Age-related functional reorganization, structural changes, and preserved cognition.

Although healthy aging is associated with general cognitive decline, there is considerable variability in the extent to which cognitive functions decline or are preserved. Preserved cognitive function in the context of age-related neuroanatomical and functional changes, has been attributed to compensatory mechanisms. However, the existing sparse evidence is largely focused on functions associated with the frontal cortex, leaving open the question of how wider age-related brain changes relate to compensation. We evaluated relationships between age-related neural and functional changes in the context of preserved cognitive function by combining measures of structure, function, and cognitive performance during spoken language comprehension using a paradigm that does not involve an explicit task. We used a graph theoretical approach to derive cognitive activation-related functional magnetic resonance imaging networks. Correlating network properties with age, neuroanatomical variations, and behavioral data, we found that decreased gray matter integrity was associated with decreased connectivity within key language regions but increased overall functional connectivity. However, this network reorganization was less efficient, suggesting that engagement of a more distributed network in aging might be triggered by reduced connectivity within specialized networks

Dominant hemisphere functional networks compensate for structural connectivity loss to preserve phonological retrieval with aging.

INTRODUCTION: Loss of hemispheric asymmetry during cognitive tasks has been previously demonstrated in the literature. In the context of language, increased right hemisphere activation is observed with aging. Whether this relates to compensation to preserve cognitive function or dedifferentiation implying loss of hemispheric specificity without functional consequence, remains unclear. METHODS: With a multifaceted approach, integrating structural and functional imaging data during a word retrieval task, in a group of younger and older adults with equivalent cognitive performance, we aimed to establish whether interactions between hemispheres or reorganization of dominant hemisphere networks preserve function. We examined functional and structural connectivity on data from our previously published functional activation study. Functional connectivity was measured using psychophysiological interactions analysis from the left inferior frontal gyrus (LIFG) and the left insula (LINS), based on published literature, and the right inferior frontal gyrus (RIFG) based on our previous study. RESULTS: Although RIFG showed increased activation, its connectivity decreased with age. Meanwhile, LIFG and LINS connected more bilaterally in the older adults. White matter integrity, measured by fractional anisotropy (FA) from diffusion tensor imaging, decreased significantly in the older group. Importantly, LINS functional connectivity to LIFG correlated inversely with FA. CONCLUSIONS: We demonstrate that left hemispheric language areas show higher functional connectivity in older adults with intact behavioral performance, and thus, may have a role in preserving function. The inverse correlation of functional and structural connectivity with age is in keeping with emerging literature and merits further investigation with tractography studies and in other cognitive domains

Combined effect of lead exposure and allostatic load on cardiovascular disease mortality-a preliminary study

This study explores the combined effect of lead (Pb) exposure and an index of chronic physiological stress on cardiovascular disease mortality using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2008 linked to 1999-2014 National Death Index data. Chronic physiological stress was measured using the allostatic load (AL) index, which was formed by analyzing markers from the cardiovascular, inflammatory, and metabolic systems, with Pb levels, assessed using blood lead levels (BLL). The dataset was analyzed with statistical techniques to explore (a) the relationship between Pb exposure and AL, and (b) the combined role of Pb and AL on cardiovascular disease mortality. Results indicated that AL was more elevated in those with BLLs above the 50th percentile in the US population and that those with elevated AL were more likely to have high BLL. Finally, the interaction of AL and BLL significantly increased the likelihood of cardiovascular disease mortality. These findings highlight the need for considering the totality of exposures experienced by populations to build holistic programs to prevent Pb exposure and reduce stressors to promote optimal health outcomes and reduce cardiovascular mortality risk

Altered Resting Functional Connectivity Is Related to Cognitive Outcome in Males With Moderate-Severe Traumatic Brain Injury.

