Trey Hedden

Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease

Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n = 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n = 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimers disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n = 10) compared with older controls (n = 29) showed high amyloid-β deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD.

Insights into the ageing mind: a view from cognitive neuroscience

As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of age-related cognitive changes.

Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization.

Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.

Models of visuospatial and verbal memory across the adult life span

The authors investigated the distinctiveness and interrelationships among visuospatial and verbal memory processes in short-term, working, and long-term memories in 345 adults. Beginning in the 20s, a continuous, regular decline occurs for processing-intensive tasks (e.g., speed of processing, working memory, and long-term memory), whereas verbal knowledge increases across the life span. There is little differentiation in the cognitive architecture of memory across the life span. Visuospatial and verbal working memory are distinct but highly interrelated systems with domain-specific short-term memory subsystems. In contrast to recent neuroimaging data, there is little evidence for dedifferentiation of function at the behavioral level in old compared with young adults. The authors conclude that efforts to connect behavioral and brain data yield a more complete understanding of the aging mind.

Amyloid deposition is associated with impaired default network function in older persons without dementia

Alzheimers disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden

Amyloid deposition is present in 20–50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n = 38, aged 60–88 years) were characterized using 11C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimers disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation.

Aging and the Neural Correlates of Successful Picture Encoding: Frontal Activations Compensate for Decreased Medial-Temporal Activity

We investigated the hypothesis that increased prefrontal activations in older adults are compensatory for decreases in medial-temporal activations that occur with age. Because scene encoding engages both hippocampal and prefrontal sites, we examined incidental encoding of scenes by 14 young and 13 older adults in a subsequent memory paradigm using functional magnetic resonance imaging (fMRI). Behavioral results indicated that there were equivalent numbers of remembered and forgotten items, which did not vary as a function of age. In an fMRI analysis subtracting forgotten items from remembered items, younger and older adults both activated inferior frontal and lateral occipital regions bilaterally; however, older adults showed less activation than young adults in the left and right parahippocampus and more activation than young adults in the middle frontal cortex. Moreover, correlations between inferior frontal and parahippocampal activity were significantly negative for old but not young, suggesting that those older adults who showed the least engagement of the parahippocampus activated inferior frontal areas the most. Because the analyses included only the unique activations associated with remembered items, these data suggest that prefrontal regions could serve a compensatory role for declines in medial-temporal activations with age.

Functional Alterations in Memory Networks in Early Alzheimer’s Disease

The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.

Cultural Influences on Neural Substrates of Attentional Control

Behavioral research has shown that people from Western cultural contexts perform better on tasks emphasizing independent (absolute) dimensions than on tasks emphasizing interdependent (relative) dimensions, whereas the reverse is true for people from East Asian contexts. We assessed functional magnetic resonance imaging responses during performance of simple visuospatial tasks in which participants made absolute judgments (ignoring visual context) or relative judgments (taking visual context into account). In each group, activation in frontal and parietal brain regions known to be associated with attentional control was greater during culturally non-preferred judgments than during culturally preferred judgments. Also, within each group, activation differences in these regions correlated strongly with scores on questionnaires measuring individual differences in culture-typical identity. Thus, the cultural background of an individual and the degree to which the individual endorses cultural values moderate activation in brain networks engaged during even simple visual and attentional tasks.

Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly

Both amyloid‐β (Aβ) deposition and brain atrophy are associated with Alzheimers disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD.