Gray-White Matter Blurring of the Temporal Pole Associated With Hippocampal Sclerosis: A Microstructural Study Involving 3 T MRI and Ultrastructural Histopathology.

Hippocampal sclerosis (HS) is often associated with gray-white matter blurring (GMB) of the anterior temporal lobe. In this study, twenty patients with unilateral temporal lobe epilepsy and HS were studied with 3 T MRI including T1 MP2RAGE and DTI/DMI sequences. Anterior temporal lobe white matter T1 relaxation times and diffusion measures were analyzed on the HS side, on the contralateral side, and in 10 normal controls. Resected brain tissue of three patients without GMB and four patients with GMB was evaluated ultrastructurally regarding axon density and diameter, the relation of the axon diameter to the total fiber diameter (G-ratio), and the thickness of the myelin sheath. Hippocampal sclerosis GMB of the anterior temporal lobe was related to prolonged T1 relaxation and axonal loss. A less pronounced reduction in axonal fraction was also found on imaging in GMB-negative temporal poles compared with normal controls. Contralateral values did not differ significantly between patients and normal controls. Reduced axonal density and axonal diameter were histopathologically confirmed in the temporopolar white matter with GMB compared to temporal poles without. These results confirm that GMB can be considered an imaging correlate for disturbed axonal maturation that can be quantified with advanced diffusion imaging.

Displaying the autonomic processing network in humans - a global tractography approach.

Regulation of the internal homeostasis is modulated by the central autonomic system. So far, the view of this system is determined by animal and human research focusing on cortical and subcortical grey substance regions. To provide an overview based on white matter architecture, we used a global tractography approach to reconstruct a network of tracts interconnecting brain regions that are known to be involved in autonomic processing. Diffusion weighted imaging data were obtained from subjects of the human connectome project (HCP) database. Resulting tracts are in good agreement with previous studies assuming a division of the central autonomic system into a cortical (CAN) and a subcortical network (SAN): the CAN consist of three subsystems that encompass all cerebral lobes and overlap within the insular cortex: a parieto-anterior-temporal pathway (PATP), an occipito-posterior-temporo-frontal pathway (OPTFP) and a limbic pathway. The SAN on the other hand connects the hypothalamus to the periaqueductal grey and locus coeruleus, before it branches into a dorsal and a lateral part that target autonomic nuclei in the rostral medulla oblongata. Our approach furthermore reveals how the CAN and SAN are interconnected: the hypothalamus can be considered as the interface-structure of the SAN, whereas the insula is the central hub of the CAN. The hypothalamus receives input from prefrontal cortical fields but is also connected to the ventral apex of the insular cortex. Thus, a holistic view of the central autonomic system could be created that may promote the understanding of autonomic signaling under physiological and pathophysiological conditions.

A detailed analysis of anatomical plausibility of crossed and uncrossed streamline rendition of the dentato-rubro-thalamic tract (DRT(T)) in a commercial stereotactic planning system.

BACKGROUND: An increasing number of neurosurgeons use display of the dentato-rubro-thalamic tract (DRT) based on diffusion weighted imaging (dMRI) as basis for their routine planning of stimulation or lesioning approaches in stereotactic tremor surgery. An evaluation of the anatomical validity of the display of the DRT with respect to modern stereotactic planning systems and across different tracking environments has not been performed. METHODS: Distinct dMRI and anatomical magnetic resonance imaging (MRI) data of high and low quality from 9 subjects were used. Six subjects had repeated MRI scans and therefore entered the analysis twice. Standardized DICOM structure templates for volume of interest definition were applied in native space for all investigations. For tracking BrainLab Elements (BrainLab, Munich, Germany), two tensor deterministic tracking (FT2), MRtrix IFOD2 ( https://www.mrtrix.org ), and a global tracking (GT) approach were used to compare the display of the uncrossed (DRTu) and crossed (DRTx) fiber structure after transformation into MNI space. The resulting streamlines were investigated for congruence, reproducibility, anatomical validity, and penetration of anatomical way point structures. RESULTS: In general, the DRTu can be depicted with good quality (as judged by waypoints). FT2 (surgical) and GT (neuroscientific) show high congruence. While GT shows partly reproducible results for DRTx, the crossed pathway cannot be reliably reconstructed with the other (iFOD2 and FT2) algorithms. CONCLUSION: Since a direct anatomical comparison is difficult in the individual subjects, we chose a comparison with two research tracking environments as the best possible "ground truth." FT2 is useful especially because of its manual editing possibilities of cutting erroneous fibers on the single subject level. An uncertainty of 2 mm as mean displacement of DRTu is expectable and should be respected when using this approach for surgical planning. Tractographic renditions of the DRTx on the single subject level seem to be still illusive.

