Wired, wireless and wearable bioinstrumentation for high-precision recording of bioelectrical signals in bidirectional neural interfaces

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. Furthermore, electrical stimulation of specific target brain regions has been shown to alleviate symptoms of neurological disorders, such as Parkinson’s disease, essential tremor, dystonia, epilepsy etc. In recent years, the traditional practice of continuously stimulating the brain using static stimulation parameters has shifted to the use of disease biomarkers to determine the intensity and timing of stimulation. The main motivation behind closed-loop stimulation is minimization of treatment side effects by providing only the necessary stimulation required within a certain period of time, as determined from a guiding biomarker. Hence, it is clear that high-quality recording of local field potentials (LFPs) or electrocorticographic (ECoG) signals 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, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording ECoG signals, which are of particular importance in closed-loop DBS and epilepsy DBS. In addition, 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. To address the problem of limited mobility often encountered by patients in the clinic and to provide a wide variety of high-precision sensor data to a closed-loop neurostimulation platform, a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless multi-instrument (55 × 80 mm2) was designed and developed. The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. 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 tool to be utilized in a wide range of applications and environments. Moreover, in order to offer the capability of sensing and stimulating via the same electrode, novel real-time artefact suppression methods that could be used in bidirectional (recording and stimulation) system architectures are proposed and validated. More specifically, a novel, low-noise and versatile analog front-end (AFE), which uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency, is presented. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, the performance of the realised AFE is assessed 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). 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. Finally, a family of tunable hardware filter designs and a novel method for real-time artefact suppression that enables wide-bandwidth biosignal recordings during stimulation are also presented. This work paves the way for the development of miniaturized research tools for closed-loop neuromodulation that use a wide variety of bioelectrical signals as control signals.Open Acces

Low-Power Integrated Circuits For Biomedical Applications

With thousands new cases of spinal cord injury reported everyday, many people suffer from paralysis and loss of sensation in both legs. Beside the healthcare costs, such a state severely deteriorates the patients' quality of life and may even lead to additional medical conditions. Therefore, there is a growing need for cyber-physical systems to restore the walking ability through bypassing the damaged spinal cord. This goal can be achieved by monitoring and processing patient's brain signals to enable brain-directed control of prosthetic legs. Among several existing methods to record brain signals, electrocorticography (ECoG) has gained popularity due to being robust to motion artifacts, having high spatial resolution and signal to noise ratio, being moderately invasive and the possibility of chronic implantation of recording grids with no or minor scar tissue formation. The latest property is of particular importance for the whole system to be a viable fully implantable solution. Furthermore, the implanted system has to operate independently with no or minimal need of external hardware (e.g. a bulky personal computer) to be individually and socially accepted. To implement a fully implantable system, low-power and miniaturized electronics are needed to reduced heat generation, increase battery life-time and be minimally intrusive. These requirements indicate that many of the system's components should be custom-designed to integrated as much functionality as possible in a given real estate. This thesis presents silicon tested prototypes of several building blocks for the envisioned system, namely, ultra low-power brain signal acquisition front-ends, a low-power and inductorless MedRadio transceiver, and a fast start-up crystal oscillator. Brain signal acquisition front-ends provide low noise amplification of weak ECoG biosignals. MedRadio transceiver enables communication between the implant and end effectors or base station (e.g. prosthetic legs or desktop computer). Crystal oscillator generates the reference signal for other system's components such as analog to digital converter. Novel techniques to improve important performance parameters (power consumption, low noise operation and interference resilience) have been introduced. Electrical, in-vitro and in-vivo experimental measurements have verified the functionality and performance of each design

