NeuroDots: From Single-Target to Brain-Network Modulation: Why and What Is Needed?

OBJECTIVES: Current techniques in brain stimulation are still largely based on a phrenologic approach that a single brain target can treat a brain disorder. Nevertheless, meta-analyses of brain implants indicate an overall success rate of 50% improvement in 50% of patients, irrespective of the brain-related disorder. Thus, there is still a large margin for improvement. The goal of this manuscript is to 1) develop a general theoretical framework of brain functioning that is amenable to surgical neuromodulation, and 2) describe the engineering requirements of the next generation of implantable brain stimulators that follow from this theoretic model. MATERIALS AND METHODS: A neuroscience and engineering literature review was performed to develop a universal theoretical model of brain functioning and dysfunctioning amenable to surgical neuromodulation. RESULTS: Even though a single target can modulate an entire network, research in network science reveals that many brain disorders are the consequence of maladaptive interactions among multiple networks rather than a single network. Consequently, targeting the main connector hubs of those multiple interacting networks involved in a brain disorder is theoretically more beneficial. We, thus, envision next-generation network implants that will rely on distributed, multisite neuromodulation targeting correlated and anticorrelated interacting brain networks, juxtaposing alternative implant configurations, and finally providing solid recommendations for the realization of such implants. In doing so, this study pinpoints the potential shortcomings of other similar efforts in the field, which somehow fall short of the requirements. CONCLUSION: The concept of network stimulation holds great promise as a universal approach for treating neurologic and psychiatric disorders.

Surface modification of multilayer graphene electrodes by local printing of platinum nanoparticles using spark ablation for neural interfacing.

In this paper, we present the surface modification of multilayer graphene electrodes with platinum (Pt) nanoparticles (NPs) using spark ablation. This method yields an individually selective local printing of NPs on an electrode surface at room temperature in a dry process. NP printing is performed as a post-process step to enhance the electrochemical characteristics of graphene electrodes. The NP-printed electrode shows significant improvements in impedance, charge storage capacity (CSC), and charge injection capacity (CIC), versus the equivalent electrodes without NPs. Specifically, electrodes with 40% NP surface density demonstrate 4.5 times lower impedance, 15 times higher CSC, and 4 times better CIC. Electrochemical stability, assessed via continuous cyclic voltammetry (CV) and voltage transient (VT) tests, indicated minimal deviations from the initial performance, while mechanical stability, assessed via ultrasonic vibration, is also improved after the NP printing. Importantly, NP surface densities up to 40% maintain the electrode optical transparency required for compatibility with optical imaging and optogenetics. These results demonstrate selective NP deposition and local modification of electrochemical properties in graphene electrodes for the first time, enabling the cohabitation of graphene electrodes with different electrochemical and optical characteristics on the same substrate for neural interfacing.

On the Stimulation Artifact Reduction during Electrophysiological Recording of Compound Nerve Action Potentials.

Recording neuronal activity triggered by electrical impulses is a powerful tool in neuroscience research and neural engineering. It is often applied in acute electrophysiological experimental settings to record compound nerve action potentials. However, the elicited neural response is often distorted by electrical stimulus artifacts, complicating subsequent analysis. In this work, we present a model to better understand the effect of the selected amplifier configuration and the location of the ground electrode in a practical electrophysiological nerve setup. Simulation results show that the stimulus artifact can be reduced by more than an order of magnitude if the placement of the ground electrode, its impedance, and the amplifier configuration are optimized. We experimentally demonstrate the effects in three different settings, in-vivo and in-vitro.

Spread-Spectrum Modulated Multi-Channel Biosignal Acquisition Using a Shared Analog CMOS Front-End.

The key challenges in designing a multi-channel biosignal acquisition system for an ambulatory or invasive medical application with a high channel count are reducing the power consumption, area consumption and the outgoing wire count. This article proposes a spread-spectrum modulated biosignal acquisition system using a shared amplifier and an analog-to-digital converter (ADC). We propose a design method to optimize a recording system for a given application based on the required SNR performance, number of inputs, and area. The proposed method is tested and validated on real pre-recorded atrial electrograms and achieves an average percentage root-mean-square difference (PRD) performance of 2.65% and 3.02% for sinus rhythm (SR) and atrial fibrillation (AF), respectively by using pseudo-random binary-sequence (PRBS) codes with a code-length of 511, for 16 inputs. We implement a 4-input spread-spectrum analog front-end in a 0.18 µm CMOS process to demonstrate the proposed approach. The analog front-end consists of a shared amplifier, a 2nd order Σ∆ ADC sampled at 7.8 MHz, used for digitization, and an on-chip 7-bit PRBS generator. It achieves a number-of-inputs to outgoing-wire ratio of 4:1 while consuming 23 µA/input including biasing from a 1.8 V power supply and 0.067 mm2 in area.

