New tissue priors for improved automated classification of subcortical brain structures on MRI.

Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

Multivariate decoding of brain images using ordinal regression.

Neuroimaging data are increasingly being used to predict potential outcomes or groupings, such as clinical severity, drug dose response, and transitional illness states. In these examples, the variable (target) we want to predict is ordinal in nature. Conventional classification schemes assume that the targets are nominal and hence ignore their ranked nature, whereas parametric and/or non-parametric regression models enforce a metric notion of distance between classes. Here, we propose a novel, alternative multivariate approach that overcomes these limitations - whole brain probabilistic ordinal regression using a Gaussian process framework. We applied this technique to two data sets of pharmacological neuroimaging data from healthy volunteers. The first study was designed to investigate the effect of ketamine on brain activity and its subsequent modulation with two compounds - lamotrigine and risperidone. The second study investigates the effect of scopolamine on cerebral blood flow and its modulation using donepezil. We compared ordinal regression to multi-class classification schemes and metric regression. Considering the modulation of ketamine with lamotrigine, we found that ordinal regression significantly outperformed multi-class classification and metric regression in terms of accuracy and mean absolute error. However, for risperidone ordinal regression significantly outperformed metric regression but performed similarly to multi-class classification both in terms of accuracy and mean absolute error. For the scopolamine data set, ordinal regression was found to outperform both multi-class and metric regression techniques considering the regional cerebral blood flow in the anterior cingulate cortex. Ordinal regression was thus the only method that performed well in all cases. Our results indicate the potential of an ordinal regression approach for neuroimaging data while providing a fully probabilistic framework with elegant approaches for model selection.

Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ).

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18-85years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Correlation between structural and functional changes in brain in an idiopathic headache syndrome.

Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Do clients with acquired brain injury use the splints prescribed by occupational therapists? A descriptive study.

Clients with acquired brain injury often demonstrate hypertonicity and decreased function in their upper limbs, requiring appropriate intervention. Splinting is one of the intervention methods that is widely used to address these issues. Literature shows that some clients are not using splints following fabrication. However, there is a paucity of research about the factors that influence clients to use or not use splints. This study aims to investigate these influential factors for clients with upper limb hypertonicity. Two survey tools including therapist and client questionnaires were developed and completed by both therapists and clients. Six therapists and 14 clients participated in this study and completed the relevant questionnaires. The results illustrate that most clients (13 out of 14) were continuing to use their splints four weeks following discharge from hospital. The main goals of choosing splints for both therapists and clients were prevention of contracture and deformity. The most indicated client reasons for adhering to the splint wearing program were therapist-related factors including clients' trust and reliance on their therapists. Further reasons for clients implementing the recommended splint-wearing program and clinical implications are discussed.

Voxel-wise analysis of diffusion tensor MRI improves the confidence of diagnosis of corticobasal degeneration non-invasively.

Corticobasal degeneration (CBD) presents with symptoms that often overlap with other neurological conditions. In many cases, diagnosis, prognosis and consequent clinical management remain uncertain. Structural and functional asymmetric brain changes represent the most consistent imaging findings that may assist in CBD diagnosis. Diffusion Tensor MRI (DT-MRI) is a quantitative technique that allows microscopic tissue abnormalities to be non-invasively assessed in vivo. A single case of clinically suspected CBD with symmetric diffuse brain atrophy on conventional-MRI scans was studied using DT-MRI by voxel-wise comparison with eight healthy subjects. The lateralized distribution of DT-MRI abnormalities was consistent with clinical features providing a substantial support to the diagnosis.

Age- and sex-related variations in the brain white matter fractal dimension throughout adulthood: an MRI study.

