Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.

Multi-spectral oscillatory dynamics serving directed and divided attention.

Attention-related amplification of neural representations of external stimuli has been well documented in the visual domain, however, research concerning the oscillatory dynamics of such directed attention is relatively sparse in humans. Specifically, it is unknown which spectrally-specific neural responses are mainly impacted by the direction and division of attention, as well as whether the effects of attention on these oscillations are spatially disparate. In this study, we use magnetoencephalography and a visual-somatosensory oddball task to investigate the whole-brain oscillatory dynamics of directed (Experiment 1; N â€‹= â€‹26) and divided (Experiment 2; N â€‹= â€‹34) visual attention. Sensor-level data were transformed into the time-frequency domain and significant responses from baseline were imaged using a frequency-resolved beamformer. We found that multi-spectral cortical oscillations were stronger when attention was sustained in the visual space and that these effects exhibited informative spatial distributions that differed by frequency. More specifically, we found stronger frontal theta (4-8 â€‹Hz), frontal and occipital alpha (8-14 â€‹Hz), occipital beta (16-22 â€‹Hz), and frontal gamma (74-84 â€‹Hz) responses when visual attention was sustained than when it was directed away from the visual domain. Similarly, in the divided attention condition, we observed stronger fronto-parietal theta activity and temporo-parietal alpha and beta oscillations when visual attention was sustained toward the visual stimuli than divided between the visual and somatosensory domains. Investigating how attentional gain is implemented in the human brain is essential for better understanding how this process is degraded in disease, and may provide useful targets for future therapies.

Numerical working memory alters alpha-beta oscillations and connectivity in the parietal cortices.

Although the neural bases of numerical processing and memory have been extensively studied, much remains to be elucidated concerning the spectral and temporal dynamics surrounding these important cognitive processes. To further this understanding, we employed a novel numerical working memory paradigm in 28 young, healthy adults who underwent magnetoencephalography (MEG). The resulting data were examined in the time-frequency domain prior to image reconstruction using a beamformer. Whole-brain, spectrally-constrained coherence was also employed to determine network connectivity. In response to the numerical task, participants exhibited robust alpha/beta oscillations in the bilateral parietal cortices. Whole-brain statistical comparisons examining the effect of numerical manipulation during memory-item maintenance revealed a difference centered in the right superior parietal cortex, such that oscillatory responses during numerical manipulation were significantly stronger than when no manipulation was necessary. Additionally, there was significantly reduced cortico-cortical coherence between the right and left superior parietal regions during the manipulation compared to the maintenance trials, indicating that these regions were functioning more independently when the numerical information had to be actively processed. In sum, these results support previous studies that have implicated the importance of parietal regions in numerical processing, but also provide new knowledge on the spectral, temporal, and network dynamics that serve this critical cognitive function during active working memory maintenance.

Altered fronto-occipital connectivity during visual selective attention in regular cannabis users.

RATIONALE AND OBJECTIVES: Cognitive processing impairments have been associated with acute cannabis use, but there is mixed evidence regarding the cognitive effects of chronic cannabis use. Several neuroimaging studies have noted selective-attention processing differences in those who chronically use cannabis, but the neural dynamics governing the altered processing is unclear. METHODS: Twenty-four adults reporting at least weekly cannabis use in the past 6 months on the Cannabis Use Disorder Identification Test - Revised were compared to 24 demographically matched controls who reported no prior cannabis use. All participants completed a visual selective attention processing task while undergoing magnetoencephalography. Time-frequency windows of interest were identified using a data-driven method, and spectrally specific neural activity was imaged using a beamforming approach. RESULTS: All participants performed within normal range on the cognitive task. Regular cannabis users displayed an aberrant cognitive interference effect in the theta (4-8 Hz) frequency range shortly after stimulus onset (i.e., 0-250 ms) in the right occipital cortex. Cannabis users also exhibited altered functional connectivity between the right prefrontal cortex and right occipital cortices in comparison to controls. CONCLUSIONS: Individuals with a history of regular cannabis use exhibited abnormal theta interference activity in the occipital cortices, as well as altered prefrontal-occipital functional connectivity in the theta range during a visual selective attention task. Such differences may reflect compensatory processing, as these participants performed within normal range on the task. Understanding the neural dynamics in chronic, regular cannabis users may provide insight on how long-term and/or frequent use may affect neural networks underlying cognitive processes.

Prefrontal gating of sensory input differentiates cognitively impaired and unimpaired aging adults with HIV.

Despite effective therapies that have extended the life expectancy of persons living with HIV, 35-70% of these adults still develop some form of cognitive impairment, and with a growing population of aging adults with HIV, the prevalence of these cognitive deficits is likely to increase. The mechanisms underlying these HIV-associated neurocognitive disorders remain poorly understood but are often accelerated by the aging process and accompanied by disturbances in sensory processing, which may contribute to the observed cognitive decline. The goal of the current study was to identify the impact of aging on HIV-related alterations in inhibitory processing and determine whether such alterations are related to cognitive impairment in neuroHIV. We used magnetoencephalographic imaging, advanced time series analysis methods, and a paired-pulse stimulation paradigm to interrogate inhibitory processing in 87 HIV-infected aging adults and 92 demographically matched uninfected controls (22-72 years old). Whole-brain maps linking age and neural indices were computed for each group and compared via Fisher's Z transformations. Peak voxel time-series data were also extracted from the resulting images to quantify the dynamics of spontaneous neural activity preceding stimulation onset in each group. Whole-brain analyses using the somatosensory gating index, a metric of inhibitory processing and age distinguished impaired adults with HIV from unimpaired HIV-infected adults and controls. Briefly, younger cognitively impaired adults with HIV strongly utilized the prefrontal cortices to gate somatosensory input, and the role of this region in gating was uniquely and significantly modulated by aging only in impaired adults with HIV. Spontaneous neural activity preceding stimulus onset was also significantly elevated in the prefrontal cortices of those with HIV-associated neurocognitive disorder, and this elevation was significantly related to the CD4 nadir across both HIV-infected groups. This is the first study to examine the impact of aging on inhibitory processing in HIV-infected adults with and without cognitive impairment. Our findings suggest that young adults with HIV-associated neurocognitive disorder utilize the prefrontal cortices to gate (i.e. suppress) redundant somatosensory input, and that this capacity uniquely diminishes with advancing age in impaired adults with HIV.

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

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.