Functional brain connectivity and cognition: effects of adult age and task demands

Previous neuroimaging research has documented that patterns of intrinsic (resting state) functional connectivity (FC) among brain regions covary with individual measures of cognitive performance. Here, we examined the relation between intrinsic FC and a reaction time (RT) measure of performance, as a function of age group and task demands. We obtained filtered, event-related functional magnetic resonance imaging data, and RT measures of visual search performance, from 21 younger adults (19–29 years old) and 21 healthy, older adults (60–87 years old). Age-related decline occurred in the connectivity strength in multiple brain regions, consistent with previous findings. Among 8 pairs of regions, across somatomotor, orbitofrontal, and subcortical networks, increasing FC was associated with faster responding (lower RT). Relative to younger adults, older adults exhibited a lower strength of this RT-connectivity relation and greater disruption of this relation by a salient but irrelevant display item (color singleton distractor). Age-related differences in the covariation of intrinsic FC and cognitive performance vary as a function of task demands.     

Influence of functional connectivity and structural MRI measures on episodic memory

Age-related memory decline is the consequence of multiple biological factors that lead to brain structural and functional change, including gray matter atrophy, white matter injury, and loss of functional coordination between regions. However, the independent roles that each of these brain changes play in mediating memory decline is not clear. Therefore, we used magnetic resonance imaging (MRI) to measure gray matter (GM) volume, white matter hyperintensity (WMH) volumes, and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging-based functional connectivity among default mode network nodes in 76 cognitive normal older adults. We found that GM, WMH, and connectivity between left inferior parietal and medial prefrontal cortex (MPF_LIP) were independently associated with episodic memory performance. Within the group with GM volumes below the median, greater MPF_LIP connectivity was associated with better memory performance, whereas this association was not present for individuals with GM volume above the median. These findings confirm the heterogeneous nature of brain-behavior relationships in cognitive aging. In addition, the relationship between resting state functional connectivity and memory performance, particularly amongst those individuals with more brain atrophy, strongly suggests compensation against the effects of neuronal injury.     

Adult age differences in the functional neuroanatomy of visual attention: a combined fMRI and DTI study

We combined measures from event-related functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and cognitive performance (visual search response time) to test the hypotheses that differences between younger and older adults in top-down (goal-directed) attention would be related to cortical activation, and that white matter integrity as measured by DTI (fractional anisotropy, FA) would be a mediator of this age-related effect. Activation in frontal and parietal cortical regions was overall greater for older adults than for younger adults. The relation between activation and search performance supported the hypothesis of age differences in top-down attention. When the task involved top-down control (increased target predictability), performance was associated with frontoparietal activation for older adults, but with occipital (fusiform) activation for younger adults. White matter integrity (FA) exhibited an age-related decline that was more pronounced for anterior brain regions than for posterior regions, but white matter integrity did not specifically mediate the age-related increase in activation of the frontoparietal attentional network.     

Measurement of spontaneous signal fluctuations in fMRI: adult age differences in intrinsic functional connectivity

Functional connectivity (FC) reflects the coherence of spontaneous, low-frequency fluctuations in functional magnetic resonance imaging (fMRI) data. We report a behavior-based connectivity analysis method, in which whole-brain data are used to identify behaviorally relevant, intrinsic FC networks. Nineteen younger adults (20–28 years) and 19 healthy, older adults (63–78 years) were assessed with fMRI and diffusion tensor imaging (DTI). Results indicated that FC involving a distributed network of brain regions, particularly the inferior frontal gyri, exhibited age-related change in the correlation with perceptual-motor speed (choice reaction time; RT). No relation between FC and RT was evident for younger adults, whereas older adults exhibited a significant age-related slowing of perceptual-motor speed, which was mediated by decreasing FC. Older adults’ FC values were in turn associated positively with white matter integrity (from DTI) within the genu of the corpus callosum. The developed FC analysis illustrates the value of identifying connectivity by combining structural, functional, and behavioral data.     