Comparison of automated and visual DWI ASPECTS in acute ischemic stroke.

BACKGROUND AND PURPOSE: To assess intra-and inter-rater agreement of the ASPECTS (Alberta Stroke Program Early CT Score) based on diffusion-weighted MRI and to compare it with fully - automated methods (eASPECTS). METHODS: DWI-ASPECTS of scans of 96 patients with acute ischemic stroke was rated by 2 experts. Automated methods based on thresholding the affected volumes of a coregistered atlas, and a regression tree learning method were established. Intra-rater, inter-rater and human-rater vs. automated methods agreements were investigated based on the intraclass correlation coefficients (ICC) and Bland Altman plots. RESULTS: Intra-rater agreement was good for both raters (ICC of 0.91 and 0.93). Inter-rater agreement was worse (ICC = 0.86) indicating a slight bias between both raters. Agreement with automated methods ranged from 0.81 to 0.87. Root-mean-squared deviation was 0.89 and 0.69 for the human raters and ranged from 0.95 to 1.24 for the automated methods. CONCLUSIONS: Agreement values are on the same order or higher compared to a literature review of CT-based ASPECTS. Automated methods perform slightly worse than human expert ratings, but they still have enough power to determine the DWI-ASPECTS with good precision in a clinical setting.

Microstructural effects of a neuro-modulating drug evaluated by diffusion tensor imaging.

In a longitudinal mouse study we evaluated whether diffusion tensor imaging (DTI) can monitor microstructural changes after administration of the neuromodulating drug EPO and whether erythropoietin (EPO) has an effect on cognitive performance. Twelve mice (2 groups with 6 mice each) were scanned in a 7T Bruker Biospin animal scanner with a highly resolved DTI sequence before and 16 days after intraperitoneal injections of EPO or saline. All mice underwent behavioral testing (Morris water maze) and histologic evaluation of hippocampal and corpus callosum cell proliferation and oligodendrogenesis. Whole brain DTI analysis showed significant Trace, RD and AD decrease within the dentate gyrus, subiculum, primary motor, somatosensory, and supplementary somatosensory areas and FA increase in the hippocampus, corpus callosum, and fimbria fornix in EPO treated mice only. ROI-based DTI analysis showed significant Trace and RD decrease and FA increase only in the corpus callosum of EPO treated mice, whereas in the dentate gyrus significant Trace, RD, and AD decrease occurred in both, EPO- and control-group. Behavioral tests showed that EPO treated mice performed better and learned faster than controls. Histologically, the number of BrdU-positive nuclei and optical density of DCX-labeled juvenile neurons significantly increased within the dentate gyrus, corpus callosum and fimbria fornix and the number of NG2-positive oligodendrocyte progenitors in corpus callosum and fimbria fornix, respectively. In conclusion we were able to monitor microstructural changes with DTI and showed EPO treatment-related alterations correlating with enhanced dentate gyrus and corpus callosum cell proliferation and better learning capabilities.

Advanced diffusion MRI provides evidence for altered axonal microstructure and gradual peritumoral infiltration in GBM in comparison to brain metastases.

