Automatic segmentation of the thalamus using a massively trained 3D convolutional neural network: higher sensitivity for the detection of reduced thalamus volume by improved inter-scanner stability.

OBJECTIVES: To develop an automatic method for accurate and robust thalamus segmentation in T1w-MRI for widespread clinical use without the need for strict harmonization of acquisition protocols and/or scanner-specific normal databases. METHODS: A three-dimensional convolutional neural network (3D-CNN) was trained on 1975 T1w volumes from 170 MRI scanners using thalamus masks generated with FSL-FIRST as ground truth. Accuracy was evaluated with 18 manually labeled expert masks. Intra- and inter-scanner test-retest stability were assessed with 477 T1w volumes of a single healthy subject scanned on 123 MRI scanners. The sensitivity of 3D-CNN-based volume estimates for the detection of thalamus atrophy was tested with 127 multiple sclerosis (MS) patients and a normal database comprising 4872 T1w volumes from 160 scanners. The 3D-CNN was compared with a publicly available 2D-CNN (FastSurfer) and FSL. RESULTS: The Dice similarity coefficient of the automatic thalamus segmentation with manual expert delineation was similar for all tested methods (3D-CNN and FastSurfer 0.86 ± 0.02, FSL 0.87 ± 0.02). The standard deviation of the single healthy subject's thalamus volume estimates was lowest with 3D-CNN for repeat scans on the same MRI scanner (0.08 mL, FastSurfer 0.09 mL, FSL 0.15 mL) and for repeat scans on different scanners (0.28 mL, FastSurfer 0.62 mL, FSL 0.63 mL). The proportion of MS patients with significantly reduced thalamus volume was highest for 3D-CNN (24%, FastSurfer 16%, FSL 11%). CONCLUSION: The novel 3D-CNN allows accurate thalamus segmentation, similar to state-of-the-art methods, with considerably improved robustness with respect to scanner-related variability of image characteristics. This might result in higher sensitivity for the detection of disease-related thalamus atrophy. KEY POINTS: • A three-dimensional convolutional neural network was trained for automatic segmentation of the thalamus with a heterogeneous sample of T1w-MRI from 1975 patients scanned on 170 different scanners. • The network provided high accuracy for thalamus segmentation with manual segmentation by experts as ground truth. • Inter-scanner variability of thalamus volume estimates across different MRI scanners was reduced by more than 50%, resulting in increased sensitivity for the detection of thalamus atrophy.

Probing real-world Central European population midfacial skeleton symmetry for maxillofacial surgery.

OBJECTIVES: Symmetry is essential for computer-aided surgical (CAS) procedures in oral and maxillofacial surgery (OMFS). A critical step for successful CAS is mirroring the unaffected side to create a template for the virtual reconstruction of the injured anatomical structure. The aim was to identify specific anatomical landmarks of the midfacial skeleton, to evaluate the symmetry in a group of the real-world Central European population, and to use these landmarks to assess midfacial symmetry in CT scans. MATERIAL AND METHODS: The retrospective cross-sectional study defined landmarks of the midface's bony contour using viscerocranial CT data. The distances of the skeletal landmarks (e.g., the frontozygomatic suture and temporozygomatic suture) of the left and right sides from the midline were measured and statistically compared. Midfacial symmetry for reference points was defined as a difference within 0 mm and their mean difference plus one standard deviation. RESULTS: We examined a total of 101 CT scans. 75% of our population shows symmetrical proportions of the midface. The means of the differences for the left and right sides ranged from 0.8 to 1.3 mm, averaging 1.1 ± 0.2 mm for all skeletal landmarks. The standard deviations ranged from 0.6 to 1.4 mm, with a computed mean of 0.9 ± 0.3 mm. CONCLUSION: We established a methodology to assess the symmetry of the bony midface. If the determined differences were equal to or lower than 2.5 mm in the mentioned midfacial skeletal landmarks, then the symmetry of the bony midface was considered present, and symmetry-based methods for CAS procedures are applicable. CLINICAL RELEVANCE: Many CAS procedures require facial symmetry. We provide an easy-to-apply method to probe for symmetry of the midface. The method may be used for population-based research, to check for proper reduction of fractures after reposition or to screen for symmetry prior to CAS planning.