基于独立成分分析和时间相关分析的脑功能连通研究方法

目的：利用静息状态功能磁共振成像（functional magnetic resonance imaging，fMRI）技术，提出联合独立成分分析（independent component analysis，ICA）和时间相关分析的人脑功能连通性研究方法。方法：首先采用空间ICA定位任务激活的脑区；然后选择一个激活区作为感兴趣区域（region of interest，ROI），采用时间相关分析方法检测静息状态大脑特定皮层的功能连通性，并通过检测人脑运动皮层的功能连通性验证方法的有效性。结果：大脑运动皮层功能连通网络包括初级运动区、辅助运动区、初级感觉皮层、背侧前运动区和后顶骨体觉区。实验结果表明，静息状态下。时间相关分析检测到的运动皮层的功能连通网络与已知的解剖连通相一致。结论：利用静息fMRI。结合空间ICA和时间相关分析方法。检测了静息时人脑运动皮层的功能连通网络。为脑区间功能连通的研究提供了一种简便的、无损的、有效的研究方法。     

基于独立成分分析和时间相关分析的脑功能连通研究方法[英文]

目的:利用静息状态功能磁共振成像(functional magnetic resonance imaging,fMRI)技术,提出联合独立成分分析(independent component analysis,ICA)和时间相关分析的人脑功能连通性研究方法。方法:首先采用空间ICA定位任务激活的脑区;然后选择一个激活区作为感兴趣区域(region of interest,ROI),采用时间相关分析方法检测静息状态大脑特定皮层的功能连通性,并通过检测人脑运动皮层的功能连通性验证方法的有效性。结果:大脑运动皮层功能连通网络包括初级运动区、辅助运动区、初级感觉皮层、背侧前运动区和后顶骨体觉区。实验结果表明,静息状态下,时间相关分析检测到的运动皮层的功能连通网络与已知的解剖连通相一致。结论:利用静息fMRI,结合空间ICA和时间相关分析方法,检测了静息时人脑运动皮层的功能连通网络,为脑区间功能连通的研究提供了一种简便的、无损的、有效的研究方法。     

Dopamine and frontostriatal networks in cognitive aging

Recent studies have linked dopamine to differences in behavior and brain activity in normal individuals. We explored these relationships in older and younger adults by investigating how functional connectivity between the striatum and prefrontal cortex is related to caudate dopamine and verbal working memory task performance. We studied 12 young and 18 older participants with functional magnetic resonance imaging (fMRI) during this task, and used positron emission tomography with the tracer 6-[¹⁸F]-fluoro-L-m-tyrosine (FMT) to assess dopamine synthesis capacity. Younger adults had a greater extent of frontal caudate functional connectivity during the load-dependent delay period of the working memory task than the older participants. Across all subjects, the extent of this functional connectivity was negatively correlated with dopamine synthesis capacity, such that participants with the greatest connectivity had the lowest caudate 6-[¹⁸F]-fluoro-L-m-tyrosine (FMT) signal. Additionally, the extent of functional connectivity was positively correlated with working memory performance. Overall these data suggest interdependencies exist between frontostriatal functional connectivity, dopamine, and working memory performance and that this system is functioning suboptimally in normal aging.     

Age-related decline in functional connectivity of the vestibular cortical network

In the elderly, major complaints include dizziness and an increasing number of falls, possibly related to an altered processing of vestibular sensory input. In this study, we therefore investigate age-related changes induced by processing of vestibular sensory stimulation. While previous functional imaging studies of healthy aging have investigated brain function during task performance or at rest, we used galvanic vestibular stimulation during functional MRI in a task-free sensory stimulation paradigm to study the effect of healthy aging on central vestibular processing, which might only become apparent during stimulation processing. Since aging may affect signatures of brain function beyond the BOLD-signal amplitude—such as functional connectivity or temporal signal variability—we employed independent component analysis and partial least squares analysis of temporal signal variability. We tested for age-associated changes unrelated to vestibular processing, using a motor paradigm, voxel-based morphometry and diffusion tensor imaging. This allows us to control for general age-related modifications, possibly originating from vascular, atrophic or structural connectivity changes. Age-correlated decreases of functional connectivity and increases of BOLD-signal variability were associated with multisensory vestibular networks. In contrast, no age-related functional connectivity changes were detected in somatosensory networks or during the motor paradigm. The functional connectivity decrease was not due to structural changes but to a decrease in response amplitude. In synopsis, our data suggest that both the age-dependent functional connectivity decrease and the variability increase may be due to deteriorating reciprocal cortico-cortical inhibition with age and related to multimodal vestibular integration of sensory inputs.     