Stent with Piezoelectric Transducers for High Spatial Resolution Ultrasound Neuromodulation- a Finite Element Analysis.

Deep brain stimulation is currently the only technique used in the clinical setting to modulate the neural activity of deep brain nuclei. Recently, low-intensity transcranial focused ultrasound (LIFU) has been shown to reversibly modulate brain activity through a transcranial pathway. Transcranial LIFU requires a low-frequency ultrasound of around 0.5 MHz due to skull attenuation, thus providing poor axial and lateral resolution. This paper proposes a new conceptual device that would use a stent to place a high-frequency ultrasound array within the brain vasculature to achieve high axial and lateral spatial resolution. The first part of this work identified the most commonly treated deep brain nuclei and examined the human brain vasculature for stent placement. Next, a finite element analysis was carried out using a piezoelectric array that follows the blood vessels curvature, and its ability to focus ultrasound waves in clinically relevant brain nuclei was evaluated. The analytical solution provided promising results for deep brain stimulation via a stent with ultrasound transducers for high spatial resolution neuromodulation.

Multilayer CVD graphene electrodes using a transfer-free process for the next generation of optically transparent and MRI-compatible neural interfaces.

Multimodal platforms combining electrical neural recording and stimulation, optogenetics, optical imaging, and magnetic resonance (MRI) imaging are emerging as a promising platform to enhance the depth of characterization in neuroscientific research. Electrically conductive, optically transparent, and MRI-compatible electrodes can optimally combine all modalities. Graphene as a suitable electrode candidate material can be grown via chemical vapor deposition (CVD) processes and sandwiched between transparent biocompatible polymers. However, due to the high graphene growth temperature (≥ 900 °C) and the presence of polymers, fabrication is commonly based on a manual transfer process of pre-grown graphene sheets, which causes reliability issues. In this paper, we present CVD-based multilayer graphene electrodes fabricated using a wafer-scale transfer-free process for use in optically transparent and MRI-compatible neural interfaces. Our fabricated electrodes feature very low impedances which are comparable to those of noble metal electrodes of the same size and geometry. They also exhibit the highest charge storage capacity (CSC) reported to date among all previously fabricated CVD graphene electrodes. Our graphene electrodes did not reveal any photo-induced artifact during 10-Hz light pulse illumination. Additionally, we show here, for the first time, that CVD graphene electrodes do not cause any image artifact in a 3T MRI scanner. These results demonstrate that multilayer graphene electrodes are excellent candidates for the next generation of neural interfaces and can substitute the standard conventional metal electrodes. Our fabricated graphene electrodes enable multimodal neural recording, electrical and optogenetic stimulation, while allowing for optical imaging, as well as, artifact-free MRI studies.

Energy Savings of Multi-Channel Neurostimulators with Non-Rectangular Current-Mode Stimuli Using Multiple Supply Rails.

In neuromodulation applications, conventional current mode stimulation is often preferred over its voltage mode equivalent due to its good control of the injected charge. However, it comes at the cost of less energy-efficient output stages. To increase energy efficiency, recent studies have explored non-rectangular stimuli. The current work highlights the importance of an adaptive supply for an output stage with programmable non-rectangular stimuli and accordingly proposes a system-level architecture for multi-channel stimulators. In the proposed architecture, a multi-output DC/DC Converter (DDC) allows each channel to choose among the available supply levels (i.e., DDC outputs) independently and based on its instant voltage/current requirement. A system-level analysis is carried out in Matlab to calculate the possible energy savings of this solution, compared to the conventional approach with a fixed supply. The energy savings have been simulated for a variety of supply levels and waveform amplitudes, suggesting energy savings of up to 83% when employing 6 DDC outputs and the lowest current amplitude explored ( 250 µA), and as high as 26% for a full-scale amplitude (4 mA).

Energy efficiency of pulse shaping in electrical stimulation: the interdependence of biophysical effects and circuit design losses.

Power efficiency in electrical stimulator circuits is crucial for developing large-scale multichannel applications like bidirectional brain-computer interfaces and neuroprosthetic devices. Many state-of-the-art papers have suggested that some non-rectangular pulse shapes are more energy-efficient for exciting neural excitation than the conventional rectangular shape. However, additional losses in the stimulator circuit, which arise from employing such pulses, were not considered. In this work, we analyze the total energy efficiency of a stimulation system featuring non-rectangular stimuli, taking into account the losses in the stimulator circuit. To this end, activation current thresholds for different pulse shapes and durations in cortical neurons are modeled, and the energy required to generate the pulses from a constant voltage supply is calculated. The proposed calculation reveals an energy increase of 14%-51% for non-rectangular pulses compared to the conventional rectangular stimuli, instead of the decrease claimed in previous literature. This result indicates that a rectangular stimulation pulse is more power-efficient than the tested alternative shapes in large-scale multichannel electrical stimulation systems.

