A current-mode system to self-measure temperature on implantable optoelectronics.

BACKGROUND: One of the major concerns in implantable optoelectronics is the heat generated by emitters such as light emitting diodes (LEDs). Such devices typically produce more heat than light, whereas medical regulations state that the surface temperature change of medical implants must stay below + 2 °C. The LED's reverse current can be employed as a temperature-sensitive parameter to measure the temperature change at the implant's surface, and thus, monitor temperature rises. The main challenge in this approach is to bias the LED with a robust voltage since the reverse current is strongly and nonlinearly sensitive to the bias voltage. METHODS: To overcome this challenge, we have developed an area-efficient LED-based temperature sensor using the LED as its own sensor and a CMOS electronic circuit interface to ensure stable bias and current measurement. The circuit utilizes a second-generation current conveyor (CCII) configuration to achieve this and has been implemented in 0.35 µm CMOS technology. RESULTS: The developed circuits have been experimentally characterized, and the temperature-sensing functionality has been tested by interfacing different mini-LEDs in saline models of tissue prior to in vivo operation. The experimental results show the functionality of the CMOS electronics and the efficiency of the CCII-based technique with an operational frequency up to 130 kHz in achieving a resolution of 0.2 °C for the surface temperature up to + 45 °C. CONCLUSIONS: We developed a robust CMOS current-mode sensor interface which has a reliable CCII to accurately convey the LED's reverse current. It is low power and robust against power supply ripple and transistor mismatch which makes it reliable for sensor interface. The achieved results from the circuit characterization and in vivo experiments show the feasibility of the whole sensor interface in monitoring the tissue surface temperature in optogenetics.

A high-performance 8 nV/√Hz 8-channel wearable and wireless system for real-time monitoring of bioelectrical signals.

BACKGROUND: It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Finally, to the best of our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording electrocorticographic (ECoG) signals. METHODS: To address this problem, we designed and developed a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless instrument (55 × 80 mm2). The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. RESULTS: To provide ex vivo proof-of-function, a wide variety of high-quality bioelectrical signal recordings are reported, including electroencephalographic (EEG), electromyographic (EMG), electrocardiographic (ECG), acceleration signals, and muscle fasciculations. Low-noise in vivo recordings of weak local field potentials (LFPs), which were wirelessly acquired in real time using segmented deep brain stimulation (DBS) electrodes implanted in the thalamus of a non-human primate, are also presented. CONCLUSIONS: The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5-500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile and reliable tool to be utilized in a wide range of applications and environments.

Ultrasound Intra Body Multi Node Communication System for Bioelectronic Medicine.

The coming years may see the advent of distributed implantable devices to support bioelectronic medicinal treatments. Communication between implantable components and between deep implants and the outside world can be challenging. Percutaneous wired connectivity is undesirable and both radiofrequency and optical methods are limited by tissue absorption and power safety limits. As such, there is a significant potential niche for ultrasound communications in this domain. In this paper, we present the design and testing of a reliable and efficient ultrasonic communication telemetry scheme using piezoelectric transducers that operate at 320 kHz frequency. A key challenge results from the multi-propagation path effect. Therefore, we present a method, using short pulse sequences with relaxation intervals. To counter an increasing bit, and thus packet, error rate with distance, we have incorporated an error correction encoding scheme. We then demonstrate how the communication scheme can scale to a network of implantable devices. We demonstrate that we can achieve an effective, error-free, data rate of 0.6 kbps, which is sufficient for low data rate bioelectronic medicine applications. Transmission can be achieved at an energy cost of 642 nJ per bit data packet using on/off power cycling in the electronics.

Optogenetic approaches to retinal prosthesis.

The concept of visual restoration via retinal prosthesis arguably started in 1992 with the discovery that some of the retinal cells were still intact in those with the retinitis pigmentosa disease. Two decades later, the first commercially available devices have the capability to allow users to identify basic shapes. Such devices are still very far from returning vision beyond the legal blindness. Thus, there is considerable continued development of electrode materials, and structures and electronic control mechanisms to increase both resolution and contrast. In parallel, the field of optogenetics--the genetic photosensitization of neural tissue holds particular promise for new approaches. Given that the eye is transparent, photosensitizing remaining neural layers of the eye and illuminating from the outside could prove to be less invasive, cheaper, and more effective than present approaches. As we move toward human trials in the coming years, this review explores the core technological and biological challenges related to the gene therapy and the high radiance optical stimulation requirement.

What Ultrasound Can and Cannot Do in Implantable Medical Device Communications.