INTEGRATION OF CMOS TECHNOLOGY INTO LAB-ON-CHIP SYSTEMS APPLIED TO THE DEVELOPMENT OF A BIOELECTRONIC NOSE

This work addresses the development of a lab-on-a-chip (LOC) system for olfactory sensing. The method of sensing employed is cell-based, utilizing living cells to sense stimuli that are otherwise not easily sensed using conventional transduction techniques. Cells have evolved over millions of years to be exquisitely sensitive to their environment, with certain types of cells producing electrical signals in response to stimuli. The core device that is introduced here is comprised of living olfactory sensory neurons (OSNs) on top of a complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC). This hybrid bioelectronic approach to sensing leverages the sensitivity of OSNs with the electronic signal processing capability of modern ICs. Intimately combining electronics with biology presents a number of unique challenges to integration that arise from the disparate requirements of the two separate domains. Fundamentally the obstacles arise from the facts that electronic devices are designed to work in dry environments while biology requires not only a wet environment, but also one that is precisely controlled and non-toxic. Design and modeling of such heterogeneously integrated systems is complicated by the lack of tools that can address the multiple domains and techniques required for integration, namely IC design, fluidics, packaging, and microfabrication, and cell culture. There also arises the issue of how to handle the vast amount of data that can be generated by such systems, and specifically how to efficiently identify signals of interest and communicate them off-chip. The primary contributions of this work are the development of a new packaging scheme for integration of CMOS ICs into fluidic LOC systems, a methodology for cross-coupled multi-domain iterative modeling of heterogeneously integrated systems, demonstration of a proof-of-concept bioelectronic olfactory sensor, and a novel event-based technique to minimize the bandwidth required to communicate the information contained in bio-potential signals produced by dense arrays of electrically active cells

Optical-Electrode: The Next Generation Brain-Machine Interface

Brain machine interfaces, or brain computer interfaces, are attracting ever increasing research interests for their promising application prospects. A number of methods and devices were proposed on this topic, but all have inherent limits particularly concerning spatial density and signal resolution. An optical-electrode is hereby proposed to overcome these limitations by transducing the electrical signal into an optical signal using liquid crystal cells. In addition, photovoltaic stimulation capabilities were added to form an integrated bidirectional interface. A recording subsystem and a stimulating subsystem were proposed for driving the sensing and stimulation parts respectively, and their benchtop characterisations were carried out. Noise performances in the recording subsystem were analysed and optimised. To provide initial validation, animal studies were conducted on rabbit sciatic nerves (in vivo and ex vivo) and on cardiac tissues (ex vivo). The recorded signals and stimulated responses were compared with those made by commonly used traditional electrical systems under the same experimental conditions. Compound action potentials, although showing differences on delays and morphology over traditional methods, were successfully recorded and evoked. The charge balance ability was also demonstrated in the experiments. Finally, a 'zero mode' photodetector is introduced, which is specifically suitable for the recording subsystem and can potentially improve the noise performance. The works in this thesis will contribute to the next iteration of the technology, i.e. help the creation of high density arrays in the form of integrated chips

Analog VLSI Circuits for Biosensors, Neural Signal Processing and Prosthetics

Stroke, spinal cord injury and neurodegenerative diseases such as ALS and Parkinson's debilitate their victims by suffocating, cleaving communication between, and/or poisoning entire populations of geographically correlated neurons. Although the damage associated with such injury or disease is typically irreversible, recent advances in implantable neural prosthetic devices offer hope for the restoration of lost sensory, cognitive and motor functions by remapping those functions onto healthy cortical regions. The research presented in this thesis is directed toward developing enabling technology for totally implantable neural prosthetics that could one day restore lost sensory, cognitive and motor function to the victims of debilitating neural injury or disease. There are three principal components to this work. First, novel integrated biosensors have been designed and implemented to transduce weak extra-cellular electrical potentials and optical signals from cells cultured directly on the surface of the sensor chips, as well as to manipulate cells on the surface of these chips. Second, a method of detecting and identifying stereotyped neural signals, or action potentials, has been mapped into silicon circuits which operate at very low power levels suitable for implantation. Third, as one small step towards the development of cognitive neural implants, a learning silicon synapse has been implemented and a neural network application demonstrated. The original contributions of this dissertation include: * A contact image sensor that adapts to background light intensity and can asynchronously detect statistically significant optical events in real-time; * Programmable electrode arrays for enhanced electrophysiological recording, for directing cellular growth, for site-specific in situ bio-functionalization, and for analyte and particulate collection; * Ultra-low power, programmable floating gate template matching circuits for the detection and classification of neural action potentials; * A two transistor synapse that exhibits spike timing dependent plasticity and can implement adaptive pattern classification and silicon learning

