The age-related trajectory of visual attention neural function is altered in adults living with HIV: A cross-sectional MEG study

Abstract

Background: Despite living a normal lifespan, at least 35% of persons with HIV (PWH) in resource-rich countries develop HIV-associated neurocognitive disorder (HAND). This high prevalence of cognitive decline may reflect accelerated ageing in PWH, but the evidence supporting an altered ageing phenotype in PWH has been mixed.

Methods: We examined the impact of ageing on the orienting of visual attention in PWH using dynamic functional mapping with magnetoencephalography (MEG) in 173 participants age 22-72 years-old (94 uninfected controls, 51 cognitively-unimpaired PWH, and 28 with HAND). All MEG data were imaged using a state-of-the-art beamforming approach and neural oscillatory responses during attentional orienting were examined for ageing, HIV, and cognitive status effects.

Findings: All participants responded slower during trials that required attentional reorienting. Our functional mapping results revealed HIV-by-age interactions in left prefrontal theta activity, alpha oscillations in the left parietal, right cuneus, and right frontal eye-fields, and left dorsolateral prefrontal beta activity (p<.005). Critically, within PWH, we observed a cognitive status-by-age interaction, which revealed that ageing impacted the oscillatory gamma activity serving attentional reorienting differently in cognitively-normal PWH relative to those with HAND in the left temporoparietal, inferior frontal gyrus, and right prefrontal cortices (p<.005).

Interpretation: This study provides key evidence supporting altered ageing trajectories across vital attention circuitry in PWH, and further suggests that those with HAND exhibit unique age-related changes in the oscillatory dynamics serving attention function. Additionally, our neural findings suggest that age-related changes in PWH may serve a compensatory function.

Funding: National Institutes of Health, USA.

Keywords: Ageing; Attentional reorientation; HIV; Magnetoencephalography; Validity effect.

Fig. 1

Flow Diagram: A total of 133 controls and 121 PWH were enroled, including 76 unimpaired PWH and 45 with HAND. Exclusions were made for current drug use, cognitive impairment (in controls), moderate to severe depressive symptoms, and missing or artifactual data. The final sample included 94 unimpaired controls, 51 unimpaired PWH and 28 participants with HAND.

