Neurovascular Mechanisms of Cognitive Aging: Sex-Related Differences in the Average Progression of Arteriosclerosis, White Matter Atrophy, and Cognitive Decline.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data ( N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like causality inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT) temporally precedes an acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.

Fast Optical Signals for Real-Time Retinotopy and Brain Computer Interface.

A brain-computer interface (BCI) allows users to control external devices through brain activity. Portable neuroimaging techniques, such as near-infrared (NIR) imaging, are suitable for this goal. NIR imaging has been used to measure rapid changes in brain optical properties associated with neuronal activation, namely fast optical signals (FOS) with good spatiotemporal resolution. However, FOS have a low signal-to-noise ratio, limiting their BCI application. Here FOS were acquired with a frequency-domain optical system from the visual cortex during visual stimulation consisting of a rotating checkerboard wedge, flickering at 5 Hz. We used measures of photon count (Direct Current, DC light intensity) and time of flight (phase) at two NIR wavelengths (690 nm and 830 nm) combined with a machine learning approach for fast estimation of visual-field quadrant stimulation. The input features of a cross-validated support vector machine classifier were computed as the average modulus of the wavelet coherence between each channel and the average response among all channels in 512 ms time windows. An above chance performance was obtained when differentiating visual stimulation quadrants (left vs. right or top vs. bottom) with the best classification accuracy of ~63% (information transfer rate of ~6 bits/min) when classifying the superior and inferior stimulation quadrants using DC at 830 nm. The method is the first attempt to provide generalizable retinotopy classification relying on FOS, paving the way for the use of FOS in real-time BCI.

Dynamics of alpha suppression index both modality specific and general attention processes.

EEG alpha power varies under many circumstances requiring visual attention. However, mounting evidence indicates that alpha may not only serve visual processing, but also the processing of stimuli presented in other sensory modalities, including hearing. We previously showed that alpha dynamics during an auditory task vary as a function of competition from the visual modality (Clements et al., 2022) suggesting that alpha may be engaged in multimodal processing. Here we assessed the impact of allocating attention to the visual or auditory modality on alpha dynamics at parietal and occipital electrodes, during the preparatory period of a cued-conflict task. In this task, bimodal precues indicated the modality (vision, hearing) relevant to a subsequent reaction stimulus, allowing us to assess alpha during modality-specific preparation and while switching between modalities. Alpha suppression following the precue occurred in all conditions, indicating that it may reflect general preparatory mechanisms. However, we observed a switch effect when preparing to attend to the auditory modality, in which greater alpha suppression was elicited when switching to the auditory modality compared to repeating. No switch effect was evident when preparing to attend to visual information (although robust suppression did occur in both conditions). In addition, waning alpha suppression preceded error trials, irrespective of sensory modality. These findings indicate that alpha can be used to monitor the level of preparatory attention to process both visual and auditory information, and support the emerging view that alpha band activity may index a general attention control mechanism used across modalities.

Stimulus-induced changes in 1/f-like background activity in EEG.

Research into the nature of 1/f-like, non-oscillatory electrophysiological activity has grown exponentially in recent years in cognitive neuroscience. The shape of this activity has been linked to the balance between excitatory and inhibitory neural circuits, which is thought to be important for information processing. However, to date, it is not known whether the presentation of a stimulus induces changes in the parameters of 1/f activity in scalp recordings, separable from event-related potentials (ERPs). Here, we analyzed event-related broadband changes in human EEG both before and after removing ERPs to demonstrate their confounding effect, and to establish whether there are genuine stimulus-induced changes in 1/f Using data from a passive and an active auditory task (n = 23, 61% female), we found that the shape of the post-event spectra between 2-25 Hz differed significantly from the pre-event spectra even after removing the frequency-content of ERPs. Further, a significant portion of this difference could be accounted for by a rotational shift in 1/f activity, manifesting as an increase in low and a decrease in high frequencies. Importantly, the magnitude of this rotational shift was related to the attentional demands of the task. This change in 1/f is consistent with increased inhibition following stimulus onset, and likely reflects a disruption of ongoing excitatory activity proportional to processing demands. Finally, these findings contradict the central assumption of baseline normalization strategies in time-frequency analyses, namely that background EEG activity is stationary across time. As such, they have far-reaching consequences relevant for several subfields of neuroscience.SIGNIFICANCE STATEMENT:Interest in the functional role of the 1/f-like background brain activity has been growing exponentially in neuroscience. Yet, no study to date has demonstrated a clear relationship between information processing and 1/f activity by investigating event-related effects on its parameters in non-invasive recordings of neural activity. Here, we demonstrate for the first time that stimuli induce rotational changes in 1/f activity, detectable at lower frequencies and independent from the occurrence of event-related potentials. These findings suggest the presence of large-scale inhibition following stimulus onset, largest when the stimulus is novel, and indicate that the assumption of stationary background activity in the analysis of neural oscillations is untenable. These results have far-reaching consequences that cut across several subfields of neuroscience.