Infratentorial lesions in multiple sclerosis patients: intra- and inter-rater variability in comparison to a fully automated segmentation using 3D convolutional neural networks.

OBJECTIVE: Automated quantification of infratentorial multiple sclerosis lesions on magnetic resonance imaging is clinically relevant but challenging. To overcome some of these problems, we propose a fully automated lesion segmentation algorithm using 3D convolutional neural networks (CNNs). METHODS: The CNN was trained on a FLAIR image alone or on FLAIR and T1-weighted images from 1809 patients acquired on 156 different scanners. An additional training using an extra class for infratentorial lesions was implemented. Three experienced raters manually annotated three datasets from 123 MS patients from different scanners. RESULTS: The inter-rater sensitivity (SEN) was 80% for supratentorial lesions but only 62% for infratentorial lesions. There was no statistically significant difference between the inter-rater SEN and the SEN of the CNN with respect to the raters. For supratentorial lesions, the CNN featured an intra-rater intra-scanner SEN of 0.97 (R1 = 0.90, R2 = 0.84) and for infratentorial lesion a SEN of 0.93 (R1 = 0.61, R2 = 0.73). CONCLUSION: The performance of the CNN improved significantly for infratentorial lesions when specifically trained on infratentorial lesions using a T1 image as an additional input and matches the detection performance of experienced raters. Furthermore, for infratentorial lesions the CNN was more robust against repeated scans than experienced raters. KEY POINTS: • A 3D convolutional neural network was trained on MRI data from 1809 patients (156 different scanners) for the quantification of supratentorial and infratentorial multiple sclerosis lesions. • Inter-rater variability was higher for infratentorial lesions than for supratentorial lesions. The performance of the 3D convolutional neural network (CNN) improved significantly for infratentorial lesions when specifically trained on infratentorial lesions using a T1 image as an additional input. • The detection performance of the CNN matches the detection performance of experienced raters.

Single-subject analysis of regional brain volumetric measures can be strongly influenced by the method for head size adjustment.

PURPOSE: Total intracranial volume (TIV) is often a nuisance covariate in MRI-based brain volumetry. This study compared two TIV adjustment methods with respect to their impact on z-scores in single subject analyses of regional brain volume estimates. METHODS: Brain parenchyma, hippocampus, thalamus, and TIV were segmented in a normal database comprising 5059 T1w images. Regional volume estimates were adjusted for TIV using the residual method or the proportion method. Age was taken into account by regression with both methods. TIV- and age-adjusted regional volumes were transformed to z-scores and then compared between the two adjustment methods. Their impact on the detection of thalamus atrophy was tested in 127 patients with multiple sclerosis. RESULTS: The residual method removed the association with TIV in all regions. The proportion method resulted in a switch of the direction without relevant change of the strength of the association. The reduction of physiological between-subject variability was larger with the residual method than with the proportion method. The difference between z-scores obtained with the residual method versus the proportion method was strongly correlated with TIV. It was larger than one z-score point in 5% of the subjects. The area under the ROC curve of the TIV- and age-adjusted thalamus volume for identification of multiple sclerosis patients was larger with the residual method than with the proportion method (0.84 versus 0.79). CONCLUSION: The residual method should be preferred for TIV and age adjustments of T1w-MRI-based brain volume estimates in single subject analyses.

Ultrasonography Grading of Internal Carotid Artery Disease: Multiparametric German Society of Ultrasound in Medicine (DEGUM) versus Society of Radiologists in Ultrasound (SRU) Consensus Criteria.

