In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this “speech production network” is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain–behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior–dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases.
diffusion tensor imaging; frontal tracts; primary progressive aphasia; speech production; tractography; white matter
Diffusion tensor MRI (DTI) has been widely used to investigate brain microstructural changes in pathological conditions as well as for normal development and aging. In particular, longitudinal changes are vital to the understanding of progression but these studies are typically designed for specific regions of interest. To analyze changes in these regions traditional statistical methods are often employed to elucidate group differences which are measured against the variability found in a control cohort. However, in some cases, rather than collecting multiple subjects into two groups, it is necessary and more informative to analyze the data for individual subjects. There is also a need for understanding changes in a single subject without prior information regarding the spatial distribution of the pathology, but no formal statistical framework exists for these voxel-wise analyses of DTI. In this study, we present PERVADE (PERmutation Voxel-wise Analysis of Diffusion Estimates), a whole brain analysis method for detecting localized FA changes between two separate points in time of any given subject, without any prior hypothesis about where changes might occur. Exploiting the nature of DTI that it is calculated from multiple diffusion-weighted images of each region, permutation testing, a non-parametric hypothesis testing technique, was modified for the analysis of serial DTI data and implemented for voxel-wise hypothesis tests of diffusion metric changes, as well as for suprathreshold cluster analysis to correct for multiple comparisons. We describe PERVADE in detail and present results from Monte Carlo simulation supporting the validity of the technique as well as illustrative examples from a healthy subject and patients in the early stages of multiple sclerosis.
diffusion tensor MRI; permutation; serial; longitudinal; voxel; cluster; fiber tracking; multiple sclerosis; white matter
Depression is very common in multiple sclerosis (MS) but the underlying biological mechanisms are poorly understood. The hippocampus plays a key role in mood regulation and is implicated in the pathogenesis of depression. This study utilizes volumetric and shape analyses of the hippocampus to characterize neuroanatomical correlates of depression in MS. A cross-section of 109 female MS patients was evaluated. Bilateral hippocampi were segmented from MRI scans (volumetric T1-weighted, 1mm3) using automated tools. Shape analysis was performed using surface mesh modeling. Depression was assessed using the Center for Epidemiologic Studies-Depression (CES-D) scale. Eighty-three subjects were classified as low depression (CES-D 0-20) versus 26 subjects with high depression (CES-D ≥ 21). Right hippocampal volumes (p=0.04) were smaller in the high depression versus the low depression groups, but there was no significant difference in left hippocampal volumes. Surface rendering analysis revealed hippocampal shape changes in depressed MS patients were clustered in the right hippocampus. Significant associations were found between right hippocampal shape and affective symptoms but not vegetative symptoms of depression. Our results suggested that regionally clustered reductions in hippocampal thickness can be detected by automated surface mesh modeling and may be a biological substrate of MS depression in female patients.
depression; autoimmunity; hippocampus; cornu ammonis; magnetic resonance imaging
Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T2-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss.
Sporadic Creutzfeldt-Jakob disease (sCJD) is considered primarily a disease of grey matter. However, Caverzasi et al. now show a global decrease in mean diffusivity in white matter. The changes appear to be associated with reactive astrocytic gliosis and activated microglia, and suggest primary involvement of the white matter in sCJD.
DTI; CJD; mean diffusivity; gliosis; microglia
The inferior fronto-occipital fasciculus (IFOF) is historically described as the longest associative bundle in the human brain and it connects various parts of the occipital cortex, temporo-basal area and the superior parietal lobule to the frontal lobe through the external/extreme capsule complex. The exact functional role and the detailed anatomical definition of the IFOF are still under debate within the scientific community. In this study we present a fiber tracking dissection of the right and left IFOF by using a q-ball residual-bootstrap reconstruction of High-Angular Resolution Diffusion Imaging (HARDI) data sets in 20 healthy subjects. By defining a single seed region of interest on the coronal fractional anisotropy (FA) color map of each subject, we investigated all the pathways connecting the parietal, occipital and posterior temporal cortices to the frontal lobe through the external/extreme capsule. In line with recent post-mortem dissection studies we found more extended anterior-posterior association connections than the “classical” fronto-occipital representation of the IFOF. In particular the pathways we evidenced showed: a) diffuse projections in the frontal lobe, b) fronto-parietal lobes connections trough the external capsule in almost all the subjects and c) widespread connections in the posterior regions. Our study represents the first consistent in vivo demonstration across a large group of individuals of these novel anterior and posterior terminations of the IFOF detailed described only by post-mortem anatomical dissection. Furthermore our work establishes the feasibility of consistent in vivo mapping of this architecture with independent in vivo methodologies. In conclusion q-ball tractography dissection supports a more complex definition of IFOF, which includes several subcomponents likely underlying specific function.