Dynamics of alpha suppression and enhancement may be related to resource competition in cross-modal cortical regions.

In the face of multiple sensory streams, there may be competition for processing resources in multimodal cortical areas devoted to establishing representations. In such cases, alpha oscillations may serve to maintain the relevant representations and protect them from interference, whereas theta band activity may facilitate their updating when needed. It can be hypothesized that these oscillations would differ in response to an auditory stimulus when the eyes are open or closed, as intermodal resource competition may be more prominent in the former than in the latter case. Across two studies we investigated the role of alpha and theta power in multimodal competition using an auditory task with the eyes open and closed, respectively enabling and disabling visual processing in parallel with the incoming auditory stream. In a passive listening task (Study 1a), we found alpha suppression following a pip tone with both eyes open and closed, but subsequent alpha enhancement only with closed eyes. We replicated this eyes-closed alpha enhancement in an independent sample (Study 1b). In an active auditory oddball task (Study 2), we again observed the eyes open/eyes closed alpha pattern found in Study 1 and also demonstrated that the more attentionally demanding oddball trials elicited the largest oscillatory effects. Theta power did not interact with eye status in either study. We propose a hypothesis to account for the findings in which alpha may be endemic to multimodal cortical areas in addition to visual ones.

Event-related brain potentials reveal strategy selection in younger and older adults.

It is well-established that younger adults prioritize information accrued during different stages of stimulus evaluation ("early" versus "late") to optimize performance. The extent to which older adults flexibly adjust their processing strategies, however, is largely unexplored. Twenty-four younger and twenty-four older participants completed a cued flanker task in which one of three cues, indicating the probability that a congruent array would appear (75 %, 50 %, or 25 %), was presented on each trial. Behavioral and ERP (CNV, LRP, N2, and P3b) analyses allowed us to infer cue-driven changes in strategy selection. Results indicate that when both younger and older adults expected an incongruent array, they prioritized late, target information, resulting in a decreased susceptibility to the performance-impairing effect of distractors, extending the conclusions of Gratton et al. (1992) to older adults and supporting the claim that strategic control remains largely intact during healthy aging.

The impact of 1/f activity and baseline correction on the results and interpretation of time-frequency analyses of EEG/MEG data: A cautionary tale.

Typically, time-frequency analysis (TFA) of electrophysiological data is aimed at isolating narrowband signals (oscillatory activity) from broadband non-oscillatory (1/f) activity, so that changes in oscillatory activity resulting from experimental manipulations can be assessed. A widely used method to do this is to convert the data to the decibel (dB) scale through baseline division and log transformation. This procedure assumes that, for each frequency, sources of power (i.e., oscillations and 1/f activity) scale by the same factor relative to the baseline (multiplicative model). This assumption may be incorrect when signal and noise are independent contributors to the power spectrum (additive model). Using resting-state EEG data from 80 participants, we found that the level of 1/f activity and alpha power are not positively correlated within participants, in line with the additive but not the multiplicative model. Then, to assess the effects of dB conversion on data that violate the multiplicativity assumption, we simulated a mixed design study with one between-subject (noise level, i.e., level of 1/f activity) and one within-subject (signal amplitude, i.e., amplitude of oscillatory activity added onto the background 1/f activity) factor. The effect size of the noise level × signal amplitude interaction was examined as a function of noise difference between groups, following dB conversion. Findings revealed that dB conversion led to the over- or under-estimation of the true interaction effect when groups differing in 1/f levels were compared, and it also led to the emergence of illusory interactions when none were present. This is because signal amplitude was systematically underestimated in the noisier compared to the less noisy group. Hence, we recommend testing whether the level of 1/f activity differs across groups or conditions and using multiple baseline correction strategies to validate results if it does. Such a situation may be particularly common in aging, developmental, or clinical studies.

