Analysis of Passive Charge Balancing for Safe Current-Mode Neural Stimulation

Charge balancing has been often considered as one of the most critical requirement for neural stimulation circuits. Over the years several solutions have been proposed to precisely balance the charge transferred to the tissue during anodic and cathodic phases. Elaborate dynamic current sources/sinks with improved matching, and feedback loops have been proposed with a penalty on circuit complexity, area or power consumption. Here we review the dominant assumptions in safe stimulation protocols, and derive mathematical models to determine the effectiveness of passive charge balancing in a typical application scenario

A Multichannel High-Frequency Power-Isolated Neural Stimulator With Crosstalk Reduction

In neuroprostheses applications requiring simultaneous stimulations on a multielectrode array, electric crosstalk, the spatial interaction between electric fields from various electrodes is a major limitation to the performance of multichannel stimulation. This paper presents a multichannel stimulator design that combines high-frequency current stimulation (using biphasic charge-balanced chopped pulse profile) with a switched-capacitor power isolation method. The approach minimizes crosstalk and is particularly suitable for fully integrated realization. A stimulator fabricated in a 0.6 & #x03BC;m CMOS high-voltage technology is presented. It is used to implement a multichannel, high-frequency, power-isolated stimulator. Crosstalk reduction is demonstrated with electrodes in physiological media while the efficacy of the high-frequency stimulator chip is proven in vivo. The stimulator provides fully independent operation on multiple channels and full flexibility in the design of neural modulation protocols

Design of a Quasi-Adiabatic Current-Mode Neurostimulator Integrated Circuit for Deep Brain Stimulation

Electrical stimulation of neural tissues is a valuable tool in the retinal prosthesis, cardiac pacemakers, and Deep Brain Stimulation (DBS). DBS is being to treat a growing number of neurological disorders, such as movement disorder, epilepsy, and Parkinson’s disease. The role of the electronic stimulator is paramount in such application, and significant design challenges are to be met to enhance safety and reliability. A current-source based stimulator can accurately deliver a charge-balanced stimulus maintaining patient safety. In this thesis, a general-purpose current-mode neurostimulator (CMS) based upon a new quasi-adiabatic driving technique is proposed which can theoretically achieve more than 80% efficiency with the help of a dynamic high voltage supply (DHVS) as opposed to most conventional general-purpose CMS having less than 25% efficiency. The high-voltage supply is required to withstand the voltage seen across the electrodes (>10V) due to the time-varying impedance presented by the electrode-tissue interface. The overall efficiency of the designed CMS is limited by the efficiency of the DHVS. A HVDD of 15V is created by the DHVS from an input voltage (VDD) of 3V. The DHVS circuit is made by cascading five charge pump circuits using the AMI 0.5µm CMOS process. It can maintain more than 60% efficiency for a wide range of load current from 25µA to 1.4mA, with peak efficiency at 67% and this is comparable with existing specific-purpose state-of-the-art high-voltage supplies used in a current stimulator. The stimulator designed in this thesis employs a new efficient charge recycling mechanism to enhance the overall efficiency, compared to the existing state-of-the-art CMSs. Thus, the overall CMS efficiency is improved by 20% to 25%. A current source, programmable by 8-bit digital input, is also designed which has an output impedance greater than 2MΩ with a dropout voltage of only 120mV. Measurements show voltage compliance exceeding +/-15V when driving a biphasic current stimulus of 10µA to 2.5mA through a simplified R-C model of the electrode-tissue interface. The voltage compliance is defined as the maximum voltage a stimulator can apply across the electrodes to achieve neural stimulation

Flexible Charge Balanced Stimulator With 5.6 fC Accuracy for 140 nC Injections

Electrical stimulations of neuronal structures must ensure net injected charges to be zero for biological safety and voltage compliance reasons. We present a novel architecture of general purpose biphasic constant current stimulator that exhibits less than 5.6 fC error while injecting 140 nC charges using 1.4 mA currents. The floating current sources and conveyor switch based system can operate in monopolar or bipolar modes. Anodic-first or cathodic-first pulses with optional inter-phase delays have been demonstrated with zero quiescent current requirements at the analog front-end. The architecture eliminates blocking capacitors, electrode shorting and complex feedbacks. Bench-top and in-vivo measurement results have been presented with emulated electrode impedances (resistor-capacitor network), Ag-AgCl electrodes in saline and in-vivo (acute) peripheral nerve stimulations in anesthetized rats

