Egill Rostrup

On Clustering fMRI Time Series

Analysis of fMRI time series is often performed by extracting one or more parameters for the individual voxels. Methods based, e.g., on various statistical tests are then used to yield parameters corresponding to probability of activation or activation strength. However, these methods do not indicate whether sets of voxels are activated in a similar way or in different ways. Typically, delays between two activated signals are not identified. In this article, we use clustering methods to detect similarities in activation between voxels. We employ a novel metric that measures the similarity between the activation stimulus and the fMRI signal. We present two different clustering algorithms and use them to identify regions of similar activations in an fMRI experiment involving a visual stimulus.

Determination of relative CMRO2 from CBF and BOLD changes: Significant increase of oxygen consumption rate during visual stimulation

The blood oxygenation level‐dependent (BOLD) effect in functional magnetic resonance imaging depends on at least partial uncoupling between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) changes. By measuring CBF and BOLD simultaneously, the relative change in CMRO2 can be estimated during neural activity using a reference condition obtained with known CMRO2 change. In this work, nine subjects were studied at a magnetic field of 1.5 T; each subject underwent inhalation of a 5% carbon dioxide gas mixture as a reference and two visual stimulation studies. Relative CBF and BOLD signal changes were measured simultaneously using the flow‐sensitive alternating inversion recovery (FAIR) technique. During hypercapnia established by an end‐tidal CO2 increase of 1.46 kPa, CBF in the visual cortex increased by 47.3 ± 17.3% (mean ± SD; n = 9), and ΔR*2 was −0.478 ± 0.147 sec−1, which corresponds to BOLD signal change of 2.4 ± 0.7% with a gradient echo time of 50 msec. During black/white visual stimulation reversing at 8 Hz, regional CBF increase in the visual cortex was 43.6 ± 9.4% (n = 18), and ΔR*2 was −0.114 ± 0.086 sec−1, corresponding to a BOLD signal change of 0.6 ± 0.4%. Assuming that CMRO2 does not change during hypercapnia and that hemodynamic responses during hypercapnia and neural stimulation are similar, relative CMRO2 change was determined using BOLD biophysical models. The average CMRO2 change in the visual cortex ranged from 15.6 ± 8.1% (n = 18) with significant cerebral blood volume (CBV) contribution to 29.6 ± 18.8% without significant CBV contribution. A weak positive correlation between CBF and CMRO2 changes was observed, suggesting the CMRO2 increase is proportional to the CBF increase. Magn Reson Med 41:1152–1161, 1999.

Impact of White Matter Hyperintensities Scoring Method on Correlations With Clinical Data The LADIS Study

Background and Purpose— White matter hyperintensities (WMH) are associated with decline in cognition, gait, mood, and urinary continence. Associations may depend on the method used for measuring WMH. We investigated the ability of different WMH scoring methods to detect differences in WMH load between groups with and without symptoms. Methods— We used data of 618 independently living elderly with WMH collected in the Leukoaraiosis And DISability (LADIS) study. Subjects with and without symptoms of depression, gait disturbances, urinary incontinence, and memory decline were compared with respect to WMH load measured qualitatively using 3 widely used visual rating scales (Fazekas, Scheltens, and Age-Related White Matter Changes scales) and quantitatively with a semiautomated volumetric technique and an automatic lesion count. Statistical significance between groups was assessed with the &khgr;2 and Mann-Whitney tests. In addition, the punctate and confluent lesion type with comparable WMH volume were compared with respect to the clinical data using Student t test and &khgr;2 test. Direct comparison of visual ratings with volumetry was done using curve fitting. Results— Visual and volumetric assessment detected differences in WMH between groups with respect to gait disturbances and age. WMH volume measurement was more sensitive than visual scores with respect to memory symptoms. Number of lesions nor lesion type correlated with any of the clinical data. For all rating scales, a clear but nonlinear relationship was established with WMH volume. Conclusions— Visual rating scales display ceiling effects and poor discrimination of absolute lesion volumes. Consequently, they may be less sensitive in differentiating clinical groups.

Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study

BACKGROUND White-matter hyperintensities are commonly found on magnetic resonance imaging (MRI) of elderly people with or without dementia. Studies of the relation between severity of white-matter hyperintensities and cognitive impairment have had conflicting results. We undertook a longitudinal study of age-related decline in intellectual function and MRI at age 80 years. METHODS From a cohort of 698 people born in 1914 and living in seven municipalities in Denmark, 68 healthy non-demented individuals had been tested with the Wechsler adult intelligence scale (WAIS) at ages 50, 60, and 70, and they agreed to further WAIS testing at age 80, and cerebral MRI at age 80-82 (mean age 82.3 years). We scored separately the numbers of periventricular and deep white-matter hyperintensities. FINDINGS Scores for periventricular hyperintensities in this sample included all possible degrees of severity, but no participant scored more than 75% of maximum for deep white-matter hyperintensities. Neither type was related to the WAIS IQs of the 80-year assessment, but both were significantly associated with decline in performance IQ from age 50 to age 80 years (bivariate correlation coefficients 0.32, p=0.0087, and 0.28, p=0.0227, respectively). An analysis based on two WAIS subtests showed that the association between white-matter hyperintensities and cognitive impairment was significant only for cognitive decline in the decade 70-80 years. INTERPRETATION Both periventricular and deep white-matter hyperintensities are related to decline in intelligence but, in healthy octogenarians, the cumulative effect of these features alone explains only a small part of the large differences among individuals in age-related decline in intelligence. Interpretation of the presence and severity of white-matter hyperintensities in a diagnostic context must be done cautiously.