Spontaneous Alpha and Theta Oscillations Are Related to Complementary Aspects of Cognitive Control in Younger and Older Adults.

The resting-state human electroencephalogram (EEG) power spectrum is dominated by alpha (8-12 Hz) and theta (4-8 Hz) oscillations, and also includes non-oscillatory broadband activity inversely related to frequency (1/f activity). Gratton proposed that alpha and theta oscillations are both related to cognitive control function, though in a complementary manner. Alpha activity is hypothesized to facilitate the maintenance of representations, such as task sets in preparation for expected task conditions. In contrast, theta activity would facilitate changes in representations, such as the updating of task sets in response to unpredicted task demands. Therefore, theta should be related to reactive control (which may prompt changes in task representations), while alpha may be more relevant to proactive control (which implies the maintenance of current task representations). Less is known about the possible relationship between 1/f activity and cognitive control, which was analyzed here in an exploratory fashion. To investigate these hypothesized relationships, we recorded eyes-open and eyes-closed resting-state EEG from younger and older adults and subsequently tested their performance on a cued flanker task, expected to elicit both proactive and reactive control processes. Results showed that alpha power and 1/f offset were smaller in older than younger adults, whereas theta power did not show age-related reductions. Resting alpha power and 1/f offset were associated with proactive control processes, whereas theta power was related to reactive control as measured by the cued flanker task. All associations were present over and above the effect of age, suggesting that these resting-state EEG correlates could be indicative of trait-like individual differences in cognitive control performance, which may be already evident in younger adults, and are still similarly present in healthy older adults.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

Age-related differences in functional brain network segregation are consistent with a cascade of cerebrovascular, structural, and cognitive effects.

Age-related declines in cognition are associated with widespread structural and functional brain changes, including changes in resting-state functional connectivity and gray and white matter status. Recently we have shown that the elasticity of cerebral arteries also explains some of the variance in cognitive and brain health in aging. Here, we investigated how network segregation, cerebral arterial elasticity (measured with pulse-DOT-the arterial pulse based on diffuse optical tomography) and gray and white matter status jointly account for age-related differences in cognitive performance. We hypothesized that at least some of the variance in brain and cognitive aging is linked to reduced cerebrovascular elasticity, leading to increased cortical atrophy and white matter abnormalities, which, in turn, are linked to reduced network segregation and decreases in cognitive performance. Pairwise comparisons between these variables are consistent with an exploratory hierarchical model linking them, especially when focusing on association network segregation (compared with segregation in sensorimotor networks). These findings suggest that preventing or slowing age-related changes in one or more of these factors may induce a neurophysiological cascade beneficial for preserving cognition in aging.

Optical measures of cerebral arterial stiffness are associated with white matter signal abnormalities and cognitive performance in normal aging.

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18-87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline.

Multidisciplinary team clinic for vocal cord dysfunction directs therapy and significantly reduces healthcare utilization.

BACKGROUND AND OBJECTIVE: Multidisciplinary team (MDT) clinics use an integrated approach to individualize care of complex medical conditions. Vocal cord dysfunction (VCD) is a challenging condition that is likely to benefit from MDT clinics but this has not been researched. METHODS: A prospective observational cohort study of a novel VCD MDT clinic was conducted in patients with suspected VCD. Relevant questionnaires, medical history, physical examination, spirometry, dynamic computerized tomography (CT) larynx and laryngoscopy were utilized and patients were allocated to treatment pathways depending on putative diagnosis. Speech pathology intervention with laryngeal retraining (LR) was offered and if LR therapy failed botulinum toxin injection was offered. Primary outcome was reductions in healthcare utilization. RESULTS: Overall, 80 consecutive patients were included in analyses. A definitive diagnosis of VCD was made in 56 of 80 (70%) patients. After LR (n = 35), emergency department (ED)/hospital admissions declined significantly in the subsequent 12 months (P = 0.001). General practice visits also reduced (P < 0.001). Botulinum toxin injections were administered in 21 patients unresponsive to LR therapy and both general practice and ED/hospital visits declined (P < 0.001 and P = 0.01, respectively) after injection. CONCLUSION: A multidisciplinary approach to VCD confers benefit and can be used to allocate appropriate management leading to a reduction in healthcare utilization.

