Charge-balanced Biphasic Pulses Research Articles

Restoration of coherent reach-grasp-pull movement via sequential intraneural peripheral nerve stimulation in rats

Objective. Peripheral nerve stimulation (PNS) has been demonstrated as an effective way to selectively activate muscles and to produce fine hand movements. However, sequential multi-joint upper limb movements, which are critical for paralysis rehabilitation, has not been tested with PNS. Here, we aimed to restore multiple upper limb joint movements through an intraneural interface with a single electrode, achieving coherent reach-grasp-pull movement tasks through sequential stimulation. Approach. A transverse intrafascicular multichannel electrode was implanted under the axilla of the rat’s upper limb, traversing the musculocutaneous, radial, median, and ulnar nerves. Intramuscular electrodes were implanted into the biceps brachii (BB), triceps brachii (TB), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) muscles to record electromyographic (EMG) activity and video recordings were used to capture the kinematics of elbow, wrist, and digit joints. Charge-balanced biphasic pulses were applied to different channels to recruit distinct upper limb muscles, with concurrent recording of EMG signals and joint kinematics to assess the efficacy of the stimulation. Finally, a sequential stimulation protocol was employed by generating coordinated pulses in different channels. Main results. BB, TB, FCR and ECR muscles were selectively activated and various upper limb movements, including elbow flexion, elbow extension, wrist flexion, wrist extension, digit flexion, and digit extension, were reliably generated. The modulation effects of stimulation parameters, including pulse width, amplitude, and frequency, on induced joint movements were investigated and reach-grasp-pull movement was elicited by sequential stimulation. Significance. Our results demonstrated the feasibility of sequential intraneural stimulation for functional multi-joint movement restoration, providing a new approach for clinical rehabilitation in paralyzed patients.

Direct measurement of oxygen reduction reactions at neurostimulation electrodes

Objective. Electric stimulation delivered by implantable electrodes is a key component of neural engineering. While factors affecting long-term stability, safety, and biocompatibility are a topic of continuous investigation, a widely-accepted principle is that charge injection should be reversible, with no net electrochemical products forming. We want to evaluate oxygen reduction reactions (ORR) occurring at different electrode materials when using established materials and stimulation protocols. Approach. As stimulation electrodes, we have tested platinum, gold, tungsten, nichrome, iridium oxide, titanium, titanium nitride, and poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate). We use cyclic voltammetry and voltage-step amperometry in oxygenated versus inert conditions to establish at which potentials ORR occurs, and the magnitudes of diffusion-limited ORR currents. We also benchmark the areal capacitance of each electrode material. We use amperometric probes (Clark-type electrodes) to quantify the O2 and H2O2 concentrations in the vicinity of the electrode surface. O2 and H2O2 concentrations are measured while applying DC current, or various biphasic charge-balanced pulses of amplitude in the range 10–30 µC cm−2/phase. To corroborate experimental measurements, we employ finite element modelling to recreate 3D gradients of O2 and H2O2. Main results. All electrode materials support ORR and can create hypoxic conditions near the electrode surface. We find that electrode materials differ significantly in their onset potentials for ORR, and in the extent to which they produce H2O2 as a by-product. A key result is that typical charge-balanced biphasic pulse protocols do lead to irreversible ORR. Some electrodes induce severely hypoxic conditions, others additionally produce an accumulation of hydrogen peroxide into the mM range. Significance. Our findings highlight faradaic ORR as a critical consideration for neural interface devices and show that the established biphasic/charge-balanced approach does not prevent irreversible changes in O2 concentrations. Hypoxia and H2O2 can result in different (electro)physiological consequences.

An Anodic Phase Can Facilitate Rather Than Weaken a Cathodic Phase to Activate Neurons in Biphasic-Pulse Axonal Stimulations.

