Biphasic Currents Research Articles

Fully Implantable Cochlear Implant Interface Electronics With 51.2-$\mu$ W Front-End Circuit

This paper presents an ultralow power interface circuit for a fully implantable cochlear implant (FICI) system that stimulates the auditory nerves inside cochlea. The input sound is detected with a multifrequency piezoelectric (PZT) sensor array, is signal-processed through a front-end circuit module, and is delivered to the nerves through current stimulation in proportion to the sound level. The front-end unit reduces the power dissipation by combining amplification and compression of the sensor output through an ultralow power logarithmic amplifier. The amplified signal is envelope detected, and fed to a voltage-controlled current source as a reference for stimulation current generation. The single channel performance has been tested with a thin film pulsed-laser deposition (PLD) PZT sensor for sound levels between 60- and 100-dB sound pressure level (SPL). The proposed front-end signal conditioning unit, which can support different back-end stimulators, dissipates only 25.4 and 51.2 $\mu \text{W}$ based on measurement, for 1- and 8-channel operation, respectively. This represents the lowest in the literature. The interface generates linear stimulation current of 110– $430~\mu \text{A}$ for the given sound range. The single-channel and eight-channel stimulator consume 105 and $691~\mu \text{W}$ , respectively, for 110- $\mu \text{A}$ biphasic stimulation current.

Diseño de un Prototipo de Electroestimulación Neuromuscular de Baja Frecuencia

Objective. Design a low frequency Neuromuscular Electrostimulation prototype with modifiable digital parameters through the Arduino platform. Methodology: The following work shows the design of a low-frequency neuromuscular electrostimulation equipment prototype with similar characteristics to conventional devices but with a unique design in its programming, this prototype allows modifying the parameters of intensity, time, pulse duration and Frequency through the Arduino platform, this HARDWARE is based on simple analog and digital boards that allow reading input and output data on the device. This prototype emits a symmetrical biphasic current of rectangular pulses and although there is a great variety of currents within the Neuromuscular Electrostimulation (EENM) focused on improving and maximizing the activation of a muscle, generally the symmetric biphasic pulses are better tolerated to the passage of a current through subcutaneous tissue, with greater effectiveness in depolarization of thick fibers of intact nerves. Contribution: To offer alternatives for the management of digital devices in electrotherapy.

Design and In Vivo Verification of a CMOS Bone-Guided Cochlear Implant Microsystem.

To develop and verify a CMOS bone-guided cochlear implant (BGCI) microsystem with electrodes placed on the bone surface of the cochlea and the outside of round window for treating high-frequency hearing loss. The BGCI microsystem consists of an external unit and an implanted unit. The external system-on-chip is designed to process acoustic signals through an acquisition circuit and an acoustic DSP processor to generate stimulation patterns and commands that are transmitted to the implanted unit through a 13.56 MHz wireless power and bidirectional data telemetry. In the wireless power telemetry, a voltage doubler/tripler (2X/3X) active rectifier is used to enhance the power conversion efficiency and generate 2 and 3 V output voltages. In the wireless data telemetry, phase-locked loop based binary phase-shift keying and load-shift keying modulators/demodulators are adopted for the downlink and uplink data through high-Q coils, respectively. The implanted chip with four-channel high-voltage-tolerant stimulator generates biphasic stimulation currents up to 800 μA. Electrical tests on the fabricated BGCI microsystem have been performed to verify the chip functions. The in vivo animal tests in guinea pigs have shown the evoked third wave of electrically evoked auditory brainstem response waveforms. It is verified that auditory nerves can be successfully stimulated and acoustic hearing can be partially preserved. Different from traditional cochlear implants, the proposed BGCI microsystem is less invasive, preserves partially acoustic hearing, and provides an effective alternative for treating high-frequency hearing loss.

A Sub-500 $\mu$ W Interface Electronics for Bionic Ears

This paper presents an ultra-low power current-mode circuit for a bionic ear interface. Piezoelectric (PZT) sensors at the system input transduce sound vibrations into multi-channel electrical signals, which are then processed by the proposed circuit to stimulate the auditory nerves consistently with the input amplitude level. The sensor outputs are first amplified and range-compressed through ultra-low power logarithmic amplifiers (LAs) into AC current waveforms, which are then rectified through custom current-mode circuits. The envelopes of the rectified signals are extracted, and are selectively sampled as reference for the stimulation current generator, armed with a 7-bit user-programmed DAC to enable patient fitting (calibration). Adjusted biphasic stimulation current is delivered to the nerves according to continuous inter-leaved sampling (CIS) stimulation strategy through a switch matrix. Each current pulse is optimized to have an exponentially decaying shape, which leads to reduced supply voltage, and hence ~20% lower stimulator power dissipation. The circuit has been designed and fabricated in 180nm high-voltage CMOS technology with up to 60 dB measured input dynamic range, and up to 1 mA average stimulation current. The 8-channel interface has been validated to be fully functional with 472μW power dissipation, which is the lowest value in the literature to date, when stimulated by a mimicked speech signal.