Changes of functional connectivity of the motor network in the resting state in Parkinson's disease

We used functional MRI (fMRI) and a network model based on graph theory to measure functional connectivity of brain motor network in the resting state in patients with Parkinson's disease (PD). FMRIs were acquired in 22 PD patients before and after levodopa administration, and in age- and sex-matched normal controls. The total connectivity degree of each region within the motor network was calculated and compared between patients and controls. We found that PD patients at off state had significantly decreased functional connectivity in the supplementary motor area, left dorsal lateral prefrontal cortex and left putamen, and had increased functional connectivity in the left cerebellum, left primary motor cortex, and left parietal cortex compared to normal subjects. Administration of levodopa relatively normalized the pattern of functional connectivity in PD patients. The functional connectivity in most of regions in the motor network correlated with the Unified Parkinson's Disease Rating Scale motor score in the patients. Our findings demonstrate that the pattern of functional connectivity of the motor network in the resting state is disrupted in PD. This change is secondary to dopamine deficiency, and related to the severity of the disease. We postulate that this abnormal functional connectivity of motor network in the baseline state is possibly an important factor contributing to some motor deficits in PD, e.g. akinesia.     

Caffeine alters resting‐state functional connectivity measured by blood oxygenation level‐dependent MRI

This study aimed to investigate the pharmacological effect of caffeine on functional connectivity measured by resting‐state blood oxygenation level‐dependent (BOLD) MRI in the motor cortex, visual cortex and default mode network (DMN). The protocols and procedures of the study were reviewed and approved by the Institutional Review Board of our institution. On a 3‐T clinical MR system, 20 healthy volunteers underwent imaging before and after oral ingestion of a 200‐mg over‐the‐counter caffeine pill (data from three individuals were excluded from further analysis because of excessive motion). The demographics of the remaining participants were as follows: female/male, 8/9; age, 21–35 years; non‐habitual caffeine consumers over the past 6 months. Functional connectivity was calculated using the general linear model, assessed in terms of connected area (voxels) and statistical significance (Student t‐values), and correlated with changes in regional cerebral blood flow as measured by arterial spin labeling MRI. Per‐subject data analysis showed that caffeine decreased functional connectivity in the motor/visual cortices, but its effects on DMN varied among subjects. Correlation analysis of the changes in functional connectivity and regional blood flow suggested that the effect of caffeine on BOLD functional connectivity was predominantly neural (motor/visual cortices) and partly vascular (DMN). Group analysis showed that, after caffeine ingestion, DMN involved more attentional networks, and more extrastriate areas were integrated into the functional connectivity of the visual cortex, which may be associated with the known pharmacological effect of caffeine in elevating alertness. Caffeine consumption should thus be considered in the experimental design and data interpretation of functional connectivity studies using resting‐state BOLD MRI. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

EEG Signatures of Dynamic Functional Network Connectivity States

The human brain operates by dynamically modulating different neural populations to enable goal directed behavior. The synchrony or lack thereof between different brain regions is thought to correspond to observed functional connectivity dynamics in resting state brain imaging data. In a large sample of healthy human adult subjects and utilizing a sliding windowed correlation method on functional imaging data, earlier we demonstrated the presence of seven distinct functional connectivity states/patterns between different brain networks that reliably occur across time and subjects. Whether these connectivity states correspond to meaningful electrophysiological signatures was not clear. In this study, using a dataset with concurrent EEG and resting state functional imaging data acquired during eyes open and eyes closed states, we demonstrate the replicability of previous findings in an independent sample, and identify EEG spectral signatures associated with these functional network connectivity changes. Eyes open and eyes closed conditions show common and different connectivity patterns that are associated with distinct EEG spectral signatures. Certain connectivity states are more prevalent in the eyes open case and some occur only in eyes closed state. Both conditions exhibit a state of increased thalamocortical anticorrelation associated with reduced EEG spectral alpha power and increased delta and theta power possibly reflecting drowsiness. This state occurs more frequently in the eyes closed state. In summary, we find a link between dynamic connectivity in fMRI data and concurrently collected EEG data, including a large effect of vigilance on functional connectivity. As demonstrated with EEG and fMRI, the stationarity of connectivity cannot be assumed, even for relatively short periods.     

