Lan Yue

Retinal stimulation strategies to restore vision: Fundamentals and systems

Retinal degeneration, a leading cause of blindness worldwide, is primarily characterized by the dysfunctional/degenerated photoreceptors that impair the ability of the retina to detect light. Our group and others have shown that bioelectronic retinal implants restore useful visual input to those who have been blind for decades. This unprecedented approach of restoring sight demonstrates that patients can adapt to new visual input, and thereby opens up opportunities to not only improve this technology but also develop alternative retinal stimulation approaches. These future improvements or new technologies could have the potential of selectively stimulating specific cell classes in the inner retina, leading to improved visual resolution and color vision. In this review we will detail the progress of bioelectronic retinal implants and future devices in this genre as well as discuss other technologies such as optogenetics, chemical photoswitches, and ultrasound stimulation. We will discuss the principles, biological aspects, technology development, current status, clinical outcomes/prospects, and challenges for each approach. The review will cover functional imaging documented cortical responses to retinal stimulation in blind patients.

Ten-Year Follow-up of a Blind Patient Chronically Implanted with Epiretinal Prosthesis Argus I

PURPOSE The Argus I implant is the first-generation epiretinal prosthesis approved for an investigational clinical trial by the United States Food and Drug Administration. Herein we report testing results obtained from a 10-year follow-up to study the physiologic effects of the bioelectronic visual implant after prolonged chronic electrical stimulation. DESIGN Case report. PARTICIPANT One man, 55 years of age when enrolled in the study, underwent surgical implantation of the Argus I in June 2004, followed by periodic tests from July 2004 through June 2014, spanning a total of 10 years. METHODS The decade-long follow-up consisted of implant system performance tests, subject visual function evaluation, and implant-retina interface analysis. MAIN OUTCOME MEASURES Changes in electrode impedance and perceptual threshold over the time course; subjects performance on visual function task, orientation, and mobility tests; and optical coherence tomography data, fundus imaging, and fluorescein angiography results for the assessment of subjects implant-retina physical interface. RESULTS Electrically elicited phosphenes were present 10 years after implantation of an epiretinal stimulator. The test subject not only was able to perceive phosphenes, but also could perform visual tasks at rates well above chance. CONCLUSIONS This decade-long follow-up report provides further support for the use of retinal prostheses as a long-lasting treatment for some types of blindness.

Monte Carlo analysis of the enhanced transcranial penetration using distributed near-infrared emitter array.

Abstract. Transcranial near-infrared (NIR) treatment of neurological diseases has gained recent momentum. However, the low NIR dose available to the brain, which shows severe scattering and absorption of the photons by human tissues, largely limits its effectiveness in clinical use. Hereby, we propose to take advantage of the strong scattering effect of the cranial tissues by applying an evenly distributed multiunit emitter array on the scalp to enhance the cerebral photon density while maintaining each single emitter operating under the safe thermal limit. By employing the Monte Carlo method, we simulated the transcranial propagation of the array emitted light and demonstrated markedly enhanced intracranial photon flux as well as improved uniformity of the photon distribution. These enhancements are correlated with the source location, density, and wavelength of light. To the best of our knowledge, we present the first systematic analysis of the intracranial light field established by the scalp-applied multisource array and reveal a strategy for the optimization of the therapeutic effects of the NIR radiation.

Retinal Prostheses: A Clinical Perspective

Artificial vision is restoring sight by electrical stimulation of the visual system at the level of retina, optic nerve, lateral geniculate body, or occipital cortex. The development of artificial vision began with occipital cortex prosthesis; however, retinal prosthesis has advanced faster in recent years. Currently, multiple efforts are focused on finding the optimal approach for restoring vision through an implantable retinal microelectrode array system. Retinal prostheses function by stimulating the inner retinal neurons that survive retinal degeneration. In these devices, the visual information, gathered by a light detector, is transformed into controlled patterns of electrical pulses, which are in turn delivered to the surviving retinal neurons by an electrode array. Retinal prostheses are classified based on where the stimulating array is implanted (ie, epiretinal, subretinal, suprachoroidal, or episcleral). Recent regulatory approval of 2 retinal prostheses has greatly escalated interest in the potential of these devices to treat blindness secondary to outer retinal degeneration. This review will focus on the technical and operational features and functional outcomes of clinically tested retinal prostheses. We will discuss the major barriers and some of the more promising solutions to improve the outcomes of restoring vision with electrical retinal stimulation.