The intensity of continuous theta burst stimulation, but not the waveform used to elicit motor evoked potentials, influences its outcome in the human motor cortex

BackgroundResponses to continuous theta burst stimulation (cTBS) applied to the human primary motor cortex are highly variable between individuals. However, little is known about how to improve the after-effects of cTBS by adjusting the protocol characteristics. ObjectiveWe examined whether current directions adopted in the measurement of cortical motor excitability indexed as motor evoked potentials (MEPs) affect the responses to cTBS. We also tested whether the stimulus intensity of cTBS influences the after-effects. MethodsThirty-one healthy volunteers participated. The after-effects of cTBS with the conventional intensity of 80% of individual active motor threshold (AMT) (cTBS80%) were tested by measuring MEP amplitudes induced by not only posterior-anterior (PA) but also anterior-posterior (AP) and biphasic (PA-AP) currents. We also investigated cTBS with 65% AMT (cTBS65%) and 100% AMT (cTBS100%) in subjects who showed depression of MEP amplitudes after cTBS80%, as well as cTBS65% in subjects in whom facilitation of MEPs was induced by cTBS80%. ResultsCurrent directions in MEP measurement had no influence on the cTBS responses. In subjects whose MEPs were depressed by cTBS80%, cTBS100% partly induced MEP facilitation, while cTBS65% abolished the after-effects. In subjects who showed MEP facilitation by cTBS80%, cTBS65% partly induced MEP depression. ConclusionsStimulus intensity of cTBS influenced the responses to cTBS, and lowering stimulus intensity induced the expected after-effects of cTBS in some subjects.

Endogenous Isoquinoline Alkaloids Agonists of Acid-Sensing Ion Channel Type 3.

Acid-sensing ion channels (ASICs) ASIC3 expressed mainly in peripheral sensory neurons play an important role in pain perception and inflammation development. In response to acidic stimuli, they can generate a unique biphasic current. At physiological pH 7.4, human ASIC3 isoform (hASIC3) is desensitized and able to generate only a sustained current. We found endogenous isoquinoline alkaloids (EIAs), which restore hASIC3 from desensitization and recover the transient component of the current. Similarly, rat ASIC3 isoform (rASIC3) can also be restored from desensitization (at pH < 7.0) by EIAs with the same potency. At physiological pH and above, EIAs at high concentrations were able to effectively activate hASIC3 and rASIC3. Thus, we found first endogenous agonists of ASIC3 channels that could both activate and prevent or reverse desensitization of the channel. The decrease of EIA levels could be suggested as a novel therapeutic strategy for treatment of pain and inflammation.

Transcranial Alternating Current Stimulation (tACS) Mechanisms and Protocols.

Perception, cognition and consciousness can be modulated as a function of oscillating neural activity, while ongoing neuronal dynamics are influenced by synaptic activity and membrane potential. Consequently, transcranial alternating current stimulation (tACS) may be used for neurological intervention. The advantageous features of tACS include the biphasic and sinusoidal tACS currents, the ability to entrain large neuronal populations, and subtle control over somatic effects. Through neuromodulation of phasic, neural activity, tACS is a powerful tool to investigate the neural correlates of cognition. The rapid development in this area requires clarity about best practices. Here we briefly introduce tACS and review the most compelling findings in the literature to provide a starting point for using tACS. We suggest that tACS protocols be based on functional brain mechanisms and appropriate control experiments, including active sham and condition blinding.

