Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway.

Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography, and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.

Henle fiber layer thickening and deficits in objective retinal function in participants with a history of multiple traumatic brain injuries.

Introduction: This study tested whether multiple traumatic brain injuries (TBIs) alter the structure of the Henle fiber layer (HFL) and degrade cell-specific function in the retinas of human participants. Methods: A cohort of case participants with multiple TBIs and a cohort of pair-matched control participants were prospectively recruited. Directional optical coherence tomography and scanning laser polarimetry measured HFL thickness and phase retardation, respectively. Full-field flash electroretinography (fERG) assessed retinal function under light-adapted (LA) 3.0, LA 30 Hz, dark-adapted (DA) 0.01, DA 3.0, and DA 10 conditions. Retinal imaging and fERG outcomes were averaged between both eyes, and paired t-tests or Wilcoxon signed-rank tests analyzed inter-cohort differences. Results: Global HFL thickness was significantly (p = 0.02) greater in cases (8.4 ± 0.9 pixels) than in controls (7.7 ± 1.1 pixels). There was no statistically significant difference (p = 0.91) between the cohorts for global HFL phase retardation. For fERG, LA 3.0 a-wave amplitude was significantly reduced (p = 0.02) in cases (23.5 ± 4.2 µV) compared to controls (29.0 ± 8.0 µV). There were no other statistically significant fERG outcomes between the cohorts. Discussion: In summary, the HFL thickens after multiple TBIs, but phase retardation remains unaltered in the macula. Multiple TBIs may also impair retinal function, indicated by a reduction in a-wave amplitude. These results support the potential of the retina as a site to detect TBI-associated pathology.

Collaborative practice competencies needed for telehealth delivery by health and social care professionals: a scoping review.

In the context of the COVID-19 pandemic, many healthcare and social services professionals have had to provide services through virtual care. In the workplace, such professionals often need to be sufficiently resourced to collaborate and address collaborative care barriers in telehealth. We performed a scoping review to identify the competencies required to support interprofessional collaboration among clinicians in telehealth. We followed Arksey and O'Malley's and the Joanna Briggs Institute's methodological guidelines, including quantitative and qualitative peer-reviewed articles published between 2010 and 2021. We expanded our data sources by searching for any organization or experts in the field via Google. The analysis of the resulting thirty-one studies and sixteen documents highlighted that health and social services professionals are generally unaware of the competencies they need to develop or maintain interprofessional collaboration in telehealth. In an era of digital innovations, we believe this gap may jeopardize the quality of the services offered to patients and needs to be addressed. Of the six competency domains in the National Interprofessional Competency Framework, it was observed that interprofessional conflict resolution was the competency that emerged least as an essential competency to be developed, while interprofessional communication and patient/client/family/community-centered care were identified as the two most reported essential competencies.

Structure and function of retinal ganglion cells in subjects with a history of repeated traumatic brain injury.

This study tested whether repeated traumatic brain injuries (TBIs) alter the objective structure or the objective function of retinal ganglion cells (RGCs) in human subjects recruited from an optometry clinic. Case subjects (n = 25) with a history of repeated TBIs (4.12 ± 2.76 TBIs over 0-41 years) and healthy pair-matched control subjects (n = 30) were prospectively recruited. Retinal nerve fiber layer (RNFL) thickness was quantified with spectral-domain optical coherence tomography, and scanning laser polarimetry measured RNFL phase retardation. Measurements of the photopic negative response were made using full-field flash electroretinography. There was no statistically significant difference (p = 0.42) in global RNFL thickness between the case cohort (96.6 ± 9.4 microns) and the control cohort (94.9 ± 7.0 microns). There was no statistically significant difference (p = 0.80) in global RNFL phase retardation between the case cohort (57.9 ± 5.7 nm) and the control cohort (58.2 ± 4.6 nm). There were no statistically significant differences in the peak time (p = 0.95) of the PhNR or in the amplitude (p = 0.11) of the PhNR between the case cohort (69.9 ± 6.9 ms and 24.1 ± 5.1 µV, respectively) and the control cohort (70.1 ± 8.9 ms and 27.8 ± 9.1 µV, respectively). However, PhNR amplitude was more variable (p < 0.025) in the control cohort than in the case cohort. Within the case cohort, there was a strong positive (r = 0.53), but not statistically significant (p = 0.02), association between time since last TBI and PhNR amplitude. There was also a modest positive (r = 0.45), but not statistically significant (p = 0.04), association between time since first TBI and PhNR amplitude. Our results suggest that there were no statistically significant differences in the objective structure or in the objective function of RGCs between the case cohort and the control cohort. Future large, longitudinal studies will be necessary to confirm our negative results and to more fully investigate the potential interaction between PhNR amplitude and time since first or last TBI.

