# On the Quest for Ophthalmological Biomarkers for Long COVID: A Scoping Review
## 4 Discussion
Within this, we highlight areas where digital ophthalmic biosignals identified in our review can be mapped to potential biologic frameworks. Most broadly, ophthalmic biosignals have the potential to identify problems relating to disordered neuromodulation, neuroenergetics, and network efficiency, and to monitor responses to therapy. Neuroenergetic disturbances may be one component driving post-COVID fatigue and brain fog as persisting inflammatory responses drive disturbed mitochondrial function and microglial activation (reviewed in [39]). Astrocytes play a vital role in neurometabolic coupling, and SARS-CoV-2 persistence in astrocytes is seen post-mortem [40]. Disturbed astrocyte control of the local metabolic environment and energy substrates negatively impacts neuronal excitability and neurotransmission. Abnormal metabolic activity seen in functional brain imaging of patients with post-COVID brain fog is thought to relate to astrocyte effects on neuroenergetics impacting glutamate neurotransmission [41; 42]. Disturbance of astrocyte neurometabolic coupling reduces lactate supply to neurons and also alters resting-state control of cortical excitability [43]. Visual symptoms reported frequently in our post-COVID clinic cohort include migraineous aura and visual snow, which are thought to reflect abnormal control of visual cortex excitability [44], possibly through neuroglial inflammatory processes [45]. A number of the ophthalmic biosignals reported relate to cortical excitability in the visual system. [PERSON] et al., 2021 [35] reported a patient with persisting post-COVID visual snow with changes in the visual evoked potential and a reduced VEP100 amplitude (such a change can be seen when manipulating increased cortical excitability with excitatory non-invasive brain stimulation) [46]. In contrast to the case report of visual evoked potential amplitude alteration in a symptomatic post-COVID patient, the larger series of [PERSON] et al. [30], measuring VEPs in 65 people after COVID infection of whom around 14-18% had persisting symptoms, concluded no difference from healthy controls in VEP amplitude (the measure shown to change with manipulated cortical excitability). Another series measuring VEPs in 44 people after COVID-19 also reported no differences in p100 amplitude compared to healthy controls [47]. VEP parameters may be useful for tracking disease trajectory or response to therapy in people with visual system symptoms. Related to visual evoked potential markers, another experiment presents an example of non-invasive neuromodulation potentially manipulating cortical network excitability. In two patients with post-COVID brain fog, the use of transcranial Alternating Current Stimulation targeting retinal neurons was suggested to improve performance in psychometric tests of attention and memory. The authors demonstrated a change in digital markers of retinal vessel dynamics (Dynamic Vascular Analyzer) and hypothesised downstream effects on synchrony in cortical networks (but this was not measured directly) [37]. A linked concept related to post-COVID brain fog and potentially measured by digital ophthalmic biosignals is that of efficiency in large-scale brain networks. This is of course influenced by neuroenergetic coupling at a local neuronal population level but also by the balance in neuromodulatory systems controlling whole-brain distributed network function (for reviews see [PERSON] and [PERSON], 2010; [PERSON] and [PERSON], 2017) [48; 49]. Infection-induced inflammatory stress states can result in an imbalance in neuromodulatory systems (reviewed by [PERSON] et al., 2017 [50]). This in turn can influence the efficiency of connectivity in major brain networks. Brain imaging studies have identified changes in effective connectivity inversely correlating with cognitive performance in people with post-COVID brain fog [51; 52] (noting that findings are variable between studies, e.g., see [PERSON] et al. [53], 2024, where no Default Mode Network functional connectivity changes were identified).