3D Neuro-electronic interface devices for neuromuscular control: Design studies and realisation steps

In order to design the shape and dimensions of new 3D multi-microelectrode information transducers properly, i. e. adapted to the scale of information delivery to and from peripheral nerve fibres, a number of studies were, and still are, being performed on modelling and simulation of electrical volume conduction inside and outside nerves, on animal experiments on stimulation and recording with single wires and linear arrays, and on new technologies for 3D micro-fabrication. This paper presents a selection of the results of these `Neurotechnology¿ studies at the University of Twente. The experimental and simulation results apply primarily to the peripheral motor nerves of the rat, but are also of interest for neural interfacing with myelinated nerves in man, as fascicles in man are about the same size as in the rat

Roadmap on semiconductor-cell biointerfaces.

This roadmap outlines the role semiconductor-based materials play in understanding the complex biophysical dynamics at multiple length scales, as well as the design and implementation of next-generation electronic, optoelectronic, and mechanical devices for biointerfaces. The roadmap emphasizes the advantages of semiconductor building blocks in interfacing, monitoring, and manipulating the activity of biological components, and discusses the possibility of using active semiconductor-cell interfaces for discovering new signaling processes in the biological world

Implantable micromechanical parylene-based pressure sensors for unpowered intraocular pressure sensing

This paper presents the first implantable, unpowered, parylene-based microelectromechanical system (MEMS) pressure sensor for intraocular pressure (IOP) sensing. From in situ mechanical deformation of the compliant spiral-tube structures, this sensor registers pressure variations without electrical or powered signal transduction of any kind. Micromachined high-aspect-ratio polymeric hollow tubes with different geometric layouts are implemented to obtain high-sensitivity pressure responses. An integrated device packaging method has been developed toward enabling minimally invasive suture-less needle-based implantation of the device. Both in vitro and ex vivo device characterizations have successfully demonstrated mmHg resolution of the pressure responses. In vivo animal experiments have also been conducted to verify the biocompatibility and functionality of the implant fixation method inside the eye. Using the proposed implantation scheme, the pressure response of the implant can be directly observed from outside the eye under visible light, with the goal of realizing convenient, direct and faithful IOP monitoring in glaucoma patients

Hardware design of LIF with Latency neuron model with memristive STDP synapses

In this paper, the hardware implementation of a neuromorphic system is presented. This system is composed of a Leaky Integrate-and-Fire with Latency (LIFL) neuron and a Spike-Timing Dependent Plasticity (STDP) synapse. LIFL neuron model allows to encode more information than the common Integrate-and-Fire models, typically considered for neuromorphic implementations. In our system LIFL neuron is implemented using CMOS circuits while memristor is used for the implementation of the STDP synapse. A description of the entire circuit is provided. Finally, the capabilities of the proposed architecture have been evaluated by simulating a motif composed of three neurons and two synapses. The simulation results confirm the validity of the proposed system and its suitability for the design of more complex spiking neural network

Restoring Upper Extremity Mobility through Functional Neuromuscular Stimulation using Macro Sieve Electrodes

The last decade has seen the advent of brain computer interfaces able to extract precise motor intentions from cortical activity of human subjects. It is possible to convert captured motor intentions into movement through coordinated, artificially induced, neuromuscular stimulation using peripheral nerve interfaces. Our lab has developed and tested a new type of peripheral nerve electrode called the Macro-Sieve electrode which exhibits excellent chronic stability and recruitment selectivity. Work presented in this thesis uses computational modeling to study the interaction between Macro-Sieve electrodes and regenerated peripheral nerves. It provides a detailed understanding of how regenerated fibers, both on an individual level and on a population level respond differently to functional electrical stimulation compared to non-disrupted axons. Despite significant efforts devoted to developing novel regenerative peripheral interfaces, the degree of spatial clustering between functionally related fibers in regenerated nerves is poorly understood. In this thesis, bioelectrical modeling is also used to predict the degree of topographical organization in regenerated nerve trunks. In addition, theoretical limits of the recruitment selectivity of the device is explored and a set of optimal stimulation paradigms used to selectively activate fibers in different regions of the nerve are determined. Finally, the bioelectrical model of the interface/nerve is integrated with a biomechanical model of the macaque upper limb to study the feasibility of using macro-sieve electrodes to achieve upper limb mobilization