Multimodal imaging and functional analysis of the chick NMDA retinal damage model.

OBJECTIVES: The chick is rapidly becoming a standardized preclinical model in vision research to study mechanisms of ocular disease. We seek to comprehensively evaluate the N-methyl-D-aspartate (NMDA) model of excitotoxic retinal damage using multimodal imaging, functional, and histologic approaches in NMDA-damaged, vehicle-treated, and undamaged chicks. METHODS: Chicks were either left undamaged in both eyes or were injected with NMDA in the left eye and saline (vehicle) in the right eye. TUNEL assay was performed on chicks to assess levels of retinal cell death one day post-injection of NMDA or saline and on age-matched untreated chicks. Spectral domain optical coherence tomography (SD-OCT) was performed weekly on chicks and age-matched controls day 1 (D1) up to D28 post-injection. Light adapted electroretinograms (ERG) were performed alongside SD-OCT measurements on post-injection chicks along with age-matched untreated controls. RESULTS: Untreated and vehicle-treated eyes had no TUNEL positive cells while NMDA-treated eyes accumulated large numbers of TUNEL positive cells in the Inner Nuclear Layer (INL), but not other layers, at D1 post injection. Significant inner retina swelling or edema was found on SD-OCT imaging at D1 post-injection which resolved at subsequent timepoints. Both the INL and the inner plexiform layer significantly thinned by one-week post-injection and did not recover for the duration of the measurements. On ERG, NMDA-treated eyes had significantly reduced amplitudes of all parameters at D1 with all metrics improving over time. The b-wave, oscillatory potentials, and ON/OFF bipolar responses were the most affected with at least 70% reduction immediately after damage compared to the fellow eye control. CONCLUSION: This study establishes a normative baseline on the retinal health and gross functional ability as well as intraocular pressures of undamaged, vehicle-treated, and NMDA-damaged chicks to provide a standard for comparing therapeutic treatment studies in this important animal model.

A patient diagnosed with Galloway-Mowat syndrome presenting with a rod-cone functional anomaly with electronegative dark-adapted ERGs.

PURPOSE: Galloway-Mowat syndrome (GAMOS) is a clinically heterogenous and rare condition classically described as the combination of nephrotic syndrome associated with brain anomaly and delays in development. It was first reported in the literature in 1968 by Galloway W.H and Mowat A.P. Reports of visual anomaly in these patients are generally limited to decreased visual acuity, nystagmus and optic nerve atrophy. To this day, little is known about retinal function in this disease. Therefore, the purpose of this case report is to reveal abnormal retinal function (including light-adapted and dark-adapted retinal function) in a female patient diagnosed with GAMOS due to mutation of the WDR73 gene. METHODS: Complete dilated pediatric ophthalmic examination and ISCEV full field standard light (10 min of light adaptation; background light: 30 cd.m-2; flash intensity: 3.0 cd.sec.m-2) and dark-adapted (20 min of dark adaptation; flash intensities: 0.01, 3.0 and 10.0 cd.sec.m-2) electroretinograms were performed on a 2-year-old female patient diagnosed with GAMOS due to a biallelic mutation in the WDR73 gene. RESULTS: Ophthalmologic evaluation under anesthesia revealed normal appearing anterior segments. Significant bilateral optic nerve pallor was noted. Fundus examination appeared to be abnormal and demonstrated mid-peripheral whitish glistening appearance with possible gliosis. Retinoscopy revealed bilateral high myopia with a refractive error of -8.00 sphere in both eyes. ISCEV standard ERG revealed residual responses under light-adapted condition. Undetectable responses were obtained after 20 min of dark adaptation when using a dim flash (DA 0.01). However, when brighter flashes were used in a dark-adapted condition (DA 3.0 and DA 10.0), the ERGs were detectable, albeit abnormal in amplitudes and of electronegative morphology. CONCLUSIONS: The results obtained showed significant retinal functional deficit affecting both the cone and the rod photoreceptor pathways, along with the inner retina, in a patient diagnosed with GAMOS due to biallelic mutations in the WDR73 gene. Our report is limited to one patient, and additional studies are needed to verify whether retinal functional anomalies, as measured by the full field electroretinogram, present a novel biomarker in all patients affected with GAMOS or only in patients with a mutation in the WDR73 gene. Given the evidence of retinal functional changes presented in this study, it is strongly suggested to include complete ophthalmic examination, retinal imaging, including OCT, and full field ERG testing in patients affected with GAMOS.

Retinal dysfunction in a presymptomatic patient with Huntington's disease.

