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Introduction: Symmetric biphasic pulses have been shown to increase the therapeutic window compared to standard cathodic pulses in ET Vim-DBS patients. Furthermore, three hours of stimulation with biphasic pulses caused less stimulation-induced ataxia compared to cathodic pulses. Therefore, an investigation of the longer-term safety of biphasic pulses is warranted. Methods: Seven ET patients were included in a randomized double-blind, cross-over design of one week home-use of symmetric biphasic stimulation (anodic phase first) versus cathodic stimulation. Amplitude was set in a doubleblinded way, at the tremor arrest threshold. The primary outcome was safety assessed by documenting the adverse events. Secondary outcome parameters were stimulation amplitude, tremor (Fahn-Tolosa-Marin Tremor Rating Scale) and ataxia (International Cooperative Ataxia Rating Scale) severity, quality of life (Quality of Life in Essential Tremor Questionnaire) and cognition (Montreal Cognitive Assessment). Three patients continued in the open-label extension phase for 3 months, during which biphasic stimulation-only was further assessed by the same outcome parameters. Results: During the 1 week testing, no adverse effects were reported. To obtain equivalent tremor control, the amplitude of the biphasic pulse was significantly higher compared to that of the cathodic pulse (p = 0.003). The other outcome parameters were not significantly different. During the open-label study, one patient used the remote control to increase the amplitude, leading to two falls caused by stimulation-induced ataxia. No other adverse effects occurred. Discussion and conclusion: In a small cohort, when tested for one week, symmetric biphasic pulses suggest to be safe, but require higher stimulation amplitudes. Further follow-up studies are needed to investigate long-term effects and safety. [ABSTRACT FROM AUTHOR]

IntroductionSymmetric biphasic pulses have been shown to increase the therapeutic window compared to standard cathodic pulses in ET Vim-DBS patients. Furthermore, three hours of stimulation with biphasic pulses caused less stimulation-induced ataxia compared to cathodic pulses. Therefore, an investigation of the longer-term safety of biphasic pulses is warranted.MethodsSeven ET patients were included in a randomized double-blind, cross-over design of one week home-use of symmetric biphasic stimulation (anodic phase first) versus cathodic stimulation. Amplitude was set in a double-blinded way, at the tremor arrest threshold. The primary outcome was safety assessed by documenting the adverse events. Secondary outcome parameters were stimulation amplitude, tremor (Fahn-Tolosa-Marin Tremor Rating Scale) and ataxia (International Cooperative Ataxia Rating Scale) severity, quality of life (Quality of Life in Essential Tremor Questionnaire) and cognition (Montreal Cognitive Assessment). Three patients continued in the open-label extension phase for 3 months, during which biphasic stimulation-only was further assessed by the same outcome parameters.ResultsDuring the 1 week testing, no adverse effects were reported. To obtain equivalent tremor control, the amplitude of the biphasic pulse was significantly higher compared to that of the cathodic pulse (p = 0.003). The other outcome parameters were not significantly different. During the open-label study, one patient used the remote control to increase the amplitude, leading to two falls caused by stimulation-induced ataxia. No other adverse effects occurred.Discussion and conclusionIn a small cohort, when tested for one week, symmetric biphasic pulses suggest to be safe, but require higher stimulation amplitudes. Further follow-up studies are needed to investigate long-term effects and safety.