PURPOSE: To observe age- and sex-related differences in the complexity of the global and hemispheric white matter (WM) throughout adulthood by means of fractal dimension (FD). METHODS: A box-counting algorithm was used to extract FD from the WM magnetic resonance images of 209 healthy adults from three structural layers, including general (gFD), skeleton (sFD), and boundaries (bFD). Model selection algorithms and statistical analyses, respectively, were used to examine the patterns and significance of the changes. RESULTS: gFD and sFD showed inverse U-shape patterns with aging, with a slighter slope of increase from young to mid-age and a steeper decrease to the old. bFD was less affected by age. Sex differences were evident, specifically in gFD and sFD, with men showing higher FDs. Age × sex interaction was significant mainly in the hemispheric analysis, with men undergoing sharper age-related changes. After adjusting for the volume effect, age-related results remained approximately the same, but sex differences changed in most of the features, with women indicating higher values, specifically in the left hemisphere and boundaries. Right hemisphere was still more complex in men. CONCLUSIONS: This study is the first that investigates the WM FD spanning adulthood, treating age both as a continuous and categorical variable. We found positive correlations between FD and volume, and our results show similarities with those investigating small-world properties of the brain networks, as well as those of functional complexity and WM integrity. These suggest that FD could yield a highly compact description of the structural changes and also might inform us about functional and cognitive variations.

Imaging transient, randomly occurring neuropsychological events in single subjects with positron emission tomography: an event-related count rate correlational analysis.

Many neuropsychiatric symptom states are idiosyncratic, involuntary, randomly occurring, subjective, and transient. The brain states associated with these clinically important mental states cannot be imaged directly with existing positron emission tomography (PET) techniques. A new PET method that brings such mental/brain states under experimental control for analysis in single subjects is described. It utilizes a slow bolus H2 15O three-dimensional (3D) regional CBF imaging technique. The analysis focuses upon natural or experimentally induced variance in the temporal distribution of specific neuropsychological events over the course of a study session. For each scan, the amount of radioactivity entering the brain during these events is calculated to derive a score reflecting the contribution of the events to the image. A statistical analysis is then performed to identify those pixels in which the intensity covaries with the scan scores over the subject's scans. This permits the identification of the brain areas associated with the mental state of interest. The method is validated using an auditory sentence-monitoring task. The detection in single subjects of cerebral activations associated with recurrent events as brief as 2 s in duration is demonstrated. This method may be used as a means of imaging ephemeral neurologic or neuropsychiatric symptom states or as an alternative to a subtraction design for activation studies.

11C-flumazenil PET, volumetric MRI, and quantitative pathology in mesial temporal lobe epilepsy.

BACKGROUND: Using statistical parametric mapping and 11C-flumazenil (FMZ) PET we have previously shown reduction of central benzodiazepine receptor (cBZR) binding restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis (HS). The limited spatial resolution of PET, however, results in partial-volume averaging that affects quantitative analysis of cBZR density. METHOD: We determined hippocampal volume loss and reduction in cBZR binding using an MRI-based method for partial-volume effect correction of 11C-FMZ volume of distribution (FMZ-Vd) in 17 patients with refractory mTLE and an MRI diagnosis of HS that was subsequently histologically verified in all cases. Quantitative neuropathology was performed with assessment of neuron density in 14 of the 17 patients. Absolute FMZ-Vd and asymmetry indices (FMZ-AI) were compared before and after partial-volume effect correction with MRI-determined hippocampal volumes (HCV), hippocampal T2 measurements, and, if available, neuronal cell densities. RESULTS: Compared with 15 age-matched healthy volunteers, significant reductions of absolute hippocampal FMZ-Vd were found before correction for partial-volume effects in 11 of 17 patients (65%) and only abnormal FMZ-AI in the other six patients. After partial-volume effects correction all 17 patients (100%) showed both significant unilateral reduction of absolute FMZ-Vd and abnormal FMZ-AI. There was no correlation between corrected absolute FMZ-Vd and HCV or neuronal cell density. After correction for partial-volume effect we found a mean 38% reduction of FMZ-Vd in the sclerosed hippocampus, over and above the reduction of HCV. CONCLUSION: Correction for partial-volume effect allows absolute quantitation of FMZ-PET and increases its sensitivity for detecting abnormalities in TLE due to HS. The lack of correlation between cBZR binding and neuronal density implies that atrophy with neuron loss is not the sole determinant of reduced cBZR binding in patients with mTLE and hippocampal sclerosis.

Kallmann's syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy.

