Neural activity of retinal ganglion cells under continuous, dynamically-modulated high frequency electrical stimulation

Objective. Current retinal prosthetics are limited in their ability to precisely control firing patterns of functionally distinct retinal ganglion cell (RGC) types. The aim of this study was to characterise RGC responses to continuous, kilohertz-frequency-varying stimulation to assess its utility in controlling RGC activity. Approach. We used in vitro patch-clamp experiments to assess electrically-evoked ON and OFF RGC responses to frequency-varying pulse train sequences. In each sequence, the stimulation amplitude was kept constant while the stimulation frequency (0.5-10 kHz) was changed every 40 ms, in either a linearly increasing, linearly decreasing or randomised manner. The stimulation amplitude across sequences was increased from 10 to 300 µA. Main results. We found that continuous stimulation without rest periods caused complex and irreproducible stimulus-response relationships, primarily due to strong stimulus-induced response adaptation and influence of the preceding stimulus frequency on the response to a subsequent stimulus. In addition, ON and OFF populations showed different sensitivities to continuous, frequency-varying pulse trains, with OFF cells generally exhibiting more dependency on frequency changes within a sequence. Finally, the ability to maintain spiking behaviour to continuous stimulation in RGCs significantly reduced over longer stimulation durations irrespective of the frequency order. Significance. This study represents an important step in advancing and understanding the utility of continuous frequency modulation in controlling functionally distinct RGCs. Our results indicate that continuous, kHz-frequency-varying stimulation sequences provide very limited control of RGC firing patterns due to inter-dependency between adjacent frequencies and generally, different RGC types do not display different frequency preferences under such stimulation conditions. For future stimulation strategies using kHz frequencies, careful consideration must be given to design appropriate pauses in stimulation, stimulation frequency order and the length of continuous stimulation duration

Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα-and Aβ-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B-and C-) indicated a stronger dependency.Clinical Relevance-Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects

Are long stimulus pulse durations the answer to improving spatial resolution in retinal prostheses?

Retinal prostheses can provide artificial vision to patients with degenerate retinae by electrically stimulating the remaining inner retinal neurons. The evoked perception is generally adequate for light localization, but of limited spatial resolution owing to the indiscriminate activation of multiple retinal cell types, leading to distortions in the perceived image. Here we present a perspective on a recent work by Weitz and colleagues who demonstrate a focal confinement of retinal ganglion cell (RGC) activation when using extended pulse durations in the stimulation waveform. Using real-time calcium imaging, they provide evidence that long pulse durations selectively stimulate inner retinal neurons, whilst avoiding unwanted axonal activations. The application of this stimulation technique may provide enhanced spatial resolution for retinal prosthesis users. These experiments provide a robust analysis of the effects of increasing pulse duration and introduce the potential for alternative stimulation paradigms in retinal prostheses

Verbal and novel multisensory associative learning in adults

To date, few studies have focused on the behavioural differences between the learning of multisensory auditory-visual and intra-modal associations. More specifically, the relative benefits of novel auditory-visual and verbal-visual associations for learning have not been directly compared. In Experiment 1, 20 adult volunteers completed three paired associate learning tasks: non-verbal novel auditory-visual (novel-AV), verbal-visual (verbal-AV; using pseudowords), and visual-visual (shape-VV). Participants were directed to make a motor response to matching novel and arbitrarily related stimulus pairs. Feedback was provided to facilitate trial and error learning. The results of Signal Detection Theory analyses suggested a multisensory enhancement of learning, with significantly higher discriminability measures (d-prime) in both the novel-AV and verbal-AV tasks than the shape-VV task. Motor reaction times were also significantly faster during the verbal-AV task than during the non-verbal learning tasks. Experiment 2 (n = 12) used a forced-choice discrimination paradigm to assess whether a difference in unisensory stimulus discriminability could account for the learning trends in Experiment 1. Participants were significantly slower at discriminating unisensory pseudowords than the novel sounds and visual shapes, which was notable given that these stimuli produced superior learning. Together the findings suggest that verbal information has an added enhancing effect on multisensory associative learning in adults

Gaze compensation as a technique for improving hand– eye coordination in prosthetic vision

Purpose: Shifting the region-of-interest within the input image to compensate for gaze shifts (‘‘gaze compensation’’) may improve hand–eye coordination in visual prostheses that incorporate an external camera. The present study investigated the effects of eye movement on hand-eye coordination under simulated prosthetic vision (SPV), and measured the coordination benefits of gaze compensation. Methods: Seven healthy-sighted subjects performed a target localization-pointing task under SPV. Three conditions were tested, modeling: retinally stabilized phosphenes (uncompensated); gaze compensation; and no phosphene movement (center-fixed). The error in pointing was quantified for each condition. Results: Gaze compensation yielded a significantly smaller pointing error than the uncompensated condition for six of seven subjects, and a similar or smaller pointing error than the center-fixed condition for all subjects (two-way ANOVA, P < 0.05). Pointing error eccentricity and gaze eccentricity were moderately correlated in the uncompensated condition (azimuth: R2 = 0.47; elevation: R2 = 0.51) but not in the gaze-compensated condition (azimuth: R2 = 0.01; elevation: R2 = 0.00). Increased variability in gaze at the time of pointing was correlated with greater reduction in pointing error in the center-fixed condition compared with the uncompensated condition (R2 = 0.64). Conclusions: Eccentric eye position impedes hand–eye coordination in SPV. While limiting eye eccentricity in uncompensated viewing can reduce errors, gaze compensation is effective in improving coordination for subjects unable to maintain fixation. Translational Relevance: The results highlight the present necessity for suppressing eye movement and support the use of gaze compensation to improve hand–eye coordination and localization performance in prosthetic vision

