40 Hz light flickering promotes sleep through cortical adenosine signaling.

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.

Ethambutol-induced optic neuropathy with rare bilateral asymmetry onset: A case report.

BACKGROUND: Ethambutol-induced optic neuropathy (EON) most commonly manifests as bilateral symmetrical loss of vision and often cause serious and irreversible visual impairment because of the lack of early detection and effective treatment. We followed a case of EON with rare binocular asymmetric clinical manifestations and observed the changes of visual function and retinal structure after drug withdrawal, so as to further understand the clinical characteristics of this disease. CASE SUMMARY: A 54-year-old man complained of gradual visual decline in the left eye. The patient presented with best-corrected visual acuity of 20/20 in the right eye and 20/50 in the left eye. Color vision examination revealed difficulty in reading green color plates in the left eye. The visual field manifested as concentric contraction in the left eye. After nearly a month of drug withdrawal, the right eye had a similar decline in visual function. At the last visit, 19 mo after drug withdrawal, the visual function significantly recovered in both eyes. During follow-up optical coherence tomography (OCT) examination, both eyes manifested the thickness of the retinal nerve fiber layer from mild thickening to thinning and finally temporal atrophy, and the ganglion cell-inner plexiform layer showed significant thinning. The difference was that a reversible structural disorder in the outer retina of the nasal macula was detected in the left eye by macular high-definition OCT. CONCLUSION: Nephropathy and high blood pressure, which damage the retinal microcirculation, may cause damage to the outer layer of the retina. Ethambutol may influence photoreceptor as well as retinal ganglion cells.

Characterisation of macular superficial vessel density alteration in preclinical ethambutol-induced optic neuropathy using optical coherence tomography angiography.

AIM: To investigate the changes in macular vessel density (mVD) and its relationship to macular ganglion cell-inner plexiform layer (mGCIPL) thickness in patients receiving ethambutol (EMB) therapy for tuberculosis without recognisable clinical symptoms or signs of EMB-induced optic neuropathy (EON). METHODS: A total of 23 eyes of 13 patients using EMB therapy for 6 months without EON (preclinical EON) as the EMB group, 40 eyes of 23 healthy individuals as the normal control group and 18 eyes of 10 patients with tuberculosis before receiving EMB therapy as the blank control group were retrospectively analysed. The mean peripapillary retinal nerve fibre layer (pRNFL) and mGCIPL thicknesses and mVD were measured using optical coherence tomography angiography. Patients in the EMB group were compared with individuals in the normal and blank control groups, and changes in macular parameters were evaluated. RESULTS: Central circle mVD (cCVD) was significantly lower in the EMB group than in both control groups (generalised estimating equation (GEE), p=0.003 and 0.029, respectively). The mGCIPL thickness in all regions and the mean pRNFL thickness were not significantly different between the EMB group and both control groups (GEE, p=1.000 for all). There were no significant differences in mVD, mGCIPL thickness and mean pRNFL thickness between the normal control and blank control groups (p>0.05). In the generalised linear model analyses, the minimum and inferonasal mGCIPL thicknesses were positively correlated with cCVD in the EMB group (ß=1.285, p=0.003 and ß=0.770, p=0.024, respectively). CONCLUSIONS: cCVD decreased with no changes in mGCIPL and mean pRNFL thicknesses in patients with preclinical EON. The minimum and inferonasal mGCIPL thicknesses were positively correlated with cCVD. cCVD might be an early indicator for monitoring early-stage EMB toxicity.

Analysis of structural injury patterns in peripapillary retinal nerve fibre layer and retinal ganglion cell layer in ethambutol-induced optic neuropathy.

BACKGROUND: We investigated structural injury patterns in the peripapillary retinal nerve fibre layer (p-RNFL) and ganglion cell inner plexiform layer (GCIPL) caused by ethambutol treatment. METHODS: Sixty-four patients undergoing ethambutol treatment at Zhejiang Chinese Medicine and Western Medicine Integrated Hospital were recruited. Fourteen (14) exhibited visual dysfunction (abnormal group), and the remaining 50 had no visual dysfunction (subclinical group). The thickness of the p-RNFL, total macular retina layer and GCIPL were measured using Cirrus-HD Optical coherence tomography (Cirrus-HD OCT, Cirrus high-definition optical coherence tomography), and compared with 60 healthy, age-matched controls. RESULTS: The p-RNFL thickness was similar in both subclinical and control groups. When compared with the control group, p-RNFL thickness in the abnormal group was significantly increased in the inferior and superior quadrants (GEE, P = 0.040, P = 0.010 respectively). In contrast with the subclinical group, p-RNFL thickness in the inferior quadrant was increased in the abnormal group (GEE, P = 0.047). The GCIPL thickness in the inferonasal and inferior sectors was significantly deceased in the subclinical group when compared with controls (GEE, P = 0.028, P = 0.047, respectively). The average and minimum value of GCIPL thickness, and thickness in the superonasal, inferior, inferotemporal, superotemporal and superior sectors were significantly decreased in the abnormal group when compared with controls (GEE, P = 0.016, P = 0.001, P = 0.028, P = 0.010, P = 0.012, P = 0.015, P = 0.010, respectively). The cube average macular thickness (CAMT) in the abnormal group was significantly thinner than controls (GEE, P = 0.027). CONCLUSIONS: GCIPL measurements using Cirrus-HD OCT detected retinal ganglion cell layer loss following ethambutol treatment, before visual dysfunction occurred.

Cooperative robot assistant for vitreoretinal microsurgery: development of the RVRMS and feasibility studies in an animal model.

PURPOSE: The purpose of the study was to describe the development of a robotic aided surgical system named RVRMS (robotic vitreous retinal microsurgery system) and to evaluate the capability for using it to perform vitreoretinal surgery. METHODS: The RVRMS was designed and built to include the key components of two independent arms. End-effectors of each arm fix various surgical instruments and perform intraocular manipulation. To evaluate properly the RVRMS, robot-assisted 23-gauge surgical tasks including endolaser for retinal photocoagulation, pars plana vitrectomy (PPV), retinal foreign body removal and retinal vascular cannulation were performed in two different sizes of an animal model. Endolaser was performed in the eye of a living Irish rabbit and the other tasks were done in a harvested porcine eye. For each evaluation, the duration and the successful completion of the task was assessed. RESULTS: Robot-assisted vitreoretinal operations were successfully performed in nine rabbit eyes and 25 porcine eyes without any iatrogenic complication such as retinal tear or retinal detachment. In the task of using an endolaser, three rows of burns around the induced retinal hole were performed in nine rabbit eyes with half size intervals of laser spots. Nine procine eyes underwent PPV followed by successful posterior vitreous detachment (PVD) induction assisted with triamcinolone acetonide (TA). Nine porcine eyes completed removal of a fine stainless steel wire, which was inserted into prepared retinal tissue. Finally, retinal vascular cannulation with a piece of stainless steel wire (6mm length, 45 µm pipe diameter and one end cut to ∼30° slope) was successfully achieved in seven porcine eyes. The average duration of each procedure was 10.91±1.22 min, 11.68±2.11min, 5.90±0.46 min and 13.5±6.2 min, respectively. CONCLUSIONS: Maneuverability, accuracy and stability of robot-assisted vitreoretinal microsurgery using the RVRMS were demonstrated in this study. Wider application research of robotic surgery and improvement of a robotic system should be continued.