Martin Ystad

Subcortical functional connectivity and verbal episodic memory in healthy elderly--a resting state fMRI study.

Imaging research into age-related changes in episodic memory has mainly focused on changes in cortical areas in the medial temporal lobe and the hippocampus. However, several lines of evidence indicate that subcortical structures such as the basal ganglia and the thalamus are also involved in episodic memory function. Recent studies have revealed age-related changes in functional connectivity between different brain areas, as measured by resting state fMRI. It remains to be shown whether functional connectivity measures in the basal ganglia and the thalamus can be associated with age-related changes in memory function. Here, we investigate this question by applying high model order spatial independent component analysis to resting state fMRI data in a cohort of 100 healthy elderly and relate connectivity features to verbal episodic memory function as assessed by the California Verbal Learning Test (CVLT). We identified five components that were located within different parts of the thalamus and the basal ganglia. Two of these components demonstrated negative correlations between their functional connectivity level and CVLT performance. We also found negative correlations between connectional strength within subcortical structures and CVLT performance. These results indicate a previously undocumented role for the putamen and the thalamus in verbal episodic memory function in aging.

Cortico-striatal connectivity and cognition in normal aging: a combined DTI and resting state fMRI study.

Resting state fMRI studies have found that cognitive decline in aging is associated with alterations in functional connectivity of distributed neural systems in the brain. While functional connections have been shown to rely on the underlying structural connectivity, direct structural connections have been studied in only a few distributed cortical systems so far. It is well known that subcortical nuclei have structural connections to the entire cortex. We hypothesized that structural subcortico-cortical connections may provide integral routes for communication between cortical resting state networks, and that changes in the integrity of these connections have a role in cognitive aging. We combined anatomical MRI, diffusion tensor MRI, and resting state fMRI in 100 healthy elderly to identify fiber bundles connecting cortical resting state networks to subcortical nuclei. In identified tracts, white matter fiber bundle integrity measures were compared to composite cognitive measures on executive function, processing speed, and memory performance. The integrity (FA values) in selected fiber bundles correlated strongly with cognitive measures on executive function and processing speed. Correlation was most pronounced between executive function and fiber bundles connecting the putamen to the dorsal attention network (r=0.73, p<0.001). Our findings show that unique cortico-subcortical fiber bundles can be identified for a range of cortical resting state networks, and indicate that these connections play an important role in cortical resting state network communication and cognition.

Hippocampal volumes are important predictors for memory function in elderly women

BackgroundNormal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).MethodsBrain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.ResultsAPOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.ConclusionGender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

Correlations between measures of executive attention and cortical thickness of left posterior middle frontal gyrus - a dichotic listening study

BackgroundThe frontal lobe has been associated to a wide range of cognitive control functions and is also vulnerable to degeneration in old age. A recent study by Thomsen and colleagues showed a difference between a young and old sample in grey matter density and activation in the left middle frontal cortex (MFC) and performance on a dichotic listening task. The present study investigated this brain behaviour association within a sample of healthy older individuals, and predicted a positive correlation between performance in a condition requiring executive attention and measures of grey matter structure of the posterior left MFC.MethodsA dichotic listening forced attention paradigm was used to measure attention control functions. Subjects were instructed to report only the left or the right ear syllable of a dichotically presented consonant-vowel syllable pair. A conflict situation appears when subjects are instructed to report the left ear stimulus, caused by the conflict with the bottom-up, stimulus-driven right ear advantage. Overcoming this processing conflict was used as a measure of executive attention. Thickness and volumes of frontal lobe regions were derived from automated segmentation of 3D magnetic resonance image acquisitions.ResultsThe results revealed a statistically significant positive correlation between the thickness measure of the left posterior MFC and performance on the dichotic listening measures of executive attention. Follow-up analyses showed that this correlation was only statistically significant in the subgroup that showed the typical bottom-up, stimulus-driven right ear advantage.ConclusionThe results suggest that the left MFC is a part of an executive attention network, and that the dichotic listening forced attention paradigm may be a feasible tool for assessing subtle attentional dysfunctions in older adults.

Automated approaches for analysis of multimodal MRI acquisitions in a study of cognitive aging

In this work we describe an integrated and automated workflow for a comprehensive and robust analysis of multimodal MR images from a cohort of more than hundred subjects. Image examinations are done three years apart and consist of 3D high-resolution anatomical images, low resolution tensor-valued DTI recordings and 4D resting state fMRI time series. The integrated analysis of the data requires robust tools for segmentation, registration and fiber tracking, which we combine in an automated manner. Our automated workflow is strongly desired due to the large number of subjects. Especially, we introduce the use of histogram segmentation to processed fMRI data to obtain functionally important seed and target regions for fiber tracking between them. This enables analysis of individually important resting state networks. We also discuss various approaches for the assessment of white matter integrity parameters along tracts, and in particular we introduce the use of functional data analysis (FDA) for this task.

Salient measures of inhibition and switching are associated with frontal lobe gray matter volume in healthy middle-aged and older adults.

OBJECTIVE To investigate brain-behavior relationships between morphometric brain measures and salient executive function (EF) measures of inhibition and switching. METHOD One hundred participants (49-80 years) performed the Color Word Interference Test from the Delis-Kaplan Executive Function System (D-KEFS). Salient measures of EF components of inhibition and switching, of which the effect of more fundamental skills were regressed out, were analyzed using linear models and a conditional inference trees analysis taking intercorrelations between predictor variables (brain volumes, age, gender, and education) into account. RESULTS The conditional inference trees analysis demonstrated a primary role of the middle frontal gyrus (MFG) in explaining variations in the salient EF measure of switching and combined inhibition/switching. Age predicted measures of inhibition. CONCLUSION The study highlights the importance of considering fundamental cognitive skills and the use of a statistical method taking possible complex relationships between predictor variables into account when interpreting standard EF test results. Further studies should include MRI measures representing neural networks that may relate to CWIT performance, and longitudinal studies are required to investigate any causal relationships.

