Ernesto J. Sanz-Arigita

Loss of 'Small-World' Networks in Alzheimer's Disease: Graph Analysis of fMRI Resting-State Functional Connectivity

Background Local network connectivity disruptions in Alzheimers disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data. Methodology/Principal Findings 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions. Conclusions/Significance We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

Sleep benefits subsequent hippocampal functioning

Sleep before learning benefits memory encoding through unknown mechanisms. We found that even a mild sleep disruption that suppressed slow-wave activity and induced shallow sleep, but did not reduce total sleep time, was sufficient to affect subsequent successful encoding-related hippocampal activation and memory performance in healthy human subjects. Implicit learning was not affected. Our results suggest that the hippocampus is particularly sensitive to shallow, but intact, sleep.

White matter tract integrity in aging and Alzheimer's disease

The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimers disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied “tract‐based spatial statistics” (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging. Hum Brain Mapp, 2009.

Combining shape and connectivity analysis: an MRI study of thalamic degeneration in Alzheimer's disease.

Alzheimers disease (AD) is associated with neuronal loss not only in the hippocampus and amygdala but also in the thalamus. Anterodorsal, centromedial, and pulvinar nuclei are the main sites of degeneration in AD. Here we combined shape analysis and diffusion tensor imaging (DTI) tractography to study degeneration in AD in the thalamus and its connections. Structural and diffusion tensor MRI scans were obtained from 16 AD patients and 22 demographically similar healthy volunteers. The thalamus, hippocampus, and amygdala were automatically segmented using our locally developed algorithm, and group comparisons were carried out for each surface vertex. We also employed probabilistic diffusion tractography to obtain connectivity measures between individual thalamic voxels and hippocampus/amygdala voxels and to segment the internal medullary lamina (IML). Shape analysis showed significant bilateral regional atrophy in the dorsal-medial part of the thalamus in AD patients compared to controls. Probabilistic tractography demonstrated that these regions are mainly connected with the hippocampus, temporal, and prefrontal cortex. Intrathalamic FA comparisons showed reductions in the anterodorsal region of thalamus. Intrathalamic tractography from this region revealed that the IML was significantly smaller in AD patients than in controls. We suggest that these changes can be attributed to the degeneration of the anterodorsal and intralaminar nuclei, respectively. In addition, based on previous neuropathological reports, ventral and dorsal-medial shape change in the thalamus in AD patients is likely to be driven by IML atrophy. This combined shape and connectivity analysis provides MRI evidence of regional thalamic degeneration in AD.

Resting-state networks in awake five- to eight-year old children

During the first 6–7 years of life children undergo a period of major neurocognitive development. Higher‐order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal‐directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting‐state functional connectivity MRI in 5‐ to 8‐year‐old children in an awake state to identify and characterize resting‐state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher‐order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered. Hum Brain Mapp, 2011.

Consequences of large interindividual variability for human brain atlases: converging macroscopical imaging and microscopical neuroanatomy

In human brain imaging studies, it is common practice to use the Talairach stereotaxic reference system for signifying the convergence of brain function and structure. In nearly all neuroimaging reports, the studied cortical areas are specified further with a Brodmann Area (BA) number. This specification is based upon macroscopic extrapolation from Brodmann’s projection maps into the Talairach atlas rather than upon a real microscopic cytoarchitectonic study. In this review we argue that such a specification of Brodmann area(s) via the Talairach atlas is not appropriate. Cytoarchitectonic studies reviewed in this paper show large interindividual differences in 3-D location of primary sensory cortical areas (visual cortex) as well as heteromodal associational areas (prefrontal cortical areas), even after correction for differences in brain size and shape. Thus, the simple use of Brodmann cortical areas derived from the Talairach atlas can lead to erroneous results in the specification of pertinent BA. This in turn can further lead to wrong hypotheses on brain system(s) involved in normal functions or in specific brain disorders. In addition, we will briefly discuss the different ‘Brodmann’ nomenclatures which are in use for the cerebral cortex.

Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA+: n = 49) and without (MA−: n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA− patients showed increased connectivity in networks involved in motor and visual processes, whereas MA+ patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.

Gender-related differences in functional connectivity in multiple sclerosis

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications. Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function. Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined. Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory (r = −0.6 and r = −0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women. Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.

Cerebral Blood Flow by Using Pulsed Arterial Spin-Labeling in Elderly Subjects with White Matter Hyperintensities

BACKGROUND AND PURPOSE: On MR imaging, white matter hyperintensities (WMH) on T2-weighted images are generally considered as a surrogate marker of ischemic small vessel disease in elderly subjects. Pulsed arterial spin-labeling (PASL) is a noninvasive MR perfusion-weighted technique. We hypothesized that elderly subjects with diffuse confluent WMH should have lower cerebral blood flow (CBF) measurements than subjects with punctiform or beginning confluent WMH. MATERIALS AND METHODS: MR images of 21 subjects (13 women; mean age, 76 years; SD, 5), stratified for the degree of WMH, from a single center within the multinational Leukoaraiosis and Disability (LADIS) study, were investigated. CBF images were obtained by means of quantitative imaging of perfusion by using a single-subtraction second version, with thin-section TI periodic saturation PASL. Values of cortical gray matter, subcortical (including white matter and deep gray matter), and global CBF were calculated. CBF measurements of subjects with diffuse confluent WMH (n = 7) were compared with those of subjects with punctiform or beginning confluent WMH (n = 14). RESULTS: Subjects with diffuse confluent WMH were found to have approximately 20% lower mean global CBF (43.5 mL/100 mL/min; SD, 6.3) than subjects with punctiform or beginning confluent WMH (57.9 mL/100 mL/min; SD, 8.6; P < .01), as well as approximately 20% lower mean subcortical (P < .01) and cortical gray matter CBF (P < .05). CONCLUSION: PASL revealed a significant reduction of CBF measurements in elderly subjects with diffuse confluent WMH.

The caudate: a key node in the neuronal network imbalance of insomnia?

Although insomnia is common and disabling, its neural correlates remain enigmatic. Stoffers et al. use structural and functional MRI to demonstrate that hyperarousal, its clearest characteristic, involves reduced recruitment and connectivity of the left caudate that may predispose to insomnia and perpetuate it.