Persistent fatigue in post-acute COVID syndrome is associated with altered T1 MRI texture in subcortical structures: a preliminary investigation.

Post-acute COVID syndrome (PACS) is a global health concern and is often associated with debilitating symptoms. Post-COVID fatigue is a particularly frequent and troubling issue, and its underlying mechanisms remain incompletely understood. One potential contributor is micropathological injury of subcortical and brainstem structures, as has been identified in other patient populations. Texture-based analysis (TA) may be used to measure such changes in anatomical MRI data. The present study develops a methodology of voxel-wise TA mapping in subcortical and brainstem regions, which is then applied to T1-weighted MRI data from a cohort of 48 individuals who had PACS (32 with and 16 without ongoing fatigue symptoms) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19. Both groups were assessed an average of 4-5 months post-infection. There were no significant differences between PACS and control groups, but significant differences were observed within the PACS groups, between those with and without fatigue symptoms. This included reduced texture energy and increased entropy, along with reduced texture correlation, cluster shade and profile in the putamen, pallidum, thalamus and brainstem. These findings provide new insights into the neurophysiological mechanisms that underlie PACS, with altered tissue texture as a potential biomarker of this debilitating condition.

The time course of stimulus-specific perceptual learning.

Practice on perceptual tasks can lead to long-lasting, stimulus-specific improvements. Rapid stimulus-specific learning, assessed 24 hours after practice, has been found with just 105 practice trials in a face identification task. However, a much longer time course for stimulus-specific learning has been found in other tasks. Here, we examined 1) whether rapid stimulus-specific learning occurs for unfamiliar, non-face stimuli in a texture identification task; 2) the effects of varying practice across a range from just 21 trials up to 840 trials; and 3) if rapid, stimulus-specific learning persists over a 1-week, as well as a 1-day, interval. Observers performed a texture identification task in two sessions separated by one day (Experiment 1) or 1 week (Experiment 2). Observers received varying amounts of practice (21, 63, 105, or 840 training trials) in session 1 and completed 840 trials in session 2. In session 2, one-half of the observers in each group performed the task with the same textures as in session 1, and one-half switched to novel textures (same vs. novel conditions). In both experiments we found that stimulus-specific learning - defined as the difference in response accuracy in the same and novel conditions - increased as a linear function of the log number of session 1 training trials and was statistically significant after approximately 100 training trials. The effects of stimulus novelty did not differ across experiments. These results support the idea that stimulus-specific learning in our task arises gradually and continuously through practice, perhaps concurrently with general learning.

Contribution of internal noise and calculation efficiency to face discrimination deficits in older adults.

Classification images (CIs) measured in a face discrimination task differ significantly between older and younger observers. These age differences are consistent with the hypothesis that older adults sample diagnostic face information less efficiently, or have higher levels of internal noise, compared to younger adults. The current experiments assessed the relative contributions of efficiency and internal noise to age differences in face discrimination using the external noise masking and double-pass response consistency paradigms. Experiment 1 measured discrimination thresholds for faces embedded in several levels of static white noise, and the resulting threshold-vs.-noise curves were used to estimate calculation efficiency and equivalent input noise: older observers had lower efficiency and higher equivalent input noise than younger observers. Experiment 2 presented observers with two identical sequences of faces embedded in static white noise to measure the association between response accuracy and response consistency and estimate the internal:external (i/e) noise ratio for each observer. We found that i/e noise ratios did not differ significantly between groups. These results suggest that age differences in face discrimination are due to differences in calculation efficiency and additive internal noise, but not to age differences in multiplicative internal noise.

Persistent post-COVID headache is associated with suppression of scale-free functional brain dynamics in non-hospitalized individuals.