Modern Active Medical Implantable Devices require communications to transmit information to the outside world or other implantable sub-systems. This can include physiological data, diagnostics, and parameters to optimise the therapeutic protocol. The available options are to use optical, radiofrequency, or ultrasonic communications. However, in all cases, transmission becomes more difficult with deeper transmission through tissue. Challenges include absorption and scattering by tissue, and the need to ensure there are no undesirable heating effects. As such, this paper aims to review research progress in using ultrasound as an alternative for deep tissue communications. We provide an empirical review of the technology and communication protocols that different groups have used, as well as comparing the implications in terms of penetration depth, implant size, and data rate. We conclude that this technique has promise for deeper implants and for intrabody communications between implantable devices (intrabody networks).

A Closed-Loop Optogenetic Platform.

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface. We include commercial components to validate performance, with the ultimate aim of translating this approach to humans. In the meantime our system is flexible and expandable for use in a variety of preclinical neuroscientific applications. The platform consists of a Controlling Abnormal Network Dynamics using Optogenetics (CANDO) Control System (CS) that interfaces with up to four CANDO headstages responsible for electrical recording and optical stimulation through custom CANDO LED optrodes. Control of the hardware, inbuilt algorithms and data acquisition is enabled via the CANDO GUI (Graphical User Interface). Here we describe the design and implementation of this system, and demonstrate how it can be used to modulate neuronal oscillations in vitro and in vivo.

Improved content aware scene retargeting for retinitis pigmentosa patients.

BACKGROUND: In this paper we present a novel scene retargeting technique to reduce the visual scene while maintaining the size of the key features. The algorithm is scalable to implementation onto portable devices, and thus, has potential for augmented reality systems to provide visual support for those with tunnel vision. We therefore test the efficacy of our algorithm on shrinking the visual scene into the remaining field of view for those patients. METHODS: Simple spatial compression of visual scenes makes objects appear further away. We have therefore developed an algorithm which removes low importance information, maintaining the size of the significant features. Previous approaches in this field have included seam carving, which removes low importance seams from the scene, and shrinkability which dynamically shrinks the scene according to a generated importance map. The former method causes significant artifacts and the latter is inefficient. In this work we have developed a new algorithm, combining the best aspects of both these two previous methods. In particular, our approach is to generate a shrinkability importance map using as seam based approach. We then use it to dynamically shrink the scene in similar fashion to the shrinkability method. Importantly, we have implemented it so that it can be used in real time without prior knowledge of future frames. RESULTS: We have evaluated and compared our algorithm to the seam carving and image shrinkability approaches from a content preservation perspective and a compression quality perspective. Also our technique has been evaluated and tested on a trial included 20 participants with simulated tunnel vision. Results show the robustness of our method at reducing scenes up to 50% with minimal distortion. We also demonstrate efficacy in its use for those with simulated tunnel vision of 22 degrees of field of view or less. CONCLUSIONS: Our approach allows us to perform content aware video resizing in real time using only information from previous frames to avoid jitter. Also our method has a great benefit over the ordinary resizing method and even over other image retargeting methods. We show that the benefit derived from this algorithm is significant to patients with fields of view 20° or less.

Designing and testing scene enhancement algorithms for patients with retina degenerative disorders.

BACKGROUND: Retina degenerative disorders represent the primary cause of blindness in UK and in the developed world. In particular, Age Related Macular Degeneration (AMD) and Retina Pigmentosa (RP) diseases are of interest to this study. We have therefore created new image processing algorithms for enhancing the visual scenes for them. METHODS: In this paper we present three novel image enhancement techniques aimed at enhancing the remaining visual information for patients suffering from retina dystrophies. Currently, the only effective way to test novel technology for visual enhancement is to undergo testing on large numbers of patients. To test our techniques, we have therefore built a retinal image processing model and compared the results to data from patient testing. In particular we focus on the ability of our image processing techniques to achieve improved face detection and enhanced edge perception. RESULTS: Results from our model are compared to actual data obtained from testing the performance of these algorithms on 27 patients with an average visual acuity of 0.63 and an average contrast sensitivity of 1.22. Results show that Tinted Reduced Outlined Nature (TRON) and Edge Overlaying algorithms are most beneficial for dynamic scenes such as motion detection. Image Cartoonization was most beneficial for spatial feature detection such as face detection. Patient's stated that they would most like to see Cartoonized images for use in daily life. CONCLUSIONS: Results obtained from our retinal model and from patients show that there is potential for these image processing techniques to improve visual function amongst the visually impaired community. In addition our methodology using face detection and efficiency of perceived edges in determining potential benefit derived from different image enhancement algorithms could also prove to be useful in quantitatively assessing algorithms in future studies.