TBI results in significant cognitive impairments and in altered brain functional connectivity. However, no studies explored so far, the relationship between global functional connectivity and cognitive outcome in chronic moderate-severe TBI. This proof of principle study employed the intrinsic connectivity contrast, an objective voxel-based metric of global functional connectivity, in a small sample of chronic moderate-severe TBI participants and a group of healthy controls matched on gender (males), age, and education. Cognitive tests assessing executive functions, verbal memory, visual memory, attention/organization, and cognitive reserve were administered. Group differences in terms of global functional connectivity maps were assessed and the association between performance on the cognitive measures and global functional connectivity was examined. Next, we investigated the spatial extent of functional connectivity in the brain regions found to be associated with cognitive performance, using traditional seed-based analyses. Global functional connectivity of the TBI group was altered, compared to the controls. Moreover, the strength of global functional connectivity in affected brain areas was associated with cognitive outcome. These findings indicate that impaired global functional connectivity is a significant consequence of TBI suggesting that cognitive impairments following TBI may be partly attributed to altered functional connectivity between brain areas involved in the specific cognitive functions

White matter changes and word finding failures with increasing age.

BACKGROUND: Increasing life expectancy necessitates the better understanding of the neurophysiological underpinnings of age-related cognitive changes. The majority of research examining structural-cognitive relationships in aging focuses on the role of age-related changes to grey matter integrity. In the current study, we examined the relationship between age-related changes in white matter and language production. More specifically, we concentrated on word-finding failures, which increase with age. METHODOLOGY/PRINCIPAL FINDINGS: We used Diffusion tensor MRI (a technique used to image, in vivo, the diffusion of water molecules in brain tissue) to relate white matter integrity to measures of successful and unsuccessful picture naming. Diffusion tensor images were used to calculate Fractional Anisotropy (FA) images. FA is considered to be a measure of white matter organization/integrity. FA images were related to measures of successful picture naming and to word finding failures using voxel-based linear regression analyses. Successful naming rates correlated positively with white matter integrity across a broad range of regions implicated in language production. However, word finding failure rates correlated negatively with a more restricted region in the posterior aspect of superior longitudinal fasciculus. CONCLUSIONS/SIGNIFICANCE: The use of DTI-MRI provides evidence for the relationship between age-related white matter changes in specific language regions and word finding failures in old age

A comparison of functional and tractography based networks in cerebral small vessel disease.

OBJECTIVE: MRI measures of network integrity may be useful disease markers in cerebral small vessel disease (SVD). We compared the sensitivity and reproducibility of MRI derived structural and functional network measures in healthy controls and SVD subjects. METHODS: Diffusion tractography and resting state fMRI were used to create connectivity matrices from 26 subjects with symptomatic MRI confirmed lacunar stroke and 19 controls. Matrices were constructed at multiple scales based on a multi-resolution cortical atlas and at multiple thresholds for the matrix density. Network parameters were calculated over the multiple resolutions and thresholds. In addition the reproducibility of structural and functional network parameters was determined in a subset of the subjects (15 SVD, 10 controls) who were scanned twice. RESULTS: Structural networks showed a highly significant loss of network integrity in SVD cases compared to controls, for all network measures. In contrast functional networks showed no difference between SVD and controls. Structural network measures were highly reproducible in both cases and controls, with ICC values consistently over 0.8. In contrast functional network measures showed much poorer reproducibility with ICC values in the range 0.4-0.6 overall, and even lower in SVD cases. CONCLUSIONS: Structural networks identify impaired network integrity, and are highly reproducible, in SVD, supporting their use as markers of SVD disease severity. In contrast, functional networks showed low reproducibility, particularly in SVD cases, and were unable to detect differences between SVD cases and controls with this sample size

Changes in resting neural connectivity during propofol sedation.

BACKGROUND: The default mode network consists of a set of functionally connected brain regions (posterior cingulate, medial prefrontal cortex and bilateral parietal cortex) maximally active in functional imaging studies under "no task" conditions. It has been argued that the posterior cingulate is important in consciousness/awareness, but previous investigations of resting interactions between the posterior cingulate cortex and other brain regions during sedation and anesthesia have produced inconsistent results. METHODOLOGY/PRINCIPAL FINDINGS: We examined the connectivity of the posterior cingulate at different levels of consciousness. "No task" fMRI (BOLD) data were collected from healthy volunteers while awake and at low and moderate levels of sedation, induced by the anesthetic agent propofol. Our data show that connectivity of the posterior cingulate changes during sedation to include areas that are not traditionally considered to be part of the default mode network, such as the motor/somatosensory cortices, the anterior thalamic nuclei, and the reticular activating system. CONCLUSIONS/SIGNIFICANCE: This neuroanatomical signature resembles that of non-REM sleep, and may be evidence for a system that reduces its discriminable states and switches into more stereotypic patterns of firing under sedation

Delta band activity contributes to the identification of command following in disorder of consciousness.