Information Power Efficiency Tradeoffs in Mixed Signal CMOS Circuits

Increasingly sensors for biological applications are implemented using mixed signal CMOS technologies. As feature sizes in modern technologies decrease with each generation, the power supply voltage also decreases, but the intrinsic noise level increases or remains the same. The performance of any sensor is quantified by the weakest detectable signal, and noise limits the ability of a sensor to detect the signal. In order to explore the trade-offs among incoming signal, the intrinsic physical noise of the circuit, and the available power resources, we apply basic concepts from information theory to CMOS circuits. In this work the circuits are modeled as communication channels with additive colored Gaussian noise and the signal transfer characteristics and noise properties are used to determine the classical Shannon capacity of the system. The waterfilling algorithm is applied to these circuits to obtain the information rate and the bit energy is subsequently calculated. In this dissertation we restricted our attention to operational transconductance amplifiers, a basic building block for many circuits and sensors and oftentimes a major source of noise in a sensor system. It is shown that for typical amplifiers the maximum information rate occurs at bandwidths above the dominant pole of the amplifier where the intrinsic physical circuit noise is diminished, but at the same time the output signal is attenuated. Thus these techniques suggest a methodology for the optimal use of the amplifier, but in many cases it is not practical to use an amplifier in this manner, that is at frequencies above its 3dB cutoff. Further, a direct consequence of applying the classic waterfilling algorithm leads to the idea of using modulation techniques to optimize system performance by shifting signals internally to higher frequencies, providing a practical means to achieve the information rates predicted by waterfilling and at the same time maintaining the real world application of these amplifiers. In addition, the information rates and bit energy for basic CMOS amplifier configurations are studied and compared across configurations and processes. Further the additional design constraints formed by adding the information rate and the bit energy to traditional design characteristics is explored

Development of a Portable and Easy-to-Use EEG System to be Employed in Emergency Situations

This thesis describes the development and evaluation of two portable devices intended for the recording of the electroencephalogram (EEG) in emergency situations. The topic originated from the EEG in Emergency Medicine (EEGEM) project, which seeks to develop the necessary technology and methodology that will help reduce the cost, the preparation time, and the overall complexity associated with EEG nowadays. The work contained herein builds upon the results obtained during previous Master theses that were completed in this project in order to obtain two systems that can be used in to investigate the feasibility and clinical value of EEG in emergency medicine (EM). Before starting the work, a thorough investigation of the EEG signal, which included its origins and its diagnostic potential, was carried out. Existing instrumentation was analyzed as well as factors that influence the quality of the recording. Since the EEG is an established diagnostic tool, it was necessary to follow existing recording guidelines. The recording guidelines of the American Clinical Neurophysiology Society (ACNS) were summarized and employed in the design stages of this study. A review of commercial EEG recorders and quick application EEG caps revealed the absence of an integrated solution for recording this signal in EM. Two systems were developed, one that is able to measure 1 channel of EEG while the other can measure six. The 1-channel system's particularity is that it allows a person's EEG to be displayed on a standard electrocardiogram (ECG) monitor. It features a high input impedance, low noise amplifier that increases the EEG signal's amplitude in order to allow it to be displayed on an ECG monitor. The amount of amplification is dynamically adjusted depending on the peak-to-peak amplitude of the EEG signal. After every gain change, the EEG recording is temporarily interrupted and a sinusoidal signal with an amplitude equivalent to 100 μV at the current gain level is outputted. The user interface is made up of a red, green and blue (RGB) light-emitting diode (LED) unit and a capacitive button that starts/stops the recording. The 6-channel system interfaces with a computer and consists of three parts: a wire-less EEG (WEEG) recording device, a quick-application cap, and recording software that runs on a computer. The WEEG device is able to measure 6 channels of EEG and tri-axial acceleration for the identification of movement artifacts. The recorded data is transmitted to a measurement computer by means of a 2.4 GHz wireless protocol. The author worked with the group from the Department of Automation Science and Engineering (ASE) that developed the previous versions of the device in order to reduce the size of the system and to improve its integration with the measurement computer. An initial prototype of a quick-application electrode cap for out-of-hospital measurements that can be performed by non-EEG specialists was designed by M.Sc. Salmi. It was made up of easily sterilizeable materials that were also elastic. Due to its many straps and adjustment points as well as the floating electrode leads, the band was not easy to apply. This study reports a simplified version of the cap that possesses only two attachment points and can be easily applied even with the patient in the supine position. Also, in the present version, the electrode leads are firmly attached to the cap. The past version of the recording software, which was developed by M.Sc. Pänkälä, had only basic functionality. It displayed the EEG signals, stored them, and allowed the WEEG device to be configured and patient information to be saved. Digital low-pass filtering of the displayed data, the ability to control the vertical sensitivity as well as the time scale, automatic uploading of the recorded file, and an implementation of the aEEG algorithm were added during this thesis. Also, information about the recording can now be stored together with the recorded signals. Furthermore, the software's us-ability was improved by means of a simple graphical user interface (GUI), which makes all functions easily accessible. During the evaluation of the two prototype systems, the electrical and software performance were ascertained. In the electrical tests, the operating time of the device, the common mode rejection (CMR), the frequency response, the noise level, and the signal to noise ratio (SNR) of the two systems were measured. In order to assess the reliability of the software of the two systems, both static and functional tests were conducted. The results obtained from the testing of the systems indicate that they offer similar performance to those offered by commercial EEG recording systems. This demonstrates that they can be used to investigate the clinical indications of EEG in EM. /Kir1