Fig. 2

Posner cueing task and behavioral performance. (a) A central crosshair was presented for 1500 ms (± 50 ms), followed by a cue (green bar) that appeared in either the left or right hemifield for 100 ms. Target presentation (box with opening at the top or bottom) was presented 200 ms after cue offset (300 ms from onset), in either hemifield for 2500 ms. The cue was predictive of the upcoming target location 50% of the time (i.e., “valid” condition) and was presented on opposite side from the target in remaining 50% of trials (i.e., “invalid” condition). Participants completed 200 trials and were instructed to respond as to whether the opening was on the bottom (right index finger) or top (right middle finger) of the box. Trials were pseudorandomized and counterbalanced in regard to target validity (valid or invalid), visual hemifield (left or right), and box opening (top or bottom). (b) Box and whisker plots showing the reaction time data in controls and PWH. Main effects of condition (valid vs. invalid) and age were observed. Scatterplots with mean reaction time (right) displayed on the y-axes and age on the x-axes indicated that participants across both groups responded slower with increasing age across both conditions. (c) Box and whisker plots showing the reaction time data in unimpaired PWH and participants with HAND. Main effects of condition (valid vs. invalid) and age were observed, similar to the analyses of PWH and controls. Scatterplots with mean reaction time (right) displayed on the y-axes and age on the x-axes indicated that all PWH responded slower with increasing age across both conditions. Note that reaction time was computed as the time from target onset (not cue onset) to button press. ** p < .01 [ANCOVA].(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Sensor level time frequency analysis. Grand averaged spectrograms for two sensors near parietal cortices with time (ms) displayed on the x-axis and frequency (Hz) denoted on the y-axis. Power is shown in percentage units relative to the baseline period (−600 to 0 ms), with a color scale bar beneath each spectrogram. The data per spectrogram have been averaged across all trials and participants. Note that statistical analyses focused on the target period (i.e., after 300 ms). (Bottom) A strong increase in theta (3–7 Hz) power was observed following cue onset and during target processing (350–700 ms). (Middle): Strong decreases in alpha (8–14 Hz, 350–950 ms) and beta (14–22 Hz, 350–950 ms) power were also observed after the onset of the target. (Top): Robust increases in gamma (46–58 Hz) activity occurred during later target processing (850–1450 ms). All four oscillatory responses statistically differed from baseline activity in the spectral and temporal windows listed above and in the text (p < .001, corrected) [Paired t-test]. These time-frequency windows are indicated using the black dotted line boundaries. Blue and grey dotted lines represent the reaction times for valid and invalid trials across all three groups, respectively.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Age-related theta validity effects in Controls and PWH. Validity maps (invalid–valid trials) were computed for each participant and were correlated with age in each group. We then compared these maps after Fisher's Z transformation to identify regions where the correlation differed statistically between controls and PWH (unimpaired and HAND groups collapsed), which revealed a cluster in the left prefrontal cortices (right). To determine the directionality, we extracted the peak voxel value in each participant, and these are shown in the scatterplot. In the scatterplot, age (in years) is represented on x-axis and the theta validity effect (3–7 Hz) in the prefrontal cortices is plotted on the y-axis in pseudo-t units, with the line of best-fit overlaid for each group. Controls exhibited a statistically significant positive correlation between the theta validity effect and age in the left prefrontal region (grey), which differed from PWH who exhibited a statistically non-significant negative correlation (green). * p < .05 [Pearson correlation].(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Age-related Alpha validity effects in Controls and PWH and their relationship to reaction time. (a) As in Fig. 4, validity maps (i.e., invalid–valid) were computed and correlated with age in each group (controls and PWH), then Fisher's Z transformation was applied to determine whether the correlation between alpha (8–14 Hz) validity effects and age differed between controls and PWH (unimpaired and HAND collapsed). These analyses revealed group differences in the left parietal, right cuneus, and right frontal eye fields (FEF). Post hoc analysis showed that the left parietal validity effect (left) was positively correlated with age in controls, but negatively leading (statistically non-significant) in PWH. A similar pattern was observed in the right cuneus (middle), although the correlation was only trending. In contrast, alpha correlations validity was found to have a strong negative association with age in PWH in the right FEF (right), while controls showed no relationship with age in this region. (b) Pearson correlational analysis between alpha validity maps in the left parietal, right cuneus and right FEFs showed statistically significant positive associations between the alpha and reaction time validity effects in left parietal regions and right FEFs. Black dotted circles in the images above each scatterplot indicate the relevant region.* p < .05. ** p < .01 [Pearson correlation].

Fig. 6

Age-related beta validity effects in Controls and PWH. As in Figs. 4 and 5, validity maps (invalid – valid trials) were computed for each participant and were correlated with age in each group. Fisher's Z transformation was then applied to identify regions where the correlation differed statistically between controls and PWH (unimpaired and HAND groups collapsed). Age (in years) is represented on x-axis and the beta validity effect (14–22 Hz) in the left dorsolateral prefrontal cortices is plotted on the y-axis in pseudo-t units, with the line of best-fit overlaid for each group. Controls exhibited a positive correlation between the beta validity effect and age in the left dorsolateral prefrontal region (grey), while PWH showed a strong statistically significant negative association between the validity effect and age in the same region. ** p < .01 [Pearson correlation].

Fig. 7

Age-related gamma validity effects in unimpaired PWH and HAND groups. Validity maps (i.e., invalid–valid) were computed and correlated with age in each group (unimpaired PWH and HAND), then Fisher's Z transformation was applied to determine whether the correlation between gamma (46–58 Hz) validity effects and age differed between unimpaired PWH and HAND groups. For reference, best line fits for controls are also plotted (grey). These analyses revealed statistically significant group differences in the left temporoparietal (left), left inferior frontal gyrus (middle), and right lateral prefrontal cortex (right). In all three regions, adults with HAND exhibited a strong positive association between the gamma validity effect and increasing age (blue), and these statistically differed from unimpaired PWH (yellow). ** p < .01 [Pearson correlation].(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)