The purpose of this study was to determine the effect of common transcranial magnetic stimulation (TMS) waveforms (monophasic and biphasic) on resting motor threshold (RMT), active motor threshold (AMT), and motor evoked potential (MEP) amplitudes in the biceps and first dorsal interosseous (FDI) because waveforms may affect motor targets differently. We also determined test-retest reliability. Ten individuals participated in two sessions of TMS delivered to the motor cortex. Monophasic stimulation to induce a posterior–anterior current in the brain (mono PA) and biphasic posterior–anterior then anterior-posterior (bi PA-AP) were applied in each session in random order. In each session, there were four blocks of measurements (2 muscles × 2 waveforms) of RMT, AMT and MEPs at the hotspot location. MEPs were normalized to the maximum EMG signal. RMTs and AMTs were lower for mono PA compared to bi PA-AP stimulation for the biceps (p <0.01) and FDI (p <0.01). Normalized MEPs were greater for mono PA compared to bi PA-AP stimulation in the FDI (p =0.01) and not different in the biceps (p =0.86). Motor thresholds were not different between sessions suggesting high reliability (p <0.01). Normalized MEPs had very low reliability across sessions in the FDI, and moderate reliability in the biceps. Preliminary investigation suggests the effect of TMS waveform on motor thresholds is similar in upper limb proximal and distal muscles, but the effect differs per motor target for MEPs. Further, test–retest reliability of waveform effects was sensitive to target muscle. These findings may contribute to improve the efficacy and reliability of TMS for clinical use. [ABSTRACT FROM AUTHOR]

The presented 16-channel Δ-modulated neural analog-to-digital converter (ADC) exhibits tolerance to input dc offsets of any value, up to the supply voltage. It employs a dynamic differential-difference comparator architecture with a super-GΩ input impedance ensuring negligible gate-leakage current and well-matched differential inputs resulting in more than 78 dB of rejection of common-mode signals and artifacts. The all-digital nature of the presented Δ-ADC enables sampling of input signals at high oversampling ratios (OSRs) making the front-end immune to stimulation artifacts with differential amplitudes up to a limit that is scalable by the OSR (e.g., 10 mVPP at OSR = 10 k). Moreover, it allows the Δ-ADC to linearly scale down the power consumption required by the application’s recording bandwidth. The oversampled Δ-ADC achieves an effective number of bits (ENOB) of 9.7-bit and 2.6-μ VRMS integrated input-referred noise over 1 Hz to 500-Hz bandwidth. It uses no large passives or statically biased circuits, such as operational amplifiers (Opamps) saving both channel area (0.011 mm2) and power consumption (0.99 μW). Experimentally measured results validate the key features of the design and include in vivo recordings in freely moving guinea pigs. The fabricated prototype system-on-a-chip (SoC) hosts an array of 16-channel neural-ADC with in-channel digitally programmable high-compliance current-mode biphasic stimulators as well as wireless circuitry for data communication and power/command reception. [ABSTRACT FROM AUTHOR]

Electric stimulators with precise and reliable outputs are an indispensable part of electrophysiological research. From single cells to deep brain or neuromuscular tissue, there are diverse targets for electrical stimulation. Even though commercial systems are available, we state the need for a low-cost, high precision, functional, and modular (hardware, firmware, and software) current stimulation system with the capacity to generate stable and complex waveforms for pre-clinical research. The system presented in this study is a USB controlled 4-channel modular current stimulator that can be expanded and generate biphasic arbitrary waveforms with 16-bit resolution, high temporal precision (μs), and passive charge balancing: the NES STiM (Neuro Electronic Systems Stimulator). We present a detailed description of the system’s structural design, the controlling software, reliability test, and the pre-clinical studies [deep brain stimulation (DBS) in hemi-PD rat model] in which it was utilized. The NES STiM has been tested with MacOS and Windows operating systems. Interfaces to MATLAB source codes are provided. The system is inexpensive, relatively easy to build and can be assembled quickly. We hope that the NES STiM will be used in a wide variety of neurological applications such as Functional Electrical Stimulation (FES), DBS and closed loop neurophysiological research.