INTRODUCTION: Post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is a growing concern, with headache being a particularly debilitating symptom with high prevalence. The long-term effects of COVID-19 and post-COVID headache on brain function remain poorly understood, particularly among non-hospitalized individuals. This study focused on the power-law scaling behavior of functional brain dynamics, indexed by the Hurst exponent (H). This measure is suppressed during physiological and psychological distress and was thus hypothesized to be reduced in individuals with post-COVID syndrome, with greatest reductions among those with persistent headache. METHODS: Resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data were collected for 57 individuals who had COVID-19 (32 with no headache, 14 with ongoing headache, 11 recovered) and 17 controls who had cold and flu-like symptoms but  tested negative for COVID-19. Individuals were assessed an average of 4-5 months after COVID testing, in a cross-sectional, observational study design. RESULTS: No significant differences in H values were found between non-headache COVID-19 and control groups., while those with ongoing headache had significantly reduced H values, and those who had recovered from headache had elevated H values, relative to non-headache groups. Effects were greatest in temporal, sensorimotor, and insular brain regions. Reduced H in these regions was also associated with decreased BOLD activity and local functional connectivity. CONCLUSIONS: These findings provide new insights into the neurophysiological mechanisms that underlie persistent post-COVID headache, with reduced BOLD scaling as a potential biomarker that is specific to this debilitating condition.

Feasibility of diffusion-tensor and correlated diffusion imaging for studying white-matter microstructural abnormalities: Application in COVID-19.

There has been growing attention on the effect of COVID-19 on white-matter microstructure, especially among those that self-isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single-shell diffusion magnetic resonance imaging (MRI) methods for detecting such effects. In this work, the performances of three single-shell-compatible diffusion MRI modeling methods are compared for detecting the effect of COVID-19, including diffusion-tensor imaging, diffusion-tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self-isolated patients at the study initiation and 3-month follow-up, along with age- and sex-matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single-shell methods to demonstrate COVID-19-related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID-19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID-19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID-19 related white-matter microstructural pathology manifests as a change in tissue diffusivity. Interestingly, different b-values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3-month follow-up, likely due to the limited size of the follow-up cohort. To summarize, correlated diffusion imaging is shown to be a viable single-shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID-19 patients, suggesting the two regions react differently to viral infection.

Effects of post-acute COVID-19 syndrome on the functional brain networks of non-hospitalized individuals.

Introduction: The long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection. Methods: Data were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded. Results: Individuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions. Discussion: These results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder.

Peripheral target detection can be modulated by target distance but not attended distance in 3D space simulated by monocular depth cues.

Most studies of visuo-spatial attention present stimuli on a 2D plane, and less is known about how attention varies in 3D space. Previous studies found better peripheral detection performance for targets at a near compared to a far depth, simulated by pictorial cues and optical flow. The current study examined whether target detectability is monotonically related to distance along the depth axis, and whether the attended distance modulates the effect of target distance. We investigated these questions in two experiments that measured how apparent distance and target eccentricity affects peripheral target detection when performed alone during passive simulated self-motion, or during a simultaneous, active central car-following task. Experiment 1 found that targets at an apparent distance of 18.5 virtual meters were detected faster and more accurately than targets at 9.25 and 37 virtual meters, and detectability declined with eccentricity. Experiment 2 examined the effect of the attended location by varying the distance between the viewer and the lead car on which participants were instructed to fixate (i.e. the headway) while equating target distances across headway conditions. Experiment 2 replicated the effects found in Experiment 1, and headway did not modulate the effect of target distance. These results are consistent with the hypothesis that target detection depends non-monotonically on the distance between the viewer and the target, and is not affected by the distance between the target and attended location. However, target detection may also have been affected by stimulus characteristics that co-varied with apparent depth, rather than depth per se.

MRI Assessment of Cerebral Blood Flow in Nonhospitalized Adults Who Self-Isolated Due to COVID-19.

BACKGROUND: Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe. PURPOSE: To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19. STUDY TYPE: Prospective observational. POPULATION: A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). FIELD STRENGTH AND SEQUENCES: A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences. ASSESSMENT: Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group. STATISTICAL TESTS: Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05. RESULTS: Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue. DATA CONCLUSION: These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Cannabis use is associated with sexually dimorphic changes in executive control of visuospatial decision-making.

When the outcome of a choice is less favorable than expected, humans and animals typically shift to an alternate choice option on subsequent trials. Several lines of evidence indicate that this "lose-shift" responding is an innate sensorimotor response strategy that is normally suppressed by executive function. Therefore, the lose-shift response provides a covert gauge of cognitive control over choice mechanisms. We report here that the spatial position, rather than visual features, of choice targets drives the lose-shift effect. Furthermore, the ability to inhibit lose-shift responding to gain reward is different among male and female habitual cannabis users. Increased self-reported cannabis use was concordant with suppressed response flexibility and an increased tendency to lose-shift in women, which reduced performance in a choice task in which random responding is the optimal strategy. On the other hand, increased cannabis use in men was concordant with reduced reliance on spatial cues during decision-making, and had no impact on the number of correct responses. These data (63,600 trials from 106 participants) provide strong evidence that spatial-motor processing is an important component of economic decision-making, and that its governance by executive systems is different in men and women who use cannabis frequently.

