Cell-specific electrical stimulation of human retinal neurons assessed by pupillary response dynamics in vivo.

Studies on the electrical excitability of retinal neurons show that photoreceptors and other cell types can be selectively activated by distinct stimulation frequencies in vitro. Yet, this principle still needs to be validated in humans in vivo. As a first step, this study explored the frequency preferences of human rods by means of transcorneal electrostimulation (TES), using the electrically-elicited pupillary responses (EEPRs) as an objective readout. The stimulation paradigm contained a 1.2 Hz sinusoidal envelope, which was superimposed on variable carrier frequencies (4-30 Hz). These currents were delivered to one of the participant's eyes via a corneal electrode and consensual pupillary reactions were recorded from the contralateral eye. The responsiveness of the retina at each frequency was assessed based on the EEPR dynamics. Differences between healthy participants and patients with retinitis pigmentosa were evaluated to identify the preferred frequency range of rods. The responsiveness of healthy individuals revealed a clear peak around 6-8 Hz. In contrast, the pupillary responses of patients were significantly reduced in the lower frequency range. These findings suggest that the responses in this frequency bin were selectively mediated by rods. This work provides evidence that different retinal cell types can be selectively activated via TES in vivo, and that this effect can be captured noninvasively using EEPRs. This knowledge may be exploited for the diagnostics and therapy of retinal diseases, e.g., to design cell-specific functional tests for the degenerating retina, or to optimize stimulation paradigms which are currently used by retinal prostheses.

[Transcorneal electrostimulation in retinitis pigmentosa : Protocol of a multicentric prospective, randomized, controlled and double-masked trial on behalf of the Joint Federal Committee (G-BA pilot regulation)]. / Transkorneale Elektrostimulation bei Retinitis pigmentosa : Prüfplan einer multizentrischen, prospektiven, randomisierten, kontrollierten und doppelblinden Studie im Auftrag des Gemeinsamen Bundesausschusses (G-BA-Erprobungsrichtlinie).

The focus of this large multicenter trial commissioned by the Joint Federal Committee (Gemeinsamer Bundesausschuss, G­BA) is to determine a benefit of transcorneal electrical stimulation for retinitis pigmentosa (RP) patients. The main criterion for benefit is the kinetic visual field and whether the deterioration progresses more slowly in the study eyes compared to the sham-stimulated fellow eyes over a treatment period of 3 years.

Phosphene perception and pupillary responses to sinusoidal electrostimulation - For an objective measurement of retinal function.

The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild-type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20 Hz; envelope frequency constantly kept at 1.2 Hz) and intensities (10, 20, 50 µA) were recorded and compared with those obtained with light stimulation (1.2 Hz sinusoidal blue, red light). A strong correlation between the sinusoidal stimulation (electrical as well as light) and the pupillary sinusoidal response was found. The difference between the lag of electrical and light stimulation allowed the estimation of an intensity threshold for pupillary responses to transcorneal electrostimulation (mean ±â€¯SD: 30 ±â€¯10 µA (10 Hz); 38 ±â€¯10 µA (20 Hz)). A comparison between the results of the two stimulation frequencies showed a not statistically significant smaller lag for 10 Hz (10 Hz: 633 ±â€¯90 ms; 20 Hz: 725 ±â€¯178 ms; 50 µA intensity). Analogous in vitro experiments on murine retinas indicated a selective stimulation of photoreceptors and bipolar cells (lower frequencies) and retinal ganglion cells (higher frequencies) and lower stimulation thresholds for the retinal network with sinusoidal compared to pulsatile stimulation - emphasizing that sinusoidal waveforms are well-suited to our purposes. We demonstrate that pupillary responses to sinusoidal transcorneal electrostimulation are measurable as an objective marker in healthy young subjects, even at very low stimulus intensities. By using this unique approach, we unveil the potential for an estimation of the individual intensity threshold and a selective activation of different retinal cell types in humans by varying the stimulation frequency. This technique may have broad clinical utility as well as specific relevance in the monitoring of patients with hereditary retinal disorders, especially as implemented in study protocols for novel therapies, e.g. retinal prostheses or gene therapies.

Analysis of retinal function using chromatic pupillography in retinitis pigmentosa and the relationship to electrically evoked phosphene thresholds.

