This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm2 chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s−1), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant's power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Aims/hypothesis Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. Methods Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n012) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity.

BackgroundInsulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named “cerebral insulin resistance”, is responsible for overeating and the development of obesity.Methodology/Principal FindingsTo analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category.Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects.Conclusions/SignificanceWe demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a “cerebral insulin resistance” in obese subjects and might be relevant in the pathogenesis of obesity.

Objective measurement of local rod and cone function using gaze-controlled chromatic pupil campimetry in healthy subjects.

BackgroundVoretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue.MethodsSeven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months.ResultsAll except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R2>0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R2=0.5).ConclusionsThe presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function.

Pupillographic campimetry allows measuring the visual field objectively by analyzing the pupil response to perimetric stimuli. One of the drawbacks of this technique, similar to static perimetry, is the need of reliable fixation of the subject. By using stimulus sizes comparable to static perimetry and applying gaze tracking, we enable a retinotopic visual field examination regardless of fixation problems and with an increased stability and improved spatial resolution. Here, we present the results of applying the method in eight normal sighted subjects as well as in three patients suffering from diseases usually diagnosed by perimetry. The results in normal sighted subjects show a reduction in the amplitude of the pupil response with increasing eccentricity as expected. We also demonstrate that gaze-controlled campimetry is able to detect organic visual field defects objectively in a patient group and classify the visual field defects without an organic background. Moreover, we show that our method is able to evaluate the visual field sensitivity loss beyond classical perimetry in patients with late-stage retinitis pigmentosa. Thus, gaze-controlled pupil campimetry can be used in addition to classical perimetry, allowing for an objective monitoring of disease progression, rendering it as a biomarker for novel treatments.

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Resting state functional connectivity of MEG data was studied in 29 children (9-10 years old). The weighted phase lag index (WPLI) was employed for estimating connectivity and compared to coherence. To further evaluate the network structure, a graph analysis based on WPLI was used to determine clustering coefficient (C) and betweenness centrality (BC) as local coefficients as well as the characteristic path length (L) as a parameter for global interconnectedness. The network's modular structure was also calculated to estimate functional segregation. A seed region was identified in the central occipital area based on the power distribution at the sensor level in the alpha band. WPLI reveals a specific connectivity map different from power and coherence. BC and modularity show a strong level of connectedness in the occipital area between lateral and central sensors. C shows different isolated areas of occipital sensors. Globally, a network with the shortest L is detected in the alpha band, consistently with the local results. Our results are in agreement with findings in adults, indicating a similar functional network in children at this age in the alpha band. The integrated use of WPLI and graph analysis can help to gain a better description of resting state networks.