P138 Influence of the difference of induced current direction on measurement of corticospinal excitability changes after continuous and intermittent theta burst stimulation

Introduction The after-effects of continuous and intermittent theta burst stimulation (cTBS and iTBS) are highly variable between individuals and only about 50% of subjects respond in expected ways (i.e. depression of motor evoked potentials (MEPs) in cTBS and facilitation in iTBS). TBS is usually applied using a biphasic stimulus pulse. It preferentially activates the brain during the second depolarizing phase of the current in the brain, that is, anterior-posterior (AP) current. In contrast, the after-effects of any plasticity inducing protocols are usually evaluated by a monophasic stimulus pulse with posterior-anterior (PA) current. Here we hypothesized that such difference in magnetic pulse configuration of transcranial magnetic stimulation (TMS) influences variability of TBS effects. Objectives To investigate whether the after-effects of TBS should be clearer if tested with MEPs generated by AP currents or biphasic currents. Methods Twenty-three healthy right-handed volunteers participated in this study. TMS was applied to the hot spot of the right first dorsal interosseous muscle and MEPs were measured at the stimulus intensities set to evoke MEPs of about 1 mV in monophasic PA, monophasic AP, and biphasic currents. Thirty MEPs for each direction were measured before and up to 30 min after cTBS or iTBS (Huang et al., 2005). Responder (i.e. depression in cTBS and facilitation in iTBS) was defined according to the grand average of MEPs. Results In cTBS, responder rates were 23.9% (5/21) in PA current, 38.1% (8/21) in AP current, and 14.2% (3/21) in biphasic current. 42.9% (9/21) of subjects showed opposite responses between PA and AP currents. As for non-responders both in PA and AP currents (47.6%, 10/21), the difference of baseline MEP latencies at rest between monophasic PA and biphasic currents was smaller than the others. In iTBS, responder rates were 60.9% (14/23) in PA current, 65.2% (15/23) in AP current, and 47.8% (11/23) in biphasic current. 47.8% (11/23) of subjects showed opposite responses between PA and AP currents. Conclusion The after-effects of TBS were highly variable regardless of current direction in measurement of MEPs. In cTBS, a tendency to early I wave recruitment in biphasic pulse might relate to MEP facilitation both in PA and AP currents.

Transcranial magnetic stimulation devices for biphasic and polyphasic ultra-high frequency protocols

Objective: This paper describes the development of ultra-high frequency transcranial magnetic stimulators for biphasic and polyphasic quadripulse stimulation (QPS) of the human cortex in order to investigate neural plasticity. QPS originally describes a set of four monophasic stimuli with an inter-stimulus-interval (ISI) in the range of 1.5 to 100 ms, typically repeated every five seconds. Besides QPS, the described devices are able to set a quadripulse at much higher repetition rates (IBIs down to 200 ms) enabling quadri-Theta-Burst-Stimulation (qTBS). Methods: Insulated gate bipolar transistors (IGBT) were used as high voltage/high speed switch to control the current flowing through the stimulation coil. Biphasic and the polyphasic stimuli were applied over the human primary motor cortex (M1-HAND) to elicit motor evoked potentials (MEP). Technically parameters of the devices were determined and applicability for qTBS proto-cols is derived. Results: We built two devices, which allow the application of quadripulses with biphasic and polyphasic pulse currents, respectively. ISI as short as 1.0 ms with a IBI down to 200 ms is possible. In addition the devices allow to apply user defined protocols enabling individualized treatment. Conclusion: The biphasic as well as the polyphasic qTBS device is able to clearly elicit MEPs and is strong enough to apply qTBS protocols to subjects. Significance: This paper describes a novel topology of a stimulation device, which enables QPS and qTBS with biphasic or polyphasic pulse shapes at ultra-high frequencies. This enables research on protocols that can modulate cortico-spinal excitability within short stimulation times.

Long-term Repeatability and Reproducibility of Phosphene Characteristics in Chronically Implanted Argus II Retinal Prosthesis Subjects

Previously published literatures of acute studies on few subjects have shown contradictory evidence on the reproducibility and characteristics of the elicited phosphenes, despite using the same stimulating parameters with epiretinal electrode arrays. In this study, we set out to investigate the long-term repeatilibity and reproducibility of phosphenes in subjects chronically implanted with the Argus II retinal prosthesis (Second Sight Medical Products, Inc., Sylmar, CA, USA). Retrospective interventional case series and reliability study. Six Argus II subjects of >5 years implantation from a single site participated. The 4-electrode cluster ("quad") closest to fovea was stimulated in each subject with a fixed biphasic current. Perceived phosphenes were depicted relative to subjective visual field center. The stimulus was applied at reducing time intervals from 20minutes to 1 second. Two sets of stimulations were performed on the same day and 2 further sets repeated on a separate visit >1week apart. Each subject depicted phosphenes of consistent shapes and sizes, and reported seeing the same colors with the fixed stimulating parameters, irrespective of the interstimuli intervals. However, there is a wide intersubject variation in the phosphene characteristics. Four subjects drew phosphenes in the same visual field quadrant, as predicted by the quad-fovea location. Two subjects depicted phosphenes in the same hemifield as the expected locations. Phosphenes for each subject were consistently reproducible in all our chronically implanted subjects. This has important implications in the development of long-term pixelated prosthetic vision for future devices.