Post-adolescent developmental changes in cortical complexity

BackgroundPost-adolescence is known to be a period of general maturation and development in the human brain. In brain imaging, volumetric and morphologic cortical grey-matter changes can easily be assessed, but the analysis of cortical complexity seems to have been broadly neglected for this age interval.MethodsMagnetic resonance imaging (MRI) was used to acquire structural brain images. The study involved 17 adolescents (mean age 14.1 ± 0.27, 11 girls) who were compared with 14 young adults (mean age 24.24 ± 2.76, 7 women) for measures of brain complexity (fractal dimension - FD), grey matter (GM) volume and surface-area of cortical ribbon. FD was calculated using box-counting and Minkowski-Bouligand methods; FD and GM volume were measured for the whole brain, each hemisphere and lobes: frontal, occipital, parietal and temporal.ResultsThe results show that the adults have a lower cortical complexity than the adolescents, which was significant for whole brain, left and right hemisphere, frontal and parietal lobes for both genders; and only for males in left temporal lobe. The GM volume was smaller in men than in boys for almost all measurements, and smaller in women than in girls just for right parietal lobe. A significant Pearson correlation was found between FD and GM volume for whole brain and each hemisphere in both genders. The decrease of the GM surface-area was significant in post-adolescence for males, not for females.ConclusionsDuring post-adolescence there are common changes in cortical complexity in the same regions for both genders, but there are also gender specific changes in some cortical areas. The sex differences from different cortical measurements (FD, GM volume and surface-area of cortical ribbon) could suggest a maturation delay in specific brain regions for each gender in relation to the other and might be explained through the functional role of the corresponding regions reflected in gender difference of developed abilities.

Fractional anisotropy shows differential reduction in frontal-subcortical fiber bundles - A longitudinal MRI study of 76 middle-aged and older adults

Motivated by the frontal- and white matter (WM) retrogenesis hypotheses and the assumptions that fronto-striatal circuits are especially vulnerable in normal aging, the goal of the present study was to identify fiber bundles connecting subcortical nuclei and frontal areas and obtain site-specific information about age related fractional anisotropy (FA) changes. Multimodal magnetic resonance image acquisitions [3D T1-weighted and diffusion weighted imaging (DWI)] were obtained from healthy older adults (N = 76, range 49–80 years at inclusion) at two time points, 3 years apart. A subset of the participants (N = 24) was included at a third time-point. In addition to the frontal-subcortical fibers, the anterior callosal fiber (ACF) and the corticospinal tract (CST) was investigated by its mean FA together with tract parameterization analysis. Our results demonstrated fronto-striatal structural connectivity decline (reduced FA) in normal aging with substantial inter-individual differences. The tract parameterization analysis showed that the along tract FA profiles were characterized by piece-wise differential changes along their extension rather than being uniformly affected. To the best of our knowledge, this is the first longitudinal study detecting age-related changes in frontal-subcortical WM connections in normal aging.

IC-P-021

Background: Multiparametric magnetic resonance imaging enables local assessment of tissue “signatures” in the aging brain. By proper alignment of data we can for each voxel, or region of interest (ROI) i obtain a pattern vector i ( i1, . . . , ip), where ij expresses a local tissue property. Such pattern vectors can jointly be combined with test results from genotyping and cognitive evaluation, and thereby give important and differentiating information in normal aging, mild cognitive impairment and Alzheimers disease. Objective(s): The present work is a feasibility study of combining advanced multispectral imaging methods and genetic and behavioral data in the study of normal aging. We apply our methods to the first subject in a large series (N 109) of recently obtained examinations. Methods: Our MR imaging protocol comprises anatomical dual-volume acquisitions for tissue segmentation and morphometric analysis (FreeSurfer), and dual-echo PD/T2 weighted acquisitions followed by diffusion tensor imaging for white matter analysis (DTIStudio). For intrasubject image registration we utilized geometric information in the DICOM headers to obtain proper spatial transformations and reslicing. To complement our pattern vectors, we have genotypes for APOE [alleles: 2 3 4], CHRNA4 [T C], BDNF [val met], and results from extensive neuropsychological testing, e.g. WASI (IQ), CVLT (verbal memory), and PASAT (attention). Results: In the present case, where we have computed mean fractional anisotropy (FA) and mean ADC [10 m/s] in the genu corpus callosum (‘gcc’) as well as total brain volume and volumes of the left and right hippocampus [ml], the following pattern vector was obtained: (subj_id, sex, age, edu, IQtot, CVLTtot, PASATsum, . . . , APOE, CHRNA4, BDNF, . . . , FA_gcc, ADC_gcc, brain_vol, hippo_left, hippo_right) (501, F, 53, 14, 122, 54, 41, . . . , 3/ 3, C/C, val/val, . . . , 0.71, 0.73, 1325, 3.7, 3.9). Conclusions: By careful planning of the MR imaging protocol and utilization of image registration techniques we can obtain voxelbased and ROI-based pattern vectors that express a rich variety of tissue information (cf. Fig). Joining these vectors with genotypes and results from neuropsychological phenotyping, multivariate statistical analysis can be used to reveal new insight into normal and abnormal aging of the brain.