Biphasic Stimulation Pulses Research Articles

Modification of brain conductivity in human focal epilepsy: A model-based estimation from stereoelectroencephalography.

We have developed a novel method for estimating brain tissue electrical conductivity using low-intensity pulse stereoelectroencephalography (SEEG) stimulation coupled with biophysical modeling. We evaluated the hypothesis that brain conductivity is correlated with the degree of epileptogenicity in patients with drug-resistant focal epilepsy. We used bipolar low-intensity biphasic pulse stimulation (.2 mA) followed by a postprocessing pipeline for estimating brain conductivity. This processing is based on biophysical modeling of the electrical potential induced in brain tissue between the stimulated contacts in response to pulse stimulation. We estimated the degree of epileptogenicity using a semi-automatic method quantifying the dynamic of fast discharge at seizure onset: the epileptogenicity index (EI). We also investigated how the location of stimulation within specific anatomical brain regions or within lesional tissue impacts brain conductivity. We performed 1034 stimulations of 511 bipolar channels in 16 patients. We found that brain conductivity was lower in the epileptogenic zone (EZ; unpaired median difference = .064, p < .001) and inversely correlated with the epileptogenic index value (p < .001, Spearman rho = -.32). Conductivity values were also influenced by anatomical site, location within lesion, and delay between SEEG electrode implantation and stimulation, and had significant interpatient variability. Mixed model multivariate analysis showed that conductivity is significantly associated with EI (F = 13.45, p < .001), anatomical regions (F = 5.586, p < .001), delay since implantation (F = 14.71, p = .003), and age at SEEG (F = 6.591, p = .027), but not with the type of lesion (F = .372, p = .773) or the delay since last seizure (F = 1.592, p = .235). We provide a novel model-based method for estimating brain conductivity from SEEG low-intensity pulse stimulations. The brain tissue conductivity is lower in EZ as compared to non-EZ. Conductivity also varies significantly across anatomical brain regions. Involved pathophysiological processes may include changes in the extracellular space (especially volume or tortuosity) in epileptic tissue.

Nonlinear analysis of neuronal firing modulated by sinusoidal stimulation at axons in rat hippocampus.

Electrical stimulation of the brain has shown promising prospects in treating various brain diseases. Although biphasic pulse stimulation remains the predominant clinical approach, there has been increasing interest in exploring alternative stimulation waveforms, such as sinusoidal stimulation, to improve the effectiveness of brain stimulation and to expand its application to a wider range of brain disorders. Despite this growing attention, the effects of sinusoidal stimulation on neurons, especially on their nonlinear firing characteristics, remains unclear. To address the question, 50 Hz sinusoidal stimulation was applied on Schaffer collaterals of the rat hippocampal CA1 region in vivo. Single unit activity of both pyramidal cells and interneurons in the downstream CA1 region was recorded and analyzed. Two fractal indexes, namely the Fano factor and Hurst exponent, were used to evaluate changes in the long-range correlations, a manifestation of nonlinear dynamics, in spike sequences of neuronal firing. The results demonstrate that sinusoidal electrical stimulation increased the firing rates of both pyramidal cells and interneurons, as well as altered their firing to stimulation-related patterns. Importantly, the sinusoidal stimulation increased, rather than decreased the scaling exponents of both Fano factor and Hurst exponent, indicating an increase in the long-range correlations of both pyramidal cells and interneurons. The results firstly reported that periodic sinusoidal stimulation without long-range correlations can increase the long-range correlations of neurons in the downstream post-synaptic area. These results provide new nonlinear mechanisms of brain sinusoidal stimulation and facilitate the development of new stimulation modes.