Morphometric and functional connectivity changes in the brain of patients with obstructive sleep apnea: A meta‐analysis

Existing evidence for brain morphometric changes and functional connectivity alterations in patients with obstructive sleep apnea is mixed. The current study aimed to meta‐analyse the neuroimaging data, and thus synthesize a brain map showing locations with morphometric and functional connectivity differences between patients with obstructive sleep apnea and controls. Published studies to 2018 were retrieved and included into the analysis if they reported such between‐group differences using voxel‐based morphometry or resting‐state functional magnetic resonance imaging, and reported the results in the form of brain coordinates based on whole‐brain analysis. Twelve voxel‐based morphometry and seven resting‐state functional magnetic resonance imaging studies that comprised a total of 1,113 participants fulfilled the inclusion criteria. Compared with healthy controls, patients with obstructive sleep apnea had reduced resting‐state connectivity in the right anterior cingulate and larger grey matter volume in the right insula. Patients with obstructive sleep apnea do have morphometric and resting‐state connectivity alterations in the brain. These neural correlates may help explain the effects of obstructive sleep apnea on the emotion, cognition and quality of life of patients, and may be used in future for evaluating its treatment outcome.     

Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion,quantitative magnetization transfer and functional magnetic resonance imaging

Spinal cord injuries (SCIs) are a leading cause of disability and can severely impact the quality of life. However, to date, the processes of spontaneous repair of damaged spinal cord remain incompletely understood, partly due to a lack of appropriate longitudinal tracking methods. Noninvasive, multiparametric magnetic resonance imaging (MRI) provides potential biomarkers for the comprehensive evaluation of spontaneous repair after SCI. In this study in rats, a clinically relevant contusion injury was introduced at the lumbar level that impairs both hindlimb motor and sensory functions. Quantitative MRI measurements were acquired at baseline and serially post‐SCI for up to 2 wk. The progressions of injury and spontaneous recovery in both white and gray matter were tracked longitudinally using pool‐size ratio (PSR) measurements derived from quantitative magnetization transfer (qMT) methods, measurements of water diffusion parameters using diffusion tensor imaging (DTI) and intrasegment functional connectivity derived from resting state functional MRI. Changes in these quantitative imaging measurements were correlated with behavioral readouts. We found (a) a progressive decrease in PSR values within 2 wk post‐SCI, indicating a progressive demyelination at the center of the injury that was validated with histological staining, (b) PSR correlated closely with fractional anisotropy and transverse relaxation of free water, but did not show significant correlations with behavioral recovery, and (c) preliminary evidence that SCI induced a decrease in functional connectivity between dorsal horns below the injury site at 24 h. Findings from this study not only confirm the value of qMT and DTI methods for assessing the myelination state of injured spinal cord but indicate that they may also have further implications on whether therapies targeted towards remyelination may be appropriate. Additionally, a better understanding of changes after SCI provides valuable information to guide and assess interventions.     

Changes in whole-brain functional networks and memory performance in aging

We used resting-functional magnetic resonance imaging data from 98 healthy older adults to analyze how local and global measures of functional brain connectivity are affected by age, and whether they are related to differences in memory performance. Whole-brain networks were created individually by parcellating the brain into 90 cerebral regions and obtaining pairwise connectivity. First, we studied age-associations in interregional connectivity and their relationship with the length of the connections. Aging was associated with less connectivity in the long-range connections of fronto-parietal and fronto-occipital systems and with higher connectivity of the short-range connections within frontal, parietal, and occipital lobes. We also used the graph theory to measure functional integration and segregation. The pattern of the overall age-related correlations presented positive correlations of average minimum path length (r = 0.380, p = 0.008) and of global clustering coefficients (r = 0.454, p < 0.001), leading to less integrated and more segregated global networks. Main correlations in clustering coefficients were located in the frontal and parietal lobes. Higher clustering coefficients of some areas were related to lower performance in verbal and visual memory functions. In conclusion, we found that older participants showed lower connectivity of long-range connections together with higher functional segregation of these same connections, which appeared to indicate a more local clustering of information processing. Higher local clustering in older participants was negatively related to memory performance.     