PURPOSE: In contrast to peritumoral edema in metastases, GBM is histopathologically characterized by infiltrating tumor cells within the T2 signal alterations. We hypothesized that depending on the distance from the outline of the contrast-enhancing tumor we might reveal imaging evidence of gradual peritumoral infiltration in GBM and predominantly vasogenic edema around metastases. We thus investigated the gradual change of advanced diffusion metrics with the peritumoral zone in metastases and GBM. METHODS: In 30 patients with GBM and 28 with brain metastases, peritumoral T2 hyperintensity was segmented in 33% partitions based on the total volume beginning at the enhancing tumor margin and divided into inner, middle and outer zones. Diffusion Tensor Imaging (DTI)-derived fractional anisotropy and mean diffusivity as well as Diffusion Microstructure Imaging (DMI)-based parameters Dax-intra, Dax-extra, V­CSF and V-intra were employed to assess group-wise differences between inner and outer zones as well as within-group gradients between the inner and outer zones. RESULTS: In metastases, fractional anisotropy and Dax-extra were significantly reduced in the inner zone compared to the outer zone (FA p = 0.01; Dax-extra p = 0.03). In GBM, we noted a reduced Dax-extra and significantly lower intraaxonal volume fraction (Dax-extra p = 0.008, V­intra p = 0.006) accompanied by elevated axial intraaxonal diffusivity in the inner zone (p = 0.035). Between-group comparison of the outer to the inner zones revealed significantly higher gradients in metastases over GBM for FA (p = 0.04) as well as the axial diffusivity in the intra- (p = 0.02) and extraaxonal compartment (p < 0.001). CONCLUSION: Our findings provide evidence of gradual alterations within the peritumoral zone of brain tumors. These are compatible with predominant (vasogenic) edema formation in metastases, whereas our findings in GBM are in line with an axonal destructive component in the immediate peritumoral area and evidence of tumor cell infiltration with accentuation in the tumor's vicinity.

Intracranial Vessel Segmentation in 3D High-Resolution T1 Black-Blood MRI.

We demonstrate the feasibility of intracranial vascular segmentation based on the hypointense signal in non-contrast-enhanced black-blood MR imaging using convolutional neural networks. We selected 37 cases. Qualitatively, we observed no degradation due to stent artifacts, a comparable recognition of an aneurysm recurrence with TOF-MRA, and consistent success in the differentiation of intracranial arteries and veins. False-positive and false-negative results were observed. Quantitatively, our model achieved a promising Dice similarity coefficient of 0.72.

Clinical feasibility of diffusion microstructure imaging (DMI) in acute ischemic stroke.

BACKGROUND: Diffusion microstructure imaging (DMI) is a fast approach to higher-order diffusion-weighted magnetic resonance imaging that allows robust decomposition and characterization of diffusion properties of brain tissue into intra-axonal, extra-axonal, and a free water-compartment. We now report the application of this technique to acute ischemic stroke and demonstrate its potential applicability to the daily clinical routine. METHODS: Thirty-eight patients diagnosed with acute ischemic stroke were scanned using an accelerated multi-shell diffusion-weighted imaging protocol (median delay between onset and MRI scan of 113 min). DMI metrics were calculated and the apparent diffusion coefficient (ADC) derived from conventional diffusion-weighted imaging was used for comparison. The resulting DMI parameter maps were analysed for their potential to improve infarct core delineation, and a receiver-operating characteristic (ROC) analysis was subsequently performed for automated infarct segmentation. RESULTS: Robust parameter maps for diffusion microstructure properties were obtained in all cases. Within the ischemic tissue, an increase in the volume fraction of the intra-axonal compartment was accompanied by a volume fraction reduction in the other two compartments. Moreover, diffusivity was reduced in all three compartments, with intra-axonal diffusivity showing the highest degree of contrast. The intra-axonal diffusion coefficient maps were subsequently found to perform better than single-shell ADC-derived segmentation in terms of automatic segmentation of the infarct core (area under the curve = 0.98 vs 0.92). CONCLUSIONS: The alterations to the ischemic core detected by DMI are in line with the "beading-model" of non-uniform neurite swelling under ischemic conditions. When compared to conventional single-shell diffusion-weighted imaging, DMI metrics are associated with improved discriminative power for delineating and characterizing ischemic changes. This might allow a more detailed assessment of infarct age, severity of damage, the degree of reversibility, and outcome.

