Graeme D. Rathbone

Suprachoroidal electrical stimulation: effects of stimulus pulse parameters on visual cortical responses

OBJECTIVE Neural responses to biphasic constant current pulses depend on stimulus pulse parameters such as polarity, duration, amplitude and interphase gap. The objective of this study was to systematically evaluate and optimize stimulus pulse parameters for a suprachoroidal retinal prosthesis. APPROACH Normally sighted cats were acutely implanted with platinum electrode arrays in the suprachoroidal space. Monopolar stimulation comprised of monophasic and biphasic constant current pulses with varying polarity, pulse duration and interphase gap. Multiunit responses to electrical stimulation were recorded in the visual cortex. MAIN RESULTS Anodal stimulation elicited cortical responses with shorter latencies and required lower charge per phase than cathodal stimulation. Clinically relevant retinal stimulation required relatively larger charge per phase compared with other neural prostheses. Increasing the interphase gap of biphasic pulses reduced the threshold of activation; however, the benefits of using an interphase gap need to be considered in light of the pulse duration and polarity used and other stimulation constraints. Based on our results, anodal first biphasic pulses between 300-1200 µs are recommended for suprachoroidal retinal stimulation. SIGNIFICANCE These results provide insights into the efficacy of different pulse parameters for suprachoroidal retinal stimulation and have implications for the design of safe and clinically relevant stimulators for retinal prostheses.

An automated system for rapid evaluation of high-density electrode arrays in neural prostheses

The success of high-density electrode arrays for use in neural prostheses depends on efficient impedance monitoring and fault detection. Conventional methods of impedance testing and fault detection are time consuming and not always suited for in vivo assessment of high-density electrode arrays. Additionally, the ability to evaluate impedances and faults such as open and short circuits, both in vitro and in vivo, are important to ensure safe and effective stimulation. In this work we describe an automated system for the rapid evaluation of high-density electrode arrays. The system uses a current pulse similar to that used to stimulate neural tissue and measures the voltage across the electrode in order to calculate the impedance. The switching of the system was validated by emulating a high-density electrode array using light-emitting diodes and a resistor-capacitor network. The system was tested in vitro and in vivo using a range of commercially available and in-house developed electrode arrays. The system accurately identified faults in an 84-electrode array in less than 20 s and reliably measured impedances up to 110 kΩ using a 200 µA, 250 µs per phase current pulse. This system has direct application for screening high-density electrode arrays in both clinical and experimental settings.

An in vivo investigation of first spike latencies in the inferior colliculus in response to multichannel penetrating auditory brainstem implant stimulation

The cochlear nucleus (CN) is the first auditory processing site within the brain and the target location of the auditory brainstem implant (ABI), which provides speech perception to patients who cannot benefit from a cochlear implant (CI). Although there is variance between ABI recipient speech performance outcomes, performance is typically low compared to CI recipients. Temporal aspects of neural firing such as first spike latency (FSL) are thought to code for many speech features; however, no studies have investigated FSL from CN stimulation. Consequently, ABIs currently do not incorporate CN-specific temporal information. We therefore systematically investigated inferior colliculus (IC) neurons FSL response to frequency-specific electrical stimulation of the CN in rats. The range of FSLs from electrical stimulation of many neurons indicates that both monosynaptic and polysynaptic pathways were activated, suggesting initial activation of multiple CN neuron types. Electrical FSLs for a single neuron did not change irrespective of the CN frequency region stimulated, indicating highly segregated projections from the CN to the IC. These results present the first evidence of temporal responses to frequency-specific CN electrical stimulation. Understanding the auditory systems temporal response to electrical stimulation will help in future ABI designs and stimulation strategies.

Spatiotemporal Interactions in the Visual Cortex Following Paired Electrical Stimulation of the Retina