The combination of mapping functional cortical neurons by intraoperative cortical stimulation and axonal architecture by diffusion tensor MRI fiber tracking can be used to delineate the pathways between functional regions. In this study the authors investigated the feasibility of combining these techniques to yield connectivity associated with motor speech and naming. Diffusion tensor MRI fiber tracking provides maps of axonal bundles and was combined with intraoperative mapping of eloquent cortex for a patient undergoing brain tumor surgery. Tracks from eight stimulated sites in the inferior frontal cortex including mouth motor, speech arrest, and anomia were generated from the diffusion tensor MRI data. The regions connected by the fiber tracking were compared to foci from previous functional imaging reports on language tasks. Connections were found between speech arrest, mouth motor, and anomia sites and the SMA proper and cerebral peduncle. The speech arrest and a mouth motor site were also seen to connect to the putamen via the external capsule. This is the first demonstration of delineation of subcortical pathways using diffusion tensor MRI fiber tracking with intraoperative cortical stimulation. The combined techniques may provide improved preservation of eloquent regions during neurological surgery, and may provide access to direct connectivity information between functional regions of the brain.
Language; Tensor imaging; Fiber tracking
Brain magnetic resonance imaging is widely used as a diagnostic and monitoring tool in multiple sclerosis and provides a non-invasive, sensitive and reproducible way to track the disease. Topological characteristics relating to the distribution and shape of lesions are recognized as important neuroradiological markers in the diagnosis of multiple sclerosis, although these have been much less well characterized quantitatively than have traditional measures such as T2 hyperintense or T1 hypointense lesion volumes. Here, we used voxel-level 3 T magnetic resonance imaging T1-weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested whether this is a heritable phenotype. To this end, we extracted the genotypes from a published genome-wide association study on these same individuals and searched for genetic associations with lesion load, shape and topological distribution. Lesion probability maps were created to identify frequently affected areas and to assess the overall distribution of T1 lesions in the subject population as a whole. We then developed an original algorithm to cluster adjacent lesional voxels (cluxels) in each subject and tested whether cluxel topology was significantly associated with any single-nucleotide polymorphism in our data set. To focus on patterns of lesion distribution, we computed the first 10 principal components. Although principal component 1 correlated with lesion load, none of the remaining orthogonal components correlated with any other known variable. We then conducted genome-wide association studies on each of these and found 31 significant associations (false discovery rate <0.01) with principal component 8, which represents a mode of variation of lesion topology in the population. The majority of the loci can be linked to genes related to immune cell function and to myelin and neural growth; some (SYK, MYT1L, TRAPPC9, SLITKR6 and RIC3) have been previously associated with the distribution of white matter lesions in multiple sclerosis. Finally, we used a bioinformatics approach to identify a network of 48 interacting proteins showing genetic associations (P < 0.01) with cluxel topology in multiple sclerosis. This network also contains proteins expressed in immune cells and is enriched in molecules expressed in the central nervous system that contribute to neural development and regeneration. Our results show how quantitative traits derived from brain magnetic resonance images of patients with multiple sclerosis can be used as dependent variables in a genome-wide association study. With the widespread availability of powerful computing and the availability of genotyped populations, integration of imaging and genetic data sets is likely to become a mainstream tool for understanding the complex biological processes of multiple sclerosis and other brain disorders.
voxel-wise; GWAS; multiple sclerosis
Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year open-label phase 1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.