PURPOSE: To analyse pupil responses to specific chromatic stimuli in patients with advanced retinitis pigmentosa (RP) to ascertain whether chromatic pupillography can be used as an objective marker for residual retinal function. To examine correlations between parameters of the pupil response and the perception threshold of electrically evoked phosphenes. METHODS: Chromatic pupillography was performed in 40 patients with advanced RP (visual acuity < 0.02 or visual field ≤5°, non-recordable ERGs) and 40 age-matched healthy subjects. Pupil responses to full-field red (605 nm) and blue (420 nm) stimuli of 28 lx corneal illumination were recorded and analysed for two stimulus durations (1 and 4 seconds). The perception threshold of phosphenes to transcorneal electrostimulation was ascertained and correlated to the pupil responses and visual acuity. RESULTS: Patients with RP showed significantly reduced pupil responses to red and blue stimuli compared with the controls. With red stimuli, pupillary escape could be observed; blue stimuli resulted in a well-preserved postillumination pupil response. Phosphene thresholds were significantly increased in patients with RP and correlated with the parameters of the pupil response if all subjects were considered. Within the RP group alone, this relationship was less pronounced and statistically not significant. CONCLUSIONS: Chromatic pupillography demonstrated a significant decrease in outer retinal photoreceptor responses but a persisting and disinhibited intrinsic photosensitive retinal ganglion cell function in advanced RP. These phenomena may be useful as an objective marker for the efficacy of any interventional treatment for hereditary retinal diseases as well as for the selection of suitable patients for an electronic retinal implant.

Safety evaluation of "retina implant alpha IMS"--a prospective clinical trial.

BACKGROUND: To restore vision in patients with retinitis pigmentosa, several types of electronic devices have been developed to stimulate neurons at different levels along the visual pathway. Subretinal stimulation of the retina with the Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) has been demonstrated to provide useful vision in daily life. Here we evaluated the safety of this device. METHODS: An interventional, prospective, multi-center, single-arm study was conducted in patients with retinitis pigmentosa with the Retina Implant Alpha IMS. The results from the first nine patients of a single center regarding safety of the device are reported. Any untoward medical occurrence related or unrelated to the tested device was documented and evaluated. RESULTS: Nine adult subjects were included in the study at the Tübingen site. Seventy-five adverse events occurred in total, and 53 affected the eye and its adnexa. Thirty-one ocular adverse events had a relationship to the implant that was classified as "certain" while 19 had a probable or possible relationship; three had no relationship to the implant. Thirty-nine ocular adverse events resolved without sequelae, two resolved with sequelae, 11 remained unresolved, and in one the status was unknown. The intensity of ocular adverse events was mild in the majority of cases (n = 45), while six were of moderate and two of severe intensity. There was no non-ocular adverse event with certain relationship to the device. One subject lost light perception (without light localization) in her study eye. CONCLUSIONS: In conclusion, this prospective study, "Safety and Efficacy of Subretinal Implants for Partial Restoration of Vision in Blind Patients," shows that the Retina Implant Alpha IMS is an option for restoring vision using a subretinal stimulation device with a clinically acceptable safety profile.

Transcorneal electrical stimulation for patients with retinitis pigmentosa: a prospective, randomized, sham-controlled exploratory study.

PURPOSE: To assess the safety of transcorneal electrical stimulation (TES) and explore its efficacy in various subjective and objective parameters of visual function in patients with retinitis pigmentosa (RP). METHODS: Twenty-four patients in this prospective, randomized, partially blinded, good-clinical-practice study underwent TES (5-ms biphasic pulses; 20 Hz; DTL electrodes) 30 minutes per week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical phosphene threshold (EPT). Visual acuity (VA), visual field (VF; kinetic, static), electroretinography (Ganzfeld, multifocal), dark-adaptation (DA), color discrimination, and EPTs were assessed at all visits or four times, according to the study plan. RESULTS: TES using DTL electrodes was tolerated well; all patients finished the study. Two adverse (foreign body sensation), but no serious adverse events were encountered. There was a tendency for most functional parameters to improve (8/18) or to remain constant (8/18) in the 150% group. VF area and scotopic b-wave amplitude reached statistical significance (P < 0.027 and P < 0.001, respectively). Only desaturated color discrimination and VF mean sensitivity decreased. There was no obvious trend in the 66% group. CONCLUSIONS: TES was found to be safe in RP patients. Positive trends were discovered, but due to the small sample size of this exploratory study, statistical significance was reached only for VF area and scotopic b-wave amplitude. Further studies with larger sample sizes and longer duration are needed to confirm the findings and to define optimal stimulation parameters. (ClinicalTrials.gov number, NCT00804102.).