Electric stimulators with precise and reliable outputs are an indispensable part of electrophysiological research. From single cells to deep brain or neuromuscular tissue, there are diverse targets for electrical stimulation. Even though commercial systems are available, we state the need for a low-cost, high precision, functional, and modular (hardware, firmware, and software) current stimulation system with the capacity to generate stable and complex waveforms for pre-clinical research. The system presented in this study is a USB controlled 4-channel modular current stimulator that can be expanded and generate biphasic arbitrary waveforms with 16-bit resolution, high temporal precision (μs), and passive charge balancing: the NES STiM (Neuro Electronic Systems Stimulator). We present a detailed description of the system's structural design, the controlling software, reliability test, and the pre-clinical studies [deep brain stimulation (DBS) in hemi-PD rat model] in which it was utilized. The NES STiM has been tested with MacOS and Windows operating systems. Interfaces to MATLAB source codes are provided. The system is inexpensive, relatively easy to build and can be assembled quickly. We hope that the NES STiM will be used in a wide variety of neurological applications such as Functional Electrical Stimulation (FES), DBS and closed loop neurophysiological research. [ABSTRACT FROM AUTHOR]

Introduction: Symmetric biphasic pulses enlarge the therapeutic window in thalamic deep brain stimulation in patients with essential tremor. Adding an interphase gap to these symmetric biphasic pulses may further affect the therapeutic window., Materials and Methods: Nine patients (16 hemispheres) were included in this study. Biphasic pulses (anodic phase first) with interphase gaps of 0, 10, 20, 50, and 100 μs were tested, in random order. The outcome parameters were the therapeutic threshold (TT) and side-effect threshold (SET), and thus also the therapeutic window (TW)., Results: Increasing interphase gaps lowered both SET and TT (linear mixed-effects model; p < 0.001 and p < 0.001). Because SET decreased predominantly, increasing interphase gaps resulted in smaller TWs (linear mixed-effects model; p < 0.001)., Discussion and Conclusions: Introducing an interphase gap in a symmetric biphasic pulse may lead to less selectivity in fiber or neuronal activation. Our findings show that, in the context of anode-first biphasic pulses, the use of zero-interphase gaps results in the largest TW., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT05177900., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Currently, electrical stimulation (ES) is used to induce changes in various tissues and cellular processes, but its effects on mitochondrial dynamics and mechanisms are unknown. The aim of this study was to compare the effects of monophasic and biphasic, anodal, and cathodal ES on apoptosis, proliferation, and mitochondrial dynamics in neuroblastoma SH‐SY5Y cells. Cells were cultured and treated with ES. Alamar blue assay was performed to measure cell proliferation. The proteins expression of apoptotic‐related proteins Bcl‐2 associated X (Bax), B cell lymphoma 2 (Bcl‐2), optic‐atrophy‐1 (OPA1), mitofusin2 (Mfn2), phosphorylated dynamin‐related protein 1 at serine 616 (p‐DRP1), and total dynamin‐related protein 1 (Total‐DRP1) were also determined. The results showed that monophasic anodal and biphasic anodal/cathodal (Bi Anod) ES for 1 hr at 125 pulses per minute (2.0 Hz) produced the most significant increase in cell proliferation. In addition, monophasic anodal and Bi Anod ES treated cells displayed a significant increase in the levels of anti‐apoptotic protein Bcl‐2, whereas the Bax levels were not changed. Moreover, the levels of Mfn2 were increased in the cells treated by Bi Anod, and OPA1 was increased by monophasic anodal and Bi Anod ES, indicating increased mitochondrial fusion in these ES‐treated cells. However, the levels of mitochondrial fission indicated by DRP1 remained unchanged compared with non‐stimulated cells. These findings were confirmed through visualization of mitochondria using Mitotracker Deep Red, demonstrating that monophasic anodal and Bi Anod ES could induce pro‐survival effects in SH‐SY5Y cells through increasing cell proliferation and mitochondrial fusion. Future research is needed to validate these findings for the clinical application of monophasic anodal and Bi Anod ES. Monophasic anodal and biphasic anodal/cathodal electrical stimulation could induce pro‐survival effects in cells through increasing cell proliferation and mitochondrial fusion. [ABSTRACT FROM AUTHOR]