Designing Closed-Loop Brain-Machine Interfaces Using Model Predictive Control

Brain-machine interfaces (BMIs) are broadly defined as systems that establish direct communications between living brain tissue and external devices, such as artificial arms. By sensing and interpreting neuronal activities to actuate an external device, BMI-based neuroprostheses hold great promise in rehabilitating motor disabled subjects, such as amputees. In this paper, we develop a control-theoretic analysis of a BMI-based neuroprosthetic system for voluntary single joint reaching task in the absence of visual feedback. Using synthetic data obtained through the simulation of an experimentally validated psycho-physiological cortical circuit model, both the Wiener filter and the Kalman filter based linear decoders are developed. We analyze the performance of both decoders in the presence and in the absence of natural proprioceptive feedback information. By performing simulations, we show that the performance of both decoders degrades significantly in the absence of the natural proprioception. To recover the performance of these decoders, we propose two problems, namely tracking the desired position trajectory and tracking the firing rate trajectory of neurons which encode the proprioception, in the model predictive control framework to design optimal artificial sensory feedback. Our results indicate that while the position trajectory based design can only recover the position and velocity trajectories, the firing rate trajectory based design can recover the performance of the motor task along with the recovery of firing rates in other cortical regions. Finally, we extend our design by incorporating a network of spiking neurons and designing artificial sensory feedback in the form of a charged balanced biphasic stimulating current.

Extrapolating microdomain Ca(2+) dynamics using BK channels as a Ca(2+) sensor.

Ca2+ ions play crucial roles in mediating physiological and pathophysiological processes, yet Ca2+ dynamics local to the Ca2+ source, either from influx via calcium permeable ion channels on plasmic membrane or release from internal Ca2+ stores, is difficult to delineate. Large-conductance calcium-activated K+ (BK-type) channels, abundantly distribute in excitable cells and often localize to the proximity of voltage-gated Ca2+ channels (VGCCs), spatially enabling the coupling of the intracellular Ca2+ signal to the channel gating to regulate membrane excitability and spike firing patterns. Here we utilized the sensitivity and dynamic range of BK to explore non-uniform Ca2+ local transients in the microdomain of VGCCs. Accordingly, we applied flash photolysis of caged Ca2+ to activate BK channels and determine their intrinsic sensitivity to Ca2+. We found that uncaging Ca2+ activated biphasic BK currents with fast and slow components (time constants being τf ≈ 0.2 ms and τs ≈ 10 ms), which can be accounted for by biphasic Ca2+ transients following light photolysis. We estimated the Ca2+-binding rate constant kb (≈1.8 × 108 M−1s−1) for mSlo1 and further developed a model in which BK channels act as a calcium sensor capable of quantitatively predicting local microdomain Ca2+ transients in the vicinity of VGCCs during action potentials.

A 0.5 V/1.8 V High Dynamic Range CMOS Imager for Artificial Retina Applications

This paper presents a 0.5 V/1.8 V high dynamic range (HDR) sense-and-stimulus (SAS) CMOS imager with adaptive gain control for artificial retina applications. The proposed dual-supply SAS pixel consists of a 0.5 V HDR pulsewidth modulation image sensor (for sense) and a 1.8 V pulse-to-current stimulator (for stimulus) to achieve a highly integrated and low-power solution. The 0.5 V operated HDR image sensor is adopted to reduce power consumption with dynamic range extension for in vivo requirement and mimicking the eyesight capability. The 1.8 V operated in-pixel pulse-to-current stimulator provides a biphasic current pulse with sufficient intensity to activate neuron cells for artificial vision recovery applications. The time-to-voltage conversion technique with a programmable gain is employed to achieve a reduced fixed-pattern-noise (FPN) and an adaptive sensitivity. A prototype chip has been implemented and verified with a sensing array of $40\times 40$ , a pixel size of $30\times 30~\mu \text{m}^{2}$ , and a fill factor of 33.3%. The maximum driving capability of biphasic stimulation current is $\pm 50~\mu \text{A}$ with a 7.5 $\text{k}\Omega $ electrode model. The measurement results show an array FPN of 0.63% and a tunable dynamic range of 36 dB. The chip consumes a total power of 2.1 mW with current stimulator at 16.9 frame/s, which achieves an imager figure of merit of 77.7 nW/frame pixel.