Flexible a‐IGZO TFT‐Based Circuit for Active Addressing in Neural Stimulation Electrode Arrays

AbstractNeural interfaces have undergone significant advancements in recent decades, aiming for flexible, compact, and high‐density electrode arrays with a large number of channels. However, the scalability of these devices is often hindered by the number of wires needed to separately connect each electrode to external electronics. To address this limitation, thin‐film transistor (TFT)‐based electronic circuits offer a promising solution by enabling active addressing of stimulation electrodes and potentially increasing the channel count with fewer interconnections. This paper presents the integration of a circuit comprising two amorphous indium–gallium–zinc‐oxide (a‐IGZO) TFTs and a titanium nitride (TiN) electrode on a flexible polymer platform. This circuit precisely controls the electrode's On/Off states and the delivery of current for nerve stimulation. Characterization studies involving frequency and electrochemical analysis demonstrate the TFT‐based circuit's capability to operate at high frequencies, deliver biphasic stimulation pulses to the electrode, and store sufficient charge for effective neural stimulation. Moreover, the a‐IGZO TFTs exhibit remarkable stability during repeated gate voltage sweeps with minimal changes in electrical performance. This circuit has the potential to be extended to active‐matrix devices that enable electrode arrays with a high number of channels and enhanced spatial resolution, which is crucial for selective neural stimulation.

Dense, 11 V-Tolerant, Balanced Stimulator IC with Digital Time-Domain Calibration for 100 nA Error.

This article presents a multichannel neurostimulator implementing a novel charge balancing technique to achieve maximal integration. Safe neurostimulation demands accurate charge balancing of the stimulation waveforms to prevent charge build-up on the electrode-tissue interface. We propose digital time-domain calibration (DTDC), which adjusts the second phase of the biphasic stimulation pulses digitally, based on a one-time characterization of all stimulator channels with an on-chip ADC. Accurate control of the stimulation current amplitude is loosened in exchange for time-domain corrections, relieving circuit matching constraints and consequentially saving channel area. A theoretical analysis of DTDC is presented, establishing expressions for the required time resolution and the new, relaxed circuit matching constraints. To validate the DTDC principle, a 16-channel stimulator was implemented in 65 nm CMOS, requiring only 0.0141 mm 2 area/channel. Despite being implemented in a standard CMOS technology, 10.4 V compliance is achieved for compatibility with high-impedance microelectrode arrays typical for high-resolution neural prostheses. To the authors' knowledge, this is the first stimulator in a 65 nm low-voltage process achieving over 10 V output swing. Measurements after calibration show the DC error is successfully reduced below 96 nA on all channels. Static power consumption is 20.3 µW/channel.

Intra-cochlear differences in the spread of excitation between biphasic and triphasic pulse stimulation in cochlear implants: A modeling and experimental study

Triphasic pulse stimulation can prevent unpleasant facial nerve stimulation in cochlear implant users. Using electromyographic measurements on facial nerve effector muscles, previous studies have shown that biphasic and triphasic pulse stimulations produce different input-output functions. However, little is known about the intracochlear effects of triphasic stimulation and how these may contribute to the amelioration of facial nerve stimulation.The present study used a computational model of implanted human cochleae to investigate the effect of pulse shape on the intracochlear spread of excitation. Biphasic and triphasic pulse stimulations were simulated from three different cochlear implant electrode contact positions. To validate the model results, experimental spread of excitation measurements were conducted with biphasic and triphasic pulse stimulation from three different electrode contact positions in 13 cochlear implant users.The model results depict differences between biphasic and triphasic pulse stimulations depending on the position of the stimulating electrode contact. While biphasic and triphasic pulse stimulations from a medial or basal electrode contact caused similar extents of neural excitation, differences between the pulse shapes were observed when the stimulating contact was located in the cochlear apex. In contrast, the experimental results showed no difference between the biphasic and triphasic initiated spread of excitation for any of the tested contact positions. The model was also used to study responses of neurons without peripheral processes to mimic the effect of neural degeneration. For all three contact positions, simulated degeneration shifted the neural responses towards the apex. Biphasic pulse stimulation showed a stronger response with neural degeneration compared to without degeneration, while triphasic pulse stimulation showed no difference.As previous measurements have demonstrated an ameliorative effect of triphasic pulse stimulation on facial nerve stimulation from medial electrode contact positions, the results imply that a complementary effect located at the facial nerve level must be responsible for reducing facial nerve stimulation.