OBJECTIVE: To investigate the etiology of mirror movements in patients with X-linked Kallmann's syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. BACKGROUND: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. METHODS: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann's syndrome (aKS) and nine age-matched normal (healthy) men. RESULTS: Hypertrophy of the corpus callosum was found in both Kallmann's syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. CONCLUSION: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.

Generation of myocardial factor images directly from the dynamic oxygen-15-water scan without use of an oxygen-15-carbon monoxide blood-pool scan.

UNLABELLED: The measurement of regional myocardial blood flow (MBF) with H2(15)O and PET requires an additional C15O blood-pool scan for the purpose of region of interest (ROI) definition. This additional scan results in a substantially increased radiation dose, study duration and risk of movement artifacts. Therefore, a method was developed to generate myocardial factor images directly from the dynamic H2(15)O study without the need for a C15O scan. METHODS: The factor sinograms were generated by means of linear dimension reduction of the dynamic sinograms, where the required variate and covariate factors (myocardial and blood time-activity curves) were modeled from the lung time-activity curve. The factor images were generated by iterative reconstruction. RESULTS: No significant difference was found between MBF values from ROIs drawn on the traditional images (using the C15O scan) and those drawn on the factor images. CONCLUSION: It is possible to generate myocardial images directly from the dynamic H2(15)O study, so that the C15O scan can be omitted from MBF studies. The proposed method is robust and results in nearly optimal signal-to-noise ratios in the factor images.

The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans.

Autism is a biological disorder which affects social cognition, and understanding brain abnormalities of the former will elucidate the brain basis of the latter. We report structural MRI data on 15 high-functioning individuals with autistic disorder. A voxel-based whole brain analysis identified grey matter differences in an amygdala centered system relative to 15 age- and IQ-matched controls. Decreases of grey matter were found in anterior parts of this system (right paracingulate sulcus, left inferior frontal gyrus). Increases were found in posterior parts (amygdala/peri-amygdaloid cortex, middle temporal gyrus, inferior temporal gyrus), and in regions of the cerebellum. These structures are implicated in social cognition by animal, imaging and histopathological studies. This study therefore provides converging evidence of the physiological basis of social cognition.

Quantitation of [11C]diprenorphine cerebral kinetics in man acquired by PET using presaturation, pulse-chase and tracer-only protocols.

The quantitation of regional cerebral in vivo opioid receptor rate constants using [11C]diprenorphine and positron emission tomography (PET) using 3 types of protocol (presaturation, pulse-chase naloxone displacement and tracer-only protocols) together with measurements of regional cerebral blood flow is described in normal volunteers. Arterial blood was sampled continuously for radioactivity and was corrected for metabolites and plasma/blood partition of radioactivity to provide a continuous plasma input function. A compartmental model involving 3 tissue compartments was used to describe the regional cerebral pharmacokinetics of the tracer. The compartments comprised: (1) free plus rapidly exchanging non-specifically bound ligand, (2) specifically bound, naloxone displaceable ligand, and (3) a kinetically distinguishable non-specifically bound pool. Regional estimates of fractional rate constants relating to specific binding were obtained using naloxone in a pulse-chase design of tracer displacement. Less precise estimates of these rate constraints were obtained from single-tracer-only studies, but when binding was expressed as the tissue total volume of distribution relative to plasma there was good correlation with regional values obtained from pulse-chase studies performed in the same individuals. The application of these protocols to the measurement of indices of regional-specific opioid receptor binding in the human brain is discussed.

Dynamic monitoring of [11C]diprenorphine in rat brain using a prototype positron imaging device.

The present work tests the feasibility of using the most recently developed positron emission tomograph detector technology to image positron-emitting radioligands in small experimental animals. A prototype imaging device, using two opposing multicrystal, high-resolution (approximately 4 mm) block detectors of bismuth germanate to produce a 2-dimensional image in the centre of the field of view, is described. To evaluate the probe's potential as a non-invasive experimental tool, the dynamic regional distribution of the established opiate receptor ligand, [11C]diprenorphine was determined in rat brain following intravenous injection. The distribution of counts in the images was consistent with the localisation of diprenorphine binding sites and the specificity of the signal obtained was confirmed by administration of non-radioactive diprenorphine and naloxone. Although the signal-to-noise ratio was reduced compared with data obtained by post mortem dissection, the dynamic data acquisition capabilities of the system demonstrate the feasibility of monitoring the kinetics of ligand binding in individual animals and encourages further design of a small-diameter detector system with tomographic capabilities.