A novel hybrid technique to fabricate silicon-based micro-implants with near defect-free quality for neuroprosthetics application.

This paper introduces a new hybrid microfabrication technique which combines ultra-precision micro-milling and a ductile sacrificial material deposition process to fabricate a silicon-based implant for neuroprosthetics applications with near defect-free quality at several hundreds of micrometres in thickness. The sacrificial materials can influence the quality of silicon during machining. The cutting mechanism and feasibility of the hybrid technique are studied by molecular dynamics (MD) simulations and experiments. Due to the complexity of modelling PMMA and SU-8 structures in MD environment, only copper was modelled as the simulation is intended to understand the performance of using a ductile sacrificial layer structure in silicon machining. MD analysis shows that the reduced stress intensity and subsurface damage were mainly attributed to workpiece plasticity enhancement, where its mechanism was contributed by better deformability of the ductile sacrificial layer and enhanced thermal softening from the heat generated by the high interfacial stress between the sacrificial layer and silicon substrate. Despite the MD simulation and experiment having different machining scale in terms of cutting parameters, phenomenal behaviours of the cutting performance when observed under the experimental conditions are in good agreement with simulation. Experimental verification shows that near defect-free quality was achieved at large cutting depth of 150 µm when silicon is coated either with PMMA or SU-8. An exemplary implant structure was also fabricated to better demonstrate the hybrid technique's capability. In addition, the hybrid technique will be beneficial for low volume high customisation applications as it is a serial process.

A scalable data transmission scheme for implantable optogenetic visual prostheses.

OBJECTIVE: This work described a video information processing scheme for optogenetic forms of visual cortical prosthetics. APPROACH: The architecture is designed to perform a processing sequence: Initially simplifying the scene, followed by a pragmatic visual encoding scheme which assumes that initially optical stimulation will be stimulating bulk neural tissue rather than driving individual phosphenes. We demonstrate an optical encoder, combined with what we called a zero-run length encoding (zRLE) video compression and decompression scheme-to wirelessly transfer information to an implantable unit in an efficient manner. In the final step, we have incorporated an even power distribution driver to prevent excessive power fluctuations in the optogenetic driving. SIGNIFICANCE: The key novelty in this work centres on the completeness of the scheme, the new zRLE compression algorithm and our even power distributor. MAIN RESULTS: Furthermore, although the paper focusses on the algorithm, we confirm that it can be implemented on real time portable processing hardware which we will use for our visual prosthetics.

Detection of Simulated Tactile Gratings by Electro-Static Friction Show a Dependency on Bar Width for Blind and Sighted Observers, and Preliminary Neural Correlates in Sighted Observers.

The three-dimensional micro-structure of physical surfaces produces frictional forces that provide sensory cues about properties of felt surfaces such as roughness. This tactile information activates somatosensory cortices, and frontal and temporal brain regions. Recent advances in haptic-feedback technologies allow the simulation of surface micro-structures via electro-static friction to produce touch sensations on otherwise flat screens. These sensations may benefit those with visual impairment or blindness. The primary aim of the current study was to test blind and sighted participants' perceptual sensitivity to simulated tactile gratings. A secondary aim was to explore which brain regions were involved in simulated touch to further understand the somatosensory brain network for touch. We used a haptic-feedback touchscreen which simulated tactile gratings using digitally manipulated electro-static friction. In Experiment 1, we compared blind and sighted participants' ability to detect the gratings by touch alone as a function of their spatial frequency (bar width) and intensity. Both blind and sighted participants showed high sensitivity to detect simulated tactile gratings, and their tactile sensitivity functions showed both linear and quadratic dependency on spatial frequency. In Experiment 2, using functional magnetic resonance imaging, we conducted a preliminary investigation to explore whether brain activation to physical vibrations correlated with blindfolded (but sighted) participants' performance with simulated tactile gratings outside the scanner. At the neural level, blindfolded (but sighted) participants' detection performance correlated with brain activation in bi-lateral supplementary motor cortex, left frontal cortex and right occipital cortex. Taken together with previous studies, these results suggest that there are similar perceptual and neural mechanisms for real and simulated touch sensations.

The Neural Engine: A Reprogrammable Low Power Platform for Closed-Loop Optogenetics.