Flexible Charge Balanced Stimulator With 5.6 fC Accuracy for 140 nC Injections

Electrical stimulations of neuronal structures must ensure net injected charges to be zero for biological safety and voltage compliance reasons. We present a novel architecture of general purpose biphasic constant current stimulator that exhibits less than 5.6 fC error while injecting 140 nC charges using 1.4 mA currents. The floating current sources and conveyor switch based system can operate in monopolar or bipolar modes. Anodic-first or cathodic-first pulses with optional inter-phase delays have been demonstrated with zero quiescent current requirements at the analog front-end. The architecture eliminates blocking capacitors, electrode shorting and complex feedbacks. Bench-top and in-vivo measurement results have been presented with emulated electrode impedances (resistor-capacitor network), Ag-AgCl electrodes in saline and in-vivo (acute) peripheral nerve stimulations in anesthetized rats

VLSI Circuits for Bidirectional Neural Interfaces

Medical devices that deliver electrical stimulation to neural tissue are important clinical tools that can augment or replace pharmacological therapies. The success of such devices has led to an explosion of interest in the field, termed neuromodulation, with a diverse set of disorders being targeted for device-based treatment. Nevertheless, a large degree of uncertainty surrounds how and why these devices are effective. This uncertainty limits the ability to optimize therapy and gives rise to deleterious side effects. An emerging approach to improve neuromodulation efficacy and to better understand its mechanisms is to record bioelectric activity during stimulation. Understanding how stimulation affects electrophysiology can provide insights into disease, and also provides a feedback signal to autonomously tune stimulation parameters to improve efficacy or decrease side-effects. The aims of this work were taken up to advance the state-of-the-art in neuro-interface technology to enable closed-loop neuromodulation therapies. Long term monitoring of neuronal activity in awake and behaving subjects can provide critical insights into brain dynamics that can inform system-level design of closed-loop neuromodulation systems. Thus, first we designed a system that wirelessly telemetered electrocorticography signals from awake-behaving rats. We hypothesized that such a system could be useful for detecting sporadic but clinically relevant electrophysiological events. In an 18-hour, overnight recording, seizure activity was detected in a pre-clinical rodent model of global ischemic brain injury. We subsequently turned to the design of neurostimulation circuits. Three critical features of neurostimulation devices are safety, programmability, and specificity. We conceived and implemented a neurostimulator architecture that utilizes a compact on-chip circuit for charge balancing (safety), digital-to-analog converter calibration (programmability) and current steering (specificity). Charge balancing accuracy was measured at better than 0.3%, the digital-to-analog converters achieved 8-bit resolution, and physiological effects of current steering stimulation were demonstrated in an anesthetized rat. Lastly, to implement a bidirectional neural interface, both the recording and stimulation circuits were fabricated on a single chip. In doing so, we implemented a low noise, ultra-low power recording front end with a high dynamic range. The recording circuits achieved a signal-to-noise ratio of 58 dB and a spurious-free dynamic range of better than 70 dB, while consuming 5.5 μW per channel. We demonstrated bidirectional operation of the chip by recording cardiac modulation induced through vagus nerve stimulation, and demonstrated closed-loop control of cardiac rhythm

Use of functional neuroimaging and optogenetics to explore deep brain stimulation targets for the treatment of Parkinson's disease and epilepsy

Deep brain stimulation (DBS) is a neurosurgical therapy for Parkinson’s disease and epilepsy. In DBS, an electrode is stereotactically implanted in a specific region of the brain and electrical pulses are delivered using a subcutaneous pacemaker-like stimulator. DBS-therapy has proven to effectively suppress tremor or seizures in pharmaco-resistant Parkinson’s disease and epilepsy patients respectively. It is most commonly applied in the subthalamic nucleus for Parkinson’s disease, or in the anterior thalamic nucleus for epilepsy. Despite the rapidly growing use of DBS at these classic brain structures, there are still non-responders to the treatment. This creates a need to explore other brain structures as potential DBS-targets. However, research in patients is restricted mainly because of ethical reasons. Therefore, in order to search for potential new DBS targets, animal research is indispensable. Previous animal studies of DBS-relevant circuitry largely relied on electrophysiological recordings at predefined brain areas with assumed relevance to DBS therapy. Due to their inherent regional biases, such experimental techniques prevent the identification of less recognized brain structures that might be suitable DBS targets. Therefore, functional neuroimaging techniques, such as functional Magnetic Resonance Imaging and Positron Emission Tomography, were used in this thesis because they allow to visualize and to analyze the whole brain during DBS. Additionally, optogenetics, a new technique that uses light instead of electricity, was employed to manipulate brain cells with unprecedented selectivity

A review of the effectiveness of lower limb orthoses used in cerebral palsy

To produce this review, a systematic literature search was conducted for relevant articles published in the period between the date of the previous ISPO consensus conference report on cerebral palsy (1994) and April 2008. The search terms were 'cerebral and pals* (palsy, palsies), 'hemiplegia', 'diplegia', 'orthos*' (orthoses, orthosis) orthot* (orthotic, orthotics), brace or AFO