Assessment of cerebrovascular development and intraventricular hemorrhages in preterm infants with optical measures of the brain arterial pulse wave.

Preterm infants (born at 24-34 weeks of gestational age) suffer from a high incidence of neurological complications. Cerebrovascular lesions (intraventricular hemorrhages, IVH, and ischemic injury) due to the immaturity of the vascular system and its inability to adapt to the extra-uterine environment are the major causes of adverse neurological outcomes. We investigated the feasibility of assessing cerebrovascular status in preterm infants using a novel non-invasive optical procedure, pulse-DOT, usable within the incubator. Pulse-DOT, validated in adults, provides estimates of cerebral arterial status based on optical measurements of the pulse wave. These measurements are taken with a high-density optode montage and provide accurate spatial and temporal information. We found that two pulse parameters (pulse relaxation function, PReFx, and pulse rise time, PRT) in the investigated frontotemporal region, correlated with infant's age at recording, indexing cerebrovascular development. Moreover, PRT differentiated infants with and without concurrent IVH (sensitivity = 100%, specificity = 70%). These values are at least as high as those of the resistivity index obtained with transcranial Doppler of the middle cerebral artery, the current clinical method of choice for investigating arterial elasticity in preterm infants. This makes pulse-DOT a promising tool for investigating cerebrovascular risk factors and related pathologies in preterm infants.

General anesthesia / sedation requirement influences the way MRI brain scans are ordered in a tertiary pediatric hospital.

BACKGROUND: MRI guidelines have been created to help clinicians order scans appropriately. Some scans in children are carried out under general anesthesia (GA) / sedation. PURPOSE: To evaluate if the requirement for GA/sedation influences the way MRI brain scans are ordered. STUDY TYPE: Retrospective. POPULATION: Children with MRI brain scans in 2015 to 2017. FIELD STRENGTH: 3T, 1.5T. ASSESSMENT: Institutional Review Board approval for waiver of consent was obtained. Clinical MRI brain reports for children were classified into whether they conformed to the American College of Radiology (ACR) 2013 guidelines by research assistants under supervision of a pediatric radiologist. Scans were sorted into those with normal brains or abnormality. STATISTICAL TEST: The statistical difference between groups was assessed using t-test for continuous variables and chi-square test for categorical variables with IBM SPSS 19. RESULTS: Of the total 1893 MRI scans, 431 were performed under GA and six under sedation. Of the 431 cases performed under GA/sedation, 383 (87.6%) were ordered according to guidelines. Of the 1456 cases that did not require GA/sedation, 710 (48.8%) conformed to guidelines. The percentage of scans ordered according to guidelines was 38.8% higher in those who had scans performed under GA/sedation (P < 0.001). MRI scans were normal in 635 (58.0%) out of the 1093 cases ordered according to guidelines and normal in 638 (79.8%) out of the 800 cases that did not follow guidelines. Scans not ordered according to guidelines had higher proportion of normal scans (21.8%) compared with those ordered according to guidelines (P < 0.001). DATA CONCLUSION: Higher adherence to imaging guidelines is seen in younger patients who were exposed to the risks of GA/sedation for the MRI. Scans not adhering to guidelines had a higher percentage of having no brain abnormality detected. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019;49:e250-e255.

The Optical Effective Attenuation Coefficient as an Informative Measure of Brain Health in Aging.

Aging is accompanied by widespread changes in brain tissue. Here, we hypothesized that head tissue opacity to near-infrared light provides information about the health status of the brain's cortical mantle. In diffusive media such as the head, opacity is quantified through the Effective Attenuation Coefficient (EAC), which is proportional to the geometric mean of the absorption and reduced scattering coefficients. EAC is estimated by the slope of the relationship between source-detector distance and the logarithm of the amount of light reaching the detector (optical density). We obtained EAC maps across the head in 47 adults (age range 18-75 years), using a high-density dual-wavelength optical system. We correlated regional and global EAC measures with demographic, neuropsychological, structural and functional brain data. Results indicated that EAC values averaged across wavelengths were strongly associated with age-related changes in cortical thickness, as well as functional and neuropsychological measures. This is likely because the EAC largely depends on the thickness of the sub-arachnoid cerebrospinal fluid layer, which increases with cortical atrophy. In addition, differences in EAC values between wavelengths were correlated with tissue oxygenation and cardiorespiratory fitness, indicating that information about cortical health can be derived non-invasively by quantifying the EAC.