Brain-machine Interfaces (BMI) hold great potential for treating neurological disorders such as epilepsy. Technological progress is allowing for a shift from open-loop, pacemaker-class, intervention towards fully closed-loop neural control systems. Low power programmable processing systems are therefore required which can operate within the thermal window of 2° C for medical implants and maintain long battery life. In this work, we have developed a low power neural engine with an optimized set of algorithms which can operate under a power cycling domain. We have integrated our system with a custom-designed brain implant chip and demonstrated the operational applicability to the closed-loop modulating neural activities in in-vitro and in-vivo brain tissues: the local field potentials can be modulated at required central frequency ranges. Also, both a freely-moving non-human primate (24-hour) and a rodent (1-hour) in-vivo experiments were performed to show system reliable recording performance. The overall system consumes only 2.93 mA during operation with a biological recording frequency 50 Hz sampling rate (the lifespan is approximately 56 hours). A library of algorithms has been implemented in terms of detection, suppression and optical intervention to allow for exploratory applications in different neurological disorders. Thermal experiments demonstrated that operation creates minimal heating as well as battery performance exceeding 24 hours on a freely moving rodent. Therefore, this technology shows great capabilities for both neuroscience in-vitro/in-vivo applications and medical implantable processing units.

Photocycles of channelrhodopsin-2.

Recent developments have used light-activated channels or transporters to modulate neuronal activity. One such genetically-encoded modulator of activity, channelrhodopsin-2 (ChR2), depolarizes neurons in response to blue light. In this work, we first conducted electrophysiological studies of the photokinetics of hippocampal cells expressing ChR2, for various light stimulations. These and other experimental results were then used for systematic investigation of the previously proposed three-state and four-state models of the ChR2 photocycle. We show the limitations of the previously suggested three-state models and identify a four-state model that accurately follows the ChR2 photocurrents. We find that ChR2 currents decay biexponentially, a fact that can be explained by the four-state model. The model is composed of two closed (C1 and C2) and two open (O1 and O2) states, and our simulation results suggest that they might represent the dark-adapted (C1-O1) and light-adapted (C2-O2) branches. The crucial insight provided by the analysis of the new model is that it reveals an adaptation mechanism of the ChR2 molecule. Hence very simple organisms expressing ChR2 can use this form of light adaptation.

Modelling Optogenetic Subthreshold Effects.

We develop a system-level approach to modelling optogenetic-neurons firing behaviour in in-vivo conditions. This approach contains three sub-modules: 1) a Mie/Rayleigh scattering mode of light penetration in tissue; 2) a classic likelihood Poisson spiking train model; 3) a 4-state model of the Channelrhodopsin-2 (ChR2) channel added to a CA3 neuron Hodgkin-Huxley model. We first investigate opto-neurons lightto-spike mechanisms in an in-vivo model: the background noise (synaptic currents) play a dominant role in generating spikes rather than light intensities as for in-vitro conditions (Typically the required light intensity is less than 0.3 mW/mm2 for in-vivo). Then the spiking fidelity is analyzed for different background noise levels. Next, by combining light penetration profiles, we show how neuron firing rates decay as tissue distance increases, for a 2D dimensional cross-section. This preliminary data clearly demonstrate that at given light stimulation protocol, the maximum effected distance in-vivo is 250 µm with small frequency decay rates, while for in-vitro is 50µm with considerable frequency decay rates. Therefore, the developed model can be used for designing sensible light stimulation strategies in-vivo and opto-electronics systems.

Wireless Ultrasonic Communication for Biomedical Injectable Implantable Device.

This paper presents a design and implementation of an ultrasonic wireless communication link for an injectable biomedical implanted device. The results address how the ultrasound link encounter from the multiple paths propagation effect. The ultrasound link characterized in term of channel impulse response and power transmission losses against the depth of the implant, the achieved data transmission rate was 70 Kbps and the signal to noise ratio was (30, 35 and 47) dB at a transmission voltage of (1.8, 3.3 and 20) V peak to peak in 12 cm depth. The transmission loss increases as the depth of the implant increases. The ultrasound link represented by two piezoelectric transducers that operate in 320 KHz radial resonance frequency.

Comparison between Different Optical Systems for Optogenetics based Head Mounted Device for Retina Pigmentosa.

Optogenetics is a fast growing neuromodulation techniques as it can remotely stimulate neural activities of a genetically modified cells. The advantage of remotely controlling the neural activity triggered researchers to implement a headset to externally stimulate retina cells for people with retina pigmentosa. The wearable device requires an efficient optical system to focus the transmitted light pattern into the retina surface. In this work, three different lenses; contact lens, folded prism and linear lenses are used to evaluate the headset performance. A 90x90 µLED display is used as a light source and the optical efficiency for each lens is measured for different points over the lens area. Moreover, the impact of each lens on the headset performance in power and processing will be discussed in this work.