Neuromorphic analogue VLSI

Neuromorphic systems emulate the organization and function of nervous systems. They are usually composed of analogue electronic circuits that are fabricated in the complementary metal-oxide-semiconductor (CMOS) medium using very large-scale integration (VLSI) technology. However, these neuromorphic systems are not another kind of digital computer in which abstract neural networks are simulated symbolically in terms of their mathematical behavior. Instead, they directly embody, in the physics of their CMOS circuits, analogues of the physical processes that underlie the computations of neural systems. The significance of neuromorphic systems is that they offer a method of exploring neural computation in a medium whose physical behavior is analogous to that of biological nervous systems and that operates in real time irrespective of size. The implications of this approach are both scientific and practical. The study of neuromorphic systems provides a bridge between levels of understanding. For example, it provides a link between the physical processes of neurons and their computational significance. In addition, the synthesis of neuromorphic systems transposes our knowledge of neuroscience into practical devices that can interact directly with the real world in the same way that biological nervous systems do

Spatio-temporal control of neurotrophin trafficking and signalling in primary neurons cultured inside microfluidic chambers

My PhD project was aimed at applying microfluidics technology to the study of longrange neurotrophin signalling. Neurotrophins are target-derived growth and survival factors that, among other functions, prevent innervating neurons from undergoing apoptosis. Neurotrophins and their receptors have been shown to be transported retrogradely in axons of spinal cord neurons, following a pathway they share with the tetanus neurotoxin binding fragment (TeNT Hc), and which is controlled by the small GTPase Rab7. The Rab7-dependent pathway is thought to trigger downstream signalling events such as the phosphorylation of the transcription factor CREB, important in promoting neuronal survival and differentiation, but direct evidence for this had not yet been provided. To provide direct evidence of this functional relationship between Rab7 activity and CREB phosphorylation, I established microfluidic cultures of spinal cord motor and sensory neurons, in which axonal networks can be treated independently of cell bodies. I used a microfabrication technique known as soft lithography to produce microfluidic chambers. They consist of two parallel compartments interconnected by an array of microgrooves. In this culture system, dorsal root ganglia (DRG) neurons cultured in one of the compartments (somato-dendritic side) can be chemoattracted by gradients of nerve growth factor (NGF) to grow their axons preferentially into the other compartment (axonal side). Control studies by immunofluorescence confocal microscopy of CREB phosphorylation following direct stimulation of DRG cell bodies with NGF in mass cultures and in microfluidic chambers showed no significant differences between these two systems, confirming that the signalling cascade remains unmodified in microfluidic cell cultures. Time-course analysis of CREB phosphorylation in DRG neurons prepared from E18.5 embryos surprisingly revealed a lack of response following NGF stimulation of axon terminals in microfluidic cultures. I tried DRG cultures from E14.5 embryos because a fraction of the total population of DRG neurons during development undergo apoptosis at around E15-E16 if they fail to reach their target tissues. In these cultures, CREB phosphorylation could be observed when stimulating axons with NGF in microfluidic chambers. These results suggest that this long-range signalling pathway is active during a period of development when DRG neurons depend critically on their supply of targetderived neurotrophins, but it is down-regulated at later developmental stages. To gain some further insight into the mechanisms controlling this long range signalling response, and specifically to study the role of Rab7 in this context, I infected E14.5 DRG neurons with lentivirus carrying wild type or a dominant negative mutant of Rab7 (Rab7T22N) coupled to a fluorescent tag. Overexpression of mCherry Rab7T22N affected CREB phosphorylation, significantly reducing the signal generated in distal axons. To confirm this result, I prepared lentivirus carrying shRNA sequences targeting Rab7, and analysed the response to axonal NGF after knocking down the endogenous protein. This different approach also abolished CREB phosphorylation after NGF stimulation of the axonal network in microfluidic chambers. My results provide a direct link between Rab7 activity and downstream effects of the signalling cascade initiated by neurotrophins at axonal networks in compartmentalised microfluidic chambers

Neuromorphic electronic systems

Biological in formation-processing systems operate on completely different principles from those with which most engineers are familiar. For many problems, particularly those in which the input data are ill-conditioned and the computation can be specified in a relative manner, biological solutions are many orders of magnitude more effective than those we have been able to implement using digital methods. This advantage can be attributed principally to the use of elementary physical phenomena as computational primitives, and to the representation of information by the relative values of analog signals, rather than by the absolute values of digital signals. This approach requires adaptive techniques to mitigate the effects of component differences. This kind of adaptation leads naturally to systems that learn about their environment. Large-scale adaptive analog systems are more robust to component degradation and failure than are more conventional systems, and they use far less power. For this reason, adaptive analog technology can be expected to utilize the full potential of wafer-scale silicon fabrication