Kilohertz alternating current neuromodulation of the pudendal nerves: effects on the anal canal and anal sphincter in rats.

The first two objectives were to establish which stimulation parameters of kilohertz frequency alternating current (KHFAC) neuromodulation influence the effectiveness of pudendal nerve block and its safety. The third aim was to determine whether KHFAC neuromodulation of the pudendal nerve can relax the pelvic musculature, including the anal sphincter. Simulation experiments were conducted to establish which parameters can be adjusted to improve the effectiveness and safety of the nerve block. The outcome measures were block threshold (measure of effectiveness) and block threshold charge per phase (measure of safety). In vivo, the pudendal nerves in 11 male and 2 female anesthetized Sprague Dawley rats were stimulated in the range of 10 Hz to 40 kHz, and the effect on anal pressure was measured. The simulations showed that block threshold and block threshold charge per phase depend on waveform, interphase delay, electrode-to-axon distance, interpolar distance, and electrode array orientation. In vivo, the average anal pressure during unilateral KHFAC stimulation was significantly lower than the average peak anal pressure during low-frequency stimulation (p < 0.001). Stimulation with 20 kHz and 40 kHz (square wave, 10 V amplitude, 50% duty cycle, no interphase delay) induced the largest anal pressure decrease during both unilateral and bilateral stimulation. However, no statistically significant differences were detected between the different frequencies. This study showed that waveform, interphase delay and the alignment of the electrode along the nerve affect the effectiveness and safety of KHFAC stimulation. Additionally, we showed that KHFAC neuromodulation of the pudendal nerves with an electrode array effectively reduces anal pressure in rats.

Towards CMOS Bulk Sensing for In-Situ Evaluation of ALD Coatings for Millimeter Sized Implants.

To meet the dimensional requirements for bioelectronic medicine, new packaging solutions are needed that could enable small, light-weight and flexible implants. For protecting the implantable electronics against biofluids, recently various atomic layer deposited (ALD) coatings have been proposed with high barrier properties. Before implantation, however, the protective coating should be evaluated for any defects which could otherwise lead to leakage and device failure. In these cases, the conventional helium leak test method can no longer be used due to the millimeter size of the implant. Therefore, an in-situ sensing platform is needed that could evaluate the coating and justify the implantation of the final device. In this work, we explore the possibility of using the CMOS bulk for such a platform. Towards this aim, as a proof of concept, test chips were made in a standard 6-metal 0.18 µm CMOS process and for the connection to the bulk, a p+ diffusion was used. A group of samples was then coated with an ALD multilayer. For coating evaluation, off-chip DC current leakage and impedance measurements were carried out in saline between the CMOS bulk and a platinum reference electrode. Results were compared between non-coated and coated chips that clearly demonstrated the potential of using the bulk as a sensing platform for coating evaluations. This novel approach could pave the way towards an all integrated in-situ hermeticity test, currently missing in mm-size implants.

A Chip Integrity Monitor for Evaluating Moisture/Ion Ingress in mm-Sized Single-Chip Implants.

For mm-sized implants incorporating silicon integrated circuits, ensuring lifetime operation of the chip within the corrosive environment of the body still remains a critical challenge. For the chip's packaging, various polymeric and thin ceramic coatings have been reported, demonstrating high biocompatibility and barrier properties. Yet, for the evaluation of the packaging and lifetime prediction, the conventional helium leak test method can no longer be applied due to the mm-size of such implants. Alternatively, accelerated soak studies are typically used instead. For such studies, early detection of moisture/ion ingress using an in-situ platform may result in a better prediction of lifetime functionality. In this work, we have developed such a platform on a CMOS chip. Ingress of moisture/ions would result in changes in the resistance of the interlayer dielectrics (ILD) used within the chip and can be tracked using the proposed system, which consists of a sensing array and an on-chip measurement engine. The measurement system uses a novel charge/discharge based time-mode resistance sensor that can be implemented using simple yet highly robust circuitry. The sensor array is implemented together with the measurement engine in a standard 0.18  µm 6-metal CMOS process. The platform was validated through a series of dry and wet measurements. The system can measure the ILD resistance with values of up to 0.504 peta-ohms, with controllable measurement steps that can be as low as 0.8 M Ω. The system works with a supply voltage of 1.8 V, and consumes 4.78 mA. Wet measurements in saline demonstrated the sensitivity of the platform in detecting moisture/ion ingress. Such a platform could be used both in accelerated soak studies and during the implant's life-time for monitoring the integrity of the chip's packaging.