After cerebral ischemia, disruption and subsequent reorganization of functional connections occur both locally and remote to the lesion. However, the unpredictable timing and extent of sensorimotor recovery reflects a gap in understanding of these underlying neural mechanisms. We aimed to identify plasticity of alpha-band functional neural connections within the perilesional area and the predictive value of functional connectivity with respect to motor recovery of the upper extremity after stroke. Our results show improvements in upper extremity motor recovery in relation to distributed changes in MEG-based alpha band functional connectivity, both in the perilesional area and contralesional cortex. Motor recovery was found to be predicted by increased connectivity at baseline in the ipsilesional somatosensory area, supplementary motor area, and cerebellum, contrasted with reduced connectivity of contralesional motor regions, after controlling for age, stroke onset-time and lesion size. These findings support plasticity within a widely distributed neural network and define brain regions in which the extent of network participation predicts post-stroke recovery potential
Stroke; magnetoencephalography; plasticity; motor recovery; brain connectivity
Diffusion MRI tractography has been increasingly used to delineate white matter pathways in vivo for which the leading clinical application is presurgical mapping of eloquent regions. However, there is rare opportunity to quantify the accuracy or sensitivity of these approaches to delineate white matter fiber pathways in vivo due to the lack of a gold standard. Intraoperative electrical stimulation (IES) provides a gold standard for the location and existence of functional motor pathways that can be used to determine the accuracy and sensitivity of fiber tracking algorithms. In this study we used intraoperative stimulation from brain tumor patients as a gold standard to estimate the sensitivity and accuracy of diffusion tensor MRI (DTI) and q-ball models of diffusion with deterministic and probabilistic fiber tracking algorithms for delineation of motor pathways.
We used preoperative high angular resolution diffusion MRI (HARDI) data (55 directions, b = 2000 s/mm2) acquired in a clinically feasible time frame from 12 patients who underwent a craniotomy for resection of a cerebral glioma. The corticospinal fiber tracts were delineated with DTI and q-ball models using deterministic and probabilistic algorithms. We used cortical and white matter IES sites as a gold standard for the presence and location of functional motor pathways. Sensitivity was defined as the true positive rate of delineating fiber pathways based on cortical IES stimulation sites. For accuracy and precision of the course of the fiber tracts, we measured the distance between the subcortical stimulation sites and the tractography result. Positive predictive rate of the delineated tracts was assessed by comparison of subcortical IES motor function (upper extremity, lower extremity, face) with the connection of the tractography pathway in the motor cortex.
We obtained 21 cortical and 8 subcortical IES sites from intraoperative mapping of motor pathways. Probabilistic q-ball had the best sensitivity (79%) as determined from cortical IES compared to deterministic q-ball (50%), probabilistic DTI (36%), and deterministic DTI (10%). The sensitivity using the q-ball algorithm (65%) was significantly higher than using DTI (23%) (p < 0.001) and the probabilistic algorithms (58%) were more sensitive than deterministic approaches (30%) (p = 0.003). Probabilistic q-ball fiber tracks had the smallest offset to the subcortical stimulation sites. The offsets between diffusion fiber tracks and subcortical IES sites were increased significantly for those cases where the diffusion fiber tracks were visibly thinner than expected. There was perfect concordance between the subcortical IES function (e.g. hand stimulation) and the cortical connection of the nearest diffusion fiber track (e.g. upper extremity cortex).
This study highlights the tremendous utility of intraoperative stimulation sites to provide a gold standard from which to evaluate diffusion MRI fiber tracking methods and has provided an object standard for evaluation of different diffusion models and approaches to fiber tracking. The probabilistic q-ball fiber tractography was significantly better than DTI methods in terms of sensitivity and accuracy of the course through the white matter. The commonly used DTI fiber tracking approach was shown to have very poor sensitivity (as low as 10% for deterministic DTI fiber tracking) for delineation of the lateral aspects of the corticospinal tract in our study. Effects of the tumor/edema resulted in significantly larger offsets between the subcortical IES and the preoperative fiber tracks. The provided data show that probabilistic HARDI tractography is the most objective and reproducible analysis but given the small sample and number of stimulation points a generalization about our results should be given with caution. Indeed our results inform the capabilities of preoperative diffusion fiber tracking and indicate that such data should be used carefully when making pre-surgical and intra-operative management decisions.
•Diffusion MRI tractography is used for presurgical brain mapping.•We use intraoperative electric stimulation as a gold standard.•We delineate motor tracts with deterministic and probabilistic DTI and q-ball models.•Probabilistic q-ball has the best sensitivity (79%).•Probabilistic q-ball fiber tracks had the smallest offset to the subcortical IES.
Diffusion MRI Tractography; Corticospinal tract; q-Ball; DTI; Brain tumor; Intraoperative electrical stimulation (IES)
Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts’ mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI