A hypoarousal model of neurological post-COVID syndrome: the relation between mental fatigue, the level of central nervous activation and cognitive processing speed

Abstract

Background: Knowledge on the nature of post-COVID neurological sequelae often manifesting as cognitive dysfunction and fatigue is still unsatisfactory.

Objectives: We assumed that cognitive dysfunction and fatigue in post-COVID syndrome are critically linked via hypoarousal of the brain. Thus, we assessed whether tonic alertness as a neurocognitive index of arousal is reduced in these patients and how this relates to the level of central nervous activation and subjective mental fatigue as further indices of arousal.

Methods: 40 post-COVID patients with subjective cognitive dysfunction and 40 matched healthy controls underwent a whole-report paradigm of briefly presented letter arrays. Based on report performance and computational modelling according to the theory of visual attention, the parameter visual processing speed (VPS) was quantified as a proxy of tonic alertness. Pupillary unrest was assessed as a measure of central nervous activation. The Fatigue Assessment Scale was applied to assess subjective mental fatigue using the corresponding subscale.

Results: VPS was reduced in post-COVID patients compared to controls (p = 0.005). In these patients, pupillary unrest (p = 0.029) and mental fatigue (p = 0.001) predicted VPS, explaining 34% of the variance and yielding a large effect with f² = 0.51.

Conclusion: In post-COVID patients with subjective cognitive dysfunction, hypoarousal of the brain is reflected in decreased processing speed which is explained by a reduced level of central nervous activation and a higher level of mental fatigue. In turn, reduced processing speed objectifies mental fatigue as a core subjective clinical complaint in post-COVID patients.

Keywords: Arousal; Cognitive dysfunction; Fatigue; Post-COVID; Pupillary unrest; Tonic alertness.

Fig. 1

TVA whole report paradigm: The task consisted of verbally reporting as many letters recognized as possible after each trial. In a trial, a central fixation point is presented for 1000 ms. After a brief delay of 250 ms, six letters in red or blue are presented in an imaginary circle for 1 of 5 individually adjusted exposure durations (that were calibrated during the pretest) appeared either masked or unmasked (for the second shortest or the longest individual exposure duration), therefore resulting in 7 effective exposure durations. This was followed by an unspeeded report of all letters seen

Fig. 2

Partial report paradigm: The task consisted of only verbally reporting red letters and ignoring blue letters. In a trial, the central fixation point is presented for 1000 ms. After a brief delay of 250 ms, the letters (T = target = red letters; D = distractor = blue letters) are presented for an individually adjusted exposure duration (calibrated during the pretest) in one of sixteen possible display conditions always masked (500 ms) and followed by an unspeeded report of red letters seen. Targets were presented in the corners of an imaginary square (7.5 cm × 7.5 cm) around the fixation point

Fig. 3

Distributions, medians (line) and means (point) in n = 40 post-COVID patients and n = 40 sociodemographically matched healthy controls for VPS = visual processing speed C (in letters per second); K = visual short-term memory capacity (maximum number of letters); t0 = visual perceptual threshold (in ms); and α = top-down control (distractor/targets)

Fig. 4

Representative whole report performance of a healthy control participant (A) and a post-COVID patient (B) as a function of exposure duration. Circles indicate observed values (= obs), dashed lines indicate predicted values based on the best model fit (= pred). The slope represents VPS (visual processing speed C in letters per second), the dashed horizontal line represents K (maximum visual short-term memory capacity in a maximum number of letters) and the intercept of the curve with the x-axis represents t0 (visual perceptual threshold in ms)

Fig. 5

VPS = visual processing speed C (letters/second) and PUI = pupillary unrest index (mm/min): Mental fatigue = subscore of the Fatigue Assessment Scale (German version); Average PD = average pupil diameter (mm); Depression = depression subscore of the Hospital Anxiety and Depression Scale (German version); Sleepiness = Epworth Sleepiness Scale (German version) score; Time from (SARS-CoV2) infection (days); Age in years; K = visual short term memory capacity (maximum number of letters); t0 = visual perceptual threshold (ms); α = top-down control (distractor/targets) within the post-COVID patient group (n = 40)