The overt or covert ability to follow commands in patients with disorders of consciousness is considered a sign of awareness and has recently been defined as cortically mediated behaviour. Despite its clinical relevance, the brain signatures of the perceptual processing supporting command following have been elusive. This multimodal study investigates the temporal spectral pattern of electrical brain activity to identify features that differentiated healthy controls from patients both able and unable to follow commands. We combined evidence from behavioural assessment, functional neuroimaging during mental imagery and high-density electroencephalography collected during auditory prediction, from 21 patients and 10 controls. We used a penalised regression model to identify command following using features from electroencephalography. We identified seven well-defined spatiotemporal signatures in the delta, theta and alpha bands that together contribute to identify DoC subjects with and without the ability to follow command, and further distinguished these groups of patients from controls. A fine-grained analysis of these seven signatures enabled us to determine that increased delta modulation at the frontal sensors was the main feature in command following patients. In contrast, higher frequency theta and alpha modulations differentiated controls from both groups of patients. Our findings highlight a key role of spatiotemporally specific delta modulation in supporting cortically mediated behaviour including the ability to follow command. However, patients able to follow commands nevertheless have marked differences in brain activity in comparison with healthy volunteers

Default Mode Contributions to Automated Information Processing

Concurrent with mental processes that require rigorous computation and control, a series of automated decisions and actions govern our daily lives, providing efficient and adaptive responses to environmental demands. Using a cognitive flexibility task, we show that a set of brain regions collectively known as the default mode network play a crucial role in such “autopilot” behavior, i.e. when rapidly selecting appropriate responses under predictable behavioral contexts. While applying learned rules, the default mode network shows both greater activity and connectivity. Furthermore, functional interactions between this network and hippocampal, parahippocampal areas as well as primary visual cortex correlate with the speed of accurate responses. These findings indicate a memory-based “autopilot role” for the default mode network, which may have important implications for our current understanding of healthy and adaptive brain processing

Examining associations between physical activity and cardiovascular mortality using negative control outcomes

Background: The purpose of a negative control is to reproduce a condition that cannot involve the hypothesized causal mechanism, but does involve the same sources of bias and confounding that may distort the primary association of interest. Observational studies suggest physical inactivity is a major risk factor for cardiovascular disease (CVD) although potential sources of bias, including reverse causation and residual confounding, make it difficult to infer causality. The aim was to employ a negative control outcome to explore the extent to which the association between physical activity and CVD mortality is explained by confounding. Methods: The sample comprised 104,851 participants (aged 47 ± 17 yrs; 45.4% male) followed up over mean [SD] 9.4±4.5 years, recruited from The Health Survey for England and the Scottish Health Surveys. Results: There were 10,309 deaths, of which 3,109 were attributed to CVD, and 157 to accidents (negative control outcome). Accidental death was related to age, male sex, smoking, longstanding illness and psychological distress, with some evidence of social patterning. This confounding structure was similar to that seen with CVD mortality, suggesting that our negative control outcome was appropriate. Physical activity (per SD unit increase in MET-hr-wk) was inversely associated with CVD (HR=0.75; 95% CI, 0.70, 0.80); the point estimate between physical activity and accidental death was in the same direction but of lesser magnitude (HR=0.86; 0.69, 1.07). A linear dose-response pattern was observed for physical activity and CVD but not with the negative control. Conclusions: Inverse associations between physical activity and risk of CVD mortality are likely causal but of a smaller magnitude than commonly observed. Negative control studies have potential to improve causal inference within the physical activity field