trial were feedback in nature, i.e. reflexes and voluntary correction of errors. However, on the second VF trial, muscle activation patterns were modified in anticipation of the effects of the force field. Feedforward cocontraction of all muscles was used to increase the viscoelastic impedance of the arm. While stiffening the arm, subjects also exerted a lateral force to counteract the perturbing effect of the force field. These anticipatory actions indicate that the central nervous system responds rapidly to counteract hitherto unfamiliar disturbances by a combination of increased viscoelastic impedance and formation of a crude internal dynamics model.

How is somatosensory information used to adapt to changes in the mechanical environment?

Recent studies examining adaptation to unexpected changes in the mechanical environment highlight the use of position error in the adaptation process. However, force information is also available. In this chapter, we examine adaptation processes in three separate studies where the mechanical environment was changed intermittently. We compare the expected consequences of using position error and force information in the changes to motor commands following a change in the mechanical environment. In general, our results support the use of position error over force information and are consistent with current computational models of motor learning. However, in situations where the change in the mechanical environment eliminates position error the central nervous system does not necessarily respond as would be predicted by these models. We suggest that it is necessary to take into account the statistics of prior experience to account for our observations. Another deficiency in these models is the absence of a mechanism for modulating limb mechanical impedance during adaptation. We propose a relatively simple computational model based on reflex responses to perturbations which is capable of accounting for iterative changes in temporal patterns of muscle co-activation.

Impedance control is tuned to multiple directions of movement

Humans are able to learn tool-handling tasks, such as carving, demonstrating their competency to make and vary the direction of movements in unstable environments. It has been shown that when a single reaching movement is repeated in unstable dynamics, the central nervous system (CNS) learns an impedance internal model to compensate for the environment instability. However, there is still no explanation for how humans can learn to move in various directions in such environments. In this study, we investigated whether and how humans compensate for instability while learning two different reaching movements simultaneously. Results show that when performing movements in two different directions, separated by a 35° angle, the CNS was able to compensate for the unstable dynamics. After adaptation, the force was found to be similar to the free movement condition, but stiffness increased in the direction of instability, specifically for each direction of movement. Our findings suggest that the CNS either learned an internal model generalizing over different movements, or alternatively that it was able to switch between specific models acquired simultaneously. © 2008 IEEE.

Impedance control is selectively tuned to multiple directions of movement

Humans are able to learn tool-handling tasks, such as carving, demonstrating their competency to make movements in unstable environments with varied directions. When faced with a single direction of instability, humans learn to selectively co-contract their arm muscles tuning the mechanical stiffness of the limb end point to stabilize movements. This study examines, for the first time, subjects simultaneously adapting to two distinct directions of instability, a situation that may typically occur when using tools. Subjects learned to perform reaching movements in two directions, each of which had lateral instability requiring control of impedance. The subjects were able to adapt to these unstable interactions and switch between movements in the two directions; they did so by learning to selectively control the end-point stiffness counteracting the environmental instability without superfluous stiffness in other directions. This finding demonstrates that the central nervous system can simultaneously tune the mechanical impedance of the limbs to multiple movements by learning movement-specific solutions. Furthermore, it suggests that the impedance controller learns as a function of the state of the arm rather than a general strategy. © 2011 the American Physiological Society.

A neuro-inspired method for data rate limited feedback control

The nervous system implements a networked control system in which the plants take the form of limbs, the controller is the brain, and neurons form the communication channels. Unlike standard networked control architectures, there is no periodic sampling, and the fundamental units of communication contain little numerical information. This paper describes a novel communication channel, modeled after spiking neurons, in which the transmitter integrates an input signal and sends out a spike when the integral reaches a threshold value. The reciever then filters the sequence of spikes to approximately reconstruct the input signal. It is shown that for appropriate choices of channel parameters, stable feedback control over these spiking channels is possible. Furthermore, good tracking performance can be achieved. The data rate of the channel increases linearly with the size of the inputs. Thus, when placed in a feedback loop, small loop gains imply a low data rate. ©2010 IEEE.

Functional requirements for reward-modulated spike-timing-dependent plasticity.

Recent experiments have shown that spike-timing-dependent plasticity is influenced by neuromodulation. We derive theoretical conditions for successful learning of reward-related behavior for a large class of learning rules where Hebbian synaptic plasticity is conditioned on a global modulatory factor signaling reward. We show that all learning rules in this class can be separated into a term that captures the covariance of neuronal firing and reward and a second term that presents the influence of unsupervised learning. The unsupervised term, which is, in general, detrimental for reward-based learning, can be suppressed if the neuromodulatory signal encodes the difference between the reward and the expected reward-but only if the expected reward is calculated for each task and stimulus separately. If several tasks are to be learned simultaneously, the nervous system needs an internal critic that is able to predict the expected reward for arbitrary stimuli. We show that, with a critic, reward-modulated spike-timing-dependent plasticity is capable of learning motor trajectories with a temporal resolution of tens of milliseconds. The relation to temporal difference learning, the relevance of block-based learning paradigms, and the limitations of learning with a critic are discussed.

