Mara Cercignani

About "axial" and "radial" diffusivities.

This article presents the potential problems arising from the use of “axial” and “radial” diffusivities, derived from the eigenvalues of the diffusion tensor, and their interpretation in terms of the underlying biophysical properties, such as myelin and axonal density. Simulated and in vivo data are shown. The simulations demonstrate that a change in “radial” diffusivity can cause a fictitious change in “axial” diffusivity and vice versa in voxels characterized by crossing fibers. The in vivo data compare the direction of the principle eigenvector in four different subjects, two healthy and two affected by multiple sclerosis, and show that the angle, α, between the principal eigenvectors of corresponding voxels of registered datasets is greater than 45° in areas of low anisotropy, severe pathology, and partial volume. Also, there are areas of white matter pathology where the “radial” diffusivity is 10% greater than that of the corresponding normal tissue and where the direction of the principal eigenvector is altered by more than 45° compared to the healthy case. This should strongly discourage researchers from interpreting changes of the “axial” and “radial” diffusivities on the basis of the underlying tissue structure, unless accompanied by a thorough investigation of their mathematical and geometrical properties in each dataset studied. Magn Reson Med, 2009.

The effect of filter size on VBM analyses of DT-MRI data

Voxel-based morphometry (VBM) has been used to analyze diffusion tensor MRI (DT-MRI) data in a number of studies. In VBM, following spatial normalization, data are smoothed to improve the validity of statistical inferences and to reduce inter-individual variation. However, the size of the smoothing filter used for VBM of DT-MRI data is highly variable across studies. For example, a literature review revealed that Gaussian smoothing kernels ranging in size (full width at half maximum) from zero to 16 mm have been used in DT-MRI VBM type studies. To investigate the effect of varying filter size in such analyses, whole brain DT-MRI data from 14 schizophrenic patients were compared with those of 14 matched control subjects using VBM, when the filter size was varied from zero to 16 mm. Within this range of smoothing, four different conclusions regarding apparent patient control differences could be made: (i) no significant patient-control differences; (ii) reduced FA in right superior temporal gyrus (STG) in patients; (iii) reduced FA in both right STG and left cerebellum in patients; and (iv) reduced FA only in left cerebellum in patients. These findings stress the importance of recognizing the effect of the matched filter theorem on VBM analyses of DT-MRI data. Finally, we investigated whether one of the underlying assumptions of parametric VBM, i.e., the normality of the residuals, is met. Our results suggest that, even with moderate smoothing, a large number of voxels within central white matter regions may have non-normally distributed residuals thus making valid statistical inferences with a parametric approach problematic in these areas.

Twenty-five pitfalls in the analysis of diffusion MRI data.

Obtaining reliable data and drawing meaningful and robust inferences from diffusion MRI can be challenging and is subject to many pitfalls. The process of quantifying diffusion indices and eventually comparing them between groups of subjects and/or correlating them with other parameters starts at the acquisition of the raw data, followed by a long pipeline of image processing steps. Each one of these steps is susceptible to sources of bias, which may not only limit the accuracy and precision, but can lead to substantial errors. This article provides a detailed review of the steps along the analysis pipeline and their associated pitfalls. These are grouped into 1 pre‐processing of data; 2 estimation of the tensor; 3 derivation of voxelwise quantitative parameters; 4 strategies for extracting quantitative parameters; and finally 5 intra‐subject and inter‐subject comparison, including region of interest, histogram, tract‐specific and voxel‐based analyses. The article covers important aspects of diffusion MRI analysis, such as motion correction, susceptibility and eddy current distortion correction, model fitting, region of interest placement, histogram and voxel‐based analysis. We have assembled 25 pitfalls (several previously unreported) into a single article, which should serve as a useful reference for those embarking on new diffusion MRI‐based studies, and as a check for those who may already be running studies but may have overlooked some important confounds. While some of these problems are well known to diffusion experts, they might not be to other researchers wishing to undertake a clinical study based on diffusion MRI. Copyright

Regional brain atrophy and functional disconnection across Alzheimer's disease evolution

Objective To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimers disease (AD) at different clinical stages. Methods Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis. Results Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD. Conclusions This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

Exploring the Relationship Between White Matter and Gray Matter Damage in Early Primary Progressive Multiple Sclerosis: An In Vivo Study With TBSS and VBM

We investigated the relationship between the damage occurring in the brain normal‐appearing white matter (NAWM) and in the gray matter (GM) in patients with early Primary Progressive multiple sclerosis (PPMS), using Tract‐Based Spatial Statistics (TBSS) and an optimized voxel‐based morphometry (VBM) approach. Thirty‐five patients with early PPMS underwent diffusion tensor and conventional imaging and were clinically assessed. TBSS and VBM were employed to localize regions of lower fractional anisotropy (FA) and lower GM volume in patients compared with controls. Areas of anatomical and quantitative correlation between NAWM and GM damage were detected. Multiple regression analyses were performed to investigate whether NAWM FA or GM volume of regions correlated with clinical scores independently from the other and from age and gender. In patients, we found 11 brain regions that showed an anatomical correspondence between reduced NAWM FA and GM atrophy; of these, four showed a quantitative correlation (i.e., the right sensory motor region with the adjacent corticospinal tract, the left and right thalamus with the corresponding thalamic radiations and the left insula with the adjacent WM). Either the NAWM FA or the GM volume in each of these regions correlated with disability. These results demonstrate a link between the pathological processes occurring in the NAWM and in the GM in PPMS in specific, clinically relevant brain areas. Longitudinal studies will determine whether the GM atrophy precedes or follows the NAWM damage. The methodology that we described may be useful to investigate other neurological disorders affecting both the WM and the GM. Hum Brain Mapp 2009.