A high-performance 4 nV (√Hz)-1 analog front-end architecture for artefact suppression in local field potential recordings during deep brain stimulation.

OBJECTIVE: Recording of local field potentials (LFPs) during deep brain stimulation (DBS) is necessary to investigate the instantaneous brain response to stimulation, minimize time delays for closed-loop neurostimulation and maximise the available neural data. To our knowledge, existing recording systems lack the ability to provide artefact-free high-frequency (>100 Hz) LFP recordings during DBS in real time primarily because of the contamination of the neural signals of interest by the stimulation artefacts. APPROACH: To solve this problem, we designed and developed a novel, low-noise and versatile analog front-end (AFE) that uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, we assessed the performance of the realised AFE by conducting both in vitro and in vivo experiments using unipolar and bipolar DBS (monophasic pulses, amplitude ranging from 3 to 6 V peak-to-peak, frequency 140 Hz and pulse width 100 µs). A full performance comparison between the proposed AFE and an identical AFE, equipped with an 8th order analog Bessel notch filter, was also conducted. MAIN RESULTS: A high-performance, 4 nV ([Formula: see text])-1 AFE that is capable of recording nV-scale signals was designed in accordance with the imposed specifications. Under both in vitro and in vivo experimental conditions, the proposed AFE provided real-time, low-noise and artefact-free LFP recordings (in the frequency range 0.5-250 Hz) during stimulation. Its sensing and stimulation artefact suppression capabilities outperformed the capabilities of the AFE equipped with the Bessel notch filter. SIGNIFICANCE: The designed AFE can precisely record LFP signals, in and without the presence of either unipolar or bipolar DBS, which renders it as a functional and practical AFE architecture to be utilised in a wide range of applications and environments. This work paves the way for the development of externalized research tools for closed-loop neuromodulation that use low- and higher-frequency LFPs as control signals.

Design Considerations for Artefact-Free Optoelectronic Systems.

This paper proposes design considerations that need to be followed in order to eliminate potential sources of artefact that could distort a recorded neural signal. The artefact that appears in a recorded signal has a combination of potential sources each of which contributes towards its formation. As such, these sources of artefact have been addressed in three main categories: a) electronics artefact, b) encapsulation artefact and c) interface artefact. Each source (component) is analyzed further and appropriate design techniques and considerations are suggested towards its mitigation.

Extraspectral Imaging for Improving the Perceived Information Presented in Retinal Prosthesis.

Retinal prosthesis is steadily improving as a clinical treatment for blindness caused by retinitis pigmentosa. However, despite the continued exciting progress, the level of visual return is still very poor. It is also unlikely that those utilising these devices will stop being legally blind in the near future. Therefore, it is important to develop methods to maximise the transfer of useful information extracted from the visual scene. Such an approach can be achieved by digitally suppressing less important visual features and textures within the scene. The result can be interpreted as a cartoon-like image of the scene. Furthermore, utilising extravisual wavelengths such as infrared can be useful in the decision process to determine the optimal information to present. In this paper, we, therefore, present a processing methodology that utilises information extracted from the infrared spectrum to assist in the preprocessing of the visual image prior to conversion to retinal information. We demonstrate how this allows for enhanced recognition and how it could be implemented for optogenetic forms of retinal prosthesis. The new approach has been quantitatively evaluated on volunteers showing 112% enhancement in recognizing objects over normal approaches.

Self-sensing of temperature rises on light emitting diode based optrodes.

OBJECTIVE: This work presents a method to determine the surface temperature of microphotonic medical implants like LEDs. Our inventive step is to use the photonic emitter (LED) employed in an implantable device as its own sensor and develop readout circuitry to accurately determine the surface temperature of the device. APPROACH: There are two primary classes of applications where microphotonics could be used in implantable devices; opto-electrophysiology and fluorescence sensing. In such scenarios, intense light needs to be delivered to the target. As blue wavelengths are scattered strongly in tissue, such delivery needs to be either via optic fibres, two-photon approaches or through local emitters. In the latter case, as light emitters generate heat, there is a potential for probe surfaces to exceed the 2 °C regulatory. However, currently, there are no convenient mechanisms to monitor this in situ. MAIN RESULTS: We present the electronic control circuit and calibration method to monitor the surface temperature change of implantable optrode. The efficacy is demonstrated in air, saline, and brain. SIGNIFICANCE: This paper, therefore, presents a method to utilize the light emitting diode as its own temperature sensor.