Normal parameters for diagnostic transcranial magnetic stimulation using a parabolic coil with biphasic pulse stimulation

BackgroundTMS is being used to aid in the diagnosis of central nervous system (CNS) illnesses. It is useful in planning rehabilitation programs and setting appropriate goals for patients. We used a parabolic coil with biphasic pulse stimulation to find normal values for diagnostic TMS parameters.Objectives1. To determine the normal motor threshold (MT), motor evoked potentials (MEP), central motor conduction time (CMCT), intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and silent period (SP) values. 2. To measure the MEP latencies of abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) at various ages, heights, and arm and leg lengths.Study designDescriptive Study.SettingDepartment of Rehabilitation Medicine, Chiang Mai University, Thailand.SubjectsForty-eight healthy participants volunteered for the study.MethodsAll participants received a single diagnostic TMS using a parabolic coil with biphasic pulse stimulation on the left primary motor cortex (M1). All parameters: MT, MEP, CMCT, ICF, SICI, and SP were recorded through surface EMGs at the right APB and EDB. Outcome parameters were reported by the mean and standard deviation (SD) or median and interquartile range (IQR), according to data distribution. MEP latencies of APB and EDB were also measured at various ages, heights, and arm and leg lengths.ResultsAPB-MEP latencies at 120% and 140% MT were 21.77 ± 1.47 and 21.17 ± 1.44 ms. APB-CMCT at 120% and 140% MT were 7.81 ± 1.32 and 7.19 ± 1.21 ms. APB-MEP amplitudes at 120% and 140% MT were 1.04 (0.80–1.68) and 2.24 (1.47–3.52) mV. EDB-MEP latencies at 120% and 140% MT were 37.14 ± 2.85 and 36.46 ± 2.53 ms. EDB-CMCT at 120% and 140% MT were 14.33 ± 2.50 and 13.63 ± 2.57 ms. EDB-MEP amplitudes at 120% and 140% MT were 0.60 (0.38–0.98) and 0.95 (0.69–1.55) mV. ICF amplitudes of APB and EDB were 2.26 (1.61–3.49) and 1.26 (0.88–1.98) mV. SICI amplitudes of APB and EDB were 0.21 (0.13–0.51) and 0.18 (0.09–0.29) mV. MEP latencies of APB at 120% and 140% MT were different between heights < 160 cm and ≥ 160 cm (p < 0.001 and p < 0.001) and different between arm lengths < 65 and ≥ 65 cm (p = 0.022 and p = 0.002).ConclusionWe established diagnostic TMS measurements using a parabolic coil with a biphasic pulse configuration. EDB has a higher MT than APB. The 140/120 MEP ratio of APB and EDB is two-fold. The optimal MEP recording for APB is 120%, whereas EDB is 140% of MT. CMCT by the F-wave is more convenient and tolerable for patients. ICF provides a twofold increase in MEP amplitude. SICI provides a ¼-fold of MEP amplitude. SP from APB and EDB are 121.58 ± 21.50 and 181.01 ± 40.99 ms, respectively. Height and MEP latencies have a modest relationship, whereas height and arm length share a strong positive correlation.

Perception thresholds and qualitative perceptions for electrocutaneous stimulation

Our long-term goal is the development of a wearable warning system that uses electrocutaneous stimulation. To find appropriate stimulation parameters and electrode configurations, we investigate perception amplitude thresholds and qualitative perceptions of electrocutaneous stimulation for varying pulse widths, electrode sizes, and electrode positions. The upper right arm was stimulated in 81 healthy volunteers with biphasic rectangular current pulses varying between 20 and 2000,upmu hbox {s}. We determined perception, attention, and intolerance thresholds and the corresponding qualitative perceptions for 8 electrode pairs distributed around the upper arm. For a pulse width of 150,upmu hbox {s}, we find median values of 3.5, 6.9, and 13.8 mA for perception, attention, and intolerance thresholds, respectively. All thresholds decrease with increasing pulse width. Lateral electrode positions have higher intolerance thresholds than medial electrode positions, but perception and attention threshold are not significantly different across electrode positions. Electrode size between 15 times 15,hbox {mm}^{2} and 40times 40,hbox {mm}^{2} has no significant influence on the thresholds. Knocking is the prevailing perception for perception and attention thresholds while mostly muscle twitching, pinching, and stinging are reported at the intolerance threshold. Biphasic stimulation pulse widths between 150,upmu hbox {s} and 250,upmu hbox {s} are suitable for electric warning wearables. Within the given practical limits at the upper arm, electrode size, inter-electrode distance, and electrode position are flexible parameters of electric warning wearables. Our investigations provide the basis for electric warning wearables.

