Pengjia Cao

C-Sight Visual Prostheses for the Blind

Visual prostheses based on a stimulating microelectrode array to restore vision offer a promising approach for the blind and has become a rapidly growing scientific field in neurorehabilitation engineering. A number of research groups from major developed countries lead the research activities in this field. The goal of the C-Sight Project is to develop an implantable microelectronic medical device that will restore useful vision to blind patients. Retinitis pigmentosa (RP) and age-related macular degeneration are the two leading causes for blindness, for which there have been no effective treatments, both surgically and biologically, until now.The ultimate goal of our project is to develop a completely implantable visual prosthesis based on a penetrating microelectrode array at the optical nerve; to implement this, it requires many technical advances. However, in our study, an implantable microcamera, the wearable information processor, and the multichannel neurostimulator are investigated. Electrophysiological experiments were also performed to provide evidence for the feasibility of our approach. Some related psychophysical studies including simulated phosphene positioning and recognition of pixelized images are also reported in this article.

Spatiotemporal Properties of Multipeaked Electrically Evoked Potentials Elicited by Penetrative Optic Nerve Stimulation in Rabbits

PURPOSE To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis. METHODS The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye. Electrically evoked potentials (EEPs) were recorded by an electrode array positioned on the visual cortex. RESULTS There were primarily four components (N1, P1, P2, P3) in EEPs with implicit times of 8.0 ± 0.6, 11.3 ± 1.3, 20.5 ± 1.4, and 26.9 ± 1.5 ms, respectively, when the ON was stimulated by penetrating electrodes. The thresholds to elicit these components were different, and the higher thresholds were seen with slower cortical components. The corresponding thresholds were 13.8 ± 3.1 μA for N1, 21.8 ± 4.7 μA for P1, 36.4 ± 11.4 μA for P2, and 68.4 ± 17.2 μA for P3. The time courses of the EEP components were also distinct. The locations of EEPs with the maximum P1 amplitude showed a spatial correspondence to the ON stimulation sites. Different profiles of cortical responses could be discriminated when the ON stimulation sites were separated by 150 μm. CONCLUSIONS Multiple components with different properties were elicited in EEPs when the ON was stimulated by penetrating electrodes. Retinotopic and localized stimulation could be achieved with this stimulating approach.

Using independent component analysis to remove artifacts in visual cortex responses elicited by electrical stimulation of the optic nerve

In visual prosthesis research, electrically evoked potentials (EEPs) can be elicited by one or more biphasic current pulses delivered to the optic nerve (ON) through penetrating electrodes. Multi-channel EEPs recorded from the visual cortex usually contain large stimulus artifacts caused by instantaneous electrotonic current spread through the brain tissue. These stimulus artifacts contaminate the EEP waveform and often make subsequent analysis of the underlying neural responses difficult. This is particularly serious when investigating EEPs in response to electrical stimulation with long duration and multi-pulses. We applied independent component analysis (ICA) to remove these electrical stimulation-induced artifacts during the development of a visual prosthesis. Multi-channel signals were recorded from visual cortices of five rabbits in response to ON electrical stimulation with various stimulus parameters. ON action potentials were then blocked by lidocaine in order to acquire cortical potentials only including stimulus artifacts. Correlation analysis of reconstructed artifacts by ICA and artifacts recorded after blocking the ON indicates successful removal of artifacts from electrical stimulation by the ICA method. This technique has potential applications in studies designed to optimize the electrical stimulation parameters used by visual prostheses.

Optical Imaging of Visual Cortical Responses Evoked by Transcorneal Electrical Stimulation With Different Parameters

PURPOSE The use of phosphenes evoked by transcorneal electrical stimulation (TcES) has been proposed as a means of residual visual function evaluation and candidate selection before implantation of retinal prostheses. Compared to the subjective measures, measurement of neuronal activity in visual cortex can objectively and quantitatively explore their response properties to electrical stimulation. The purpose of this study was to investigate systematically the properties of cortical responses evoked by TcES. METHODS The visual cortical responses were recorded using a multiwavelength optical imaging of intrinsic signals (OIS) combining with electrophysiological recording by a multichannel electrode array. The effects of different parameters of TcES on cortical responses, including the changes of hemoglobin oxygenation and cerebral blood volume, were examined. RESULTS We found consistent OIS activation regions in visual cortex after TcES, which also showed strong evoked field potentials according to electrophysiological results. The OIS response regions were located mainly in cortical areas representing peripheral visual field. The extent of activation areas and strength of intrinsic signals were increased with higher current intensities and longer pulse widths, and the largest responses were acquired in the frequency range 10 to 20 Hz. CONCLUSIONS Use of TcES through the ERG-jet corneal electrode may preferentially activate peripheral retina. Revealing the hemodynamic changes in visual cortex occurred after electrical stimulation can contribute to comprehension of neurophysiological underpinnings underlying prosthetic vision. This study provided an objective foundation for optimizing parameters of TcES and would bring considerable benefits in the application of TcES for assessment and screening in patients.