Defining Meyer's loop–temporal lobe resections, visual field deficits and diffusion tensor tractography

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyers loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyers loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T1-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyers loop to the temporal pole was 24–43 mm (mean 34 mm), and the range of distance from the tip of Meyers loop to the temporal horn was −15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyers loop to the temporal pole was 24–47 mm (mean 35 mm), and the range of distance from the tip of Meyers loop to the temporal horn was −11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyers loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyers loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patients risk of postoperative VFDs following anterior temporal lobe resection.

The corpus callosum in first episode schizophrenia: a diffusion tensor imaging study.

Background: Neuropathological and imaging studies suggest that corpus callosum abnormalities (CC) are present in schizophrenia, but it remains to be determined whether these abnormalities are present at illness onset. Diffusion tensor imaging (DTI), which is more sensitive than conventional magnetic resonance imaging (MRI) in detecting subtle structural changes in the organisation and integrity of white matter tracts, is an ideal tool to investigate this question. Objective: To determine whether CC abnormalities are present at illness onset in schizophrenia. Methods: Twenty patients (14 men, six women) with first episode schizophrenia and 29 controls (11 men, 18 women) were studied. Both high resolution volumetric T1-weighted images and DTI were acquired. Regions of interest (ROI) were placed in the splenium and genu of the CC and fractional anisotropy (FA) and diffusivity (D) measured. Results: No differences in FA or D were detected in these regions between patients and controls. In women, irrespective of group membership, FA was significantly lower and there was a trend for D to be higher than in men, indicating less barriers to diffusion in females. Conclusion: The negative findings of this study suggest that in the early stages of schizophrenia there is no disruption to the integrity of the CC and raise the possibility that the neuropathological abnormalities may appear later and be progressive, at least in some patients.

White matter abnormalities in bipolar disorder: a voxel‐based diffusion tensor imaging study

OBJECTIVES In bipolar disorder (BD), dysregulation of mood may result from white matter abnormalities that disrupt fronto-subcortical circuits. In this study, we explore such abnormalities using diffusion tensor imaging (DTI), an imaging technique capable of detecting subtle changes not visible with conventional magnetic resonance imaging (MRI), and voxel-based analysis. METHODS Thirty-six patients with BD, all but two receiving antidepressants or mood stabilizers, and 28 healthy controls matched for age and gender were studied. Diffusion-weighted echoplanar images (DW-EPI) were obtained using a 1.5T scanner. Voxel-based analysis was performed using SPM 2. Differences between the groups in mean diffusivity and fractional anisotropy (FA) were explored. RESULTS In the patient group, mean diffusivity was increased in the right posterior frontal and bilateral prefrontal white matter, while FA was decreased [corrected] in the inferior, middle temporal and middle occipital regions. The areas of increased mean diffusivity overlapped with those previously found to be abnormal using volumetric MRI and magnetization transfer imaging (MTI) in the same group of patients. CONCLUSIONS White matter abnormalities, predominantly in the fronto-temporal regions, can be detected in patients with BD using DTI. The neuropathology of these abnormalities is uncertain, but neuronal and axonal loss, myelin abnormalities and alterations in axonal packing density are likely to be relevant. The neuroprotective effects of some antidepressants and mood stabilizers make it unlikely that medication effects could explain the abnormalities described here, although minor effects cannot be excluded.

Abnormal brain connectivity in first-episode psychosis: A diffusion MRI tractography study of the corpus callosum

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique. We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia. In addition, the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions. Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study. A probabilistic tractography algorithm (PICo) was used to study fractional anisotropy (FA). Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions, and a multi-threshold approach to study the probability of connection was used. Multiple linear regressions were used to explore group differences. FA, a measure of tract coherence, was reduced in tracts crossing the genu, and to a lesser degree the splenium, in patients compared with controls. FA was also lower in the genu in females across both groups, but there was no gender-by-group interaction. The FA reduction in patients may be due to aberrant myelination or axonal abnormalities, but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness.

In vivo definition of parieto-motor connections involved in planning of grasping movements

We combined bifocal transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) tractography to investigate in humans the contribution of connections originating from different parietal areas in planning of different reaching to grasp movements. TMS experiments revealed that in the left hemisphere functional connectivity between the primary motor cortex (M1) and a portion of the angular gyrus (AG) close to the caudal intraparietal sulcus was activated during early preparation of reaching and grasping movements only when the movement was made with a whole hand grasp (WHG) towards objects in contralateral space. In contrast, a different pathway, linking M1 with a part of the supramarginal gyrus (SMG) close to the anterior intraparietal sulcus, was sensitive only to the type of grasp required (precision grasping) but not to the position of the object in space. A triple coil experiment revealed that inactivation of the ventral premotor area (PMv) by continuous theta burst stimulation interfered with some of these interactions. Anatomical DTI tractography revealed that AG and SMG are strongly connected with PMv and with M1 by different bundles of the superior longitudinal fasciculus (SLF). These results demonstrate the existence of segregated parieto-premotor-motor pathways crucial for preparation of different grasping actions and indicate that these may process information relevant to both the position of the object and the hand shape required to use it.