Hexagonal Stimulation Digital Controller Design and Verification for Wireless Subretinal Implant Device.

Significant progress has been made in the field of micro/nano-retinal implant technologies. However, the high pixel range, power leakage, reliability, and lifespan of retinal implants are still questionable. Active implantable devices are safe, cost-effective, and reliable. Although a device that can meet basic safety requirements set by the Food and Drug Administration and the European Union is reliable for long-term use and provides control on current and voltage parameters, it will be expensive and cannot be commercially successful. This study proposes an economical, fully controllable, and configurable wireless communication system based on field-programmable gated arrays (FPGAs) that were designed with the ability to cope with the issues that arise in retinal implantation. This system incorporates hexagonal biphasic stimulation pulses generated by a digital controller that can be fully controlled using an external transmitter. The integration of two separate domain analog systems and a digital controller based on FPGAs is proposed in this study. The system was also implemented on a microchip and verified using in vitro results.

A Flexible Pulse Generator Based on a Field Programmable Gate Array Architecture for Functional Electrical Stimulation.

Non-invasive Functional Electrical Stimulation (FES) is a technique applied for motor rehabilitation of patients with central nervous system injury. This technique requires programmable multichannel systems to configure the stimulation parameters (amplitude, frequency, and pulse width). Most FES systems are based on microcontrollers with fixed architecture; this limits the control of the parameters and the scaling to multiple channels. Although field programmable gate arrays (FPGA) have been used in FES systems as alternative to microcontrollers, most of them focus on signal acquisition, processing, or communication functions, or are for invasive stimulation. A few FES systems report using FPGAs for parameter configuration and pulse generation in non-invasive FES. However, generally they limit the value of the frequency or amplitude parameters to enable multichannel operation. This restricts free selection of parameters and implementation of modulation patterns, previously reported to delay FES-induced muscle fatigue. To overcome those limitations, this paper presents a proof-of-concept (technology readiness level three-TRL 3) regarding the technical feasibility and potential use of an FPGA-based pulse generator for non-invasive FES applications (PG-nFES). The main aims were: (1) the development of a flexible pulse generator for FES applications and (2) to perform a proof-of-concept of the system, comprising: electrical characterization of the stimulation parameters, and verification of its potential for upper limb FES applications. Biphasic stimulation pulses with high linearity (r2 > 0.9998) and repeatability (>0.81) were achieved by combining the PG-nFES with a current-controlled output stage. Average percentage error in the characterizations was under 3% for amplitude (1–48 mA) and pulse width (20–400 μs), and 0% for frequency (10–150 Hz). A six-channel version of the PG-nFES was implemented to demonstrate the scalability feature. The independence of parameters was tested with three patterns of co-modulation of two parameters. Moreover, two complete FES channels were implemented and the claimed features of the PG-nFES were verified by performing upper limb functional movements involving the hand and the arm. Finally, the system enabled implementation of a stimulation pattern with co-modulation of frequency and pulse width, applied successfully for efficient elbow during repetitions of a functional movement.

Residual voltage as an ad-hoc indicator of electrode damage in biphasic electrical stimulation

Objective. We derive and demonstrate how residual voltage (RV) from a biphasic electrical stimulation pulse can be used to recognize degradation at the electrode-tissue interface. Approach. Using a first order model of the electrode-tissue interface and a rectangular biphasic stimulation current waveform, we derive the equations for RV as well as RV growth over several stimulation pulses. To demonstrate the use of RV for damage detection, we simulate accelerated damage on sputtered iridium oxide film (SIROF) electrodes using potential cycling. RV measurements of the degraded electrodes are compared against standard characterization methods of cyclic voltammetry and electrochemical impedance spectroscopy. Main results. Our theoretical discussion illustrates how an intrinsic RV arises even from perfectly balanced biphasic pulses due to leakage via the charge-transfer resistance. Preliminary data in in-vivo rat experiments follow the derived model of RV growth, thereby validating our hypothesis that RV is a characteristic of the electrode-tissue interface. RV can therefore be utilized for detecting damage at the electrode. Our experimental results for damage detection show that delamination of SIROF electrodes causes a reduction in charge storage capacity, which in turn reflects a measurable increase in RV. Significance. Chronically implanted electrical stimulation systems with multi-electrode arrays have been the focus of physiological engineering research for the last decade. Changes in RV over time can be a quick and effective method to identify and disconnect faulty electrodes in large arrays. Timely diagnoses of electrode status can ensure optimal long term operation, and prevent further damage to the tissue near these electrodes.