Brain structure and function in people recovering from COVID-19 after hospital discharge or self-isolation: a longitudinal observational study protocol.

BACKGROUND: The detailed extent of neuroinvasion or deleterious brain changes resulting from COVID-19 and their time courses remain to be determined in relation to "long-haul" COVID-19 symptoms. Our objective is to determine whether there are alterations in functional brain imaging measures among people with COVID-19 after hospital discharge or self-isolation. METHODS: This paper describes a protocol for NeuroCOVID-19, a longitudinal observational study of adults aged 20-75 years at Sunnybrook Health Sciences Centre in Toronto, Ontario, that began in April 2020. We aim to recruit 240 adults, 60 per group: people who contracted COVID-19 and were admitted to hospital (group 1), people who contracted COVID-19 and self-isolated (group 2), people who experienced influenza-like symptoms at acute presentation but tested negative for COVID-19 and self-isolated (group 3, control) and healthy people (group 4, control). Participants are excluded based on premorbid neurologic or severe psychiatric illness, unstable cardiovascular disease, and magnetic resonance imaging (MRI) contraindications. Initial and 3-month follow-up assessments include multiparametric brain MRI and electroencephalography. Sensation and cognition are assessed alongside neuropsychiatric assessments and symptom self-reports. We will test the data from the initial and follow-up assessments for group differences based on 3 outcome measures: MRI cerebral blood flow, MRI resting state fractional amplitude of low-frequency fluctuation and electroencephalography spectral power. INTERPRETATION: If neurophysiologic alterations are detected in the COVID-19 groups in our NeuroCOVID-19 study, this information could inform future research regarding interventions for long-haul COVID-19. The study results will be disseminated to scientists, clinicians and COVID-19 survivors, as well as the public and private sectors to provide context on how brain measures relate to lingering symptoms.

The effect of apparent distance on peripheral target detection.

Previous research suggests that peripheral target detection is modulated by viewing distance and distance simulated by pictorial cues and optic flow. In the latter case, it is unclear what cues contribute to the effect of distance. The current study evaluated the effect of distance on peripheral detection in a virtual three-dimensional environment. Experiments 1-3 used a continuous, dynamic central task that simulated observers traveling either actively or passively through a virtual environment following a car. Peripheral targets were flashed on checkerboard-covered walls to the left and right of the path of motion, at a near and a far distance from the observer. The retinal characteristics of the targets were identical across distances. Experiment 1 found more accurate and faster detection for near targets compared to far targets, especially for larger eccentricities. Experiment 2 equated the predictability of target onset across distances and found the near advantage for larger eccentricities in accuracy but a much smaller effect in reaction time (RT). Experiment 3 removed the checkerboard background implemented in Experiments 1 and 2, and Experiment 4 manipulated several static, monocular cues. Experiments 3 and 4 found that the variation in the density of the checkerboard backgrounds could explain the main effect of distance on accuracy but could not completely account for the interaction between target distance and eccentricity. These results suggest that attention is modulated by target distance, but the effect is small. Finally, there were consistent divided attention costs in the central car-following task but not the peripheral detection task.

Phase integration bias in a motion grouping task.

The perception of the direction of global motion depends on our ability to integrate local motion signals over space and time. We examined motion binding using a task requiring integration of relative phase. Observers completed multiple tasks involving clockwise and counter clockwise motion in a stimulus comprising four sets of linearly arranged dots, two moving horizontally and two moving vertically along sinusoidal trajectories differing in phase. Noise jitter was added along the trajectory perpendicular to each dot's motion. The noise acts as a global grouping cue that improves direction discrimination, but surprisingly, the absence of noise causes consistent below-chance performance (Lorenceau, 1996). We explore this phenomenon and subsequently test the hypothesis that observers perceive reverse motion because their representation of the relative phase of the motion components is systematically biased. We employ a number of different objective and subjective measures of motion integration and measure the phenomenon in both younger and older adults. Taken together, the results presented in the current article demonstrate that noise can promote global grouping in the stimulus and that confident, incorrect responses can be observed in the absence of correct global grouping. Generally, the current result raises the possibility that an integration bias could exist in other motion tasks.