PURPOSE: We sought to determine the diagnostic agreement between the revised ultrasonography approach by the German Society of Ultrasound in Medicine (DEGUM) and the established Society of Radiologists in Ultrasound (SRU) consensus criteria for the grading of carotid artery disease. MATERIALS AND METHODS: Post-hoc analysis of a prospective multicenter study, in which patients underwent ultrasonography and digital subtraction angiography (DSA) of carotid arteries for validation of the DEGUM approach. According to DEGUM and SRU ultrasonography criteria, carotid arteries were independently categorized into clinically relevant NASCET strata (normal, mild [1-49 %], moderate [50-69 %], severe [70-99 %], occlusion). On DSA, carotid artery findings according to NASCET were considered the reference standard. RESULTS: We analyzed 158 ultrasonography and DSA carotid artery pairs. There was substantial agreement between both ultrasonography approaches for severe (κw 0.76, CI95 %: 0.66-0.86), but only fair agreement for moderate (κw 0.38, CI95 %: 0.19-0.58) disease categories. Compared with DSA, both ultrasonography approaches were of equal sensitivity (79.7 % versus 79.7 %; p = 1.0) regarding the identification of severe stenosis, yet the DEGUM approach was more specific than the SRU approach (70.2 % versus 56.4 %, p = 0.0002). There was equality of accuracy parameters (p > 0.05) among both ultrasonography approaches for the other ranges of carotid artery disease. CONCLUSION: While the sensitivity was equivalent, false-positive identification of severe carotid artery stenosis appears to be more frequent when using the SRU ultrasonography approach than the revised multiparametric DEGUM approach.

Individual odor hedonic perception is coded in temporal joint network activity.

INTRO: The human sense of smell is highly individual and characterized by a strong variability in the perception and evaluation of olfactory stimuli, depending on cultural imprint and current physiological conditions. Since this individual perspective has often been neglected in fMRI studies on olfactory hedonic coding, this study focuses on the neuronal activity and connectivity patterns resulting from subject-specific olfactory stimulation. METHODS: Thirty-one normosmic participants took part in a fMRI block designed paradigm consisting of three olfactory stimulation sessions. The most pleasant and unpleasant odors were individually specified during a pre-test for each participant and validated in the main experiment. Mean activation and functional connectivity analysis focusing on the right and left piriform cortex were performed for the predefined olfactory regions-of-interest (ROIs) and compared between the three olfactory conditions. RESULTS: Individual unpleasant olfactory stimulation as compared to pleasant or neutral did not alter mean BOLD activation in the predefined olfactory ROIs but led to a change in connectivity pattern in the right piriform cortex. CONCLUSION: Our data suggests that the individual pleasantness of odors is not detectable by average BOLD magnitude changes in primary or secondary olfactory brain areas, but reflected in temporal patterns of joint activation that create a network between the right piriform cortex, the left insular cortex, the orbitofrontal cortex, and the precentral gyrus. This network may serve the evolutionary defense mechanism of olfaction by preparing goal-directed action.

Interoceptive accuracy and its impact on neuronal responses to olfactory stimulation in the insular cortex.

The insular cortex plays a key role in the integration of multimodal information and in interoceptive and exteroceptive processing. For instance, neurons in the central dorsal insula that are active during interoceptive tasks, also show an adaptation to gustatory stimulation. We tested the link between interoception and exteroception for the olfactory system (i.e., the second domain of chemosensation). In a sample of 31 participants, olfactory function was assessed in a two dimensional approach while the Heartbeat Perception Task served as a measurement for cardiac interoceptive accuracy. Subsequent fMRI sessions were performed on a 3-Tesla MR scanner containing 12-15 olfactory stimulation trials with a mildly pleasant food-related odor (coffee). Persons scoring high in the cardiac interoceptive accuracy task presented stronger smelling abilities as well as enhanced BOLD responses following olfactory stimulation. The olfactory stimulation triggered enhanced insular activation patterns in the central dorsal insular cortex. Consistent with prior findings on the coherence of gustatory and interoceptive processing in the central dorsal insula, these results base the insula as a common region for the integration of interoception and exteroception. We propose an explanatory model of how exteroception triggers the integration of intero- and exteroceptive sensations in the central dorsal insular cortex.

Aberrancies of Brain Network Structures in Patients with Anosmia.