Madala maksumusega elektromüograafide rakendatavus ergonoomikalises hindamises

A thesis for applying for the degree of Doctor of Philosophy in Engineering Sciences.Every year a considerable amount of gross domestic product in several countries is lost due to work-related musculoskeletal disorders (WMSDs). Thus, one of the goals of ergonomics is to prevent WMSDs. A body of knowledge required to prevent WMSDs has existed for decades; however, the exploitation of this knowledge is hindered by the shortcomings in the risk assessment methods. As a rule, objective methods should be preferred to subjective methods, though often access to objective methods is restricted by the cost of the apparatus. The potential to make one of such devices more accessible by reducing the costs was investigated in the thesis. The thesis focused on the electromyograph – a device to study and monitor the electrical activity produced by skeletal muscles. Nowadays one can assemble an electromyograph from low-cost semi-universal components; however, the functionality and usability of such a device is unknown. At first the technical characteristics of components that can be used to assemble an electromyograph were evaluated. Then the electromyographs were assembled and tested in the laboratory and in the field. The results showed that the low-cost electromyographs may be partially utilised in ergonomic risk assessment; however, the use of such equipment in comparison to commercial high-cost apparatus increases the demands on user knowledge, skills and time expenditure. On the other hand, the functionality of the do-it-yourself electromyograph may exceed the commercial device.Tööga seotud luu- ja lihaskonna ülekoormushaiguste tõttu kaotavad riigid igal aastal märkimisväärse osa sisemajanduse kogutoodangust. Seetõttu on üheks ergonoomika eesmärgiks luu- ja lihaskonna ülekoormushaiguste ennetamine. Teadmised töötaja ülekoormuse ennetamiseks on olemas juba aastakümneid. Paraku takistavad teadmiste tõhusat rakendamist puudused riskihindamise meetodites. Riskide hindamisel tuleb subjektiivsetele meetoditele eelistada objektiivseid meetodeid, kuid sageli piirab objektiivsete meetodite kasutamist mõõteseadmete maksumus. Doktoritöös uuriti ühe sellist liiki mõõteseadme, lihaste elektrilise aktiivsuse uurimiseks mõeldud seireseadme ehk elektrimüograafi kättesaadavuse ja rakendamise suurendamise võimalust seadme maksumuse vähendamisega. Nüüdisajal on võimalus elektromüograafe kokku panna madala maksumusega ja pool-universaalsetest komponentidest. Samas pole selge, milline on sellisel viisil valmistatud elektromüograafi funktsionaalsus ja kasutatavus. Doktoritöös hinnati esmalt elektromüograafi madala maksumusega komponentide tehnilisi omadusi ning seejärel katsetati koostatud elektromüograafe laboris ja töökeskkonnas. Doktoritöö andis kinnitust, et madala maksumusega elektromüograafe on võimalik riskihindamisel osaliselt rakendada, kuid selliste seadmete kasutamine eeldab riskihindajalt põhjalikumaid teadmisi ja oskusi ning suuremat ajakulu kui kallite kommertsseadmete kasutamine. Samas võib spetsialisti kokkupandud elektromüograafi funktsionaalsus kommertsseadmeid ületada.Publication of this thesis is supported by the Estonian University of Life Sciences. This research was supported by European Regional Development Fund’s Doctoral Studies and Internationalisation Programme DoR