Fully Implantable Plantar Cutaneous Augmentation System for Rats Using Closed-loop Electrical Nerve Stimulation.

Plantar cutaneous feedback plays an important role in stable and efficient gait, by modulating the activity of ankle dorsi- and plantar-flexor muscles. However, central and peripheral nervous system trauma often decrease plantar cutaneous feedback and/or interneuronal excitability in processing the plantar cutaneous feedback. In this study, we tested a fully implantable neural recording and stimulation system augmenting plantar cutaneous feedback. Electromyograms were recorded from the medial gastrocnemius muscle for stance phase detection, while biphasic stimulation pulses were applied to the distal-tibial nerve during the stance phase to augment plantar cutaneous feedback. A Bluetooth low energy and a Qi-standard inductive link were adopted for wireless communication and wireless charging, respectively. To test the operation of the system, one intact rat walked on a treadmill with the electrical system implanted into its back. Leg kinematics were recorded to identify the stance phase. Stimulation was applied, with a 250-ms onset delay from stance onset and 200-ms duration, resulting in the onset at 47.58±2.82% of stance phase and the offset at 83.49±4.26% of stance phase (Mean±SEM). The conduction velocity of the compound action potential (31.2 m/s and 41.6 m/s at 1·T and 2·T, respectively) suggests that the evoked action potential was characteristic of an afferent volley for cutaneous feedback. We also demonstrated successful wireless charging and system reset functions. The experimental results suggest that the presented implantable system can be a valuable neural interface tool to investigate the effect of plantar cutaneous augmentation on gait in a rat model.

Subthreshold Electrical Stimulation for Controlling Protein-Mediated Impedance Increases in Platinum Cochlear Electrode.

This study evaluated subthreshold biphasic stimulation pulses as a strategy to stabilize electrode impedance via control of protein adsorption. Following implantation, cochlear electrodes undergo impedance fluctuations thought to be caused by protein adsorption and/or inflammatory responses. Impedance increases can impact device power consumption, safe charge injection limits, and long-term stability of electrodes. Protein-mediated changes in polarization impedance (Zp) were measured by voltage transient responses to biphasic current pulses and electrochemical impedance spectroscopy, with and without protein solutions. Four subthreshold stimulation regimes were studied to assess their effects on protein adsorption and impedance; (1) symmetric charge-balanced pulses delivered continuously, (2) at 10% duty cycle, (3) at 1% duty cycle, and (4) an asymmetric charge balanced pulse delivered continuously with a cathodic phase twice as long as the anodic phase. The Zp of electrodes incubated in protein solutions without stimulation for 2 h increased by between ∼28% and ∼55%. Subthreshold stimulation reduced the rate at which impedance increased following exposure to all protein solutions. Decreases in Zp were dependent on the type of protein solution and the stimulation regime. Subthreshold stimulation pulses were more effective when delivered continuously compared to 1% and 10% duty cycles. These results support the potential of subthreshold stimulation pulses to mitigate protein-mediated increase in impedance. This research highlights the potential of clinically translatable stimulation pulses to mitigate perilymph protein adsorption on cochlear electrodes, a key phenomenon precursor of the inflammatory response.

Soft peripheral nerve interface made from carbon nanotubes embedded in silicone

Electrodes for interfacing implantable electronics and neural tissue are of great importance to gain a better understanding of the nervous system and to help people suffering from impaired body functions due to nerve lesions or lost organ functionality. In particular, neurostimulation techniques for bioelectronic medicine rely on the development of mechanically and electrochemically stable electrodes. While contemporary electrodes are based mainly on metals, new materials are being designed to enhance the mechanical and electrochemical properties of the interface. In this work, a nerve interface based on carbon nanotubes (CNTs) embedded in polydimethylsiloxane (PDMS) is fabricated and investigated. The fabrication process relies on the selective vacuum filtration of CNT suspensions through a printed wax pattern. The mechanical and electrochemical stability of the nerve interface was validated by 10 000 stretching cycles up to 20% strain and &amp;gt;4 × 106 biphasic stimulation pulses with 32 μC cm−2 per phase. The feedline resistance and electrode impedance showed only minor alterations after the stress tests. The functionality of the nerve interface was demonstrated by successful stimulation of the central nerve cord of a horse leech applying stimulation conditions within the water window of the CNT/PDMS electrodes. This work shows the practical usability of CNT/PDMS composites as electrodes and feedlines in peripheral nerve interfaces for future neuroprosthetic devices.