Electrical pulses have been promisingly utilized in neural stimulations to treat various diseases. Usually, charge-balanced biphasic pulses are applied in the clinic to eliminate the possible side effects caused by charge accumulations. Because of its reversal action to the preceding cathodic phase, the subsequent anodic phase has been commonly considered to lower the activation efficiency of biphasic pulses. However, an anodic pulse itself can also activate axons with its “virtual cathode” effect. Therefore, we hypothesized that the anodic phase of a biphasic pulse could facilitate neuronal activation in some circumstances. To verify the hypothesis, we compared the activation efficiencies of cathodic pulse, biphasic pulse, and anodic pulse applied in both monopolar and bipolar modes in the axonal stimulation of alveus in rat hippocampal CA1 region in vivo. The antidromically evoked population spikes (APS) were recorded and used to evaluate the amount of integrated firing of pyramidal neurons induced by pulse stimulations. We also used a computational model to investigate the pulse effects on axons at various distances from the stimulation electrode. The experimental results showed that, with a small pulse intensity, a cathodic pulse recruited more neurons to fire than a biphasic pulse. However, the situation was reversed with an increased pulse intensity. In addition, setting an inter-phase gap of 100 μs was able to increase the activation efficiency of a biphasic pulse to exceed a cathodic pulse even with a relatively small pulse intensity. Furthermore, the latency of APS evoked by a cathodic pulse was always longer than that of APS evoked by a biphasic pulse, indicating different initial sites of the neuronal firing evoked by the different types of pulses. The computational results of axon modeling showed that the subsequent anodic phase was able to relieve the hyperpolarization block in the flanking regions generated by the preceding cathodic phase, thereby increasing rather than decreasing the activation efficiency of a biphasic pulse with a relatively great intensity. These results of both rat experiments and computational modeling firstly reveal a facilitation rather than an attenuation effect of the anodic phase on biphasic-pulse stimulations, which provides important information for designing electrical stimulations for neural therapies.

Cathodic- and anodic-pulses can alternately activate different sub-populations of neurons during sustained high-frequency stimulation of axons in rat hippocampus

Objective. Charge-balanced biphasic-pulses are commonly used in neural stimulations to prevent possible damages caused by charge accumulations. The lagging anodic-phases of biphasic-pulses may decrease the activation efficiency of stimulations by counteracting the depolarization effect of the leading cathodic-phases. However, a monophasic anodic-pulse alone can itself activate neurons by depolarizing neuronal membrane through a mechanism of virtual cathode. This study aimed to verify the hypothesis that the anodic-phases/pulses in charge-balanced stimulations could play an activation role during sustained high-frequency stimulations (HFSs). Approach. Two types of antidromic HFS (A-HFS) were applied on the alveus of hippocampal CA1 region of anesthetized rats: monophasic-pulse A-HFS of alternate opposite pulses and biphasic-pulse A-HFS with the same frequency of 100 or 200 Hz. The antidromically-evoked population spike was used as a biomarker to evaluate the activation effects of A-HFS pulses. Main results. Despite a significant difference in the initial abilities of anodic- and cathodic-pulses to activate neurons, an anodic-pulse was able to induce similar amount of neuronal firing as a cathodic-pulse during sustained monophasic-pulse A-HFS. Additionally, the amount of neuronal firing induced by the monophasic-pulse A-HFS was similar to that induced by the biphasic-pulse A-HFS consuming a double amount of electrical energy. Furthermore, the alternate cathodic- and anodic-pulses respectively activated different sub-populations of neurons during steady A-HFS. Significance. The anodic-phases/pulses in charge-balanced HFS at axons can play an activation role in addition to a role of charge balance. The study provides important information for designing charge-balanced stimulations and reveals new mechanisms of neural stimulations.

Effects of electrical pulse polarity shape on intra cochlear neural responses in humans: Triphasic pulses with anodic and cathodic second phase