PURPOSE: Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Studies have shown retinal abnormalities in patients and mouse models with HD; however, to our knowledge, no prior research papers evaluated retinal structure and function in a presymptomatic patient with HD. The aim of this report is to present a case of retinal dysfunction in a presymptomatic patient with HD. METHODS: We investigated retinal structure and function in a 25-year-old male who tested positive for the gene that causes HD, but did not have any symptoms normally associated with HD. Vision and ocular testing included a comprehensive dilated ophthalmic examination, 24-2 full-threshold Humphrey visual field, spectral-domain optical coherence tomography (SD-OCT), fundus photography, full-field electroretinogram (ERG), and multifocal electroretinogram (mfERG). RESULTS: Visual electrophysiology testing showed rod and cone functional anomalies in both eyes. Full-field ERG amplitudes were subnormal in both eyes for the dark-adapted (DA) 0.01 ERG, DA 3 ERG, DA 3 oscillatory potentials (OPs), DA 10 ERG, light-adapted (LA) 3 ERG, and LA 30 Hz flicker, but peak times for the six standard ERG responses were not significantly different from normals. mfERGs revealed functional anomalies of the central retina with attenuated P1 amplitudes for five of the six concentric rings in the right eye and all six rings in the left eye. mfERG P1 peak times were normal at all eccentricities. Dilated fundus examination, SD-OCT, and fundus photography were unremarkable in both eyes. The visual field was normal in the right eye, but there was a mild paracentral field defect in the left eye. CONCLUSIONS: Our results illustrate that the ERG and mfERG detected early retinal dysfunction in a presymptomatic patient with HD consistent with electroretinogram findings in animal models of HD. However, our report was limited to one patient and additional studies are needed to verify whether the ERG and/or mfERG can uncover neural dysfunction before motor, behavioral, and cognitive abnormalities are discernible in patients with HD.

Electroretinogram Findings in Early-Stage Sickle Cell Retinopathy According to Hemoglobin Type.

Purpose: Although extensive clinical research has been performed on structural analysis of sickle cell (SC) retinopathy, functional aspects have been poorly investigated. Our purpose was to report full-field electroretinogram (ffERG) findings in patients with early SC retinopathy according to the following hemoglobin types: HbSS or HbSC (homozygous or heterozygous mutations, respectively). Methods: In this monocentric retrospective observational study, patients affected by nonproliferative SC retinopathy were included from November 2014 to April 2016. Patients were separated into one of the following three groups: HbSS, HbSC, and control. All groups underwent full ophthalmologic examination (fundus examination) and ffERG. For SC patients, additional imaging testing was also performed (fluorescein angiography and spectral domain optical coherence tomography). Results: A total of 24 eyes from 12 patients (6 HbSS and 6 HbSC) and 12 eyes from 6 controls were included. The HbSS group exhibited a dramatic decrease of the b-wave amplitudes for all dark-adapted (DA) ffERG responses when compared with the control group (P = 0.02, P = 0.003, P = 0.005, respectively, after DA 0.01, DA 3.0, and DA 10.0 cd.s.m-2 stimulations) and decreased a-wave amplitudes for light-adapted responses (P = 0.03 after light-adapted 3.0 cd.s.m-2 stimulations). The a-Wave amplitudes were significantly reduced for all dark-adapted and light-adapted responses in HbSC group compared to the control group (P = 0.03, P = 0.01, P = 0.03, respectively, after DA 3.0, DA 10.0, and light-adapted 3.0 cd.s.m-2 stimulations). The HbSS+HbSC groups presented decreased a-wave amplitudes for DA and light-adapted responses and decreased b-wave amplitude after DA 0.01 and 10.0 cd.s.m-2 stimulations when compared to the control group. Conclusions: These results could suggest an early involvement of the inner retinal cells in the disease process in HbSS patients and of the outer retinal cells in HbSC patients. This could provide new insights on the pathophysiology of the retinal affection in HbSS/HbSC SC disease.

Decision making by urgency gating: theory and experimental support.

It is often suggested that decisions are made when accumulated sensory information reaches a fixed accuracy criterion. This is supported by many studies showing a gradual build up of neural activity to a threshold. However, the proposal that this build up is caused by sensory accumulation is challenged by findings that decisions are based on information from a time window much shorter than the build-up process. Here, we propose that in natural conditions where the environment can suddenly change, the policy that maximizes reward rate is to estimate evidence by accumulating only novel information and then compare the result to a decreasing accuracy criterion. We suggest that the brain approximates this policy by multiplying an estimate of sensory evidence with a motor-related urgency signal and that the latter is primarily responsible for neural activity build up. We support this hypothesis using human behavioral data from a modified random-dot motion task in which motion coherence changes during each trial.