Recent multidisciplinary studies in the field of visual prosthesis rely on electrically stimulating retinal tissue by placing electrode array into different part of it, bypassing the nerve cells of the visual pathway which have lost their functionality due to various degenerative diseases. The visual prosthesis systems could be more efficient by mimicking physiologically natural electrical signals. In this study, the responses of the retina to biphasic and monophasic electrical stimulations were compared temporally using in-vitro rabbit retina. The retinal tissue was electrically stimulated with charge-balanced biphasic and monophasic pulses. When temporal diversity was comparatively analyzed, spike activity was observed to intensify in the first 20 ms after the moment of stimulation for biphasic stimulation. On the other hand, the spike activity was observed to form in a way that it can be classified into two categories, the primary one forming in the first 20 ms and the secondary delayed one forming between 80 and 100 ms for monophasic stimulation. Moreover, the effect of retina stimulation amplitude was also analyzed. The spike distribution was observed to cumulate mostly in the post-stimulation time interval of the first 20 ms as the stimulation amplitude for biphasic stimulation increased. In monophasic stimulation, secondary delayed spike activity was observed over 80 μA. The obtained experimental findings suggested that lower amplitude charge-balanced short biphasic waveforms could better elicit the precise and proper stimulation patterns necessary to mimic the neural activity of retinal circuitry that resembles the natural ones when it was compared with monophasic stimulation. [ABSTRACT FROM AUTHOR]

Symmetric biphasic pulses have been shown to acutely increase the therapeutic window of ventralis intermedius deep brain stimulation (Vim-DBS) for essential tremor (ET) compared to cathodic pulses. Acute supratherapeutic stimulation can induce ataxic side effects in Vim-DBS. To investigate the effect on tremor, ataxia and dysarthria of 3 h of biphasic stimulation in patients with DBS for ET. A randomized, doubled-blind, cross-over design was used to compare standard cathodic pulses with symmetric biphasic pulses (anode-first) during a 3-h period per pulse shape. During each 3-h period, all stimulation parameters were identical, except for the pulse shape. Tremor (Fahn-Tolosa-Marin Tremor Rating Scale), ataxia (International Cooperative Ataxia Rating Scale) and speech (acoustic and perceptual measures) were assessed hourly during the 3-h periods. Twelve ET patients were included. During the 3-h stimulation period, tremor control was equivalent between the two pulse shapes. Biphasic pulses elicited significantly less ataxia than cathodic pulses (p = 0.006). Diadochokinesis rate of speech was better for the biphasic pulse (p = 0.048), but other measures for dysarthria were not significantly different between the pulses. Symmetric biphasic pulses induce less ataxia than conventional pulses after 3 h of stimulation DBS in ET patients. • When compared for 3 h, at supratherapeutic thresholds: • Biphasic pulses induce less stimulation-induced ataxia compared to cathodic pulses. • Biphasic pulses induce equivalent tremor control compared to cathodic pulses. • Diadochokinesis rate of speech was better for biphasic than cathodic pulses. [ABSTRACT FROM AUTHOR]