Modern cochlear implants employ charge-balanced biphasic and triphasic pulses. However, the effectiveness of electrical pulse shape and polarity is still a matter of debate. For this purpose, a previous study (Bahmer & Baumann, 2013) conducted electrophysiological and psychophysical measurements following triphasic pulse stimulation with constant cathodic second phase and varying anodic first and third phases. Pulse stimulation with constant anodic second phase was not investigated.Therefore, in this study, pulse stimulation with cathodic and anodic second phase was applied for the recording of electrically evoked compound action potentials (ECAPs) as well as for psychophysical thresholds in cochlear implant (CI) recipients. First it was investigated whether the temporal polarity distribution has a different effect on neuronal stimulation when the second phase is cathodic or anodic; second, whether the electrophysiological and psychophysical results show a comparable difference between triphasic stimulation with anodic and cathodic second phases.The results showed that variation of the temporal polarity distribution of the triphasic pulse had a smaller effect on the ECAP response when the second phase was anodic compared to when it was cathodic, whereas for psychophysical detection thresholds this variation had a similar effect for both polarities. While electrophysiological responses and psychophysical detection thresholds showed a high correlation for variations of the triphasic pulse with cathodic second phase, the results for variations of the triphasic pulse with anodic second phase showed only moderate correlation. Furthermore, the difference between triphasic stimulation with cathodic and anodic second phases did not correlate between the electrophysiological and psychophysical results.In summary, after stimulation with different configurations of triphasic pulses used in the present study, the polarity of the second phase has an effect on electrophysiological response at suprathreshold level but not on the psychophysical detection thresholds. Thus, at different stimulation levels a possible substitution of the psychophysical test by an electrophysiological measurement (e.g. neural health measurement of the cochlea) could not be corroborated by the present results.

Regulatory Mechanism for Absence Seizures in Bidirectional Interactive Thalamocortical Model via Different Targeted Therapy Schemes.

Recent clinical practice has found that the spike-wave discharge (SWD) scopes of absence seizures change from small cortical region to large thalamocortical networks, which has also been proved by theoretical simulation. The best biophysics explanation is that there are interactions between coupled cortico-thalamic and thalamocortical circuits. To agree with experiment results and describe the phenomena better, we constructed a coupled thalamocortical model with bidirectional channel (CTMBC) to account for the causes of absence seizures which are connected by the principle of two-way communication of neural pathways. By adjusting the coupling strength of bidirectional pathways, the spike-wave discharges are reproduced. Regulatory mechanism for absence seizures is further applied to CTMBC via four different targeted therapy schemes, such as deep brain stimulation (DBS), charge-balanced biphasic pulse (CBBP), coordinated reset stimulation (CRS) 1 : 0, and (CRS) 3 : 2. The new CTMBC model shows that neurodiversity in bidirectional interactive channel could supply theory reference for the bidirectional communication mode of thalamocortical networks and the hypothesis validation of pathogenesis.

Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats.

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Furthermore, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH versus 2 wk of dAIH preconditioning on spontaneous and evoked phrenic responses in anesthetized, paralyzed, and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at the C2 spinal level delivered before and 60 min post-AIH (or the equivalent in time controls). Charge-balanced biphasic pulses (100 μs/phase) of progressively increasing intensity (100-700 μA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (∼60% from baseline) was observed after a single exposure to moderate AIH (3 × 5 min; 5-min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration.NEW & NOTEWORTHY Two weeks of daily acute intermittent hypoxia (dAIH) preconditioning enhanced stimulus-evoked phrenic responses to lateral funiculus stimulation (targeting respiratory bulbospinal projection to phrenic motor neurons). Furthermore, dAIH preconditioning enhanced baseline phrenic motor output responses to maximal chemoreflex activation in intact rats.

A Miniaturized, Programmable Deep-Brain Stimulator for Group-Housing and Water Maze Use.

Pre-clinical deep-brain stimulation (DBS) research has observed a growing interest in the use of portable stimulation devices that can be carried by animals. Not only can such devices overcome many issues inherent with a cable tether, such as twisting or snagging, they can also be utilized in a greater variety of arenas, including enclosed or large mazes. However, these devices are not inherently designed for water-maze environments, and their use has been restricted to individually-housed rats in order to avoid damage from various social activities such as grooming, playing, or fighting. By taking advantage of 3D-printing techniques, this study demonstrates an ultra-small portable stimulator with an environmentally-protective device housing, that is suitable for both social-housing and water-maze environments. The miniature device offers 2 channels of charge-balanced biphasic pulses with a high compliance voltage (12 V), a magnetic switch, and a diverse range of programmable stimulus parameters and pulse modes. The device's capabilities have been verified in both chronic pair-housing and water-maze experiments that asses the effects of nucleus reuniens DBS. Theta-burst stimulation delivered during a reference-memory water-maze task (but not before) had induced performance deficits during both the acquisition and probe trials of a reference memory task. The results highlight a successful application of 3D-printing for expanding on the range of measurement modalities capable in DBS research.