Slowness: an objective for spike-timing-dependent plasticity?

Our nervous system can efficiently recognize objects in spite of changes in contextual variables such as perspective or lighting conditions. Several lines of research have proposed that this ability for invariant recognition is learned by exploiting the fact that object identities typically vary more slowly in time than contextual variables or noise. Here, we study the question of how this "temporal stability" or "slowness" approach can be implemented within the limits of biologically realistic spike-based learning rules. We first show that slow feature analysis, an algorithm that is based on slowness, can be implemented in linear continuous model neurons by means of a modified Hebbian learning rule. This approach provides a link to the trace rule, which is another implementation of slowness learning. Then, we show analytically that for linear Poisson neurons, slowness learning can be implemented by spike-timing-dependent plasticity (STDP) with a specific learning window. By studying the learning dynamics of STDP, we show that for functional interpretations of STDP, it is not the learning window alone that is relevant but rather the convolution of the learning window with the postsynaptic potential. We then derive STDP learning windows that implement slow feature analysis and the "trace rule." The resulting learning windows are compatible with physiological data both in shape and timescale. Moreover, our analysis shows that the learning window can be split into two functionally different components that are sensitive to reversible and irreversible aspects of the input statistics, respectively. The theory indicates that irreversible input statistics are not in favor of stable weight distributions but may generate oscillatory weight dynamics. Our analysis offers a novel interpretation for the functional role of STDP in physiological neurons.

Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing.

We have investigated whether inkjet printing technology can be extended to print cells of the adult rat central nervous system (CNS), retinal ganglion cells (RGC) and glia, and the effects on survival and growth of these cells in culture, which is an important step in the development of tissue grafts for regenerative medicine, and may aid in the cure of blindness. We observed that RGC and glia can be successfully printed using a piezoelectric printer. Whilst inkjet printing reduced the cell population due to sedimentation within the printing system, imaging of the printhead nozzle, which is the area where the cells experience the greatest shear stress and rate, confirmed that there was no evidence of destruction or even significant distortion of the cells during jet ejection and drop formation. Importantly, the viability of the cells was not affected by the printing process. When we cultured the same number of printed and non-printed RGC/glial cells, there was no significant difference in cell survival and RGC neurite outgrowth. In addition, use of a glial substrate significantly increased RGC neurite outgrowth, and this effect was retained when the cells had been printed. In conclusion, printing of RGC and glia using a piezoelectric printhead does not adversely affect viability and survival/growth of the cells in culture. Importantly, printed glial cells retain their growth-promoting properties when used as a substrate, opening new avenues for printed CNS grafts in regenerative medicine.

In vitro recording of neural activity using carbon nanosheet microelectrodes

The advent of nanotechnology has revolutionised our ability to engineer electrode interfaces. These are particularly attractive to measure biopotentials, and to study the nervous system. In this work, we demonstrate enhanced in vitro recording of neuronal activity using electrodes decorated with carbon nanosheets (CNSs). This material comprises of vertically aligned, free standing conductive sheets of only a few graphene layers with a high surfacearea- to-volume ratio, which makes them an interesting material for biomedical electrodes. Further, compared to carbon nanotubes, CNSs can be synthesised without the need for metallic catalysts like Ni, Co or Fe, thereby reducing potential cytotoxicity risks. Electrochemical measurements show a five times higher charge storage capacity, and an almost ten times higher double layer capacitance as compared to TiN. In vitro experiments were performed by culturing primary hippocampal neurons from mice on micropatterned electrodes. Neurophysiological recordings exhibited high signal-to-noise ratios of 6.4, which is a twofold improvement over standard TiN electrodes under the same conditions. © 2013 Elsevier Ltd. All rights reserved.

Learning legged locomotion

Legged locomotion of biological systems can be viewed as a self-organizing process of highly complex system-environment interactions. Walking behavior is, for example, generated from the interactions between many mechanical components (e.g., physical interactions between feet and ground, skeletons and muscle-tendon systems), and distributed informational processes (e.g., sensory information processing, sensory-motor control in central nervous system, and reflexes) [21]. An interesting aspect of legged locomotion study lies in the fact that there are multiple levels of self-organization processes (at the levels of mechanical dynamics, sensory-motor control, and learning). Previously, the self-organization of mechanical dynamics was nicely demonstrated by the so-called Passive Dynamic Walkers (PDWs; [18]). The PDW is a purely mechanical structure consisting of body, thigh, and shank limbs that are connected by passive joints. When placed on a shallow slope, it exhibits natural bipedal walking dynamics by converting potential to kinetic energy without any actuation. An important contribution of these case studies is that, if designed properly, mechanical dynamics can generate a relatively complex locomotion dynamics, on the one hand, and the mechanical dynamics induces self-stability against small disturbances without any explicit control of motors, on the other. The basic principle of the mechanical self-stability appears to be fairly general that there are several different physics models that exhibit similar characteristics in different kinds of behaviors (e.g., hopping, running, and swimming; [2, 4, 9, 16, 19]), and a number of robotic platforms have been developed based on them [1, 8, 13, 22]. © 2009 Springer London.