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Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly.

Structural deformity of the hippocampus is characteristic of individuals with very mild and mild forms of dementia of the Alzheimer type (DAT). The purpose of this study was to determine whether a similar deformity of the hippocampus can predict the onset of dementia in nondemented elders. Using high dimensional diffeomorphic transformations of a neuroanatomical template, hippocampal volumes and surfaces were defined in 49 nondemented elders; the hippocampal surface was subsequently partitioned into three zones (i.e., lateral, superior and inferior-medial), which were proximal to the underlying CA1 subfield, CA2-4 subfields plus dentate gyrus, and subiculum, respectively. Annual clinical assessments using the Clinical Dementia Rating scale (CDR), where CDR 0 indicates no dementia and CDR 0.5 indicates very mild dementia, were then performed for a mean of 4.9 years (range 0.9-7.1 years) to monitor subjects who converted from CDR 0 to CDR 0.5. Inward variation of the lateral zone and left hippocampal volume significantly predicted conversion to CDR 0.5 in separate Cox proportional hazards models. When hippocampal surface variation and volume were included in a single model, inward variation of the lateral zone of the left hippocampal surface was selected as the only significant predictor of conversion. The pattern of hippocampal surface deformation observed in nondemented subjects who later converted to CDR 0.5 was similar to the pattern of hippocampal surface deformation previously observed to discriminate subjects with very mild DAT and nondemented subjects. These results suggest that inward deformation of the left hippocampal surface in a zone corresponding to the CA1 subfield is an early predictor of the onset of DAT in nondemented elderly subjects.

Aged↗

Conjunction revisited.

The aim of this note is to revisit the analysis of conjunctions in imaging data. We review some conceptual issues that have emerged from recent discussion (Nichols, T., Brett, M., Andersson, J., Wager, T., Poline, J.-B., 2004. Valid Conjunction Inference with the Minimum Statistic.) and reformulate the conjunction of null hypotheses as a conjunction of k or more effects. Analyses based on minimum statistics have typically used the null hypothesis that k = 0. This enables inferences about one or more effects (k > 0). However, this does not provide control over false-positive rates (FPR) for inferences about a conjunction of k = n effects, over n tests. This is the key point made by Nichols et al., who suggest a procedure based on supremum P values that provides an upper bound on FPR for k = n. Although valid, this is a very conservative procedure, particularly in the context of multiple comparisons. We suggest that an inference on a conjunction of k = n effects is generally unnecessary and distinguish between congruent contrasts that test for the same treatment and incongruent contrasts of the sort used in cognitive conjunctions. For congruent contrasts, the usual inference, k > 0, is sufficient. With incongruent contrasts it is sufficient to infer a conjunction of k >u effects, where u is the number of contrasts that share some uninteresting effect. The issues highlighted by Nichols et al., have important implications for the design and analysis of cognitive conjunction studies and have motivated a change to the SPM software, that affords a test for the more general hypothesis k >u. This more general conjunction test is described.

Arousal↗

Parametric modulation of cortical activation during smooth pursuit with and without target blanking. an fMRI study.

Smooth pursuit eye movements (SPEM) are performed to track slowly moving visual targets and are accompanied by saccades whenever foveal representation is lost. In the present study, we correlated the cerebral activation as assessed by functional magnetic resonance imaging with parameters of eye movement performance in order to determine the cortical areas involved in the retinal and extraretinal processing of maintaining smooth pursuit velocity (SPV) and generating saccades in 16 healthy males. The stimulus consisted of a target moving at a constant velocity of 10 degrees/s with and without target blanking. During constant target presentation, SPV was positively correlated with the BOLD signal in the right V5 complex and negatively correlated with the BOLD response in the left dorsolateral prefrontal cortex (DLPFC). In the condition with target blanking, additional negative correlations with SPV were found in the left frontal eye field (FEF), the left parietoinsular vestibular cortex (PIVC) and the left angular gyrus. Saccadic frequency was negatively correlated with activations of the right mesial intraparietal sulcus (IPS) during both conditions and the right premotor area during continuous target presentation. We conclude that V5 is directly related to the maintenance of an optimal smooth pursuit velocity during visual feedback, whereas the FEF, PFC, angular gyrus and PIVC are involved in reconstitution and prediction whenever SPV decreases, especially during maintenance of smooth pursuit in the absence of a visual target. Furthermore, we suggest that parietal areas are related to the suppression of saccades during smooth pursuit.

