The CDC estimates there were nearly 69,000 deaths related to traumatic brain injury (TBI) in 2021 in the U.S. In response, there are, as of August 2024, over 200 clinical trials listed on clinicaltrials.gov that are recruiting or about to recruit subjects for studies of new proposed TBI therapies. Objective, quantified, and sensitive diagnostic tests designed to assess function for patients affected by TBI can play a significant role in determining the efficacy of these new therapies.
The most common TBI diagnostic tests in use today require a highly trained clinician to administer and analyze. They are all either observational tests, images of brain structure, or protein analysis from blood samples. The tests include the Glasgow Coma Scale (GCS), computerized tomography (CT), magnetic resonance imaging (MRI) and other observational skill tests. By comparison, electroretinography (ERG) is an objective and quantitative test in visual electrophysiology and ERG is being considered as a potentially promising endpoint to evaluate TBI. ERG measures electrical waveforms generated by the retina in response to light flashes, using electrodes placed on or near the eye.
The full-field flash ERG recorded under photopic conditions has an initial negative deflection, the photopic a-wave, which originates from cone photoreceptor and off bipolar cell activity. The a-wave is followed by a positive b-wave, originating from the combined activity of on- and off-cone bipolar cells. Finally, there is a slow negative potential, the photopic negative response (PhNR) that primarily originates from the retinal ganglion cell (RGC) spiking activity.
Reductions in the PhNR is a potential biomarker for TBI. It may reflect deficits in physiological activity of specific retinal neurons caused by TBI. It has been posited that brain trauma causes neuronal membranes to become leakier to calcium ions and exhibit more depolarized membrane potentials. As a result, RGCs become relatively depolarized, and their gain control is altered. Gain is the ratio of the number of RGC spikes fired in response to the magnitude of the light stimulus. With increased RGC depolarization in the dark, the range of RGC responses to light stimuli would be compressed, resulting in an altered ability of these neurons to adapt to changing ambient illumination.
Clinically, TBI is classified as mild, moderate, or severe based on the duration of the loss of consciousness and presence of prolonged amnesia following the injury. About 70-90% of affected individuals experience mild TBI, with brief or no loss of consciousness. The adjective ‘mild’, however, is not meant to describe the severity of the consequences that occur following the injury. On the contrary, a significant number of subjects with mild TBI can exhibit cognitive, emotional, behavioral and physical impairments that can persist for many months or years.
New proposed therapies for TBI are undergoing clinical trials and more will follow. The ERG test, through the measurement of the PhNR, is emerging as a promising endpoint for TBI to evaluate the efficacy of those proposed treatments. This showcases how visual electrophysiology continues to evolve to support clinical translation from neuroscience to effective therapies.