Patients with anosmia exhibit structural and functional brain abnormalities. The present study explored changes in brain white matter (WM) in non-neurodegenerative anosmia using diffusion-tensor-based network analysis. Twenty patients with anosmia and sixteen healthy controls were recruited in the cross-sectional, case-control study. Participants underwent olfactory tests (orthonasal and retronasal), neuropsychological assessment (cognitive function and depressive symptoms) and diffusion tensor imaging measurement. Tract-Based Spatial Statistics, graph theoretical analysis and Network-Based Statistics were used to explore the white matter. There was no significant difference in fractional anisotropy (FA) between patients and controls. In global network topological properties comparisons, patients exhibited higher γ and λ levels than controls, and both groups satisfied the criteria of small-world (σ > 1). In local network topological properties, patients had reduced betweenness, degree and efficiency (global and local), as well as increased shortest path length and cluster coefficient in olfactory-related brain areas (anterior cingulum, lenticular nucleus, putamen, hippocampus, amygdala, caudate nucleus, orbito-frontal gyrus). Olfactory threshold scores and the retronasal score were negatively correlated with γ and λ, and the retronasal score was positively correlated with FA values in certain WM tracts, i.e. middle cerebellar peduncle, right inferior cerebellar peduncle, left inferior cerebellar peduncle, right cerebral peduncle, left cerebral peduncle, left cingulum (cingulate gyrus), right cingulum (hippocampus), superior fronto-occipital fasciculus, and, left tapetum. Patients with anosmia demonstrated relevant WM network dysfunction though their structural integrity remained intact. Their retronasal olfaction deficits revealed to be more strongly associated with WM alterations compared with orthonasal olfactory scores.

Parcellation of the Subthalamic Nucleus in Parkinson's Disease: A Retrospective Analysis of Atlas- and Diffusion-Based Methods.

BACKGROUND: Deep brain stimulation (DBS) is an established method of treatment for Parkinson's disease (PD). A stimulation sweet spot at the interface between the motor and associative clusters of the subthalamic nucleus (STN) has recently been postulated. The aim of this study was to analyze the available clustering methods for the STN and their correlation to outcome. METHODS: This is a retrospective analysis of a group of 20 patients implanted with a DBS device for PD. Atlas-based and diffusion tractography-based parcellation of the STN was performed. The distances of the electrode to the obtained clusters were compared to each other and to outcome parameters, which included levodopa equivalent dose (LED) reduction, Unified Parkinson's Disease Rating Scale (UPDRS)-III scores, and reduction in scores for items 32 and 36 of the UPDRS-IV. RESULTS: The implanted electrodes were located nearest to the motor clusters of the STN. The following significant associations with postoperative LED reduction were found: (1) distance of the electrode to the motor cluster in the Accolla and DISTAL atlases (p < 0.01) and (2) distance of the electrode to the supplementary motor area cluster (p = 0.02). There was no association with either the UPDRS-III or the UPDRS-IV score. CONCLUSIONS: The results of this study suggest the possibility that atlas-based clustering, as well as diffusion tractography-based parcellation, can be useful in estimating the stimulation target ("sweet spot") for STN-DBS in PD patients. Atlas-based as well as diffusion-based clustering might become a useful tool in DBS trajectory planning.

Somatosensory functional MRI tractography for individualized targeting of deep brain stimulation in patients with chronic pain after brachial plexus injury.

BACKGROUND: The optimal targets for deep brain stimulation (DBS) in patients with refractory chronic pain are not clearly defined. We applied sensory functional MRI (fMRI)- and diffusion tensor imaging (DTI)-based DBS in chronic pain patients into 3 different targets to ascertain the most beneficial individual stimulation site. METHODS: Three patients with incapacitating chronic pain underwent DBS into 3 targets (periventricular gray (PVG), ventroposterolateral thalamus (VPL), and posterior limb of the internal capsule according to fMRI and DTI (PLIC). The electrodes were externalized and double-blinded tested for several days. Finally, the two electrodes with the best pain reduction were kept for permanent stimulation. The patients were then followed up for 12 months. Outcome measures comprised the numerical rating scale (NRS), short-form McGill's score (SF-MPQ), and health-related quality of life (SF-36). RESULTS: Continuous pain (mean NRS 6.6) was reduced to NRS 3.6 after 12 months. Only with stimulation of the PLIC pain attacks, that occurred at least 3 times a week (mean NRS 9.6) resolved in 2 patients and improved in one patient concerning both intensity (NRS 5) and frequency (twice a month). The mean SF-MPQ decreased from 92.7 to 50. The health-related quality of life improved considerably. CONCLUSION: fMRI- and DTI-based DBS to the PLIC was the only target with a significant effect on pain attacks and seems to be the most promising target in chronic pain patients after brachial plexus injury. The combination with PVG or VPL can further improve patients' outcome especially in terms of reducing the continuous pain.

Reduced olfactory bulb volume in depression-A structural moderator analysis.