Contrast Bolus Interference in a Multimodal CT Stroke Protocol.

BACKGROUND AND PURPOSE: Whether CTP is performed before or after CTA varies within multimodal CT stroke protocols. CTA after CTP might show venous filling, and CTP metrics might be disturbed by prior CTA. Therefore, we compared CTP metrics conducted before and after CTA in a large cohort of patients with stroke and analyzed interferences of the CTA bolus with the CTP measurement. MATERIALS AND METHODS: We analyzed 1980 patients (368 patients with CTP performed before CTA [group A] versus 1612 patients with CTP performed after [group B]) in a retrospective study. Mean curves, histograms of CTP baseline Hounsfield units, CBF, CBV, time-to-maximum, hypoperfusion, and core volumes were calculated using the software VEOcore. CTA and CTP interferences were analyzed, and a detection and correction method was proposed. RESULTS: Mean CTP baseline values were significantly different in both groups (41 versus 45 HU within the groups A and B, respectively). However, perfusion metrics, hypoperfusion, and core volumes yielded no significant differences. In 49 patients, the descending flank of the CTA bolus interfered with the baseline of the CTP measurement, leading to erroneously low CBV values. These errors vanished when a correction method was applied. CONCLUSIONS: CTP can be reliably performed after CTA without a relevant net effect on perfusion metrics. However, when measuring CTP after CTA, either a short pause on the order of 30 seconds should be observed or an appropriate correction method should be applied. It may help to avoid excluding patients from mechanical thrombectomy by overestimating infarct cores.

Alterations of intracerebral connectivity in epilepsy patients with secondary bilateral synchrony.

INTRODUCTION: The aim of our study was to evaluate intracerebral network changes in epilepsy patients demonstrating secondary bilateral synchrony (SBS) in EEG by applying a new Diffusion Tensor Imaging (DTI) method using an energy-based global tracking algorithm. MATERIALS AND METHODS: 10 MRI negative epilepsy patients demonstrating SBS in 10-20 surface EEG were included. EEG findings were analyzed for irritative zones characterized by focal interictal epileptiform discharges (IEDs) triggering SBS. In addition, DTI including an energy-based global tracking algorithm was applied to analyze fiber tract alterations in irritative zones. To measure the deviation of a certain cortical connection in comparison to healthy controls, normalized differences of fiber tract streamline counts (SC) and their p-values were evaluated in comparison to corresponding fibers of the control group. RESULTS: In 6 patients the irritative zone initiating SBS was located in the frontal lobe, in 3 patients in the temporal lobe and in 1 patient in the region surrounding the right central sulcus. All patients demonstrated significantly altered SC in brain lobes where the irritative zone triggering SBS was located (p ≤ 0.05). Seven out of 10 patients demonstrated SC alterations in tracts connecting brain lobes between the ipsilateral and the contralateral hemisphere (p ≤ 0.05). CONCLUSION: Our data demonstrate that alterations in fiber tracts in irritative zones triggering SBS are not necessarily associated with intracerebral lesions visible in high resolution MRI. Our study gives evidence that diffusion tensor imaging is a promising non-invasive additive tool for intracerebral network analyses even in MRI-negative epilepsy patients.

Ventral tegmental area connections to motor and sensory cortical fields in humans.