An Ultra High-Frequency 8-Channel Neurostimulator Circuit With [Formula: see text] Peak Power Efficiency.

In order to recruit neurons in excitable tissue, constant current neural stimulators are commonly used. Recently, ultra high-frequency (UHF) stimulation has been proposed and proven to have the same efficacy as constant-current stimulation. UHF stimulation uses a fundamentally different way of activating the tissue: each stimulation phase is made of a burst of current pulses with adjustable amplitude injected into the tissue at a high (e.g., [Formula: see text]) frequency. This paper presents the design, integrated circuit (IC) implementation, and measurement results of a power efficient multichannel UHF neural stimulator. The core of the neurostimulator is based on our previously proposed architecture of an inductor-based buck-boost dc-dc converter without the external output capacitor. The ultimate goal of this work is to increase the power efficiency of the UHF stimulator for multiple-channel operation, while keeping the number of external components minimal. To this end, a number of novel approaches were employed in the integrated circuit design domain. More specifically, a novel zero-current detection scheme is proposed. It allows to remove the freewheel diode typically used in dc-dc converters to prevent current to flow back from the load to the inductor. Furthermore, a gate-driver circuit is implemented which allows the use of thin gate-oxide transistors as high-voltage switches. By doing so, and exploiting the fundamental working principle of the proposed current-controlled UHF stimulator, the need for a high-voltage supply is eliminated and the stimulator is powered up from a [Formula: see text] input voltage. Both the current detection technique and the gate driving circuit of the current implementation allow to boost the power efficiency up to [Formula: see text] when compared to previous UHF stimulator works. A peak power efficiency of [Formula: see text] is achieved, while 8 independent channels with 16 fully configurable electrodes are used. The circuit is implemented in a [Formula: see text] HV process, and the total chip area is [Formula: see text].

Comments on "Compact, Energy-Efficient High-Frequency Switched Capacitor Neural Stimulator With Active Charge Balancing".

This manuscript points out some mistakes in the Introduction and in the table of comparison of a paper already published in this journal by Hsu and Schmid [1]. Although the main claim of [1] is still preserved, we believe the paper needs to be rectified for scientific correctness of the work.

An Energy-Efficient, Inexpensive, Spinal Cord Stimulator with Adaptive Voltage Compliance for Freely Moving Rats.

This paper presents the design and fabrication of an implantable control unit intended for epidural spinal cord stimulation (ESCS) in rats. The device offers full programmability over stimulation parameters and delivers a constant current to an electrode array to be located within the spinal canal. It implements an adaptive voltage compliance in order to reduce the unnecessary power dissipation often experienced in current-controlled stimulation (CCS) devices. The compliance is provided by an adjustable boost converter that offers a voltage output in the range of 6.24 V to 28 V, allowing the device to deliver currents up to 1 mA through loads up to $25 \mathrm {k}\Omega $. The system has been fabricated using discrete components, paving the way to an inexpensive product that can easily be manufactured and batch produced. The control unit occupies a total volume of ~13.5 cm3 and therefore fulfills the size restrictions of a system to be implanted in a rat. Results indicate that by adjusting the voltage compliance a total power efficiency up to 35.5% can be achieved, saving around 60 mW when using lower stimulation currents or operating on smaller impedances. The achieved efficiency is the highest compared to similar stateof-the-art systems.

Mixed-Signal IC With Pulse Width Modulation Wireless Telemetry for Implantable Cardiac Pacemakers in 0.18-µm CMOS.

A low-power mixed-signal IC for implantable pacemakers is presented. The proposed system features three independent intracardiac signal readout channels with pulse-width-modulated outputs. Also, the proposed system is capable of measuring the amplitude and phase of the bioimpedance with pulse-width-modulated outputs for use in rate adaptive pacemakers. Moreover, a stimulation system is embedded, offering 16 different amplitudes from 1 to 7.8 V. A backscattering transmitter transfers the output signals outside the body with very little power consumption. The proposed low-power mixed-signal IC is fabricated in a 0.18-µm HV CMOS process and occupies 2.38 mm2. The biopotential channels extract the heart signals with 9.2 effective number of bits and the bioimpedance channels measure the amplitude and phase of the heart impedance with 1.35 Ωrms accuracy. The complete IC consumes only 4.2 µA from a 1-V power supply.