Interactions between Auditory and Vestibular Modalities during Stimulation with a Combined Vestibular and Cochlear Prosthesis

Background: A combined vestibular and cochlear prosthesis may restore hearing and balance to patients who have lost both. To do so, the device should activate each sensory system independently. Objectives: In this study, we quantify auditory and vestibular interactions during interleaved stimulation with a combined 16-channel cochlear and 6-channel vestibular prosthesis in human subjects with both hearing and vestibular loss. Methods: Three human subjects were implanted with a combined vestibular and cochlear implant. All subjects had severe-to-profound deafness in the implanted ear. We provided combined stimulation of the cochlear and vestibular arrays and looked for interactions between these separate inputs. Our main outcome measures were electrically evoked slow-phase eye velocities during nystagmus elicited by brief trains of biphasic pulse stimulation of the vestibular end organs with and without concurrent stimulation of the cochlea, and Likert scale assessments of perceived loudness and pitch during stimulation of the cochlea, with and without concurrent stimulation of the vestibular ampullae. Results: All subjects had no auditory sensation resulting from semicircular canal stimulation alone, and no sensation of motion or slow-phase eye movement resulting from cochlear stimulation alone. However, interleaved cochlear stimulation did produce changes in the slow-phase eye velocities elicited by electrical stimulation. Similarly, interleaved semicircular canal stimulation did elicit changes in the perceived pitch and loudness resulting from stimulation at multiple sites in the cochlea. Conclusions: There are significant interactions between different sensory modalities during stimulation with a combined vestibular and cochlear prosthesis. Such interactions present potential challenges for stimulation strategies to simultaneously restore auditory and vestibular function with such an implant.

Triphasic Pulses in Cochlear Implant Patients With Facial Nerve Stimulation.

Evaluation of triphasic pulse stimulation in comparison to the traditional biphasic pulse stimulation in cochlear implant (CI) patients with unintended facial nerve costimulation. Retrospective case review. Cochlear Implant Center of a University Department of Otolaryngology, Head and Neck Surgery. Fifteen CI patients (MED-EL, Innsbruck, Austria) received a triphasic fitting map instead of a biphasic fitting map due to a previous diagnosis of facial nerve stimulation or stimulus induced pain during the years 2014 to 2017. Application of a triphasic stimulation strategy. Reduction of facial nerve costimulation and speech understanding. Biphasic and triphasic fitting maps were compared to accurately assess the effects of the switch, and hearing tests (monosyllables and sentences in noise tests) were analyzed. Triphasic pulse stimulation showed a significant reduction of unintended side effects and resulted in an observed improved quality of life in most cases. Although there was no significant change in the understanding of speech with CI in all test situations, in many cases, improvement was observed. Triphasic pulse stimulation had a beneficial effect for CI patients with severe, unintended costimulation and should be considered a valuable tool during CI fitting.

Design of a Prototype for Vision Prosthesis

This article describes how the field of vision prostheses is currently being developed around the world to restore useful vision for people suffering from retinal degenerative diseases. The vision prosthesis system (VPS) maps visual images to electrical pulses and stimulates the surviving healthy parts in the retina of the eye, i.e. ganglion cells, using electric pulses applied through an electrode array. The retinal neurons send visual information to the brain. This article presents the design of a prototype vision prosthesis system which converts images/video into biphasic electric stimulation pulses for the excitation of electrodes simulated by an LED array. The proposed prototype laboratory model has been developed for the design of flexible high-resolution 1024-electrode VPS, using an embedded computer-based efficient control algorithm for better visual prediction. The prototype design for the VPS is verified visually through a video display on an LCD/LED array. The experimental results of VPS are enumerated for the test objects, such as, palm, human face and large font characters. The results were found to be satisfactory.