A high‐voltage stimulation chip for wearable stroke rehabilitation systems

SummaryIn this work, an 8‐channel high‐voltage (HV) stimulation chip for the rehabilitation of stroke patients through surface stimulation is presented. The chip receives control data through its serial peripheral interface and can be controlled by an external microcontroller. It can accordingly generate biphasic stimulation currents with different amplitudes, duration time, frequencies, and polarities for each channel independently. The chip was designed and fabricated using X‐FAB 0.35 µm HV mixed‐signal process. Circuits were carefully designed to ensure their operations under HVs. Our measurement results showed that a supply voltage of as high as 75 V can be achieved, and the current driver can generate biphasic stimuli with current amplitudes up to 4 mA. Copyright © 2015 John Wiley &amp; Sons, Ltd.

Functional electrical stimulation of lower limb muscles as an alternative mode of exercise training in chronic heart failure: practical considerations and proposed algorithm.

Functional electrical stimulation of lower limb muscles as an alternative mode of exercise training in chronic heart failure: practical considerations and proposed algorithm.

Efficacy and safety of a form of cranial electrical stimulation (CES) as an add-on intervention for treatment-resistant major depressive disorder: A three week double blind pilot study

We examined efficacy and safety of one specific cranial electrical stimulator (CES) device at a fixed setting in subjects with treatment-resistant major depressive disorder (MDD). Thirty subjects (57% female, mean age 48.1 ± 12.3 years) with MDD and inadequate response to standard antidepressants were randomized to 3 weeks of treatment with CES (15/500/15,000 Hz, symmetrical rectangular biphasic current of 1–4 mAmp, 40 V) or sham CES (device off) for 20 min, 5 days per week. The primary outcome measure was improvement in the 17-item Hamilton Depression Rating Scale (HAM-D-17). Adverse effects (AEs) were assessed using the Patient Related Inventory of Side Effects (PRISE). Completion rates were 88% for CES, 100% for sham. Both treatment groups demonstrated improvement of about 3–5 points in HAM-D-17 scores (p < 0.05 for both), and no significant differences were observed between groups. Remission rates were 12% for CES, and 15% for sham, a nonsignificant difference. CES was deemed safe, with good tolerability; poor concentration and malaise were the only distressing AEs that differed significantly between CES and sham (p = 0.019 and p = 0.043, respectively). Limitations include a small sample and lack of an active comparator therapy. Although both treatment groups improved significantly, this CES at the setting chosen did not separate from sham in this sample. Thus we cannot rule out that the benefit from this setting used in this particular form of CES was due to placebo effects. Since this form of CES has other settings, future studies should test these settings and compare it against other CES devices.Clinicaltrials.gov ID: NCT01325532

Molecular identification of P2X receptors in vascular smooth muscle cells from rat anterior, posterior, and basilar arteries.

Purinergic P2X receptors in vascular smooth muscle cells (VSMCs) play an important role in physiological stimulatory responses to the extracellularly released ATP. The aim of this work was to identify molecular P2X receptor subunits in VSMCs isolated from rat anterior, posterior and basilar arteries using a number of contemporary laboratory techniques. P2X mediated ionic currents were recorded using amphotericin B perforated patch clamp method. Gene expression analysis was performed using RT-PCR in manually collected VSMCs. The expression of proteins was confirmed by fluorescent immunocytochemistry. Under voltage clamp conditions VSMCs stimulated by application of 10 μmol/l selective P2X receptor agonist αβ-meATP, the biphasic currents consisting of rapidly rising rapidly desensitizing and slowly desensitizing components were observed in freshly isolated myocytes from all three arteries. Using RT-PCR, the expression of genes encoding only P2X1 and P2X4 receptor subunits was detected in preparations from all three arteries. The expression of corresponding P2X1 and P2X4 receptor subunit proteins was confirmed in isolated VSMCs. Our work therefore identified that in major arteries of rat cerebral circulation VSMCs express only P2X1 and P2X4 receptors subunits. We can propose that these P2X receptor subunits participate in functional P2X receptor structures mediating ATP-evoked stimulatory responses in cerebral vascular myocytes in vivo.