BACKGROUND: Removal of the olfactory bulb (OB) leads to depression like behavior in rodents. A link between depression and olfactory function is also established in humans. We hypothesized that the human OB volume relates to depressive state and tested whether such a potential coherence is moderated by structural alterations in other brain regions. METHODS: Eighty-three participants (32 patients with major depression and 51 matched healthy controls) underwent structural MR scanning. Individual OB volumes were compared between patients and controls and the impact of depression and comorbidity was analyzed with multiple regression analysis. Whole-brain voxel-based morphometry revealed structures co-varying with both depressive state and OB volume. RESULTS: The OB volume of patients was significantly reduced and this reduction averaged out at 17% compared to the controls. The OB volume was correlated to the volume of the insula, superior temporal cortex, and amygdala. The independent variables of depression (ß = -.37), age (ß = -.25), and gender (ß = -.40) explained the individual OB volume variation (R2 = .37). The correlation between OB volume and depression was moderated by volumetric reductions in a cluster including the insula and superior temporal gyrus (STG). CONCLUSIONS: The OB volume relates to depression in humans and to the volume of structures which are critical for salience detection. We assume that a reduced OB volume causes diminished neural olfactory input which facilitates volume reduction in the insula and STG. The OB volume may hence constitute a factor of vulnerability to depression. Olfactory-based deep brain stimulation is discussed as a future therapeutic approach.

Validation of Multiparametric Ultrasonography Criteria with Digital Subtraction Angiography in Carotid Artery Disease: A Prospective Multicenter Study.

PURPOSE: The German Society of Ultrasound in Medicine (DEGUM) recently revised its multiparametric criteria for duplex ultrasonography (DUS) grading of internal carotid artery (ICA) disease. We determined the diagnostic accuracy of the revised DEGUM criteria for ultrasonography grading of ICA disease in a prospective multicenter study. MATERIALS AND METHODS: We evaluated consecutive patients who underwent digital subtraction angiography of the extracranial carotid arteries at four tertiary care hospitals. Blinded investigators graded ICA disease according to DEGUM-recommended ultrasonography criteria and calculated NASCET-type percent stenosis from angiography images. Endpoints included overall classification accuracy, prediction of clinically relevant disease categories and between-test agreement in the continuous range of percent stenosis. RESULTS: A total of 121 patients (median age: 69 [IQR, 16] years; 74 % men; median time between DUS and angiography: 1 day [IQR, 2]) provided 163 DUS-angiography carotid artery pairs. The classification accuracy of the DEGUM criteria to predict stenosis within 10 % increments as compared to angiography was 34.9 % (95 % CI, 28.0 - 42.6). The sensitivity of DUS for the detection of moderate (50 - 69 %) and severe (70 - 99 %) stenosis was 35 % and 81 %, with an overall accuracy of 73 % and 74 %, respectively. The specificity was 89 % and 69 %, respectively. Considering the continuous spectrum of the disease (0 - 100 %), the Bland-Altman interval limit of agreement was 51 %. CONCLUSION: At laboratories experienced with ultrasound grading of the extracranial ICA, the revised DEGUM multiparametric ultrasonography criteria do not eliminate the need for a confirmatory test for the identification of clinically relevant grades of the disease.

Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery.

Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis.

Multi-parametric ultrasound criteria for internal carotid artery disease-comparison with CT angiography.

INTRODUCTION: The German Society of Ultrasound in Medicine (known by its acronym DEGUM) recently proposed a novel multi-parametric ultrasound approach for comprehensive and accurate assessment of extracranial internal carotid artery (ICA) steno-occlusive disease. We determined the agreement between duplex ultrasonography (DUS) interpreted by the DEGUM criteria and CT angiography (CTA) for grading of extracranial ICA steno-occlusive disease. METHODS: Consecutive patients with acute cerebral ischemia underwent DUS and CTA. Internal carotid artery stenosis was graded according to the DEGUM-recommended criteria for DUS. Independent readers manually performed North American Symptomatic Carotid Endarterectomy Trial-type measurements on axial CTA source images. Both modalities were compared using Spearman's correlation and Bland-Altman analyses. RESULTS: A total of 303 acute cerebral ischemia patients (mean age, 72 ± 12 years; 58 % men; median baseline National Institutes of Health Stroke Scale score, 4 [interquartile range 7]) provided 593 DUS and CTA vessel pairs for comparison. There was a positive correlation between DUS and CTA (r s = 0.783, p < 0.001) with mean difference in degree of stenosis measurement of 3.57 %. Bland-Altman analysis further revealed widely varying differences (95 % limits of agreement -29.26 to 22.84) between the two modalities. CONCLUSION: Although the novel DEGUM criteria showed overall good agreement between DUS and CTA across all stenosis ranges, potential for wide incongruence with CTA underscores the need for local laboratory validation to avoid false screening results.