Adult↗

Gray matter reduction is correlated with white matter hyperintensity volume: a voxel-based morphometric study in a large epidemiological sample.

Both brain atrophy and T2-weighted white matter hyperintensities (WMH) are common findings in the brains of asymptomatic elderly individuals as well as in disease-specific brains. The study of the relationship between these two salient features is therefore important. To investigate such a relationship, we performed a brain magnetic resonance imaging (MRI) study on 397 asymptomatic individuals aged between 60 and 64 years, who were recruited randomly from a large community sample. WMH were delineated on T2-weighted fluid attenuation inversion recovery (FLAIR) whole brain scans using an automated procedure. The results showed that gray matter reduction, subarachnoid CSF (SA-CSF) increase and lateral ventricular dilation were significantly correlated with WMH load. Deep white matter hyperintensity (DWMH) had significant correlation with all three global atrophy indices, but periventricular white matter hyperintensity (PVWMH) was correlated only with gray matter volume. Voxel-based morphometric (VBM) analysis showed that regional gray matter reduction correlated more closely with WMH load of the proximate region than with WMH elsewhere. The results suggest that WMH have a relationship with brain atrophy in middle age, although the study cannot determine which process, i.e. the development of WMH or atrophy, is primary. The study also demonstrates that DWMH has a more significant relationship with structural brain changes, and may therefore be more functionally relevant than PVWMH. Further delineation of this relationship needs a longitudinal study of the changes in both WMH and indices of brain atrophy.

Age Factors↗

Resolving fiber crossing using advanced fast marching tractography based on diffusion tensor imaging.

Magnetic resonance diffusion tensor tractography is a powerful tool for the non-invasive depiction of the white matter architecture in the human brain. However, due to limitations in the underlying tensor model, the technique is often unable to reconstruct correct trajectories in heterogeneous fiber arrangements, such as axonal crossings. A novel tractography method based on fast marching (FM) is proposed which is capable of resolving fiber crossings and also permits trajectories to branch. It detects heterogeneous fiber arrangements by incorporating information from the entire diffusion tensor. The FM speed function is adapted to the local tensor characteristics, allowing in particular to maintain the front evolution direction in crossing situations. In addition, the FM's discretization error is reduced by increasing the number of considered possible front evolution directions. The performance of the technique is demonstrated in artificial data and in the healthy human brain. Comparisons with standard FM tractography and conventional line propagation algorithms show that, in the presence of interfering structures, the proposed method is more accurate in reconstructing trajectories. The in vivo results illustrate that the elucidated major white matter pathways are consistent with known anatomy and that multiple crossings and tract branching are handled correctly.

Algorithms↗

Dependence of amygdala activation on echo time: results from olfactory fMRI experiments.

Echo time dependence of the BOLD sensitivity is an important topic in fMRI whenever brain regions are considered where the EPI data quality suffers from susceptibility gradients. Here, an fMRI study is presented showing that a reduced echo time EPI sequence significantly enhances the statistical inference in subcortical (limbic) brain regions, with special focus on the amygdala. As a consequence, to facilitate whole-brain fMRI with optimal echo times, a sequence with slice-dependent echo time is demonstrated with a focus on structures suffering from susceptibility changes. The applicability of this method is shown in a second fMRI study aimed at both, cortical, and limbic brain regions. The results are in good agreement with theoretical descriptions of the BOLD sensitivity under the influence of susceptibility gradients.