Dysfunctional breathing is more frequent in chronic obstructive pulmonary disease than in asthma and in health.

Involuntary adaptations of breathing patterns to counter breathlessness may lead to dysfunctional breathing in obstructive lung diseases. However, no studies examining dysfunctional breathing in Chronic Obstructive Pulmonary Disease (COPD) have been reported. Patients with verified COPD (n=34), asthma (n=37) and a healthy control group (n=41) were recruited. All participants completed the Nijmegen questionnaire for dysfunctional breathing as well as measures of disease activity. Comparisons between groups employed analysis of variance with post-hoc Bonferroni analyses and Pearson correlation for associations. Patients with COPD had significantly higher Nijmegen questionnaire scores than asthmatics (COPD: 23.4±10.6 versus 17.3±10.6, p=0.016) and healthy individuals (14.3±9.6, p=0.002). Significantly more patients with COPD had severe dysfunctional breathing with Nijmegen scores >23 (47%; 16/34) compared to asthma (27%; 10/37) and healthy controls (17%; 7/41) respectively (p=0.019). Dysfunctional breathing was detected in ∼50% of patients with COPD, more so than in asthma or health. Strategies to reduce abnormal breathing behaviours may have important benefits for treatment of breathlessness in COPD.

Shedding light on gray(ing) areas: Connectivity and task switching dynamics in aging.

Control-demanding tasks rely on communication among regions of the frontoparietal network, areas that undergo significant age-related decline. Here, we integrate data from brain anatomy, electrophysiology (ERPs), and optical imaging (event-related optical signals, EROS) to characterize the spatial and temporal dynamics of preparatory control processes in middle to old age. Older adults participated in an experiment that required switching between a position and a meaning task (spatial Stroop), a paradigm that has been shown to primarily recruit prefrontal cortex in opposite hemispheres and is thought to involve the corpus callosum (CC). In middle-aged participants, switch trials resulted in greater negativity over F3 early in the preparatory period. Across the whole older adult sample, this switch-related frontal negativity was correlated with reaction time (RT) switch costs and EROS switch-related upregulation in the left middle frontal gyrus (MFG). Anterior CC volume was not directly correlated with switch costs, although CC volume predicted task-dependent coupling of left MFG and right MFG. Crucially, left MFG-seeded lagged cross-correlations revealed task-dependent connectivity; in the right-hemisphere-dependent position task, the timing and strength of switch-related coupling between left MFG and right MFG significantly predicted RT switch costs, even after controlling for age, CC volume, and the F3 switch effect. Together, these results suggest that a strong functional connectivity, likely hinged on the integrity of the underlying structural connections, is critical to being able to meet the demands of shifting processing across hemispheres, and that difficulty engaging such control dynamics leads to suboptimal performance.

Individual differences in regional cortical volumes across the life span are associated with regional optical measures of arterial elasticity.

Aging is often accompanied by changes in brain anatomy and cerebrovascular health. However, the specific relationship between declines in regional cortical volumes and loss of cerebral arterial elasticity is less clear, as only global or very localized estimates of cerebrovascular health have been available. Here we employed a novel tomographic optical method (pulse-DOT) to derive local estimates of cerebral arterial elasticity and compared regional volumetric estimates (obtained with FreeSurfer) with optical arterial elasticity estimates from the same regions in 47 healthy adults (aged 18-75). Between-subject analyses revealed a global correlation between cortical volume and cortical arterial elasticity, which was a significant mediator of the association between age and cortical volume. Crucially, a novel within-subject analysis highlighted the spatial association between regional variability in cortical volumes and arterial elasticity in the same regions. This association strengthened with age. Gains in the predictability of cortical volumes from arterial elasticity data were obtained by sharpening the resolution up to individual cortical regions. These results indicate that some of the variance of sub-clinical age-related brain atrophy is associated with differences in the status of cerebral arteries, and can help explain the unique patterns of brain atrophy found within each individual.