Motion or activity: their role in intra- and inter-subject variation in fMRI.

Functional MRI (fMRI) carries the potential for non-invasive measurements of brain activity. Typically, what are referred to as activation images are actually thresholded statistical parametric maps. These maps possess large inter-session variability. This is especially problematic when applying fMRI to pre-surgical planning because of a higher requirement for intra-subject precision. The purpose of this study was to investigate the impact of residual movement artefacts on intra-subject and inter-subject variability in the observed fMRI activation. Ten subjects were examined using three different word-generation tasks. Two of the subjects were examined 10 times on 10 different days using the same paradigms. We systematically investigated one approach of correcting for residual movement effects: the inclusion of regressors describing movement-related effects in the design matrix of a General Linear Model (GLM). The data were analysed with and without modeling the residual movement artefacts and the impact on inter-session variance was assessed using F-contrasts. Inclusion of motion parameters in the analysis significantly reduced both the intra-subject as well as the inter-subject-variance.

Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

Generalizable patterns in neuroimaging: how many principal components?

Generalization can be defined quantitatively and can be used to assess the performance of principal component analysis (PCA). The generalizability of PCA depends on the number of principal components retained in the analysis. We provide analytic and test set estimates of generalization. We show how the generalization error can be used to select the number of principal components in two analyses of functional magnetic resonance imaging activation sets.

Cerebral Blood Flow Response to Functional Activation

Cerebral blood flow (CBF) and cerebral metabolic rate are normally coupled, that is an increase in metabolic demand will lead to an increase in flow. However, during functional activation, CBF and glucose metabolism remain coupled as they increase in proportion, whereas oxygen metabolism only increases to a minor degree—the so-called uncoupling of CBF and oxidative metabolism. Several studies have dealt with these issues, and theories have been forwarded regarding the underlying mechanisms. Some reports have speculated about the existence of a potentially deficient oxygen supply to the tissue most distant from the capillaries, whereas other studies point to a shift toward a higher degree of non-oxidative glucose consumption during activation. In this review, we argue that the key mechanism responsible for the regional CBF (rCBF) increase during functional activation is a tight coupling between rCBF and glucose metabolism. We assert that uncoupling of rCBF and oxidative metabolism is a consequence of a less pronounced increase in oxygen consumption. On the basis of earlier studies, we take into consideration the functional recruitment of capillaries and attempt to accommodate the cerebral tissues increased demand for glucose supply during neural activation with recent evidence supporting a key function for astrocytes in rCBF regulation.

Cerebral Perfusion and Cerebrovascular Reactivity Are Reduced in White Matter Hyperintensities

Background and Purpose— There is growing evidence that white matter hyperintensities (WMH) should not be considered as benign age-dependent changes on MR images but indicate pathological changes with clinical consequences. Previous studies comparing subjects with WMH to normal controls have reported global reductions in cerebral blood flow (CBF) and cerebral vascular reactivity. In this study, we examined localized hemodynamic status to compare WMH to normal appearing white matter (NAWM). Methods— A group of 21 normal 85-year-old subjects were studied using dynamic contrast-enhanced MRI together with administration of acetazolamide. From a combination of anatomic images with different signal weighting, regions of interest were generated corresponding to gray and white matter and WMH. Localized measurements of CBF and cerebral blood volume (CBV) and mean transit time were obtained directly within WMH and NAWM. Results— When comparing WMH to NAWM, measurements showed significantly lower CBF (P =0.004) and longer mean transit time (P < 0.001) in WMH but no significant difference in CBV (P =0.846). The increases in CBF and CBV induced by acetazolamide were significantly smaller in WMH than in NAWM (P =0.026, P <0.001). Conclusion— These results show that a change in the hemodynamic status is present within the WMH, making these areas more likely to be exposed to transient ischemia inducing myelin rarefaction. In the future, MRI may be used to examine the effect of therapeutic strategies designed to prevent or normalize vascular changes.

Long-term global and regional brain volume changes following severe traumatic brain injury: A longitudinal study with clinical correlates

Traumatic brain injury (TBI) results in neurodegenerative changes that progress for months, perhaps even years post-injury. However, there is little information on the spatial distribution and the clinical significance of this late atrophy. In 24 patients who had sustained severe TBI we acquired 3D T1-weighted MRIs about 8 weeks and 12 months post-injury. For comparison, 14 healthy controls with similar distribution of age, gender and education were scanned with a similar time interval. For each subject, longitudinal atrophy was estimated using SIENA, and atrophy occurring before the first scan time point using SIENAX. Regional distribution of atrophy was evaluated using tensor-based morphometry (TBM). At the first scan time point, brain parenchymal volume was reduced by mean 8.4% in patients as compared to controls. During the scan interval, patients exhibited continued atrophy with percent brain volume change (%BVC) ranging between -0.6% and -9.4% (mean -4.0%). %BVC correlated significantly with injury severity, functional status at both scans, and with 1-year outcome. Moreover, %BVC improved prediction of long-term functional status over and above what could be predicted using functional status at approximately 8 weeks. In patients as compared to controls, TBM (permutation test, FDR 0.05) revealed a large coherent cluster of significant atrophy in the brain stem and cerebellar peduncles extending bilaterally through the thalamus, internal and external capsules, putamen, inferior and superior longitudinal fasciculus, corpus callosum and corona radiata. This indicates that the long-term atrophy is attributable to consequences of traumatic axonal injury. Despite progressive atrophy, remarkable clinical improvement occurred in most patients.