Adult↗

MRI-based volumetry of head compartments: normative values of healthy adults.

The size of head compartments (head and brain volume, intracranial volume, gray and white matter volume, cerebrospinal fluid volume) and their ratios were determined on the basis of magnetic resonance images of the head acquired in a reference population of 502 healthy subjects. Age-matched subgroups were selected to reveal gender-related differences and changes with age. Normative data are provided in the form of simple equations that allow transforming measured compartment volumes into z scores, offering the possibility to relate individual data to a larger population.

Adolescent↗

The multiscale character of evoked cortical activity.

Both the architecture and the dynamics of the brain have characteristic features at different spatial scales. However, the existence, nature and function of dynamical interdependencies between such scales have not been investigated. We studied the multiscale properties of functional magnetic resonance imaging (fMRI) data acquired while human subjects viewed a visual image. Traditional "region of interest" analysis of this data set revealed evoked activity in primary and extrastriate visual cortex. Wavelet transform in the spatial domain provides a multiscale representation of this evoked brain activity. Studying the correlation structure of this representation revealed strong and novel interdependencies in these data within and between different spatial scales. We found that such correlations are stronger than those evident in the original data and comparable in magnitude to those obtained after Gaussian smoothing. However, analysis of the data in the wavelet domain revealed additional structure such as positive correlations, strong anti-correlations and phase-lagged interdependencies. Statistical significance of these effects was inferred through nonparametric bootstrap techniques. We conclude that the spatial analysis of functional neuroimaging data in the wavelet domain provides novel information which may reflect complex spatiotemporal neuronal activity and information encoding. It also affords a quantitative means of testing hierarchical and multiscale models of cortical activity.

Adult↗

Analysis and validation of automated skull stripping tools: a validation study based on 296 MR images from the Honolulu Asia aging study.

As population-based epidemiologic studies may acquire images from thousands of subjects, automated image post-processing is needed. However, error in these methods may be biased and related to subject characteristics relevant to the research question. Here, we compare two automated methods of brain extraction against manually segmented images and evaluate whether method accuracy is associated with subject demographic and health characteristics. MRI data (n = 296) are from the Honolulu Asia Aging Study, a population-based study of elderly Japanese-American men. The intracranial space was manually outlined on the axial proton density sequence by a single operator. The brain was extracted automatically using BET (Brain Extraction Tool) and BSE (Brain Surface Extractor) on axial proton density images. Total intracranial volume was calculated for the manually segmented images (ticvM), the BET segmented images (ticvBET) and the BSE segmented images (ticvBSE). Mean ticvBSE was closer to that of ticvM, but ticvBET was more highly correlated with ticvM than ticvBSE. BSE had significant over (positive error) and underestimated (negative error) ticv, but net error was relatively low. BET had large positive and very low negative error. Method accuracy, measured in percent positive and negative error, varied slightly with age, head circumference, presence of the apolipoprotein eepsilon4 polymorphism, subcortical and cortical infracts and enlarged ventricles. This epidemiologic approach to the assessment of potential bias in image post-processing tasks shows both skull-stripping programs performed well in this large image dataset when compared to manually segmented images. Although method accuracy was statistically associated with some subject characteristics, the extent of the misclassification (in terms of percent of brain volume) was small.

Aged↗

Common MRI acquisition non-idealities significantly impact the output of the boundary shift integral method of measuring brain atrophy on serial MRI.