Deciphering the Kinetic and Gating Properties of Purinergic P2X7 Receptor Channels

Purinergic P2X7 receptors (P2X7Rs) are trimeric nonselective cation channels possessing three intrasubunit orthosteric binding sites and unidentified number of allosteric binding sites. In previous work, we showed that the same receptor is capable of exhibiting sensitization and pore dilation (leading to the formation of biphasic currents and cell death) and/or desensitization (leading to a decline in current amplitude and cell life signaling) during sustained application of orthosteric agonists, depending on their concentrations. This was done in part by developing a 12-state Markov model consisting of naive (not previously exposed to orthosteric agonist), desensitized, and sensitized/dilated states that reproduced whole-cell current recordings generated experimentally. In this model, we assumed that the occupancy of one or two ATP-binding sites of naive receptors favored transition from open to desensitized states, whereas the occupancy of the third binding site favored receptor sensitization. Our goal here is to extend this modeling study by examining how these model cells behave under various ionic conditions in the medium, including those that contain large organic cation N-methylD-glucamine (NMDG + ) or divalent cation such as Ca 2+ . We illustrate how the two main gating patterns behave under these ionic conditions and determine why the shift in reversal potential and the dilation of the channels are accompanied paradoxically by a decrease in the total conductance during voltage ramp protocols. The model adds more evidence to our previous hypothesis, suggesting that dilation is masking desensitization. Our results also indicate that the allosteric sites through which divalent cations inhibit P2X7R should be extracellularly located.

A Fully Intraocular High-Density Self-Calibrating Epiretinal Prosthesis

This paper presents a fully intraocular self-calibrating epiretinal prosthesis with 512 independent channels in 65 nm CMOS. A novel digital calibration technique matches the biphasic currents of each channel independently while the calibration circuitry is shared among every 4 channels. Dual-band telemetry for power and data with on-chip rectifier and clock recovery reduces the number of off-chip components. The rectifier utilizes unidirectional switches to prevent reverse conduction loss in the power transistors and achieves an efficiency > 80%. The data telemetry implements a phase-shift keying (PSK) modulation scheme and supports data rates up to 20 Mb/s. The system occupies an area of 4.5 ×3.1 mm². It features a pixel size of 0.0169 mm² and arbitrary waveform generation per channel. In vitro measurements performed on a Pt/Ir concentric bipolar electrode in phosphate buffered saline (PBS) are presented. A statistical measurement over 40 channels from 5 different chips shows a current mismatch with μ = 1.12 μA and σ = 0.53 μA. The chip is integrated with flexible MEMS origami coils and parylene substrate to provide a fully intraocular implant.

Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel

Acid-sensing ion channels (ASICs) are proton-sensitive, sodium-selective channels expressed in the nervous system that sense changes in extracellular pH. These ion channels are sensitive to an increasing number of nonproton ligands that include natural venom peptides and guanidine compounds. In the case of chicken ASIC1, the spider toxin Psalmotoxin-1 (PcTx1) activates the channel, resulting in an inward current. Furthermore, a growing class of ligands containing a guanidine group has been identified that stimulate peripheral ASICs (ASIC3), but exert subtle influence on other ASIC subtypes. The effects of the guanidine compounds on cASIC1 have not been the focus of previous study. Here, we investigated the interaction of the guanidine compound 2-guanidine-4-methylquinazoline (GMQ) on cASIC1 proton activation and PcTx1 stimulation. Exposure of expressed cASIC1 to PcTx1 resulted in biphasic currents consisting of a transient peak followed by an irreversible cASIC1 PcTx1 persistent current. This cASIC1 PcTx1 persistent current may be the result of locking the cASIC1 protein into a desensitized transition state. The guanidine compound GMQ increased the apparent affinity of protons on cASIC1 and decreased the half-maximal constant of the cASIC1 steady-state desensitization profile. Furthermore, GMQ stimulated the cASIC1 PcTx1 persistent current in a concentration-dependent manner, which resulted in a non-desensitizing inward current. Our data suggests that GMQ may have multiple sites within cASIC1 and may act as a “molecular wedge” that forces the PcTx1-desensitized ASIC into an open state. Our findings indicate that guanidine compounds, such as GMQ, may alter acid-sensing ion channel activity in combination with other stimuli, and that additional ASIC subtypes (along with ASIC3) may serve to sense and mediate signals from multiple stimuli.