[Display omitted] • Designed and implemented a novel ex vivo stimulation paradigm. • Demonstrated enhanced efficacy of current-controlled BPMP application. • Cathodal amplitude impacts NPC expansion and migration. • Directed cathodal migration of NPCs is independent of pulse width. • Ex vivo defined stimulation parameters activate NPCs in vivo. Endogenous neural stem cells and their progeny (together termed neural precursor cells (NPCs)) are promising candidates to facilitate neuroregeneration. Charge-balanced biphasic monopolar stimulation (BPMP) is a clinically relevant approach that can activate NPCs both in vitro and in vivo. Herein, we established a novel ex vivo stimulation system to optimize the efficacy of BPMP electric field (EF) application in activating endogenous NPCs. Using the ex vivo system, we discerned that cathodal amplitude of 200 μA resulted in the greatest NPC pool expansion and enhanced cathodal migration. Application of the same stimulation parameters in vivo resulted in the same NPC activation in the mouse brain. The design and implementation of the novel ex vivo model bridges the gap between in vitro and in vivo systems, enabling a moderate throughput stimulation system to explore and optimize EF parameters that can be applied to clinically relevant brain injury/disease models. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: The cause of the double peak observed at submaximal stimulation of sensory nerves is unknown. The first peak is generated under the cathode and the second under the anode. The double peak is thought to arise from intradermal nerves or skin receptors, and in this study we tested this assumption. Methods: We studied the effect of different stimulus durations on anodal peak latency in volunteers. Biphasic anodal stimulation was used to investigate the latent additive effect of the trailing negative phase on the partial depolarization induced by the initial positive phase. We further tested the maximal amplitude of anode-generated potentials to estimate the number of neural structures involved in their generation. Results: Increased stimulus duration caused anode-generated potential delay. Biphasic stimulation increased anode-generated amplitude 4-fold compared with monophasic stimulation. The anode-generated potential produced up to 85% of the supramaximal cathode-generated amplitude. Conclusions: The results suggest that the double peak arises from anodal break excitation and not from intradermal nerves or receptors. Muscle Nerve 52: 103-106, 2015 [ABSTRACT FROM AUTHOR]

In this paper we present an ASIC, built in a 350 nm CMOS technology, as a component for a neural measurement and stimulation system. The ASIC consists of an adjustable current source and a switch matrix, which allows selecting sources and sinks out of 8 connected electrodes. The ASIC also contains a microsequencer and a memory, which can be configured and programmed using a serial data interface. The circuit allows to apply charge-balanced biphasic current stimulation to nervous tissue, as needed in implantable neural interfaces. [ABSTRACT FROM AUTHOR]

Conductive hydrogel (CH) coatings for biomedical electrodes have shown considerable promise in improving electrode mechanical and charge transfer properties. While they have desirable properties as a bulk material, there is limited understanding of how these properties translate to a microelectrode array. This study evaluated the performance of CH coatings applied to Nucleus Contour Advance cochlear electrode arrays. Cyclic voltammetry and biphasic stimulation were carried out to determine electrical properties of the coated arrays. Electrical testing demonstrated that CH coatings supported up to 24 times increase in charge injection limit. Reduced impedance was also maintained for over 1 billion stimulations without evidence of delamination or degradation. Mechanical studies performed showed negligible effect of the coating on the pre-curl structure of the Contour Advance arrays. Testing the coating in a model human scala tympani confirmed that adequate contact was maintained across the lateral wall. CH coatings are a viable, stable coating for improving electrical properties of the platinum arrays while imparting a softer material interface to reduce mechanical mismatch. Ultimately, these coatings may act to minimize scar tissue formation and fluid accumulation around electrodes and thus improve the electrical performance of neural implants. [ABSTRACT FROM AUTHOR]

We report on a vestibular prosthesis signal processor realized using an experimental field programmable analog array (FPAA). Completing signal processing functions in the analog domain, the processor is designed to help replace a malfunctioning inner ear sensory organ, a semicircular canal. Relying on angular head motion detected by an inertial sensor, the signal processor maps angular velocity into meaningful control signals to drive a current stimulator. To demonstrate biphasic pulse control a 1 k\Omega resistive load was placed across an H-bridge circuit. When connected to a 2.4 V supply, a biphasic current of 100 \muA was maintained at stimulation frequencies from 50–350 Hz, pulsewidths from 25–400 \musec, and interphase gaps ranging from 25–250 \musec. [ABSTRACT FROM PUBLISHER]