PURPOSE Retinal prostheses use spatiotemporal patterns of electrical stimulation across multiple electrodes to provide visual percepts to blind patients. It is generally assumed that percepts produced by individual electrodes are independent of one another, which may not be the case. In this study, we aimed to quantify interactions between pairs of electrical stimuli delivered to the retina. METHODS Normally sighted cats were implanted with a suprachoroidal electrode array. The retina was stimulated with a paired-pulse paradigm that consisted of a conditioning stimulus followed by a test stimulus, while recording multiunit activity in the visual cortex. Conditioning current, and spatial and temporal separation between the conditioning and test stimuli were varied. Cortical interactions were quantified by changes in multiunit activity elicited by stimulation with the paired-pulse paradigm, compared to stimulation of the test stimulus alone (control). RESULTS Interactions varied as a function of conditioning current and temporal separation between the two stimulating pulses. Cortical activity increased compared to the control condition at an interstimulus delay of 1.025 ms and was significantly suppressed for delays between 20 and 90 ms, returning to near control levels for longer delays. The level of interactions increased when the conditioning current was increased. Interactions were found to be similar for electrode separations up to 3 mm. CONCLUSIONS Interactions between sequential stimulation of pairs of electrodes in a suprachoroidal retinal prosthesis occur for delays up to 100 ms and electrode separations of several millimeters. Knowledge of these spatiotemporal interactions is essential for developing effective patterns of stimulation for retinal prostheses.

Acute Cochlear Nucleus Compression Alters Tuning Properties of Inferior Colliculus Neurons

Auditory brainstem implants (ABI) have been used in neurofibromatosis type 2 (NF2) patients in an attempt to restore hearing sensation, with limited clinical success. Factors associated with poor clinical outcomes for NF2 ABI patients include larger tumour size, longer duration of hearing loss, and brainstem distortion and/or deformation caused by tumours that compress the brainstem. The present study investigated changes in tuning properties of inferior colliculus (IC) neurons following compression of the contralateral cochlear nucleus (CN). The left CN in adult rats (n = 8) was exposed and a 32-channel acute recording probe inserted along the tonotopic gradient of the right IC. In 4 animals, an ethylene vinyl acetate bead was applied to the exposed CN. Three recordings were made corresponding to T1 = 0 min (before compression), T2 = 45 min (during compression) and T3 = 225 min (following bead removal/recovery). Recordings consisted of a response area protocol using pure tones of various frequencies and intensities (1–44 kHz; 10–70 dB SPL) to determine the characteristic frequency for each probe site. Compression of the CN led to sharpened tuning curves, decreased spike rate, and increased threshold and characteristic frequency in the IC. Reversal of compression enabled these variables, excluding threshold, to recover to baseline. NF2 patients may have poorer ABI performance due to damage to the physical structure of the CN, resulting in alterations to the tonotopic organisation of the auditory pathway which may complicate ABI implantation and activation.

Inferior colliculus responses to dual-site intralamina stimulation in the ventral cochlear nucleus.

A major limitation of the present auditory brainstem implant (ABI) is its inability to access the tonotopic organization of the ventral cochlear nucleus (VCN). A previous study by our group indicated that stimulation of single sites within a given VCN frequency region did not always elicit frequency‐specific responses within the central nucleus of the inferior colliculus (CIC) and in some cases did not elicit a response at all. For this study, we hypothesized that sequential stimulation (with a short interpulse delay of 320 μsec) of two VCN sites in similar frequency regions would enhance responsiveness in CIC neurons. Multiunit neural recordings in response to pure tones were obtained at 58 VCN and 164 CIC sites in anesthetized rats. Among the 58 VCN sites, 39 pairs of sites with similar characteristic frequencies were chosen for electrical stimulation. Each member of a VCN pair was electrically stimulated individually, followed by sequential stimulation of the pair, while recording CIC responses. On average, CIC sites were found to respond to dual‐site VCN stimulation with significantly lower thresholds, wider dynamic ranges, a greater extent of activation with increasing current levels, and a higher degree of frequency specificity compared with single‐site stimulation. Although these effects were positive for the most part, in some cases dual‐site stimulation resulted in increased CIC thresholds and decreased dynamic ranges, extent of activation, and frequency specificity. The results suggest that multisite stimulation within VCN isofrequency laminae using penetrating electrodes could significantly improve ABI stimulation strategies and implant performance. J. Comp. Neurol. 518:4226–4242, 2010.

Neural synchrony in ventral cochlear nucleus neuron populations is not mediated by intrinsic processes but is stimulus induced: implications for auditory brainstem implants.