A 1.55 µW Bio-Impedance Measurement System for Implantable Cardiac Pacemakers in 0.18 µm CMOS.

This paper presents an implantable bio-impedance measurement system for cardiac pacemakers. The fully integrated system features a low power analog front-end and pulse width modulated output. The bio-impedance readout benefits from voltage to time conversion to achieve a very low power consumption for wirelessly transmitting the data outside the body. The proposed IC is fabricated in a 0.18 µm CMOS process and is capable of measuring the bio-impedance at 2 kHz over a wide dynamic range from to with accuracy and maximum current injection while consuming just from a 1 V supply.

Realizing flexible bioelectronic medicines for accessing the peripheral nerves - technology considerations.

Patients suffering from conditions such as paralysis, diabetes or rheumatoid arthritis could in the future be treated in a personalised manner using bioelectronic medicines (BEms) (Nat Rev Drug Discov 13:399-400, 2013, Proc Natl Acad Sci USA 113:8284-9, 2016, J Intern Med 282:37-45, 2017). To deliver this personalised therapy based on electricity, BEms need to target various sites in the human body and operate in a closed-loop manner. The specific conditions and anatomy of the targeted sites pose unique challenges in the development of BEms. With a focus on BEms based on flexible substrates for accessing small peripheral nerves, this paper discusses several system-level technology considerations related to the development of such devices. The focus is mainly on miniaturisation and long-term operation. We present an overview of common substrate and electrode materials, related processing methods, and discuss assembly, miniaturisation and long-term stability issues.

An Autonomous Wireless Sensor Node With Asynchronous ECG Monitoring in 0.18 µ m CMOS.

The design of a 13.56 MHz/402 MHz autonomous wireless sensor node with asynchronous ECG monitoring for near field communication is presented. The sensor node consists of an RF energy harvester (RFEH), a power management unit, an ECG readout, a data encoder and an RF backscattering transmitter. The energy harvester supplies the system with 1.25 V and offers a power conversion efficiency of 19% from a -13 dBm RF source at 13.56 MHz. The power management unit regulates the output voltage of the RFEH to supply the ECG readout with VECG = 0.95 V and the data encoder with VDE = 0.65 V . The ECG readout comprises an analog front-end (low noise amplifier and programmable voltage to current converter) and an asynchronous level crossing ADC with 8 bits resolution. The ADC output is encoded by a pulse generator that drives a backscattering transmitter at 402 MHz. The total power consumption of the sensor node circuitry is 9.7 µ W for a data rate of 90 kb/s and a heart rate of 70 bpm. The chip has been designed in a 0.18 µm CMOS process and shows superior RF input power sensitivity and lower power consumption when compared to previous works.

A Power-Efficient Multichannel Neural Stimulator Using High-Frequency Pulsed Excitation From an Unfiltered Dynamic Supply.

This paper presents a neural stimulator system that employs a fundamentally different way of stimulating neural tissue compared to classical constant current stimulation. A stimulation pulse is composed of a sequence of current pulses injected at a frequency of 1 MHz for which the duty cycle is used to control the stimulation intensity. The system features 8 independent channels that connect to any of the 16 electrodes at the output. A sophisticated control system allows for individual control of each channel's stimulation and timing parameters. This flexibility makes the system suitable for complex electrode configurations and current steering applications. Simultaneous multichannel stimulation is implemented using a high frequency alternating technique, which reduces the amount of electrode switches by a factor 8. The system has the advantage of requiring a single inductor as its only external component. Furthermore it offers a high power efficiency, which is nearly independent on both the voltage over the load as well as on the number of simultaneously operated channels. Measurements confirm this: in multichannel mode the power efficiency can be increased for specific cases to 40% compared to 20% that is achieved by state-of-the-art classical constant current stimulators with adaptive power supply.

Does a coupling capacitor enhance the charge balance during neural stimulation? An empirical study.

Due to their DC-blocking characteristic, coupling capacitors are widely used to prevent potentially harmful charge buildup at the electrode-tissue interface. Although the capacitors can be an effective safety measure, it often seems overlooked that coupling capacitors actually introduce an offset voltage over the electrode-tissue interface as well. This work investigates this offset voltage both analytically and experimentally. The calculations as well as the experiments using bipolar-driven platinum electrodes in a saline solution confirm that coupling capacitors introduce an offset, while they barely contribute to the passive charge balancing. In particular cases, this offset is shown to reach potentially dangerous voltage levels that could induce irreversible electrochemical reactions. This work therefore suggests that when the use of coupling capacitors is required, the offset voltage should be analyzed for all operating conditions to ensure it remains within safe boundaries.