Comparison of Monophasic and Biphasic Electrical Stimulation by Using Temporal Analysis for Different Inter-electrode Spacings in the Hexagonal Arrays

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 \({\upmu }\hbox {A}\). 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.

Miniature Elastomeric Valve Design for Safe Direct Current Stimulator.

For safety reasons, commercial neural implants use charge-balanced biphasic pulses to interact with target neurons using metal electrodes. Short biphasic pulses are used to avoid irreversible electrochemical reactions at the electrode-tissue interfaces. Biphasic pulses are effective at exciting neurons, but quite limited in inhibiting their activity. In contrast, direct current can both excite and inhibit neurons, however delivered to metal electrodes, it causes toxic electrochemical reactions. We recently introduced Safe Direct Current Stimulator (SDCS) technology, which can excite or inhibit neurons without violating the safety criteria. Instead of direct current, SDCS generates an ionic direct current (iDC) from a biphasic input signal using a network of fluidic channels and mechanical valves. A key enabler towards transforming SDCS concept from a benchtop design to an implantable neural prosthesis is the design of a miniature valve. In this work, we present poly-dimethylsiloxane (PDMS) based elastomeric valves, squeeze valve (SV) and plunger valve (PV) capable of being actuated using a shape memory alloy wire.

Optimization of Interphase Intervals to Enhance the Evoked Muscular Responses of Transcutaneous Neuromuscular Electrical Stimulation.

Neuromuscular electrical stimulation (NMES) is a widely used technique for clinical diagnostic, treatment, and research. Normally, it applies charge-balanced biphasic pulses, which several publications have reported to be less efficient than monophasic pulses. A good alternative is the use of interphase intervals (IPI) on biphasic pulses that allows to achieve similar responses than those evoked by monophasic stimulation. This study analyzes the enhancing mechanism of the IPI and provides guidelines on how to optimize the IPI in order to reduce secondary effects such as the electrode corrosion. The tibial nerve was excited by NMES biphasic pulses with different IPI durations and polarities. Then, the elicited responses were recorded on the soleus muscle via electromyography. When cathodic-first pulses were applied, the responses increased proportionally to the IPI until the duration of 250 µs, where the increase saturated at 30% of the original amplitude. The responses evoked during anodic-first were 6% to 30% smaller than those evoked during cathodic-first pulses and continuously increased until the IPI duration of 2500 µs, where the responses reached an increase of around 30%. The results suggest that when a cathodic-first pulse is used, the IPI could be optimized (based on the setup geometry) to allow the action potentials to travel out of the hyperpolarization zone induced by the anodic phase. When anodic-first stimuli are applied, the IPI duration allows the fiber to recover from an apparent insensitive state induced by the anodic phase. The use of IPI is a viable option to improve the efficiency of actual stimulation systems, since only small modifications are required to significantly reduce the electrical charge required and boost the stimulation efficiency.

Closed-loop deep brain stimulation by pulsatile delayed feedback with increased gap between pulse phases

Computationally it was shown that desynchronizing delayed feedback stimulation methods are effective closed-loop techniques for the control of synchronization in ensembles of interacting oscillators. We here computationally design stimulation signals for electrical stimulation of neuronal tissue that preserve the desynchronizing delayed feedback characteristics and comply with mandatory charge deposit-related safety requirements. For this, the amplitude of the high-frequency (HF) train of biphasic charge-balanced pulses used by the standard HF deep brain stimulation (DBS) is modulated by the smooth feedback signals. In this way we combine the desynchronizing delayed feedback approach with the HF DBS technique. We show that such a pulsatile delayed feedback stimulation can effectively and robustly desynchronize a network of model neurons comprising subthalamic nucleus and globus pallidus external and suggest this approach for desynchronizing closed-loop DBS. Intriguingly, an interphase gap introduced between the recharging phases of the charge-balanced biphasic pulses can significantly improve the stimulation-induced desynchronization and reduce the amount of the administered stimulation. In view of the recent experimental and clinical studies indicating a superiority of the closed-loop DBS to open-loop HF DBS, our results may contribute to a further development of effective stimulation methods for the treatment of neurological disorders characterized by abnormal neuronal synchronization.

The Appearance of Phosphenes Elicited Using a Suprachoroidal Retinal Prosthesis.