Neural circuit analysis of the dorsal nucleus of the lateral lemniscus and new viral approaches to neural circuit analysis in Mongolian gerbils

Auditory stimuli are processed by several parallel and serial neural circuits in the auditory brainstem. In the first part of this PhD thesis, synaptic integration of excitatory inputs in the neural network of the dorsal nucleus of the lateral lemniscus (DNLL) in Mongolian gerbils is investigated. The second part of this study analyses the feasibility of the use of viral vectors in Mongolian gerbils. This work aims to add to the available methods for neural circuit analysis in these animals by establishing tools for genetic manipulation. The DNLL receives excitatory inputs from the superior olivary complex (SOC) and provides GABAergic inhibition to its contralateral counterpart and both inferior colliculi (ICs). This GABAergic inhibition can outlast the triggering auditory stimulus by tens of milliseconds and thus differs substantially from the fast glycinergic inhibition prevailing in the SOC. It is thought that this persistent inhibition (PI) suppresses further processing of sound source information cues of lagging sounds, thereby providing the neuronal basis for sound localisation in reverberant environments. The mechanisms which PI is generated are still under debate. One hypothesized mechanism focuses on the output mechanism in DNLL neurons, favouring transmitter spillover or asynchronous release to evoke PI. A second mechanism states that integration of excitatory inputs leads to temporally extended activity in DNLL neurons, thereby prolonging the GABAergic output. Here, we tested in vitro the feasibility of the integration based mechanism in Mongolian gerbils. We analyzed the integration of excitatory inputs to DNLL neurons and found that five simultaneously stimulated excitatory fibres, each releasing on average ~18 vesicles are sufficient to trigger a single action potential (AP) in a DNLL neuron. A strong presynaptic stimulation pulse could trigger multiple APs. The input-output functions (IO-Fs) of DNLL neurons were dependent on NMDA receptor (NMDAR) mediated currents, which temporally extended the neuron's activity. The synaptic IO-Fs of DNLL neurons could also be modulated by voltage gated potassium, but not by calcium conductances.The NMDAR dependent activity amplification, which is maintained into adult stages, is shown to prolong the GABAergic output of DNLL neurons, thus contributing to PI generation. Viral vectors are widely used to alter the genetic content of a host organism. In Mongolian gerbils this approach may be suitable to compensate for the lack of genetic strategies in neural circuit analysis such as transgenic animal lines. Lentiviral and Semliki forest viral vectors were stereotactically injected into the IC or the medial nucleus of the trapezoid body (MNTB) in Mongolian gerbils. The lentiviral constructs were able to induce expression of the transgenic protein in the IC but not in MNTB principal neurons. The Semliki forest viral vector induced expression in both nuclei but also caused strong cytotoxic effects in the infected cells. In a further experiment, an eGFP expressing pseudorabies virus based on the attenuated Bartha strain (PRV-152) was stereotactically injected into the IC and was able to retrogradely infect the nuclei of the auditory brain stem in juvenile and adult Mongolian gerbils. PRV-152 spread synaptically to 2nd order neurons by ~20 hours after injection. Infection could also be started in the DNLL and showed a strongly pronounced neurotropism. The virus induced eGFP expression was high and allowed for a detailed visualization of the infected neurons, establishing PRV-152 as an effective tool for anatomical circuit analysis. The feasibility of using this virus in conjunction with electrophysiological investigations was also tested. 