Sensitivity to curvature deformations along closed contours.

Human observers are exquisitely sensitive to curvature deformations along a circular closed contour (Wilkinson, Wilson, & Habak, 1998; Hess, Wang, & Dakin, 1999; Loffler, Wilson, & Wilkinson, 2003). Such remarkable sensitivity has been attributed to the curvature encoding scheme used by V4 neurons, which typically are assumed to be equally sensitive to curvature at all polar angles (Pasupathy & Connor, 2001, 2002; Carlson, Rasquinha, Zhang, & Connor, 2011). To test the assumption that detection thresholds for curvature deformations are invariant across polar angles, we used a novel stimulus class we call Difference of Gaussian (DoG) contours that allowed us to independently manipulate the amplitude, angular frequency, and polar angle of curvature of a closed-contour shape while measuring contour-curvature thresholds. Our results demonstrate that (a) detection thresholds were higher when observers were uncertain about the location of the curvature deformation, but on average, thresholds did not vary significantly across 24 polar angles; (b) the direction and magnitude of the oblique effect varies across individuals; (c) there is a strong association between detecting a contour deformation and identifying its location; (d) curvature detectors may serve as labeled lines.

Evaluating spatiotemporal interactions between shapes.

Spatiotemporal interactions between stimuli can alter the perceived curvature along the outline of a shape (Habak, Wilkinson, Zakher, & Wilson, 2004; Habak, Wilkinson, & Wilson, 2006). To better understand these interactions, we used a forward and backward masking paradigm with radial frequency (RF) contours while measuring RF detection thresholds. In Experiment 1, we presented a mask alongside a target contour and altered the stimulus onset asynchrony between this target-mask pair and a temporal mask. We found that a temporal mask increased thresholds when it preceded the target-mask stimulus by 130-180 ms but decreased thresholds when it followed the target-stimulus mask by 180 ms. Furthermore, Experiment 2 demonstrated that the effects of temporal and spatial masks are approximately additive. We discuss these findings in relation to theories of transient and sustained channels in vision.

The role of horizontal facial structure on the N170 and N250.

Recent studies have shown that horizontal facial structure is important for face identification (Dakin and Watt, 2009; Goffaux and Dakin, 2010). Also, sensitivity to horizontal structure is associated with the size of the face inversion effect (Pachai et al., 2013). However, it is unclear how the N170 and N250, two components of visual event-related potentials ERPs that have been implicated in face perception, are modulated by oriented facial structure in an upright face identification task. Here, we recorded ERPs and behavioural accuracy from adult observers performing a 1-of-6 face identification task in conditions that parametrically manipulated the orientation structure of upright faces. Faces were filtered with ideal orientation filters centred on either 0 (horizontal) or 90 deg (vertical). Filter bandwidth was varied across conditions from ±45 to ±90 deg in steps of ±9 deg. As has been reported previously, response accuracy was significantly higher for faces that contained horizontal structure than vertical structure, and the horizontal-vertical difference was correlated with accuracy for unfiltered faces. In addition, the N170 and N250 were affected by the manipulation of horizontal facial structure. Furthermore, for the N250, but not the N170, the relative sensitivity to horizontal compared to vertical facial structure was significantly correlated with identification accuracy for unfiltered faces. We suggest that in a face identification task, the N250 but not the N170 is modulated by the amount of diagnostic information conveyed by horizontal structure.

The effect of training with inverted faces on the selective use of horizontal structure.

A growing body of evidence demonstrates that selective processing of structure conveyed by horizontally oriented spatial frequency components is associated with upright face discrimination accuracy and the magnitude of the face inversion effect. In this study, we examined whether the increase in discrimination accuracy for inverted faces that is known to result from practice would coincide with more selective processing of horizontal structure in inverted faces. To assess this hypothesis, our observers practiced discrimination of inverted faces for three training sessions and we measured accuracy, efficiency relative to an ideal observer, and horizontal selectivity before and after training. As hypothesized, we observed more efficient discrimination and more selective processing of horizontal structure after training. However, the effects of training did not generalize reliably to novel face exemplars.

Phase-selective masking with radial frequency contours.