Phosphenes are the fundamental building blocks for presenting meaningful visual information to the visually impaired using a bionic eye device. The aim of this study was to characterize the size, shape, and location of phosphenes elicited using a suprachoroidal retinal prosthesis. Three patients with profound vision loss due to retinitis pigmentosa were implanted with a suprachoroidal electrode array, which was used to deliver charge-balanced biphasic constant-current pulses at various rates, amplitudes, and durations to produce phosphenes. Tasks assessing phosphene appearance, location, overlap, and the patients' ability to recognize phosphenes were performed using a custom psychophysics setup. Phosphenes were reliably elicited in all three patients, with marked differences in the reported appearances between patients and between electrodes. Phosphene shapes ranged from simple blobs to complex forms with multiple components in both space and time. Phosphene locations within the visual field generally corresponded to the retinotopic position of the stimulating electrodes. Overlap between phosphenes elicited from adjacent electrodes was observed with one patient, which reduced with increasing electrode separation. In a randomized recognition task, two patients correctly identified the electrode being stimulated for 57.2% and 23% of trials, respectively. Phosphenes of varying complexity were successfully elicited in all three patients, indicating that the suprachoroidal space is an efficacious site for electrically stimulating the retina. The recognition scores obtained with two patients suggest that a suprachoroidal implant can elicit phosphenes containing unique information. This information may be useful when combining phosphenes into more complex and meaningful images that provide functional vision.

Optimal control of directional deep brain stimulation in the parkinsonian neuronal network

The effect of conventional deep brain stimulation (DBS) on debilitating symptoms of Parkinson’s disease can be limited because it can only yield the spherical field. And, some side effects are clearly induced with influencing their adjacent ganglia. Recent experimental evidence for patients with Parkinson’s disease has shown that a novel DBS electrode with 32 independent stimulation source contacts can effectively optimize the clinical therapy by enlarging the therapeutic windows, when it is applied on the subthalamic nucleus (STN). This is due to the selective activation in clusters of various stimulation contacts which can be steered directionally and accurately on the targeted regions of interest. In addition, because of the serious damage to the neural tissues, the charge-unbalanced stimulation is not typically indicated and the real DBS utilizes charge-balanced bi-phasic (CBBP) pulses. Inspired by this, we computationally investigate the optimal control of directional CBBP-DBS from the proposed parkinsonian neuronal network of basal ganglia–thalamocortical circuit. By appropriately tuning stimulation for different neuronal populations, it can be found that directional steering CBBP-DBS paradigms are superior to the spherical case in improving parkinsonian dynamical properties including the synchronization of neuronal populations and the reliability of thalamus relaying the information from cortex, which is in a good agreement with the physiological experiments. Furthermore, it can be found that directional steering stimulations can increase the optimal stimulation intensity of desynchronization by more than 1 mA compared to the spherical case. This is consistent with the experimental result with showing that there exists at least one steering direction that can allow increasing the threshold of side effects by 1 mA. In addition, we also simulate the local field potential (LFP) and dominant frequency (DF) of the STN neuronal population induced by the activation of 32 different contacts with optimal stimulation intensity and immediately after the stimulation, respectively. These can reveal regional differences in pathological activity within STN nucleus. It is shown that in line with the experimental results directional steering stimulation can induce the low-amplitude LFP which implies the occurrence of desynchronizing regime, as well as the distribution of DF can locate at the 13–40 Hz of beta frequency range. Hopefully, the obtained results can provide theoretical evidences in exploring pathophysiologic activity of brain.

Effect of Stimulus Waveform of Biphasic Current Pulse on Retinal Ganglion Cell Responses in Retinal Degeneration (rd1) mice.