A digitally invertible universal amplifier for recording and processing of bioelectric signals

Indiana University-Purdue University Indianapolis (IUPUI)The recording and processing of bioelectric signals over the decades has led to the development of many different types of analog filtering and amplification techniques. Meanwhile, there have also been many advancements in the realm of digital signal processing that allow for more powerful analysis of these collected signals. The issues with present acquisition schemes are that (1) they introduce irreversible distortion to the signals and may ultimately hinder analyses that rely on the unique morphological differences between bioelectric signal events and (2) they do not allow the collection of frequencies in the signal from direct-current (DC) to high-frequencies. The project put forth aims to overcome these two issues and present a new scheme for bioelectric signal acquisition and processing. In this thesis, a system has been developed, verified, and validated with experimental data to demonstrate the ability to build an invertible universal amplifier and digital restoration scheme. The thesis is primarily divided into four sections which focus on (1) the introduction and background information, (2) theory and development, (3) verification implementation and testing, and (4) validation implementation and testing. The introduction and background provides pertinent information regarding bioelectric signals and recording practices for bioelectric signals. It also begins to address some of the issues with the classical and present methods for data acquisition and make the case for why an invertible universal amplifier would be better. The universal amplifier transfer function and architecture are discussed and presented along with the development and optimization of the characterization and the inversion, or restoration, filter process. The developed universal amplifier, referred to as the invertible universal amplifier (IUA), while the universal amplifier and the digital restoration scheme together are referred to as the IUA system. The IUA system is then verified on the bench using typical square, sine, and triangle waveforms with varying offsets and the results are presented and discussed. The validation is done with in-vivo experiments showing that the IUA system may be used to acquire and process bioelectric signals with percent error less than to 6% when post-processed using estimated characteristics of and when compared to a standard flat bandwidth high-pass cutoff amplifier

Transmitting Biological Waveforms Using a Cellular Phone

There exists a need to remotely monitor fully mobile patients in their natural environments. Monitoring a patient's biological waveforms can track a patient's vital signs or facilitate the diagnosis of a disease, which could then be treated to help prolong and/or improve the subject's life. If a patient must be monitored without the delay associated with delivering data stored on a recording device, biotelemetry is necessary. Biotelemetry entails transmitting biological waveforms to a remote site for recording, processing and analysis. Due to the limitations of the currently popular methods of biotelemetry, this thesis proposes the use of the increasingly prevalent cellular phone system. An adaptor design is developed to facilitate biotelemetry utilizing the most common features of a cell phone, barring the need for cell phone modification, as required for affordability. As cell phones notoriously confound sensitive medical equipment, especially patient-connected devices, their use is often distanced from sensitive equipment. However, the desire to use cell phones to transmit biological waveforms requires their joint-proximity to patient-connected devices. The adaptor must amplify the waveforms while rejecting cell phone interference to achieve an adequate signal-to-noise ratio. As the frequency range of most biological data does not conform to the passband of the phone system, the adapter must modulate the biological data. To limit the adapter's size and weight, this design exploits the cell phone's battery power. Methods are also introduced to receive and reconstruct high-fidelity representations of the original biological waveform