Endovascular treatment of ischaemic stroke patients - new evidence and old challenges.

An overwhelming benefit from endovascular treatment of ischaemic stroke could be shown in recent clinical trials, making it the new evidence-based standard of care for ischaemic stroke due to large vessel occlusion. To provide all eligible stroke patients with this therapy at any time, stroke networks and hospitals should streamline their workflow to rapidly image, select, and treat stroke patients. Interdisciplinary cooperation is vital for effective emergency endovascular stroke treatment, which is one of the most complex multidisciplinary functions a hospital can undertake.

Body size interacts with the structure of the central nervous system: A multi-center in vivo neuroimaging study.

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1±6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44≤r≤0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21≥r≥-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20≥r≥-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39≤r≤0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22≥r≥-0.25). Linear mixture of sex and age explained 26±10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33±11% when body height was added into the mixture model. Age itself explained only 2±2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.

Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI.

Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2=0.37; p<0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p<0.001) and discriminated relapsing-remitting from secondary-progressive patients (p<0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.

Exploring in vivo lesion myelination dynamics: Longitudinal Myelin Water Imaging in early Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) lesions are pathologically heterogeneous and the temporal behavior in terms of growth and myelination status of individual lesions is highly variable, especially in the early phase of the disease. Thus, monitoring the development of individual lesion myelination by using quantitative magnetic resonance myelin water imaging (MWI) could be valuable to capture the variability of disease pathology and get an individual insight into the subclinical disease activity. OBJECTIVE: The goal of this work was (1) to observe the variation and longitudinal change of in vivo lesion myelination by means of MWI and its parameter Myelin Water Fraction (MWF), and, (2) to identify individual lesion myelination patterns in early MS. METHODS: In this study n = 12 patients obtained conventional MRI and quantitative MWI derived from multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) within four weeks after presenting a clinically isolated syndrome and remained within the study if clinically definitive MS was diagnosed within the 12 months study period. Four MRI sessions were acquired at baseline, 3, 6, and 12 months. The short-term and long-term variability of MWF maps was evaluated by scan-rescan measures and the coefficient of variation was determined in four healthy controls. Tracking of individual lesions was performed using the Automatic Follow-up of Individual Lesions (AFIL) algorithm. Lesion volume and MWF were evaluated for every individual lesion in all patients. Median lesion MWF change was used to define lesion categories as decreasing, varying, increasing and invariant for MWF variation. RESULTS: In total n = 386 T2 lesions were detected with a subset of n = 225 permanent lesions present at all four time-points. Among those, a heterogeneous lesion MWF reduction was found, with the majority of lesions bearing only mild MWF reduction, approximately a third with an intermediate MWF decrease and highest MWF reduction in acute-inflammatory active lesions. A moderate negative correlation was determined between individual lesion volumes and median MWF consistent across all time-points. Permanent lesions featured variable temporal dynamics with the majority of varying MWF (58 %), however decreasing (16 %), increasing (15 %) and invariant (11 %) subgroups could be identified resembling demyelinating activity and post-demyelinating inactivity known from histopathology studies. Inflammatory-active enhancing lesions showed a distinct pattern of MWF reduction followed by partial recovery after 3 months. This was similar in new enhancing lesions and those with a non-enhancing precursor lesion. CONCLUSION: This work provides in vivo evidence for an individual evolution of early demyelinated MS lesions measured by means of MWF imaging. Our results support the hypothesis, that MS lesions undergo multiple demyelination and remyelination episodes in the early acute phase. The in vivo MRI surrogate of myelin turnover bears capacity as a novel biomarker to select and potentially monitor personalized MS treatment.