BACKGROUND. A long-held goal of vision therapy is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists. METHODS. We implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a 6-month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation. RESULTS. Implantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes was associated with a significant reduction in thresholds (P < 0.001, ANOVA) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries. CONCLUSIONS. Our results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind. TRIAL REGISTRATION. ClinicalTrials.gov identifier NCT02983370. FUNDING. The Spanish Ministerio de Ciencia Innovación y Universidades, the Generalitat Valenciana (Spain), the Europan Union’s Horizon 2020 programme, the Bidons Egara Research Chair of the University Miguel Hernández (Spain), and the John Moran Eye Center of the University of Utah.

The emerging field of neuroprosthetics is focused on the development of new therapeutic interventions that will be able to restore some lost neural function by selective electrical stimulation or by harnessing activity recorded from populations of neurons. As more and more patients benefit from these approaches, the interest in neural interfaces has grown significantly and a new generation of penetrating microelectrode arrays are providing unprecedented access to the neurons of the CNS. These microelectrodes have active tip dimensions that are similar in size to neurons and because they penetrate the nervous system, they provide selective access to these cells (within a few microns). However, the very long-term viability of chronically implanted microelectrodes and the capability of recording the same spiking activity over long time periods still remain to be established and confirmed in human studies. Here we review the main responses to acute implantation of microelectrode arrays, and emphasize that it will become essential to control the neural tissue damage induced by these intracortical microelectrodes in order to achieve the high clinical potentials accompanying this technology.

The development of novel non-viral delivery vehicles is essential in the search of more efficient strategies for retina and brain diseases. Herein, optimized niosome formulations prepared by oil-in water (o/w) and film-hydration techniques were characterized in terms of size, PDI, zeta potential, morphology and stability. Three ionizable glycerol-based cationic lipids containing a primary amine group (lipid 1), a triglycine group (lipid 2) and a dimethylamino ethyl pendent group (lipid 3) as polar head-groups were part of such niosomes. Upon the addition of pCMS-EGFP plasmid, nioplexes were obtained at different cationic lipid/DNA ratios (w/w). The resultant nioplexes were further physicochemically characterized and evaluated to condense, release and protect the DNA against enzymatic digestion. In vitro experiments were performed to evaluate transfection efficiency and cell viability in HEK-293, ARPE-19 and PECC cells. Interestingly, niosome formulations based on lipid 3 showed better transfection efficiencies in ARPE-19 and PECC cells than the rest of cationic lipids showed in this study. In vivo experiments in rat retina after intravitreal and subretinal injections together with in rat brain after cerebral cortex administration showed promising transfection efficiencies when niosome formulations based on lipid 3 were used. These results provide new insights for the development of non-viral vectors based on cationic lipids and their applications for efficient delivery of genetic material to the retina and brain.

MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression –a neuroprotective agent–remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

This study finds that thalamic interneurons and downstream projecting relay cells have opposite response properties. Computational modeling suggests that such complementary mechanisms may help preserve more spike-timing information. Synapses made by local interneurons dominate the thalamic circuits that process signals traveling from the eye downstream. The anatomical and physiological differences between interneurons and the (relay) cells that project to cortex are vast. To explore how these differences might influence visual processing, we made intracellular recordings from both classes of cells in vivo in cats. Macroscopically, all receptive fields were similar, consisting of two concentrically arranged subregions in which dark and bright stimuli elicited responses of the reverse sign. Microscopically, however, the responses of the two types of cells had opposite profiles. Excitatory stimuli drove trains of single excitatory postsynaptic potentials in relay cells, but graded depolarizations in interneurons. Conversely, suppressive stimuli evoked smooth hyperpolarizations in relay cells and unitary inhibitory postsynaptic potentials in interneurons. Computational analyses suggested that these complementary patterns of response help to preserve information encoded in the fine timing of retinal spikes and to increase the amount of information transmitted to cortex.

We designed niosomes based on three lipids that differed only in the polar-head group to analyze their influence on the transfection efficiency. These lipids were characterized by small-angle X-ray scattering before being incorporated into the niosomes which were characterized in terms of pK_a, size, zeta potential, morphology and physical stability. Nioplexes were obtained upon the addition of a plasmid. Different ratios (w/w) were selected to analyze the influence of this parameter on size, charge and the ability to condense, release and protect the DNA. In vitro transfection experiments were performed in HEK-293, ARPE-19 and MSC-D1 cells. Our results show that the chemical composition of the cationic head-group clearly affects the physicochemical parameters of the niosomes and especially the transfection efficiency. Only niosomes based on cationic lipids with a dimethyl amino head group (lipid 3) showed a transfection capacity when compared with their counterparts amino (lipid 1) and tripeptide head-groups (lipid 2). Regarding cell viability, we clearly observed that nioplexes based on the cationic lipid 3 had a more deleterious effect than their counterparts, especially in ARPE-19 cells at 20/1 and 30/1 ratios. Similar studies could be extended to other series of cationic lipids in order to progress in the research on safe and efficient non-viral vectors for gene delivery purposes.