The aim of this investigation was to elucidate if neural synchrony forms part of the spike time-based theory for coding of sound information in the ventral cochlear nucleus (VCN) of the auditory brainstem. Previous research attempts to quantify the degree of neural synchrony at higher levels of the central auditory system have indicated that synchronized firing of neurons during presentation of an acoustic stimulus could play an important role in coding complex sound features. However, it is unknown whether this synchrony could in fact arise from the VCN as it is the first station in the central auditory pathway. Cross-correlation analysis was conducted on 499 pairs of multiunit clusters recorded in the urethane-anesthetized rat VCN in response to pure tones and combinations of two tones to determine the presence of neural synchrony. The shift predictor correlogram was used as a measure for determining the synchrony owing to the effects of the stimulus. Without subtraction of the shift predictor, over 65% of the pairs of multiunit clusters exhibited significant correlation in neural firing when the frequencies of the tones presented matched their characteristic frequencies (CFs). In addition, this stimulus-evoked neural synchrony was dependent on the physical distance between electrode sites, and the CF difference between multiunit clusters as the number of correlated pairs dropped significantly for electrode sites greater than 800 microm apart and for multiunit cluster pairs with a CF difference greater than 0.5 octaves. However, subtraction of the shift predictor correlograms from the raw correlograms resulted in no remaining correlation between all VCN pairs. These results suggest that while neural synchrony may be a feature of sound coding in the VCN, it is stimulus induced and not due to intrinsic neural interactions within the nucleus. These data provide important implications for stimulation strategies for the auditory brainstem implant, which is used to provide functional hearing to the profoundly deaf through electrical stimulation of the VCN.

An in vivo investigation of inferior colliculus single neuron responses to cochlear nucleus pulse train stimulation

The auditory brain stem implant (ABI) is being used clinically to restore hearing to patients unable to benefit from a cochlear implant (CI). Speech perception outcomes for ABI users are typically poor compared with most CI users. The ABI is implanted either on the surface of or penetrating through the cochlear nucleus in the auditory brain stem and uses stimulation strategies developed for auditory nerve stimulation with a CI. Although the stimulus rate may affect speech perception outcomes with current stimulation strategies, no studies have systematically investigated the effect of stimulus rate electrophysiologically or clinically. We therefore investigated rate response properties and temporal response properties of single inferior colliculus (IC) neurons from penetrating ABI stimulation using stimulus rates ranging from 100 to 1,600 pulses/s in the rat. We found that the stimulus rate affected the proportion of response types, thresholds, and dynamic ranges of IC activation. The stimulus rate was also found to affect the temporal properties of IC responses, with higher rates providing more temporally similar responses to acoustic stimulation. Suppression of neural firing and inhibition in IC neurons was also found, with response properties varying with the stimulus rate. This study demonstrated that changes in the ABI stimulus rate results in significant differences in IC neuron response properties. Due to electrophysiological differences, the stimulus rate may also change perceptual properties. We suggest that clinical evaluation of the ABI stimulus rate should be performed.

Ring and Peg Electrodes for Minimally-Invasive and Long-Term Sub-scalp EEG Recordings

OBJECTIVE Minimally-invasive approaches are needed for long-term reliable Electroencephalography (EEG) recordings to assist with epilepsy diagnosis, investigation and more naturalistic monitoring. This study compared three methods for long-term implantation of sub-scalp EEG electrodes. METHODS Three types of electrodes (disk, ring, and peg) were fabricated from biocompatible materials and implanted under the scalp in five ambulatory ewes for 3months. Disk electrodes were inserted into sub-pericranial pockets. Ring electrodes were tunneled under the scalp. Peg electrodes were inserted into the skull, close to the dura. EEG was continuously monitored wirelessly. High resolution CT imaging, histopathology, and impedance measurements were used to assess the status of the electrodes at the end of the study. RESULTS EEG amplitude was larger in the peg compared with the disk and ring electrodes (p<0.05). Similarly, chewing artifacts were lower in the peg electrodes (p<0.05). Electrode impedance increased after long-term implantation particularly for those within the bone (p<0.01). Micro-CT scans indicated that all electrodes stayed within the sub-scalp layers. All pegs remained within the burr holes as implanted with no evidence of extrusion. Eight of 10 disks partially eroded into the bone by 1.0mm from the surface of the skull. The ring arrays remained within the sub-scalp layers close to implantation site. Histology revealed that the electrodes were encapsulated in a thin fibrous tissue adjacent to the pericranium. Overlying this was a loose connective layer and scalp. Erosion into the bone occurred under the rim of the sub-pericranial disk electrodes. CONCLUSIONS The results indicate that the peg electrodes provided high quality EEG, mechanical stability, and lower chewing artifact. Whereas, ring electrode arrays tunneled under the scalp enable minimal surgical techniques to be used for implantation and removal.