Inverted optical intrinsic response accompanied by decreased cerebral blood flow are related to both neuronal inhibition and excitation

Negative hemodynamic response has been widely reported in blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies, however its origin is still controversial. Optical intrinsic signal (OIS) imaging can be used to study brain activity by simultaneously recording hemodynamic signals at different wavelengths with high spatial resolution. In this study, we found transcorneal electrical stimulation (TcES) could elicit both positive OIS response (POR) and negative OIS response (NOR) in cats’ visual cortex. We then investigated the property of this negative response to TcES and its relationship with cerebral blood flow (CBF) and neuronal activity. Results from laser speckle contrast imaging showed decreased CBF in the NOR region while increased CBF in the POR region. Both planar and laminar electrophysiological recordings in the middle (500–700 μm) cortical layers demonstrated that decreased and increased neuronal activities were coexisted in the NOR region. Furthermore, decreased neuronal activity was also detected in the deep cortical layers in the NOR region. This work provides evidence that the negative OIS together with the decreased CBF should be explained by mechanisms of both neuronal inhibition and excitation within middle cortical layers. Our results would be important for interpreting neurophysiological mechanisms underlying the negative BOLD signals.

Negative hemodynamic response without neuronal inhibition investigated by combining optical imaging and electrophysiological recording

Understanding the mechanisms underlying negative hemodynamic responses is critical for the interpretation of functional brain imaging signals. Negative imaging signals have been found in the visual, somatosensory and motor cortices in functional magnetic resonance imaging (fMRI) and intrinsic signal optical imaging (ISOI) studies. However, the origin of negative imaging signals is still controversial. The present study investigated the visual cortical responses to peripheral grating stimuli using multi-wavelength ISOI and electrophysiological recording. We found an increased cerebral blood volume (CBV) in the stimulus-induced regions and a decreased CBV in the adjacent regions in the visual cortex. Nevertheless, there was no significant change in blood oxygenation in the negative CBV regions. Furthermore, by combining the planar and laminar electrophysiological recordings, we did not observe significantly decreased neuronal activity in the negative CBV regions. Our results suggest that the negative hemodynamic response does not necessarily originate in decreased neuronal activity. Therefore, caution should be taken when interpreting a negative hemodynamic response as neuronal inhibition.

A visual prosthesis based on Optic Nerve Stimulation: In vivo Electrophysiological Study in Rabbits

A visual prosthesis based on optic nerve stimulation has been suggested as a possible way to restore functional vision for the blind. In this study, we investigated the feasibility and basic spatiotemporal properties of cortical responses evoked by optic nerve stimulation with penetrating electrodes, using multi-channel recording electrode array positioned at the visual cortex area in rabbits.

Evoked Cortical Potential and Optic Nerve Response after Direct Electrical Stimulation of the Optic Nerve in Rabbits

We use rabbits as experiment model to investigate the feasibility of visual prosthesis based on penetrating optic nerve electrical stimulation. A tungsten electrode was inserted into the exposed intraorbital optic nerve as stimulating electrode. The electrical evoked potentials (EEPs) and optic nerve responses (EEONRs) were recorded after direct electrical stimulation of the optic nerve to compare with the visual evoked potentials (VEPs) and visual evoked optic nerve responses (VEONRs).

Penetrative Optic Nerve-Based Visual Prosthesis Research

A number of research groups around the world have been dedicated to restoring some functional vision for blind patients through visual prostheses. The C-sight project (Chinese Project for Sight) proposed a visual prosthesis with penetrative stimulating electrode array implanted into the ON as a neural interface to couple the encoded electrical stimuli for vision recovery, since then a decade of effort has been devoted to the development of the first-generation prototype. In this article, the outcomes of this approach and its status quo were briefly summarized and introduced from different perspectives. Besides hardware system and surgical methods description, the cortical response characteristics in response to penetrating ON stimulation in in vivo animal experiments were extensively introduced. Firstly, as a widely used methodology of evaluating the effect of a certain electrical stimulus, the basic spatiotemporal properties of the electrically evoked cortical potentials (EEPs) elicited by penetrating ON stimulation were investigated. Secondly, the exact implantation sites of ON electrode array were considered and evaluated taking account of realizing fine visuotopic correspondence between ON electrical stimulation sites and the visual field. Thirdly, the optimal stimulus parameters were explored, as well as the relationship between response properties of electrical vs. visual stimulation. Furthermore, several potential future directions of this approach were also briefly discussed.

Electrically Evoked Responses in the Rabbit Cortex Induced by Current Steering With Penetrating Optic Nerve Electrodes.

Purpose Current steering is a neural stimulation strategy that uses simultaneous stimulation of adjacent electrodes to produce additional intermediate stimulation sites and thus improves spatial resolution. We investigated the feasibility of current steering using electrophysiological and computational methods after implanting paired penetrating electrodes into the rabbits optic nerve (ON). Methods Penetrating electrodes at different interelectrode distances were implanted into the ON and electrically evoked cortical potentials (EEPs) in V1 recorded with a 6 × 8 array. The current thresholds, EEP amplitudes, and spatial distributions were analyzed during current steering. Computational simulation studies were performed based on finite element models to calculate the area and spatial distribution of recruited ON fibers using a current steering stimulation strategy. Results Threshold reduction and EEP amplitude enhancement were found with simultaneous stimulation of closely spaced electrode pairs. Spatially shifted cortical responses were achieved using current steering, whereas the amplitudes and spatial spreads of the responses were similar to that elicited by a single electrode. Computational simulations suggested that the centroid of the ON recruitment area could be modulated by current steering while the total recruitment area did not show any appreciable variability at a fixed current intensity. Conclusions Current steering is a useful strategy to enhance the spatial resolution of an ON prosthesis without increasing the number of physical electrodes. This study provides useful information for optimizing the design of stimulation strategies with a penetrating ON prosthesis.