# On the Quest for Ophthalmological Biomarkers for Long COVID: A Scoping Review
## 4 Discussion
Even in people not reporting significant cognitive complaints after COVID-19 infection, psychometric testing identified deficits in networks serving episodic memory and sustained attention [54]. In relation to this, ophthalmic biosignals are potentially useful, firstly because the pupillary light reflex can provide information on the balance between major neuromodulatory systems, and secondly, because efficiency in brain networks controlling eye movement strategies may have parallels to functions in other major brain networks. Changes in pupil dilatation have been shown to correlate with activity in brain networks very relevant to the most commonly reported post-COVID cognitive complaints. Pupil parameters vary with increasing cognitive loads during tasks demanding attention, salience, and working memory networks. Pupil reactivity is shown to correlate with activity in these brain networks using functional brain imaging during tasks [55; 56]. This corresponds to adrenergic neuromodulatory systems guiding attention, and balancing bottom-up control from the brainstem locus coeruleus [57] and top-down control from the Prefrontal Cortex [58]. Two series compared pupillary light reflex parameters in people recovering from COVID-19 to healthy controls using automated pupillometry. A finding common to both studies was shorter pupil contraction duration [24; 59]. [PERSON] et al. [59] also reported shorter dilation latency, and [PERSON] et al. [24] reported prolonged latency of contraction. Interpretation of these observations is complicated, noting that these parameters are sympathetically driven but ultimately represent the interaction between parasympathetic vagal afferents and sympathetic locus coeruleus outputs, which then inhibit ongoing parasympathetic activity and activate pupil dilator muscles. This interaction is influenced by persisting inflammatory responses to infection, which impose neuroimmunomodulatory influence on the vagal response [60]. Useful information to note in interpreting these pupillary light reflex parameters comes from a longitudinal study of people with autonomic dysfunction, measured serially, prior to and following COVID-19 infection. Following COVID-19 infection, there was a reversal of the dominant presentation toward parasympathetic excess being more problematic than sympathetic withdrawal [61]. Irrespective of the precise interpretation of the mechanism underlying the pupillary light reflex changes, the findings of these studies demonstrate that on an individual level, automated pupillometry may usefully track changes in the balance of neuromodulatory systems. A study measuring continuous oscillation of pupil diameter with the Low/High Index of Pupillary Activity (LHIPA) during a virtual reality task did not identify differences between a post-COVID sample and healthy controls [34]. Eye-tracking technology offers another digital marker of efficiency in brain networks. There are parallels between brain networks controlling visual search strategy [62] and salience network-controlled interactions between the Default Mode Network and central executive networks [48]. Eye movement tasks can be scaled to increase demands of network connectivity, such as adding a requirement for impulse inhibition in anti-saccades or memory-guided saccades. An eye-tracking study reported a reduced accuracy rate in memory-guided saccades, and prolonged latency in anti-saccades compared to healthy controls (noting the sample size was nine participants in each group) [29]. Other studies also report abnormalities of antisaccades [20; 27]. Consistent with these observations of eye-tracking abnormalities becoming more prominent in tasks with higher demands of network function is the observation from a series of 77 people following COVID-19 infection assessed with a battery of 14 eye-tracking tasks in the Oculomotor Vestibular Reaction Time Cognitive test (OVRT-C) [28].