In humans, sensorimotor cortical areas receive relevant dopaminergic innervation-although an anatomic description of the underlying fiber projections is lacking so far. In general, dopaminergic projections towards the cortex originate within the ventral tegmental area (VTA) and are organized in a meso-cortico-limbic system. Using a DTI-based global tractography approach, we recently characterized the superolateral branch of the medial forebrain bundle (slMFB), a prominent pathway providing dopaminergic (and other transmitters) innervation for the pre-frontal cortex (Coenen et al., NeuroImage Clin 18:770-783, 2018). To define the connections between VTA and sensory-motor cortical fields that should contain dopaminergic fibers, we use the slMFB as a key structure to lead our fiber selection procedure: using a similar tracking-seed and tractography algorithm, we describe a dorsal extension of this slMFB that covers sensorimotor fields that are dorsally appended to pre-frontal cortical areas. This "motorMFB", that connects the VTA to sensorimotor cortical fields, can be further segregated into three sub-bundles with a seed-based fiber-selection strategy: A PFC bundle that is attendant to the pre-frontal cortex, passes the lateral VTA, runs through the border zone between the posterior and lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus. An MB bundle that is attendant to the mammillary bodies runs directly through the medial VTA, passes the lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus as well as the supplementary motor area (SMA) and the dorsal premotor cortex (dPMC). Finally, a BC bundle that is attendant to the brainstem and cerebellum runs through the lateral VTA, passes the anterior ventral thalamic nucleus, and covers the SMA, pre-SMA, and the dPMC. We, furthermore, included a fiber tracking of the well-defined dentato-rubro-thalamic tract (DRT) that is known to lie in close proximity with respect to fiber orientation and projection areas. As expected, the tract is characterized by a decussation at the ponto-mesencephal level and a projection covering the superior-frontal and precentral cortex. In addition to the physiological role of these particular bundles, the physiological and pathophysiological impact of dopaminergic signaling within sensorimotor cortical fields becomes discussed. However, some limitations have to be taken into account in consequence of the method: the transmitter content, the directionality, and the occurrence of interposed synaptic contacts cannot be specified.

Bilateral cingulum fiber reductions in temporal lobe epilepsy with unilateral hippocampal sclerosis.

PURPOSE: To evaluate whether white matter tracts within the Papez circuit are altered in patients with unilateral hippocampal sclerosis (HS). METHODS: Twenty patients with histologically proven unilateral HS and 20 age-matched controls were studied with a 3T Epilepsy-dedicated MRI protocol including a MPRAGE sequence for hippocampus volumetry and a diffusion tensor imaging (DTI) sequence (61 diffusion-encoding directions, 2×2×2mm3 voxels) for diffusion tensor tractography (DTT). An energy-based global tracking algorithm was used to calculate streamline counts (SC) and fractional anisotropy (FA) of cingulate, fornix, and mammillo-thalamic tracts, respectively. RESULTS: Sclerotic hippocampi were significantly smaller compared to the contralateral side and to age-matched controls. Cingulum SC but not FA were reduced on the hippocampal sclerosis (258+81.0) and contralateral side (271+85.6) compared to age-matched controls (447+138). CONCLUSION: Focusing on white matter tracts of the Papez circuit we showed that in patients with intractable temporal lobe epilepsy unilateral hippocampal sclerosis is associated with a bilateral reduction of cingulum association fibers projecting from the cingulate gyrus to the parahippocampal gyrus.

Tractography of Association Fibers Associated with Language Processing.

INTRODUCTION: Several major association fiber tracts are known to be part of the language processing system. There is evidence that high angular diffusion-based MRI is able to separate these fascicles in a constant way. In this study, we wanted to proof this thesis using a novel whole brain "global tracking" approach and to test for possible lateralization. METHODS: Global tracking was performed in six healthy right-handed volunteers for the arcuate fascicle (AF), the medial longitudinal fascicle (MdLF), the inferior fronto-occipital fascicle (IFOF), and the inferior longitudinal fascicle (ILF). These fiber tracts were characterized quantitatively using the number of streamlines (SL) and the mean fractional anisotropy (FA). RESULTS: We were able to characterize the AF, the MdLF, the IFOF, and the ILF consistently in six healthy volunteers using global tracking. A left-sided dominance (LI > 0.2) for the AF was found in all participants. The MdLF showed a left-sided dominance in four participants (one female, three male). Regarding the FA, no lateralization (LI > 0.2) could be shown in any of the fascicles. CONCLUSION: Using a novel global tracking algorithm we confirmed that the courses of the primary language processing associated fascicles can consistently be differentiated. Additionally we were able to show a streamline-based left-sided lateralization in the AF of all right-handed healthy subjects.

Local and global fiber tractography in patients with epilepsy.

