Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia.

Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and myopia usually results from an excessively long eye. The common variant most strongly associated with myopia is near the GJD2 gene, encoding connexin-36, which forms retinal gap junctions. Light-evoked responses of retinal neurons can be recorded noninvasively as the electroretinogram (ERG). We analyzed these responses from 186 adult twin volunteers who had been genotyped at this locus. Participants underwent detailed ERG recordings incorporating international standard stimuli as well as experimental protocols aiming to separate dark-adapted rod- and cone-driven responses. A mixed linear model was used to explore association between allelic dosage at the locus and international standard ERG parameters after adjustment for age, sex, and family structure. Significant associations were found for parameters of light-adapted, but not dark-adapted, responses. Further investigation of isolated rod- and cone-driven ERGs confirmed associations with cone-driven, but not rod-driven, a-wave amplitudes. Comparison with responses to similar experimental stimuli from a patient with a prior central retinal artery occlusion, and from two patients with selective loss of ON-bipolar cell signals, was consistent with the associated parameters being derived from signals from cone-driven OFF-bipolar cells. Analysis of single-cell transcriptome data revealed strongest GJD2 expression in cone photoreceptors; bipolar cell expression appeared strongest in OFF-bipolar cells and weakest in rod-driven ON-bipolar cells. Our findings support a potential role for altered signaling in cone-driven OFF pathways in myopia development.

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms.

PURPOSE: Both rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones. METHODS: ERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m-2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m-2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. RESULTS: Mean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age. CONCLUSIONS: Over 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background.

Relative Genetic and Environmental Contributions to Variations in Human Retinal Electrical Responses Quantified in a Twin Study.

PURPOSE: To estimate heritability of parameters of human retinal electrophysiology and to explore which parameters change with age. DESIGN: Prospective, classic twin study. PARTICIPANTS: Adult monozygotic and dizygotic twin pairs recruited from the TwinsUK cohort. METHODS: Electroretinogram responses were recorded using conductive fiber electrodes in response to stimuli incorporating standards set by the International Society for the Clinical Electrophysiology of Vision. These parameters were extracted; in addition, photopic negative-response (PhNR; originating from retinal ganglion cells) and i-wave components were extracted from responses to the photopic single flash. Parameter values were averaged from both eyes. MAIN OUTCOME MEASURES: Mean values were calculated for the cohort. Correlation coefficients with age were calculated (averaging parameters from both twins from each pair). Coefficients of intrapair correlation were calculated for monozygotic and dizygotic twins. Age-adjusted heritability estimates were derived using standard maximum likelihood structural equation twin modeling. RESULTS: Responses were recorded from 210 participants in total (59 monozygotic and 46 dizygotic twin pairs). Ninety-three percent were women. Mean age for the cohort was 62.4 years (standard deviation, 11.4 years). In general, response amplitudes correlated negatively, and implicit times positively, with age. Correlations were statistically significant (P < 0.05) and moderate or strong (coefficient, >0.35) for the following parameters: scotopic standard and bright-flash a-wave implicit times, photopic 30-Hz flicker and single-flash b-wave implicit times, and PhNR and i-wave implicit times. Intrapair correlations were higher for monozygotic than dizygotic twins, suggesting important genetic influences. Age-adjusted estimates of heritability were significant for all parameters (except scotopic dim-flash b-wave implicit time), ranging from 0.34 to 0.85. Highest estimates were for photopic single-flash a-wave and b-wave amplitudes (0.84 and 0.85, respectively). CONCLUSIONS: This study explored heritability of retinal electrophysiologic parameters and included measurements reflecting ganglion cell function. Most parameters showed significant heritability, indicating that genetic factors are important, determining up to 85% of the variance in some cone system response parameters. Scotopic responses tended to show lower heritability (possibly relating to greater rod system susceptibility to environmental factors). Future studies can explore the identity of these genetic factors, improving our understanding of how they shape retinal function.

Establishing the Foundations of Emotional Intelligence in Care Companion Robots to Mitigate Agitation Among High-Risk Patients With Dementia: Protocol for an Empathetic Patient-Robot Interaction Study.

