Rapid vigilance and episodic memory decrements in COVID-19 survivors

Abstract

Recent studies indicate that COVID-19 infection can lead to serious neurological consequences in a small percentage of individuals. However, in the months following acute illness, many more suffer from fatigue, low motivation, disturbed mood, poor sleep and cognitive symptoms, colloquially referred to as 'brain fog'. But what about individuals who had asymptomatic to moderate COVID-19 and reported no concerns after recovering from COVID-19? Here, we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial-visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation. However, they displayed significantly worse episodic memory (up to 6 months post-infection) and greater decline in vigilance with time on task (for up to 9 months). Overall, the results show that specific chronic cognitive changes following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after 6-9 months, demonstrating evidence of recovery over time.

Keywords: COVID-19; cognitive deficits; long-COVID; memory; sustained attention.

Graphical Abstract

Figure 1

Study population flow chart. Number of participants eligible for each experimental session. Note that as some participants might fall into multiple exclusion criteria, the totals may not add up exactly.

Figure 2

Twelve cognitive tasks measured distinct aspects of human cognition, memory, attention, motor control, planning and verbal reasoning abilities. The vigilance task was tested through the online experiment hosting server Pavlovia and conducted first. The rest of the 11 tasks were provided by Cognitron and ran in the following order: Motor control, Object Memory (immediate), Word memory (immediate), Simple reaction task, Choice reaction time, 2D mental rotations, 3D mental rotations, Spatial span, Target detection, Tower of London, Verbal analogies, Object Memory (delayed) and Word memory (delayed). The Object Memory and word memory tasks were both tested twice: once at the beginning (‘immediate’) and again at the end of the experiment (‘delayed’), with an interval of about 30 min. The delayed task was solely testing memory of the stimuli displayed in the first instance of the task so the memory probes were not displayed before the delayed task.

Figure 3

COVID group showed a larger and faster vigilance decline on the task. (A) Accuracy rate was computed for every minute (i.e. every block) of the vigilance test and plotted against the time. The y-value at t = 0 corresponds to the accuracy rate over the 1 min-long practice block. The shaded area shows ±1 SEM and the black horizontal line at the bottom indicates time intervals where bootstrap statistics confirmed significant differences between the two groups (P < 0.05, details see ‘Time-series analysis’ in ‘Vigilance test’); the divergence was significant from the fourth minute to the eighth minute. (B) Group average of self-reported ratings of motivation against time (shaded area shows ±1 SEM). The rating at t = 0 corresponds to the rating after the practice block. No group difference was found in the motivation rating over time. (C) COVID-19 survivors felt more tired from the beginning (shaded area shows ±1 SEM). (D) However, the fatigue rating (averaged over all 10 ratings) did not correlate with the size of the vigilance decrement in neither the COVID group nor the control group. The Spearman’s correlation coefficient and their two-tailed P-values was shown for each group. (E) Vigilance decrement showed a significant correlation with the time from COVID-19 diagnosis. Both Spearman’s and Pearson’s correlation coefficients and their two-tailed P-values are shown above the plot. (F) Participants who had COVID-19 within the last 9 months displayed significantly larger vigilance decrements than the controls. The number of participants for each bin was labelled above each bar. Each grey dot represents individual data and the error bar indicates 1 SE. Group comparison performed by permutation test (with 10 000 iterations). *P < 0.05, m (months).

Figure 4

COVID group showed a mild episodic memory deficit compared with age-matched controls. (A) The distribution of the short-term memory, measured as the correct percent in the memory test immediately after viewing the sequence of objects, is plotted as a violin for COVID (n = 36), Control (n = 44) and Elderly Control (n = 52, all above 50 years old, data collected separately). Group comparison performed by t-test. There were no statistical differences between groups in the short-term memory [COVID versus Control: t(78) = −0.02, P = 1.0, BF = 4.3; Control versus Elderly Control: t(94) = −0.4, P = 0.7, BF = 4.4; COVID versus Elderly Control: t(86) = −0.5, P = 0.6, BF = 4.0]. (B) Approximately 30 min later, their memory was tested again. COVID and Elderly controls showed significantly larger memory decrements than the younger controls [COVID versus Control: t(78) = −3.0, P = 0.004, BF = 10.7; Control versus Elderly Control: t(94) = 2.8, P = 0.007, BF = 6.0; COVID versus Elderly Control: t(86) = −1.4, P = 0.2, BF = 1.9]. (C) In COVID-19 survivors who contracted COVID-19 within 1 year, the size of memory decrement was positively correlated with the time from COVID-19 diagnosis. Both Spearman’s and Pearson’s correlation coefficients and their two-tailed P-values are shown above the plot. (D) Participants who had COVID-19 within the last 6 months showed significantly larger memory decrement than the age-matched controls. The number of participants for each bin was labelled above each bar. Each grey dot represents individual data and the error bar indicates 1 SE. Group comparison performed by permutation test (with 10 000 iterations). *P < 0.05, **P < 0.01, m (months).

Figure 5

Cognitive decrements sorted by COVID-19 symptom and long-COVID symptom severity. Fifty-one out of 64 COVID-19 survivors (including the three participants who stayed hospital overnight for COVID-19) reported their COVID-19 symptom severity (A) and long-COVID symptom severity (C). In both (A) and (C), the number of participants for each severity level is labelled above the corresponding bar. (B) The vigilance (left) and memory (right) decrements binned by COVID-19 symptom severity. Each grey dot represents individual data and the error bar indicates 1 SE. An LMM with participant as a random effect showed that COVID-19 severity level had main effect on vigilance decrement [F(1,8) = 6.8, P = 0.03] and main effect on memory decmrenet [F(1,6) = 15.3, P = 0.008]. Similarly, (D) shows the cognitive decrements for each long-COVID symptom severity level. An LMM with participant as a random effect showed that long-COVID symptoms had no effect on vigilance decrement [F(1,8) = 4.5, P = 0.07] or memory decrement [F(1,6) = 0.09, P = 0.8].

Figure 6

Demographics and socioeconomics profile of the participants. T-test was used to assess between-group difference in age (A) and subjective SES (I). For the measures with binary outcomes, including gender (B), first language (C), country of current residence (D), and essential workers (J), χ²-test was used to assess between-group differences. Their P-values were unadjusted for multiple comparison. For the measures with multiple categories—ethnicity (E), education (F), annual income (G) and employment status (H), χ²-test was run for each category of each measure and P-values were adjusted using the Bonferroni method (i.e. multiplying the number of categories in that measure). Amongst all measures, only one measure showed significant difference: the COVID group showed a significantly higher subjective SES [H, t(96) = 2.5, P = 0.02]. No difference was found in other measures and annotated as n.s. (not significant).

Figure 7

Work, smoking history and vaccination status of the participants. For the measures with multiple categories—transport means used to commute (A), work sector (E) and work from home status (F), χ²-test was run for each category of each measure and P-values were adjusted using the Bonferroni method (i.e. multiplying the number of categories in that measure). For the measures with binary outcomes, including smoking history (B and C) and COVID-19 vaccination history (D), χ²-test was used to assess between-group differences. Amongst all measures, only one measure showed significant difference: the COVID group showed a lower rate of COVID-19 vaccination [D, χ²(1,N = 15) = 8.6, P = 0.003]. No difference was found in other measures and annotated as n.s. (not significant).