37% of 1st and 78% of 2nd order infected neurons show a significant decrease of excitability, which impedes the use of PRV-152 in combination with electrophysiological recordings for physiological analysis of neural circuits.Auditorische Stimuli werden in verschiedenen parallel und in Serie angeordneten neuralen Netzwerken des auditorischen Hirnstamms verarbeitet. Im ersten Teil dieser Dissertation wird die synaptische Integration exzitatorischer Eingänge zu Neuronen des dorsalen Nukleus des lateralen Lemniscus (DNLL) der mongolischen Wüstenrennmaus untersucht. Der zweite Teil der Arbeit betrachtet die Möglichkeit des Einsatzes viraler Vektoren in der mongolischen Wüstenrennmaus. Das Ziel war es, die Palette der verfügbaren Methoden zur Analyse neuronaler Netzwerke in diesen Tieren um einen genetischen Ansatz zu erweitern. Der DNLL erhält exzitatorische Eingänge vom superioren Olivenkernkomplex (SOC) und sendet GABAerge inhibitorische Projektionen zum kontralateralen DNLL und zu beiden inferioren Colliculi (ICs). Diese GABAerge Inhibition kann den auslösenden auditorischen Reiz für mehrere Millisekunden überdauern und unterscheidet sich damit grundsätzlich von der im SOC vorherrschenden schnellen, glycinergen Inhibition. Es wird vermutet, daß diese persistierende Inhibition (PI) die weitere Verarbeitung räumlicher Information von Echos unterdrückt und damit eine neuronale Grundlage zur Schallquellenlokalisation in nachhallenden Umgebungen bildet. Die Mechanismen zur Generierung der PI sind nicht vollständig erklärt. Eine mögliche Erklärung zielt auf den Mechanismus der Neurotrnasmitterausschüttung in DNLL Neuronen. Demzufolge könnten Neurotransmitter "spill over" oder asynchrone Transmitterausschüttung die GABAerge Inhibition der DNLL Neurone zeitlich verlängern. Ein zweiter Mechanismus argumentiert, daß die Aktivität in DNLL Neuronen durch die Integration exzitatorischer synaptischer Eingänge zeitlich ausgedehnt wird und somit auch die Inhibition die die DNLL Neurone auf ihre Zielzellen ausüben. In dieser Arbeit wurde mit Hilfe der "patch-clamp" Methode die Integration exzitatorischer Eingänge in DNLL Neuronen untersucht mit dem Ziel die mögliche Existenz dieses zweiten Mechanismus zu zeigen. Die Ergebnisse zeigen, daß fünf simultan erregte exzitatorische Fasern benötigt werden, die im Durchschnitt ~18 Vesikel ausschütten, um ein Aktionspotential (AP) in einem DNLL Neuron auszulösen. Ein einzelner starker präsynaptischer Stimulationspuls ist außerdem ausreichend mehrere APs auszulösen. Die Input-Output Funktionen (IO-Fs) von DNLL Neuronen sind abhängig von NMDA Rezeptorströmen, welche die Aktivität von DNLL Neuronen zeitlich verlängern. Anders als Kalziumleitfähigkeiten sind auch Kaliumleitfähigkeiten in der Lage die IO-Fs von DNLL Neuronen zu beeinflussen. Die NMDA Rezeptorstrom abhängige Aktivitätsverlängerung in DNLL Neuronen ist sowohl in juvenilen, als auch in adulten Tieren vorhanden und gipfelt in einer Verlängerung der GABAergen Inhibition die von DNLL Neuronen generiert wird. Somit ist die Integration exzitatorischer Eingänge in DNLL Neuronen grundsätzlich geeignet zum Enstehen der PI beizutragen. Virale Vektoren werden benutzt um den genetischen Inhalt eines Organismus zu verändern. In mongolischen Wüstenrennmäusen, von denen es derzeit keine transgenen Tierlinien gibt, können virale Vektoren benutzt werden diesen Nachteil auszugleichen. Wir haben lentivirale Vektoren und Vektoren basierend auf dem Semliki Forest Virus (SFV) stereotaktisch in den IC und den medialen Nukleus des Trapezkörpers (MNTB) von mongolischen Wüstenrennmäusen injiziert. Die lentiviralen Konstrukte induzieren die Expression des transgenen Proteins im IC, nicht aber in MNTB Neuronen. Der SFV-Vektor ist in der Lage in beiden Nuklei Expression auszulösen, entfaltet aber zusätzlich eine stark zytotoxische Wirkungen. In einer weiteren Experimentreihe wurde ein eGFP exprimierender attenuierter Pseudorabiesstamm (PRV-152) in den IC injiziert. Dieser Vektor ist in der Lage alle Nuklei des auditorischen Hirnstamms retrograd der Injektionsstelle in juvenilen und adulten mongolischen Wüstenrennmäusen zu infizieren. Die PRV-152 Infektion breitet sich nach etwa 20 Stunden über die erste Synapse zu infizierten Zellen zweiter Ordnung aus. Die PRV-152 Infektion kann ebenfalls vom DNLL ausgehend ausgelöst werden und zeigt einen ausgeprägten Neurotropismus. Die induzierte Expression des eGFPs ist hoch und ermöglicht eine deutliche Darstellung der infizierten Neurone, so daß PRV-152 ein vielversprechendes Werkzeug zur anatomischen Untersuchung neuronaler Netzwerke darstellt. Ebenfalls wurde untersucht, ob die PRV-152 Infektion zusätzlich die elektrophysiologische Untersuchung der infizierten Neurone erlaubt. 37% der infizierten Neurone erster Ordnung und 78% der infizierten Neurone zweiter Ordnung zeigen eine signifikant heruntergesetzte Erregbarkeit. Diese Ergebnisse zeigen deutlich, daß PRV-152 eine anatomische, nicht aber eine elektrophysiologische Untersuchung neuronale Netzwerke ermöglicht