A retinal prosthesis is being developed for the restoration of vision in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Determining optimal electrical stimulation parameters for the prosthesis is one of the most important elements for the development of a viable retinal prosthesis. Here, we investigated the effects of different charge-balanced biphasic pulses with regard to their effectiveness in evoking retinal ganglion cell (RGC) responses. Retinal degeneration (rd1) mice were used (n=17). From the ex-vivo retinal preparation, retinal patches were placed ganglion cell layer down onto an 8×8 multielectrode array (MEA) and RGC responses were recorded while applying electrical stimuli. For asymmetric pulses, 1st phase of the pulse is the same with symmetric pulse but the amplitude of 2nd phase of the pulse is less than 10 µA and charge balanced condition is satisfied by lengthening the duration of the pulse. For intensities (or duration) modulation, duration (or amplitude) of the pulse was fixed to 500 µs (30 µA), changing the intensities (or duration) from 2 to 60 µA (60 to 1000 µs). RGCs were classified as response-positive when PSTH showed multiple (3~4) peaks within 400 ms post stimulus and the number of spikes was at least 30% more than that for the immediate pre-stimulus 400 ms period. RGC responses were well modulated both with anodic and cathodic phase-1st biphasic pulses. Cathodic phase-1st pulses produced significantly better modulation of RGC activity than anodic phase-1st pulses regardless of symmetry of the pulse.

A linear-nonlinear model accurately predicts cortical responses to simultaneous electrical stimulation with a retinal implant

Retinal implants for restoring partial vision to people with degenerative photoreceptor diseases consist of an array of electrodes implanted on the retina which can be driven according to images captured by a camera via stimulation electronics. In the past two decades this technology has progressed from prototypes, through clinical trials, through to the first commercial devices available in the U.S. last year (2013). Currently, the functional benefit to patients is largely as an aid to mobility and navigation. Improved outcomes, for example to the ability to perform useful object recognition, will likely require higher density electrode arrays. There is also likely to be benefit from attaining greater spatial control of electrically evoked neural activity by choosing appropriate stimulation parameters. As a first step towards this goal we investigated the ability of simple linear-nonlinear models to capture the response of visual cortical neurons driven by a retinal implant. Using an electrode array containing 21 platinum electrodes in the suprachoroidal space of the retina in an anaesthetized cat, spatially white and temporally sparse electrical pulses were delivered to the retina simultaneously across several electrodes. Each pulse was either an anodic-first or cathodic-first charge-balanced biphasic current pulse. Multi-unit spiking responses were recorded using 6x10 arrays (Blackrock Microsystems, UT) in the primary visual cortex. We formulated a model to predict spiking responses observed in the cortex in response to electrical stimulation of the retina. The pathway between the retina and the cortex was modelled as a set of spatial linear filters, each followed by a static nonlinearity. To encapsulate the effects of both anodic-first and cathodic-first current pulses, two different linear filters (one for anodic-first and one for cathodic-first stimuli) and their associated nonlinearities acted on the input separately. The output of these two nonlinearities was combined to produce an estimate of the spike rate at a given site in the cortex. The parameters of the model were optimized with a non-linear fitting algorithm. We used 83% of the available experimental data to fit the model parameters. After fitting the model parameters, the model accurately predicted the pulse-by-pulse spike count for the remaining 17% of the data (r=0.83). The spatial linear filter can be considered to be the weighting matrix for the effect of the stimulating electrodes on a cortical site. We anticipate that the model may provide a basis for devising ideal stimulation strategies for shaping the activity in the cortex.

Effects of amygdala–hippocampal stimulation on synchronization

Changes in EEG synchronization, i.e., spatio-temporal correlation, with amygdala-hippocampal stimulation were studied in patients with temporal lobe epilepsy. Synchronization was evaluated for high frequency, 130 Hz, pseudo-monophasic or biphasic charge-balanced pulses. Desynchronization was most frequently induced by stimulation. There was no correlation between the changes in synchronization and the changes in interictal epileptiform discharge rates. Changes in synchronization do not appear yet to be a marker of stimulation efficiency in reducing seizures.

Penetrating electrode stimulation of the rabbit optic nerve: parameters and effects on evoked cortical potentials