Virtual Electrodes by Current Steering in Retinal Prostheses

Full text Embargoed until: 2015-06-21PURPOSE: Retinal prostheses are an approved treatment for vision restoration in retinal degenerative diseases; however, present implants have limited resolution and simply increasing the number of electrodes is limited by design issues. In cochlear implants, virtual electrodes can be created by simultaneous stimulation of adjacent physical electrodes (current steering). The present study assessed whether this type of current steering can be adapted for retinal implants. METHODS: Suprachoroidal electrode arrays were implanted in four normally sighted cat eyes. Electrode pairs were driven simultaneously at different current levels and current ratios. Multiunit spiking activity in the visual cortex was recorded. Spike distribution across channels enabled generation of cortical activation maps and calculation of centroid positions. For each current configuration, centroid shifts between two virtual electrodes were compared to shifts obtained from physical electrode stimulation. RESULTS: Using current steering, virtual electrodes with different cortical activation maps could be created. Cortical centroids were found to shift as a function of the current ratio used for virtual electrodes and were similar to the centroid shifts seen when using physical electrodes. In addition, the cortical response to stimulation of a physical electrode could be reproduced by applying current steering to electrodes on either side of the physical electrode. CONCLUSIONS: These results suggest that current steering can alter activation patterns in the visual cortex and could enhance visual perception in retinal implants by eliciting phosphene percepts intermediate between those elicited by physical electrodes. These results inform development of new electrode arrays that can take advantage of current steering

Verbal and novel multisensory associative learning in adults.

To date, few studies have focused on the behavioural differences between the learning of multisensory auditory-visual and intra-modal associations. More specifically, the relative benefits of novel auditory-visual and verbal-visual associations for learning have not been directly compared. In Experiment 1, 20 adult volunteers completed three paired associate learning tasks: non-verbal novel auditory-visual (novel-AV), verbal-visual (verbal-AV; using pseudowords), and visual-visual (shape-VV). Participants were directed to make a motor response to matching novel and arbitrarily related stimulus pairs. Feedback was provided to facilitate trial and error learning. The results of Signal Detection Theory analyses suggested a multisensory enhancement of learning, with significantly higher discriminability measures (d-prime) in both the novel-AV and verbal-AV tasks than the shape-VV task. Motor reaction times were also significantly faster during the verbal-AV task than during the non-verbal learning tasks.  Experiment 2 (n = 12) used a forced-choice discrimination paradigm to assess whether a difference in unisensory stimulus discriminability could account for the learning trends in Experiment 1. Participants were significantly slower at discriminating unisensory pseudowords than the novel sounds and visual shapes, which was notable given that these stimuli produced superior learning. Together the findings suggest that verbal information has an added enhancing effect on multisensory associative learning in adults

The interplay between multisensory associative learning and IQ in children

This study assessed the developmental profile of unisensory and multisensory processes, and their contribution to children's intellectual abilities (8‐ and 11‐year olds, N = 38, compared to adults, N = 19) using a simple audiovisual detection task and three incidental associative learning tasks with different sensory signals: visual‐verbal with pseudowords, novel audiovisual, and visual‐visual. The level of immaturity throughout childhood was dependent on both, the sensory signal type and the task. Associative learning was significantly enhanced with verbal sounds, compared to novel audiovisual and unisensory visual learning. Visual‐verbal learning was also the best predictor of children's general intellectual abilities. The results demonstrate a separate developmental trajectory for visual and verbal multisensory processes and independent contributions to the development of cognitive abilities throughout childhood

The interplay between multisensory associative learning and IQ in children

This study assessed the developmental profile of unisensory and multisensory processes, and their contribution to children's intellectual abilities (8‐ and 11‐year olds, N = 38, compared to adults, N = 19) using a simple audiovisual detection task and three incidental associative learning tasks with different sensory signals: visual‐verbal with pseudowords, novel audiovisual, and visual‐visual. The level of immaturity throughout childhood was dependent on both, the sensory signal type and the task. Associative learning was significantly enhanced with verbal sounds, compared to novel audiovisual and unisensory visual learning. Visual‐verbal learning was also the best predictor of children's general intellectual abilities. The results demonstrate a separate developmental trajectory for visual and verbal multisensory processes and independent contributions to the development of cognitive abilities throughout childhood