In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography.

In vivo opioid receptor binding in the cortical projections of the medial (cingulate and prefrontal cortex) and lateral pain system (primary somatosensory cortex) in male volunteers has been quantitated using [11C]diprenorphine and positron emission tomography. High levels of opioid receptor binding were seen in the cortical projections of the medial pain system in the cingulate and prefrontal cortex as has previously been observed in post-mortem studies. However, a focal reduction of opioid receptor binding was observed and quantitated in the primary motor/sensory strip when compared to surrounding parietal cortex. This new finding suggests that the medial pain system is likely to be more susceptible to exogenous and endogenous opioid neuromodulation than the so-called lateral pain system.

Linear dimension reduction of sequences of medical images: II. Direct sum decomposition.

Using unitary transformations together with a previously described statistical theory for optimal linear dimension reduction it is shown how pixels in a sequence of images can be decomposed into a sum of variates, covariates, and residual vectors, with all covariances equal to zero. It is demonstrated that this decomposition is optimal with respect to noise. In addition, it results in simplified and well conditioned equations for dimension reduction and elimination of covariates. The factor images are not degraded by subdivision of the time intervals. In contrast to traditional factor analysis, the factors can be measured directly or calculated based on physiological models. This procedure not only solves the rotation problem associated with factor analysis, but also eliminates the need for calculation of the principal components altogether. Examples are given of factor images of the heart, generated from a dynamic study using oxygen-15-labelled water and positron emission tomography. As a special application of the method, it is shown that the factor images may reveal any contamination of the blood curve derived from the original dynamic images with myocardial activity.

An assessment of the ability of diplomates, practitioners, and students to describe and interpret recordings of heart murmurs and arrhythmia.

The ability of clinicians, ie, 10 veterinary students, 10 general practitioners, and 10 board certified internists, to describe and interpret common normal and abnormal heart sounds was assessed. Recordings of heart sounds from 7 horses with a variety of normal and abnormal rhythms, heart sounds, and murmurs were analyzed by digital sonography. The perception of the presence or absence of the heart sounds S1, S2, and S4 was similar for clinicians irrespective of their level of training and was in agreement with the sonographic interpretation on 89, 82, and 78% of occasions, respectively. However, practitioners were less likely to correctly describe the presence of S3. The heart rhythm was correctly described as being regular or irregular on 89% of occasions, and this outcome was not affected by level of training. Differentiation of the type of irregularity was less reliable. The perception of the intensity of a heart murmur was accurate and correlated with the grade assigned in the living horses, R2 = .68, and with sonographic measurements of the murmur's intensity, R2 = .69. Clinicians overestimated the duration of cardiac murmurs, particularly that of the loud systolic murmur. Only diplomates could reliably differentiate systolic from diastolic murmurs. The ability to diagnose the underlying cardiac problem was significantly affected by training; diplomates, practitioners, and undergraduates made the correct diagnosis on 53, 33, and 29% of occasions, respectively. The poor diagnostic ability of practitioners and the lack of improvement in diagnostic skill after the 2nd year of veterinary school emphasizes the need for better teaching of these skills. Digital sonograms that combine sound files with synchronous visual interpretations may be useful in this regard.

Computational neuroanatomy: new perspectives for neuroradiology.

Computational neuroanatomy is emerging as an exciting new methodology to characterise shape and neuroanatomical configuration of different brains. It encompasses a triad of techniques: Voxel-based morphometry (VBM), which compares neuroanatomical differences on a voxel by voxel basis, Deformation-based morphometry (DBM), which provides information about global differences in brain shape and Tensor-based morphometry (TBM) which provides information about local shape differences. This review will describe the methodology and clinical applications of these techniques.