3D printing nano conductive multi-walled carbon nanotube scaffolds for nerve regeneration

Objective. Nanomaterials, such as carbon nanotubes (CNTs), have been introduced to modify the surface properties of scaffolds, thus enhancing the interaction between the neural cells and biomaterials. In addition to superior electrical conductivity, CNTs can provide nanoscale structures similar to those present in the natural neural environment. The primary objective of this study is to investigate the proliferative capability and differential potential of neural stem cells (NSCs) seeded on a CNT incorporated scaffold. Approach. Amine functionalized multi-walled carbon nanotubes (MWCNTs) were incorporated with a PEGDA polymer to provide enhanced electrical properties as well as nanofeatures on the surface of the scaffold. A stereolithography 3D printer was employed to fabricate a well-dispersed MWCNT-hydrogel composite neural scaffold with a tunable porous structure. 3D printing allows easy fabrication of complex 3D scaffolds with extremely intricate microarchitectures and controlled porosity. Main results. Our results showed that MWCNT-incorporated scaffolds promoted neural stem cell proliferation and early neuronal differentiation when compared to those scaffolds without the MWCNTs. Furthermore, biphasic pulse stimulation with 500 µA current promoted neuronal maturity quantified through protein expression analysis by quantitative polymerase chain reaction. Significance. Results of this study demonstrated that an electroconductive MWCNT scaffold, coupled with electrical stimulation, may have a synergistic effect on promoting neurite outgrowth for therapeutic application in nerve regeneration.

(Invited) Effect of Surface Area to Perimeter Ratio on Charge Storage Capacity of Microelectrodes for Neurostimulation

Implantable neuroprosthetic devices are widely used to restore and replace lost bodily functions in a number of neurological impairments including neuromotor deficit, hearing loss, chronic pain, and epilepsy (Hambrecht, 1979; Merrill et al., 2005). In 2015, the total market size for various neural stimulation devices that target spinal cord, cochlear, cerebral cortex, and other peripheral nerves (e.g., sacral, vagus nerve), exceeded $4.9 billion with the annual growth rate of 17% (Pikov, 2015). This is partly driven by advances made in basic neuroscience to better understand underlying neural mechanisms linked to various ailments and aging population that demands more advanced therapeutic options for chronic neurological disorders. With advances in neurostimulation technologies, the demand for more precise targeting of neural substrate has fueled the development of higher density electrode arrays to improve the resolution of stimulation outcomes while minimizing unwanted side effects (Patil and Thakor, 2016; Rossi et al., 2016). The race to increase the number of input/output channels with smaller electrodes have resulted in a number of different microelectrode arrays (MEA) for various stimulation and recording applications (Jimbo, 1992; Jimbo et al., 2003; Luan et al., 2017). However, there has not been thorough investigation on subsequent consequences of delivering the same electrical current through smaller electrodes. This is especially important because chronic overstimulation is known to cause nerve damage via a number of different mechanisms. Prevailing hypotheses on neurostimulation-induced tissue damage include hyperactivity of many neurons firing simultaneously that can lead to metabolic overload; and generation of toxic electrochemical byproducts during stimulation including dissolved metallic ions from the electrode, reactive oxygen species, water electrolysis byproducts (Merrill et al., 2011). In most neurostimulation systems, Platinum (Pt) is used as the material of choice due to its relatively high charge injection capacity via redox reactions, chemical resistance, and biocompatibility (Cogan, 2008). However, dissolution of Pt electrodes during stimulation is also known to lead to corrosion of Pt electrodes which is undesirable (Kovach et al., 2016; William F. Agnew et al., 1977). With smaller electrodes, the charge injection limit plays an important role in minimizing generation of toxic electrochemical byproduct during neurostimulation. The increased perimeter-to-surface area (PSA) in microscale electrodes can lead to significant non-uniformity in current density, which can alter charge injection capability and generation of noxious electrochemical byproducts. Although the impact of pulse parameters, electrode surface finish, and stimulation environment on charge transfer capacity of stimulating electrodes have previously been examined in Pt MEAs, very little work has been done to investigate the effects of electrode geometry and the inter-electrode distances in charge transfer capability of microscale stimulating electrodes (Cogan et al., 2014; Kumsa et al., 2016). Here we examined the role of electrode geometry (PSA) using custom microfabricated MEAs. The inter-electrode distances were varied to examine the impact of diffusion limit of electrochemical reactions. Four types of electrodes were created: circular, fractal, serpentine I, and serpentine II (Fig. 1, Table 1). Electrical contact to the electrodes was made using a custom 3D printed platform. Each electrode was characterized using cyclic voltammetry and electrochemical impedance spectroscopy. Cyclic voltammetry was measured in phosphate buffered solution (pH: 7.4) between potential limits from -0.65 to 0.85 V (Ag/AgCl) with sweep rate of 50 mV s-1(Fig. 2a). The cathodal and the total charge storage capacity of each electrode were calculated from the time integral of the current in cyclic voltammogram, which positively correlated with increasing PSA (Fig. 2b). The electrode impedance was measured using electrochemical impedance spectroscopy in 10 Hz to 100 kHz range, which showed elevated impedance value for higher PSA (Fig. 2c, 2d). Our preliminary results suggest that increasing PSA may alter the charge injection capability of electrode due to highly non-uniform current density facilitated by the edge effects. However, the increased non-uniformity and current density may also adversely affect the electrode surface integrity and facilitate the release of noxious byproducts. Our future work will focus on quantifying the dissolution rate of the platinum and other materials from the different shaped electrodes with different inter-electrode spacing at various electrode potentials. Moreover, we will compare voltage transient response from these electrodes in a biphasic stimulation pulse experiments to correlate our results. Figure 1