BACKGROUND: An estimated 6.7 million persons are living with dementia in the United States, a number expected to double by 2060. Persons experiencing moderate to severe dementia are 4 to 5 times more likely to fall than those without dementia, due to agitation and unsteady gait. Socially assistive robots fail to address the changing emotional states associated with agitation, and it is unclear how emotional states change, how they impact agitation and gait over time, and how social robots can best respond by showing empathy. OBJECTIVE: This study aims to design and validate a foundational model of emotional intelligence for empathetic patient-robot interaction that mitigates agitation among those at the highest risk: persons experiencing moderate to severe dementia. METHODS: A design science approach will be adopted to (1) collect and store granular, personal, and chronological data using Personicle (an open-source software platform developed to automatically collect data from phones and other devices), incorporating real-time visual, audio, and physiological sensing technologies in a simulation laboratory and at board and care facilities; (2) develop statistical models to understand and forecast the emotional state, agitation level, and gait pattern of persons experiencing moderate to severe dementia in real time using machine learning and artificial intelligence and Personicle; (3) design and test an empathy-focused conversation model, focused on storytelling; and (4) test and evaluate this model for a care companion robot (CCR) in the community. RESULTS: The study was funded in October 2023. For aim 1, architecture development for Personicle data collection began with a search for existing open-source data in January 2024. A community advisory board was formed and met in December 2023 to provide feedback on the use of CCRs and provide personal stories. Full institutional review board approval was received in March 2024 to place cameras and CCRs at the sites. In March 2024, atomic marker development was begun. For aim 2, after a review of open-source data on patients with dementia, the development of an emotional classifier was begun. Data labeling was started in April 2024 and completed in June 2024 with ongoing validation. Moreover, the team established a baseline multimodal model trained and validated on healthy-person data sets, using transformer architecture in a semisupervised manner, and later retrained on the labeled data set of patients experiencing moderate to severe dementia. In April 2024, empathy alignment of large language models was initiated using prompt engineering and reinforcement learning. CONCLUSIONS: This innovative caregiving approach is designed to recognize the signs of agitation and, upon recognition, intervene with empathetic verbal communication. This proposal has the potential to have a significant impact on an emerging field of computational dementia science by reducing unnecessary agitation and falls of persons experiencing moderate to severe dementia, while reducing caregiver burden. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/55761.

Prevalence of electronegative electroretinograms in a healthy adult cohort.

OBJECTIVE: An electronegative electroretinogram (ERG) can indicate important ocular or systemic disease. This study explored the prevalence of electronegative responses to dark-adapted stimuli in a largely healthy cohort. METHODS AND ANALYSIS: 211 participants recruited from the TwinsUK cohort underwent ERG testing incorporating international standard (International Society for Clinical Electrophysiology of Vision (ISCEV)) protocols and additional stimuli. Responses were recorded using conductive fibre electrodes, following pupil dilation and 20 min dark adaptation. Responses analysed were to the ISCEV standard and strong flashes (3.0 and 10 cd/m2 s), and to additional white flashes (0.67-67 cd/m2 s). A-wave and b-wave amplitudes were extracted; b:a ratios were calculated and proportions of eyes with ratios<1 were noted. RESULTS: Mean (SD) age was 62.4 (11.4) years (median, 64.3; range 23-86 years). 93% were female. Mean (SD) b:a ratios for right and left eyes, respectively, were 1.86 (0.33) and 1.81 (0.29) for the standard flash, and 1.62 (0.25) and 1.58 (0.23) for the stronger flash; average b:a ratio was lower for the stronger flash (p<0.0001). No waveforms were electronegative. For additional flashes, b:a ratio decreased with increasing flash strength. No electronegative waveforms were seen except in three eyes (0.7%) for the strongest flash; in some cases, drift in the waveform may have artefactually reduced the b:a ratio. CONCLUSION: For standard dark-adapted stimuli, no participants had electronegative waveforms. The findings support the notion that electronegative waveforms (in response to standard flash strengths) are unusual, and should prompt further investigation.