A preliminary study of functional connectivity in comorbid adolescent depression

Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD (n = 12) and healthy adolescents (n = 14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD.     

Sleep and resting‐state functional magnetic resonance imaging connectivity in middle‐aged adults and the elderly: A population‐based study

Sleep problems increase with ageing. Increasing evidence suggests that sleep problems are not only a consequence of age‐related processes, but may independently contribute to developing vascular or neurodegenerative brain disease. Yet, it remains unclear what mechanisms underlie the impact sleep problems may have on brain health in the general middle‐aged and elderly population. Here, we studied sleep's relation to brain functioning in 621 participants (median age 62 years, 55% women) from the population‐based Rotterdam Study. We investigated cross‐sectional associations of polysomnographic and subjectively measured aspects of sleep with intrinsic neural activity measured with resting‐state functional magnetic resonance imaging on a different day. We investigated both functional connectivity between regions and brain activity (blood‐oxygen‐level‐dependent signal amplitude) within regions, hierarchically towards smaller topographical levels. We found that longer polysomnographic total sleep time is associated with lower blood‐oxygen‐level‐dependent signal amplitude in (pre)frontal regions. No objective or subjective sleep parameters were associated with functional connectivity between or within resting‐state networks. The findings may indicate a pathway through which sleep, in a ‘real‐life’ population setting, impacts brain activity or regional brain activity determines total sleep time.     

Evidence for motor cortex dedifferentiation in older adults

Older adults (OA) show more diffuse brain activity than young adults (YA) during the performance of cognitive, motor, and perceptual tasks. It is unclear whether this overactivation reflects compensation or dedifferentiation. Typically, these investigations have not evaluated the organization of the resting brain, which can help to determine whether more diffuse representations reflect physiological or task-dependent effects. In the present study we used transcranial magnetic stimulation (TMS) to determine whether there are differences in motor cortex organization of both brain hemispheres in young and older adults. We measured resting motor threshold, motor evoked potential (MEP) latency and amplitude, and extent of first dorsal interosseous representations, in addition to a computerized measure of reaction time. There was no significant age difference in motor threshold, but we did find that OA had larger contralateral MEP amplitudes and a longer contralateral MEP latency. Furthermore, the spatial extent of motor representations in OA was larger. We found that larger dominant hemisphere motor representations in OA were associated with higher reaction times, suggesting dedifferentiation rather than compensation effects.     

Combining structural and functional neuroimaging data for studying brain connectivity: a review

Different brain areas are thought to be integrated into large-scale networks to support cognitive function. Recent approaches for investigating structural organization and functional coordination within these networks involve measures of connectivity among brain areas. We review studies combining in vivo structural and functional brain connectivity data, where (a) structural connectivity analysis, mostly based on diffusion tensor imaging is paired with voxel-wise analysis of functional neuroimaging data or (b) the measurement of functional connectivity based on covariance analysis is guided/aided by structural connectivity data. These studies provide insights into the relationships between brain structure and function. Promising trends involve (a) studies where both functional and anatomical connectivity data are collected using high-resolution neuroimaging methods and (b) the development of advanced quantitative models of integration.     

Aging influence on functional connectivity of the motor network in the resting state

We used functional MRI (fMRI) to study the aging influence on functional connectivity of the motor network in the resting state. A network model based on graph theory was used to measure functional connectivity. The total connectivity degree of each region within the motor network was calculated and compared between aged and young groups. We found that the pattern of functional connectivity was changed in aged subjects, including a significant decrease in the functional connectivity degree of the right cingulate motor area and left premotor area compared to young subjects. Our study demonstrates that normal aging modulates the functional connectivity of motor network in the resting state. We postulate that this abnormal functional connectivity of motor network in the baseline state is an important reason contributing to the deteriorated motor ability in aged subjects.