Measuring rates of brain atrophy from serial magnetic resonance imaging (MRI) studies is an attractive way to assess disease progression in neurodegenerative disorders, particularly Alzheimer's disease (AD). A widely recognized approach is the boundary shift integral (BSI). The objective of this study was to evaluate how several common scan non-idealities affect the output of the BSI algorithm. We created three types of image non-idealities between the image volumes in a serial pair used to measure between-scan change: inconsistent image contrast between serial scans, head motion, and poor signal-to-noise (SNR). In theory the BSI volume difference measured between each pair of images should be zero and any deviation from zero should represent corruption of the BSI measurement by some non-ideality intentionally introduced into the second scan in the pair. Two different BSI measures were evaluated, whole brain and ventricle. As the severity of motion, noise, and non-congruent image contrast increased in the second scan, the calculated BSI values deviated progressively more from the expected value of zero. This study illustrates the magnitude of the error in measures of change in brain and ventricle volume across serial MRI scans that can result from commonly encountered deviations from ideal image quality. The magnitudes of some of the measurement errors seen in this study exceed the disease effect in AD shown in various publications, which range from 1% to 2.78% per year for whole brain atrophy and 5.4% to 13.8% per year for ventricle expansion (Table 1). For example, measurement error may exceed 100% if image contrast properties dramatically differ between the two scans in a measurement pair. Methods to maximize consistency of image quality over time are an essential component of any quantitative serial MRI study.

Adult↗

Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy.

Magnetic resonance imaging (MRI) measures of brain atrophy are often considered to be a marker of axonal loss in multiple sclerosis (MS) but evidence is limited. Optic neuritis is a common manifestation of MS and results in optic nerve atrophy. Retinal nerve fibre layer (RNFL) imaging is a non-invasive way of detecting axonal loss following optic neuritis. We hypothesise that if the optic nerve atrophy that develops following optic neuritis is contributed to by axonal loss, it will correlate with thinning of the RNFL. Twenty-five patients were studied at least 1 year after a single unilateral attack of optic neuritis without recurrence, with a selection bias towards incomplete recovery. They had MR quantification of optic nerve cross-sectional area and optic nerve lesion length, as well as optical coherence tomography (OCT) measurement of mean RNFL thickness and macular volume, quantitative visual testing, and visual evoked potentials (VEPs). Fifteen controls were also studied. Significant optic nerve atrophy (mean decrease 30% versus controls), RNFL thinning (mean decrease 33% versus controls), and macular volume loss occurred in patients' affected eyes when compared with patients' unaffected eyes and healthy controls. The optic nerve atrophy was correlated with the RNFL thinning, macular volume loss, visual acuity, visual field mean deviation, and whole field VEP amplitude but not latency. These findings suggest that axonal loss contributes to optic nerve atrophy following a single attack of optic neuritis. By inference, axonal loss due to other post-inflammatory brain lesions is likely to contribute to the global MRI measure of brain atrophy in multiple sclerosis.

Adult↗

Decrease of thalamic gray matter following limb amputation.

Modern neuroscience has elucidated general mechanisms underlying the functional plasticity of the adult mammalian brain after limb deafferentation. However, little is known about possible structural alterations following amputation and chronic loss of afferent input in humans. Using voxel-based morphometry (VBM), based on high-resolution magnetic resonance images, we investigated the brain structure of 28 volunteers with unilateral limb amputation and compared them to healthy controls. Subjects with limb amputation exhibited a decrease in gray matter of the posterolateral thalamus contralateral to the side of the amputation. The thalamic gray matter differences were positively correlated with the time span after the amputation but not with the frequency or magnitude of coexisting phantom pain. Phantom limb pain was unrelated to thalamic structural variations, but was positively correlated to a decrease in brain areas related to the processing of pain. No gray matter increase was detected. The unilateral thalamic differences may reflect a structural correlate of the loss of afferent input as a secondary change following deafferentation.

Adolescent↗

fMRI pattern classification using neuroanatomically constrained boosting.

