Spectral ERG analysis of hypersensitivity to light in traumatic brain injury Abstract Concussion-induced hypersensitivity to light, or traumatic photalgia, can be a lifelong debilitating problem for upwards of 60% of the millions of mild Traumatic Brain Injury (mTBI) cases. There is no current explanation for the pain of this persistent light sensitivity and no previous report of brain trauma affecting retinal processing. We propose to employ spectral analysis of light-adapted electroretinographic (ERG) responses as a function of intensity and wavelength to assess unsuspected damage to the retina of the human eye and determine its retinal-cell source. Our preliminary data show a shift from a photopic to a scotopic b-wave in photalgic brain trauma, which implies both that there is rod suppression by cones operating under normal conditions and that this suppression is blocked by the effects of the brain trauma in the cases of enhanced light sensitivity. These novel insights into the previously unknown retinal mechanisms of traumatic photalgia suggest that a primary etiology of the painful light sensitivity is loss of rod suppression mediated by AII amacrine cells, causing overactivation of the rods at higher light levels. The novel hypothesis of rod overactivation in enhanced light sensitivity in mTBI will be evaluated in a full- scope study of the full-field ERG as a function of wavelength and light adaptation level. To fully characterize the established components of the ERG waveforms of the conjoint rod and cone pathway responses, the complex ERG waveforms will be analyzed by a neuroanalytic modeling approach that will characterize the ERG components from each of the main retinal processing levels and their interactions across the range of stimulus conditions. In particular, we will track the a-wave, b-wave and photopic negative response (PhNR) of both the rod and the cone photoreceptor systems as a function of both light wavelength and light adaptation level for controls and mTBI as a function of photalgia level. In addition, the role of the melanopsin system will be assessed in terms of the spectral sensitivity of the sustained pupil size to assess the hypothesis that pupil size is not affected under conditions that induce traumatic photalgia, and hence does not compensate for the observed changes in rod sensitivity. The neuroanalytic model will allow the effective control ERG waveform to be computed for any degree of photalgic intensity setting, providing a baseline for precise specification of the recorded ERG waveform changes due to the effects of the mTBI. The correlated waveform changes in the light-adapted ERG waveforms will provide a powerful non-invasive diagnostic biomarker for the painful light sensitivity of traumatic photalgia and the persistent retinal effects of mTBI. The neuroanalytic modeling approach will provide an enhanced methodology for the analysis of ERG waveform changes in retinal diseases in general.