Paired Associative Stimulation Targeting the Tibialis Anterior Muscle using either Mono or Biphasic Transcranial Magnetic Stimulation.

Paired associative stimulation (PAS) protocols induce plastic changes within the motor cortex. The objectives of this study were to investigate PAS effects targeting the tibialis anterior (TA) muscle using a biphasic transcranial magnetic stimulation (TMS) pulse form and, to determine whether a reduced intensity of this pulse would lead to significant changes as has been reported for hand muscles using a monophasic TMS pulse. Three interventions were investigated: (1) suprathreshold PAbi-PAS (n = 11); (2) suprathreshold PAmono-PAS (n = 11) where PAS was applied using a biphasic or monophasic pulse form at 120% resting motor threshold (RMT); (3) subthreshold PAbi-PAS (n = 10) where PAS was applied as for (1) at 95% active motor threshold (AMT). The peak-to-peak motor evoked potentials (MEPs) were quantified prior to, immediately following, and 30 min after the cessation of the intervention. TA MEP size increased significantly for all interventions immediately post (61% for suprathreshold PAbi-PAS, 83% for suprathreshold PAmono-PAS, 55% for subthreshold PAbi-PAS) and 30 min after the cessation of the intervention (123% for suprathreshold PAbi-PAS, 105% for suprathreshold PAmono-PAS, 80% for subthreshold PAbi-PAS. PAS using a biphasic pulse form at subthreshold intensities induces similar effects to conventional PAS.

Design and analysis of energy recyclable bidirectional converter with digital controller for multichannel microstimulators

The power supply modulated microstimulator system can drive an expandable electrode array with reduced heat generation across the current drivers and high stimulation efficiency. Here, we present a comprehensive analytical modelling of the system to investigate internal and external energy flow during biphasic stimulation pulses spanning over varying loading configurations (e.g. number of electrodes, and stimulation current amplitude) that were not covered by existing works on the power supply modulated microstimulators. This paper fills the research gap by presenting the systematic tools for attaining insights of a stimulator system featuring a bidirectional DC---DC converter with an algorithmic digital controller. The models employed here are based on traditional analytical methods such as transfer functions and state-space dynamic models incorporating various circuit elements incurring power loss. With the models, the behaviour and power efficiency under a wide range of parameters associated with stimulator are attained. Numerical assessment reveals that the digital controller can track the output supply voltage at the phase transition boundaries just in tens of switching cycles. The system was also studied on a verification platform, where the internal signals of the digital controller were carefully examined. Measurement results show that the system behavior well matched to the simulation results, demonstrating the effectiveness of the analytical system model for obtaining key insights for generic large-scale micro-stimulator designs.