Pattern classification in functional MRI (fMRI) is a novel methodology to automatically identify differences in distributed neural substrates resulting from cognitive tasks. Reliable pattern classification is challenging due to the high dimensionality of fMRI data, the small number of available data sets, interindividual differences, and dependence on the acquisition methodology. Thus, most previous fMRI classification methods were applied in individual subjects. In this study, we developed a novel approach to improve multiclass classification across groups of subjects, field strengths, and fMRI methods. Spatially normalized activation maps were segmented into functional areas using a neuroanatomical atlas and each map was classified separately using local classifiers. A single multiclass output was applied using a weighted aggregation of the classifier's outputs. An Adaboost technique was applied, modified to find the optimal aggregation of a set of spatially distributed classifiers. This Adaboost combined the region-specific classifiers to achieve improved classification accuracy with respect to conventional techniques. Multiclass classification accuracy was assessed in an fMRI group study with interleaved motor, visual, auditory, and cognitive task design. Data were acquired across 18 subjects at different field strengths (1.5 T, 4 T), with different pulse sequence parameters (voxel size and readout bandwidth). Misclassification rates of the boosted classifier were between 3.5% and 10%, whereas for the single classifier, these were between 15% and 23%, suggesting that the boosted classifier provides a better generalization ability together with better robustness. The high computational speed of boosting classification makes it attractive for real-time fMRI to facilitate online interpretation of dynamically changing activation patterns.

Attention↗

Voxel-based morphometry in patients with idiopathic generalized epilepsies.

Idiopathic generalized epilepsies (IGE) are a group of frequent age-related epilepsy syndromes. IGE are clinically characterized by generalized tonic-clonic, myoclonic and absence seizures. According to predominant seizure type and age of onset, IGE are divided in subsyndromes: childhood absence and juvenile absence epilepsy (AE), juvenile myoclonic epilepsy (JME) and generalized tonic-clonic seizures on awakening (GTCS). The limits between these subsyndromes are not well defined, supporting the existence of only one major syndrome. Visual assessment of routine magnetic resonance imaging (MRI) in patients with IGE is normal. MRI voxel-based morphometry (VBM) uses automatically segmented gray and white matter for comparisons, eliminating the investigator bias. We used VBM to study 120 individuals (47 controls, 44 with JME, 24 with AE and 15 with GTCS) to investigate the presence of subtle structural abnormalities in IGE subsyndromes. VBM was performed searching for abnormalities on gray matter concentration (GMC) between patients groups and controls. Compared to controls, JME presented increased GMC in frontobasal region and AE showed increased GMC in the superior mesiofrontal region. The GTCS group did not differ from controls. There were no areas of reduced GMC with the statistical level selected. Region of interest analysis showed increased GMC in the anterior portion of the thalamus in patients with absence seizures. Our results support subtle GMC abnormalities in patients with JME and AE when compared to controls. These findings suggest the existence of different patterns of cortical abnormalities in IGE subsyndromes.

Adolescent↗

BOLD correlates of EMG spectral density in cortical myoclonus: description of method and case report.

The recording of electrophysiological data during BOLD fMRI is highly challenging but provides the opportunity to develop a more thorough account of brain function than either modality alone. To develop new techniques in this area has often required the study of pathological electrophysiological measures because such measures can be unusually strong (e.g., epileptic EEG spikes) and hence more easily detectable during fMRI than weaker normal phenomena. In this paper, we have studied pathologically strong EMG signals in a patient with cortical myoclonus. First, we studied the patient outside of scanning: The pathological corticospinal drive to muscle was concentrated over 6-30 Hz so that EMG components at higher frequency could be used to control for non-corticospinal contributions to the EMG during scanning. Additionally, there was very strong EMG-EMG and EMG-EEG coherence in this frequency band. Furthermore, analysis of spectral phase showed that this exaggerated coherence was produced by efferent drive from brain to muscle. Hence, the exaggerated peak in distal muscle EMG power spectrum reflected brain activity producing the efferent drive. Subsequently, we modified equipment and data analysis techniques previously developed for simultaneous EEG-fMRI to record polychannel EMG from distal upper limbs during simultaneous BOLD fMRI. After artefact reduction, the EMG recorded during fMRI retained the essential frequency and phase characteristics of EMG recorded outside of scanning. The BOLD signal was significantly correlated with time-varying 6- to 30-Hz power in a frontoparietal network compatible with the neurophysiological characteristics of our patient and compatible with prior hypotheses explaining the origin of cortical myoclonus.