Simulation and measurement of transcranial near infrared light penetration

We are studying the transmission of LED array-emitted near-infrared (NIR) light through human tissues. Herein, we simulated and measured transcranial NIR penetration in highly scattering human head tissues. Using finite element analysis, we simulated photon diffusion in a multilayered 3D human head model that consists of scalp, skull, cerebral spinal fluid, gray matter and white matter. The optical properties of each layer, namely scattering and absorption coefficient, correspond to the 850 nm NIR light. The geometry of the model is minimally modified from the IEEE standard and the multiple LED emitters in an array were evenly distributed on the scalp. Our results show that photon distribution produced by the array exhibits little variation at similar brain depth, suggesting that due to strong scattering effects of the tissues, discrete spatial arrangements of LED emitters in an array has the potential to create a quasi-radially symmetrical illumination field. Measurements on cadaveric human head tissues excised from occipital, parietal, frontal and temporal regions show that illumination with an 850 nm LED emitter rendered a photon flux that closely follows simulation results. In addition, prolonged illumination of LED emitted NIR showed minimal thermal effects on the brain.

Retinal Prostheses: A Brief History

Retinal prostheses deliver controlled electrical impulses to retina which elicit light perception in patients with damaged/degenerated photoreceptors. It has been shown that retinal prostheses are able to restore simple but useful vision to those who have been otherwise blind for decades. The idea of using electricity to stimulate the visual system is as old as two centuries, but the development of the retinal prostheses only took off in the most recent two decades. During this period, a variety of devices have been developed and investigated, among which two have received regulatory approvals for clinical use, Argus II and Alpha-IMS. Meanwhile new technologies and stimulation strategies are being pursued to improve the visual experience of the blind. Given the momentum of the field, it is anticipated that the next generation prostheses will enable the blind patients to perform more complex visual tasks such as reading. This chapter will overview the historical aspects of the representative retinal prostheses, briefly accounting the background and the current status.

Temporal Neuromodulation of Retinal Ganglion Cells by Low-Frequency Focused Ultrasound Stimulation

Significant progress has been made recently in treating neurological blindness using implantable visual prostheses. However, implantable medical devices are highly invasive and subject to many safety, efficacy, and cost issues. The discovery that ultrasound (US) may be useful as a noninvasive neuromodulation tool has aroused great interest in the field of acoustic retinal prostheses (ARPs). We have investigated the responsiveness of rat retinal ganglion cells (RGCs) to low-frequency focused US stimulation (LFUS) at 2.25 MHz and characterized the neurophysiological properties of US responses by performing in vitro multielectrode array recordings. The results show that LFUS can reliably activate RGCs. The US-induced responses did not correspond to the standard light responses and varied greatly among cell types. Moreover, dual-peak responses to US stimulation were observed that have not been reported previously. The temporal response properties of RGCs, including their latency, firing rate, and response type, were modulated by the acoustic intensity. These findings suggest the presence of a temporal neuromodulation effect of LFUS and potentially open a new avenue in the development of ARP.

Retina stimulation on rat in vivo with low-frequency ultrasound

More and more researches are exploring the neurostimulation effect of ultrasound (US) on the central nervous system (e.g. brain and retina) and the peripheral nervous system (such as skin). US stimulation has been regarded as a new noninvasive neurostimulation approach by many researchers. Our previous studies had shown that the temporal response patterns of RGCs could be stimulated by US in vitro. In this article, we apply low-frequency (2.25 MHz) focused US stimulation to the rat retina in vivo to investigate the effect on the primary visual cortex.