This study proposes a novel biphasic stimulation technique to solve the issue of phase drifts in steady-state visual evoked potential (SSVEPs) in phase-tagged systems. Phase calibration was embedded in stimulus sequences using a biphasic flicker, which is driven by a sequence with alternating reference and phase-shift states. Nine subjects were recruited to participate in off-line and online tests. Signals were bandpass filtered and segmented by trigger signals into reference and phase-shift epochs. Frequency components of SSVEP in the reference and phase-shift epochs were extracted using the Fourier method with a 50% overlapped sliding window. The real and imaginary parts of the SSVEP frequency components were organized into complex vectors in each epoch. Hotelling's t-square test was used to determine the significances of nonzero mean vectors. The rejection of noisy data segments and the validation of gaze detections were made based on p values. The phase difference between the valid mean vectors of reference and phase-shift epochs was used to identify user's gazed targets in this system. Data showed an average information transfer rate of 44.55 and 38.21 bits/min in off-line and online tests, respectively. [ABSTRACT FROM PUBLISHER]

Abstract: Surface Functional Electrical Stimulation (FES) requires high stimulation voltages. A step-up transformer in the output stage of the stimulation circuit is often used. In the present technical paper a voltage controlled current source (VCCS) is presented as an alternative to the transformer coupling. Two (master–slave) coupled transconductance amplifiers (TAs)—in series with pre-charged capacitors—are used to drive the output current. After each stimulation pulse the capacitors are recharged to a high voltage by a switch mode power supply (SMPS). A multiplexer in the output stage is used to provide biphasic output. Output rise-time (10–90%) was less than 2μs at 100mA output. Biphasic charge balanced stimulation current can be produced with a net current to ground of less than 20nA, thus virtually separated from ground. The circuit permits recording of the volitional myoelectric signal from the stimulated muscle. It is part of a portable myoelectrically controlled FES system powered by 2 AA batteries and currently used in clinical trials. [Copyright &y& Elsevier]

The descending spinal volleys evoked by monophasic and biphasic magnetic stimulation of the motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of four conscious human subjects. The results suggest that both phases of the biphasic pulse are capable of activating descending motor output. The pattern of recruitment of descending activity depends on the intensity of the stimulus and the relative threshold of each volley to each direction of current flow. [ABSTRACT FROM AUTHOR]

Currently, electrical stimulation (ES) is used to induce changes in various tissues and cellular processes, but its effects on mitochondrial dynamics and mechanisms are unknown. The aim of this study was to compare the effects of monophasic and biphasic, anodal, and cathodal ES on apoptosis, proliferation, and mitochondrial dynamics in neuroblastoma SH-SY5Y cells. Cells were cultured and treated with ES. Alamar blue assay was performed to measure cell proliferation. The proteins expression of apoptotic-related proteins Bcl-2 associated X (Bax), B cell lymphoma 2 (Bcl-2), optic-atrophy-1 (OPA1), mitofusin2 (Mfn2), phosphorylated dynamin-related protein 1 at serine 616 (p-DRP1), and total dynamin-related protein 1 (Total-DRP1) were also determined. The results showed that monophasic anodal and biphasic anodal/cathodal (Bi Anod) ES for 1 hr at 125 pulses per minute (2.0 Hz) produced the most significant increase in cell proliferation. In addition, monophasic anodal and Bi Anod ES treated cells displayed a significant increase in the levels of anti-apoptotic protein Bcl-2, whereas the Bax levels were not changed. Moreover, the levels of Mfn2 were increased in the cells treated by Bi Anod, and OPA1 was increased by monophasic anodal and Bi Anod ES, indicating increased mitochondrial fusion in these ES-treated cells. However, the levels of mitochondrial fission indicated by DRP1 remained unchanged compared with non-stimulated cells. These findings were confirmed through visualization of mitochondria using Mitotracker Deep Red, demonstrating that monophasic anodal and Bi Anod ES could induce pro-survival effects in SH-SY5Y cells through increasing cell proliferation and mitochondrial fusion. Future research is needed to validate these findings for the clinical application of monophasic anodal and Bi Anod ES., (© 2018 Wiley Periodicals, Inc.)