Adult↗

Functional MRI of memory in the hippocampus: Laterality indices may be more meaningful if calculated from whole voxel distributions.

Lateralization of memory by functional MRI (fMRI) may be helpful for surgical planning related to the medial temporal lobe (MTL). Most fMRI memory studies have calculated lateralization indices (LI) in the MTL from suprathreshold voxels only, but the selection of threshold remains highly arbitrary. We hypothesized that LIs could be reliably extracted from the distribution of voxels encompassing all positive T statistical values, each weighted by their own statistical significance. We also hypothesized that patient LIs that are two or more standard deviations (SD) away from the control group mean LI may be more clinically relevant than LIs that are not compared to control group. Thirteen healthy subjects had memory fMRI, and five epilepsy patients had both fMRI and the intracarotid amobarbital procedure (IAP). The fMRI task consisted of encoding patterns, scenes, and words. We found that normal subjects' LIs extracted from whole weighted statistical distributions tended to lateralize to the left for words, to the right for patterns, and intermediately for scenes, consistent with previous research. Weighted LIs were less variable than those calculated from suprathreshold voxels only. Using this approach, all patients had fMRI memory lateralizations consistent with IAP results. The weighted LIs provided a more clear-cut distinction of patients from the normal group (in terms of SDs from the group mean) than the suprathreshold voxel count approach. Our results suggest that using weighted distributions can be a useful strategy for assessing memory lateralization by fMRI in the MTL.

Adult↗

Dimensional complexity of the EEG in patients with posttraumatic stress disorder.

Recent electrophysiological studies have reported evidence of information processing abnormalities in patients with posttraumatic stress disorder (PTSD). The aim of this study is to examine dynamical complexity of the EEG in PTSD patients, which is thought to reflect information processing of the brain. Resting EEG recordings (32,800 data points acquired continuously from 82 s of an EEG record) were obtained in 16 channels of 27 patients with PTSD from a mixed civilian trauma population and 14 healthy subjects. The correlation dimension (D2) of the EEG was used to quantify the complexity of the cortical dynamics underlying the EEG signal. The PTSD patients were found to have lower D2 values than those of the healthy subjects in most channels (Fp1, F8, C4, P4, T3, T4, T5, T6, and O1), indicating that PTSD patients have globally reduced complexity in their EEG waveforms. This study supports the hypotheses that PTSD patients exhibit disturbed cortical information processing, and that non-linear dynamical analysis of the EEG can be a tool for detecting changes in neurodynamics of the brain in PTSD.

Adult↗

MRI volumetry of the vermis and the cerebellar hemispheres in men with schizophrenia.

An association between cerebellar abnormalities and different manifestations of schizophrenia is increasingly hypothesized, either at the motor (anterior vermis), affective/psychotic (posterior vermis), or cognitive (cerebellar hemispheres) level. However, morphometric and volumetric cerebellar measurements have yielded highly divergent results. The main goal of this study was to use magnetic resonance imaging (MRI) to separately estimate the volumes of the entire vermis, the cerebellar hemispheres and three midsaggital vermian areas among 38 men with schizophrenia and 26 healthy men. Compared with the control group, persons with schizophrenia had significantly smaller volumes of the whole vermis, but not of the cerebellar hemispheres, a difference that approached significance when only the patients without a comorbid diagnosis of alcohol abuse/dependence were considered. Significant anomalies of the posterior vermian areas (lobules VI and VII) were detected in both subgroups of patients, while abnormalities of the anterior vermis (lobules I-V) were observed only among patients with a dual diagnosis of alcoholism. No difference emerged between the groups at the inferior vermian level (lobules VIII-X). Overall, these findings corroborate the hypothesized association between schizophrenia and specific posterior vermian anomalies, which might not necessarily be the consequence of alcohol abuse. However, the suggestion that schizophrenia is related to abnormal volumes of the lateral cerebellum is not supported.

Adult↗