BACKGROUND AND PURPOSE: Fiber tractography is increasingly used in the preoperative evaluation of endangered fiber bundles. From a clinical point of view, an accurate and methodologically transparent procedure is desired. Our aim was to evaluate the recently described global tracking algorithm compared with other established methods, such as deterministic and probabilistic tractography. MATERIALS AND METHODS: Twenty patients, candidates for excision of epileptogenic lesions, were subjected to higher-angular resolution diffusion imaging-based fiber tractography. Seed points were created without manual bias, predominantly by FreeSurfer and voxel-based atlases. We focused on 2 important fiber bundles, namely the descending motor pathways and the optic radiation. Postoperatively, the accuracy of the predicted fiber route was controlled by structural MR imaging and by inflicted functional deficits. RESULTS: Among the 3 evaluated methods, global tracking was the only method capable of reconstructing the full extent of the descending motor pathways, including corticobulbar fibers from the area of face representation. Still, probabilistic tractography depicted the optic radiation better, especially the Meyer loop. The deterministic algorithm performed less adequately. CONCLUSIONS: The probabilistic method seems to be the best balance between computational time and effectiveness and seems to be the best choice in most cases, particularly for the optic radiation. If, however, a detailed depiction of the fiber anatomy is intended and tract crossings are implicated, then the computationally time-consuming global tracking should be preferred.

Global tracking in human gliomas: a comparison with established tracking methods.

PURPOSE: Global tracking (GT) is a recently published fibre tractography (FT) method that takes simultaneously all fibres into account during their reconstruction. The purpose of this study was to compare this new method with fibre assignment by continuous tracking (FACT) and probabilistic tractography (PT) for the detection of the corticospinal tract (CST) in patients with gliomas. METHODS: Tractography of the CST was performed in 17 patients with eight low grade and nine anaplastic astrocytomas located in the motor cortex or the corticospinal tract. Diffusions metrics as fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) were obtained. The methods were additionally applied on a physical phantom to assess their accuracy. RESULTS: PT was successful in all (100 %), GT in 16 (94 %) and FACT in 15 patients (88 %). The case where GT and FACT, both, missed the CST showed the highest AD and RD, whereas the one where FACT algorithm, alone, was not successfully showed the lowest AD and RD of the group. FA was reduced on the pathologic side (FApath 0.35 ± 0.16 (mean ± SD) versus FAcontralateral 0.51 ± 0.15, pcorr < 0.03). RD was increased on the pathologic side (RDpath 0.67 ± 0.29 × 10(-3) mm(2)/s versus RDcontralateral 0.46 ± 0.08 × 10(-3) mm(2)/s, pcorr < 0.03). In the phantom measurement, only GT did not detect false positive fibres at fibre crossings. CONCLUSION: PT performed well even in areas of increased diffusivities indicating a severe oedema or disintegration of tissue. FACT was also susceptible to a decrease of diffusivities and to a susceptibility artefact, where GT was robust.

MITK diffusion imaging.

BACKGROUND: Diffusion-MRI provides a unique window on brain anatomy and insights into aspects of tissue structure in living humans that could not be studied previously. There is a major effort in this rapidly evolving field of research to develop the algorithmic tools necessary to cope with the complexity of the datasets. OBJECTIVES: This work illustrates our strategy that encompasses the development of a modularized and open software tool for data processing, visualization and interactive exploration in diffusion imaging research and aims at reinforcing sustainable evaluation and progress in the field. METHODS: In this paper, the usability and capabilities of a new application and toolkit component of the Medical Imaging and Interaction Toolkit (MITK, www.mitk.org), MITK-DI, are demonstrated using in-vivo datasets. RESULTS: MITK-DI provides a comprehensive software framework for high-performance data processing, analysis and interactive data exploration, which is designed in a modular, extensible fashion (using CTK) and in adherence to widely accepted coding standards (e.g. ITK, VTK). MITK-DI is available both as an open source software development toolkit and as a ready-to-use installable application. CONCLUSIONS: The open source release of the modular MITK-DI tools will increase verifiability and comparability within the research community and will also be an important step towards bringing many of the current techniques towards clinical application.