Stimulus parameters, in particular pulse shape, are an important consideration in the application of electrical stimulation when experimentally testing a visual prosthesis. We changed the biphasic pulse shape of several asymmetric charge-balanced pulses to investigate their effect on optic nerve (ON) stimulation and the recorded cortical response. Monopolar platinum-iridium electrodes were implanted into the rabbit's ON behind the eyeball. Electrical evoked potentials (EEPs) were recorded with silver ball electrodes placed on the cortex, and the results quantified. Our results indicate that changing the shape of cathodic-first charge-balanced biphasic pulse (CA) while maintaining charge balance could reduce the current thresholds for stimulation. When stimulated at the same charge density, the stimulus having high-amplitude short-duration (HASD) cathodic phase produced a higher amplitude response, with a larger spatial spread but with a lower current threshold compared with other stimuli. Adding an inter-phase gap between the two phases of the stimulus increased the EEP amplitude, but was saturated at a gap of ∼0.2 ms; this was most obvious with CA stimulation, which was able to elicit a larger cortical response than that elicited by asymmetrical charge-balanced stimulus pulses with HASD cathodic phase, in contrast to CA without a gap. As the stimulating frequency increased, the amplitudes of the EEP components elicited by CA monotonically decreased. The fastest component (P0) was present with stimulating frequencies as high as 80 Hz, while the slower P1 and P2 disappeared with stimulating frequencies higher than 40 and 20 Hz, respectively. A CA stimulus waveform with an inter-phase gap of 0.2 ms was more efficacious for ON stimulation than other stimulus combinations, and therefore should result in less tissue damage, minimal electrode etching, and lower power consumption if used in a visual prosthesis.

Visual Signal Pathway Reorganization in theCacna1fMutant Rat Model

To elucidate the underlying pathologic mechanism of congenital stationary night blindness (CSNB) by examining the characteristics of electrical signal transmission within the inner retinal circuit after Cacna1f gene mutation. Retinas isolated from the spontaneous Cacna1f mutant rats or wild-type rats were placed into a recording chamber, with the ganglion cell layer facing the biochip electrode array. The light-driven responses of the retinal ganglion cells (RCGs) were recorded using a multielectrode array (MEA) system. In the electrical stimulus cases, charge-balanced biphasic current pulse trains were generated and applied to the central electrode of MEA to stimulate the RCGs. Chemical compounds were bath-applied through an active perfusion system. The acquired data were further analyzed off-line. Typical electrical responses were successfully recorded in the retinas of both wild-type rats and Cacna1f gene mutated rats. In the Cacna1f mutant retinas, the amplitude of the light-induced a-wave was decreased, paralleling the vanished b-wave. The responsive a-wave was not blocked by the application of 100 μM 2-amino-4-phosphobutyric acid. The increased spontaneous firing rate and the decreased robustness of light-driven signaling reflected a loss in the ability of ganglion cells to encode visual signals reliably and economically. Moreover, the ON pathway is somehow disconnected from ganglion cells, whereas OFF pathways may be preferentially selected by the CSNB retinas. In the electrical stimulus cases, the long-latency responses of RGCs evoked by the indirect synaptic inputs from outer layers of retina were weaker in the CSNB rats compared with that of SD rats. Using MEA recording, we provide evidences of functional changes for visual signal pathway plasticity in the Cacna1f mutated retinas. Our results suggest that the dysfunctions in photoreceptor neurotransmitter release and the loss of signaling efficiency both occur during CSNB, and the latter is possibly reversible.

EFFICACY OF A NEW CHARGE-BALANCED BIPHASIC ELECTRICAL STIMULUS IN THE ISOLATED SCIATIC NERVE AND THE HIPPOCAMPAL SLICE

Most deep brain stimulators apply rectangular monophasic voltage pulses. By modifying the stimulus shape, it is possible to optimize stimulus efficacy and find the best compromise between clinical effect, minimal side effects and power consumption of the stimulus generator. In this study, we compared the efficacy of three types of charge-balanced biphasic pulses (CBBPs, nominal duration 100 μs) in isolated sciatic nerves and in in vitro hippocampal brain slices of the rat. Using these two models, we tested the efficacy of several stimulus shapes exclusively on axons (in the sciatic nerve) and compared the effect with that of stimuli in the more complex neuronal network of the hippocampal slice by considering the stimulus-response relation. We showed that (i) adding an interphase gap (IPG, range 100-500 μs) to the CBBP enhances stimulus efficacy in the rat sciatic nerve and (ii) that this type of stimuli (CBBP with IPG) is also more effective in hippocampal slices. This benefit was similar for both models of voltage and current stimulation. In our two models, asymmetric CBBPs were less beneficial. Therefore, CBBPs with IPG appear to be well suited for application to DBS, since they enhance efficacy, extend battery life and potentially reduce harmful side effects.