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.

Objective. The Argus I implant is a first-generation epiretinal prosthesis approved for an investigational clinical trial in the U.S. Its successor, the Argus II implant, has a higher electrode density for increased spatial resolution and covers a larger retinal area to accommodate a wider visual angle. Both generations of Argus restored some vision to end-stage RP patients, but it remains unclear how the increased electrode count affected the visual percepts. Here we report a study of the first person on earth with two ‘bionic eyes’, with an Argus I implanted in one eye and Argus II in the other, to compare the retina–electrode interface and the visual outcome of the two devices. Approach. The retina–electrode interface was examined by electrode impedance, perceptual threshold, and ophthalmic images such as ocular coherence tomography data and fundus imaging. The subject’s visual outcomes were evaluated by computer-based visual function tests and subjective feedback. Main results. The electrode impedance of both Argus I and II slowly decreased overtime after implantation, accompanied by a gradual increase in the perceptual threshold. A quantitative analysis of the impedance and retina–electrode distance revealed somewhat different causes of impedance change in Argus I vs. II. Evaluation of the visual functions restored and feedback from the subject suggest that the Argus II device enables improved spatial visual ability over Argus I, but adaptation to prosthetic vision did not lead to a measurable performance improvement in the standard visual function tests. Significance. This study of Argus I and II in the same subject directly compares for the first time the interface properties and prosthetic vision in two eyes that share the same disease mechanism and converged visual pathway in higher visual centers, offering exciting new insights into the influence of the electrode parameters and layout to prosthetic vision. Trial registration: Data collected within clinical trials registered at NIH (NCT00279500 & NCT01860092).

Ultrasound is an emerging method for non-invasive neuromodulation. Studies in the past have demonstrated that ultrasound can reversibly activate and inhibit neural activities in the brain. Recent research shows the possibility of using ultrasound ranging from 0.5 to 43 MHz in acoustic frequency to activate the retinal neurons without causing detectable damages to the cells. This review recapitulates pilot studies that explored retinal responses to the ultrasound exposure, discusses the advantages and limitations of the ultrasonic stimulation, and offers an overview of engineering perspectives in developing an acoustic retinal prosthesis. For comparison, this article also presents studies in the ultrasonic stimulation of the visual cortex. Despite that, the summarized research is still in an early stage; ultrasonic retinal stimulation appears to be a viable technology that exhibits enormous therapeutic potential for non-invasive vision restoration.

Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.