Sensitivity to changes in the shape of a closed-contour figure is affected by surrounding figures (Vision Research 44 (2004) 2815-2823). We examined how between-contour masking depends on radial frequency. Experiment 1 replicated previous studies that found that masking between adjacent radial frequency (RF) patterns was greatest when the two shapes were phase aligned, and that the magnitude of masking declined approximately linearly with increasing phase offsets. In addition, we found that the effect of phase offset on masking was very similar for RFs ranging from 3 to 8, a result that suggests that sensitivity to phase decreases with increasing radial frequency. Experiment 2 tested this idea and found that phase discrimination threshold for single cycles of curvature was approximately proportional to radial frequency. Experiment 3 showed that both curvature maxima and minima contribute to phase dependent masking between RF contours. Together, Experiments 1-3 demonstrate that the strength of phase-dependent masking does not depend on RF, but is related to sensitivity for phase shifts in isolated contours, and is affected by both positive and negative curvature extrema. We discuss these results in relation to properties of curvature sensitive neurons.

Classification images characterize age-related deficits in face discrimination.

Face perception is impaired in older adults, but the cause of this decline is not well understood. We examined this issue by measuring Classification Images (CIs) in a face discrimination task in younger and older adults. Faces were presented in static, white visual noise, and face contrast was varied with a staircase to maintain an accuracy rate of ≈71%. The noise fields were used to construct a CI using the method described by Nagai et al. (2013) and each observer's CI was cross-correlated with the visual template of a linear ideal discriminator to obtain an estimate of the absolute efficiency of visual processing. Face discrimination thresholds were lower in younger than older adults. Like Sekuler, Gaspar, Gold, and Bennett (2004), we found that CIs from younger adults contained structure near the eyes and brows, suggesting that those observers consistently relied on information conveyed by pixels in those regions of the stimulus. CIs obtained from older adults were noticeably different: CIs from only two older adults exhibited structure near the eye/brow regions, and CIs from the remaining older observers showed no obvious structure. Nevertheless, face discrimination thresholds in both groups were strongly and similarly correlated with the cross-correlation between the CI and the ideal template, suggesting that despite older observers' lack of consistent structure, the CI method is sensitive to between-subject differences in older observers' perceptual strategy.

The Bandwidth of Diagnostic Horizontal Structure for Face Identification.

Horizontally oriented spatial frequency components are a diagnostic source of face identity information, and sensitivity to this information predicts upright identification accuracy and the magnitude of the face-inversion effect. However, the bandwidth at which this information is conveyed, and the extent to which human tuning matches this distribution of information, has yet to be characterized. We designed a 10-alternative forced choice face identification task in which upright or inverted faces were filtered to retain horizontal or vertical structure. We systematically varied the bandwidth of these filters in 10° steps and replaced the orientation components that were removed from the target face with components from the average of all possible faces. This manipulation created patterns that looked like faces but contained diagnostic information in orientation bands unknown to the observer on any given trial. Further, we quantified human performance relative to the actual information content of our face stimuli using an ideal observer with perfect knowledge of the diagnostic band. We found that the most diagnostic information for face identification is conveyed by a narrow band of orientations along the horizontal meridian, whereas human observers use information from a wide range of orientations.

Implicit Valuation of the Near-Miss is Dependent on Outcome Context.

Gambling studies have described a "near-miss effect" wherein the experience of almost winning increases gambling persistence. The near-miss has been proposed to inflate the value of preceding actions through its perceptual similarity to wins. We demonstrate here, however, that it acts as a conditioned stimulus to positively or negatively influence valuation, dependent on reward expectation and cognitive engagement. When subjects are asked to choose between two simulated slot machines, near-misses increase valuation of machines with a low payout rate, whereas they decrease valuation of high payout machines. This contextual effect impairs decisions and persists regardless of manipulations to outcome feedback or financial incentive provided for good performance. It is consistent with proposals that near-misses cause frustration when wins are expected, and we propose that it increases choice stochasticity and overrides avoidance of low-valued options. Intriguingly, the near-miss effect disappears when subjects are required to explicitly value machines by placing bets, rather than choosing between them. We propose that this task increases cognitive engagement and recruits participation of brain regions involved in cognitive processing, causing inhibition of otherwise dominant systems of decision-making. Our results reveal that only implicit, rather than explicit strategies of decision-making are affected by near-misses, and that the brain can fluidly shift between these strategies according to task demands.