Standardized reporting for Head CT Scans in patients suspected of traumatic brain injury (TBI): An international expert endeavor.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) is a major source of health loss and disability worldwide. Accurate and timely diagnosis of TBI is critical for appropriate treatment and management of the condition. Neuroimaging plays a crucial role in the diagnosis and characterization of TBI. Computed tomography (CT) is the first-line diagnostic imaging modality typically utilized in patients with suspected acute mild, moderate and severe TBI. Radiology reports play a crucial role in the diagnostic process, providing critical information about the location and extent of brain injury, as well as factors that could prevent secondary injury. However, the complexity and variability of radiology reports can make it challenging for healthcare providers to extract the necessary information for diagnosis and treatment planning. METHODS/RESULTS/CONCLUSION: In this article, we report the efforts of an international group of TBI imaging experts to develop a clinical radiology report template for CT scans obtained in patients suspected of TBI and consisting of fourteen different subdivisions (CT technique, mechanism of injury or clinical history, presence of scalp injuries, fractures, potential vascular injuries, potential injuries involving the extra-axial spaces, brain parenchymal injuries, potential injuries involving the cerebrospinal fluid spaces and the ventricular system, mass effect, secondary injuries, prior or coexisting pathology).

Probing brain tissue microstructure with MRI: principles, challenges, and the role of multidimensional diffusion-relaxation encoding.

Diffusion MRI uses the random displacement of water molecules to sensitize the signal to brain microstructure and to properties such as the density and shape of cells. Microstructure modeling techniques aim to estimate these properties from acquired data by separating the signal between virtual tissue 'compartments' such as the intra-neurite and the extra-cellular space. A key challenge is that the diffusion MRI signal is relatively featureless compared with the complexity of brain tissue. Another challenge is that the tissue microstructure is wildly different within the gray and white matter of the brain. In this review, we use results from multidimensional diffusion encoding techniques to discuss these challenges and their tentative solutions. Multidimensional encoding increases the information content of the data by varying not only the b-value and the encoding direction but also additional experimental parameters such as the shape of the b-tensor and the echo time. Three main insights have emerged from such encoding. First, multidimensional data contradict common model assumptions on diffusion and T2 relaxation, and illustrates how the use of these assumptions cause erroneous interpretations in both healthy brain and pathology. Second, many model assumptions can be dispensed with if data are acquired with multidimensional encoding. The necessary data can be easily acquired in vivo using protocols optimized to minimize Cramér-Rao lower bounds. Third, microscopic diffusion anisotropy reflects the presence of axons but not dendrites. This insight stands in contrast to current 'neurite models' of brain tissue, which assume that axons in white matter and dendrites in gray matter feature highly similar diffusion. Nevertheless, as an axon-based contrast, microscopic anisotropy can differentiate gray and white matter when myelin alterations confound conventional MRI contrasts.

Tissue response curve-shape analysis of dynamic glucose-enhanced and dynamic contrast-enhanced magnetic resonance imaging in patients with brain tumor.

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism.

European recommendations on practices in pediatric neuroradiology: consensus document from the European Society of Neuroradiology (ESNR), European Society of Paediatric Radiology (ESPR) and European Union of Medical Specialists Division of Neuroradiology (UEMS).

Pediatric neuroradiology is a subspecialty within radiology, with possible pathways to train within the discipline from neuroradiology or pediatric radiology. Formalized pediatric neuroradiology training programs are not available in most European countries. We aimed to construct a European consensus document providing recommendations for the safe practice of pediatric neuroradiology. We particularly emphasize imaging techniques that should be available, optimal site conditions and facilities, recommended team requirements and specific indications and protocol modifications for each imaging modality employed for pediatric neuroradiology studies. The present document serves as guidance to the optimal setup and organization for carrying out pediatric neuroradiology diagnostic and interventional procedures. Clinical activities should always be carried out in full agreement with national provisions and regulations. Continued education of all parties involved is a requisite for preserving pediatric neuroradiology practice at a high level.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

Towards robust glucose chemical exchange saturation transfer imaging in humans at 3 T: Arterial input function measurements and the effects of infusion time.

Dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) has shown potential for tumor imaging using D-glucose as a biodegradable contrast agent. The DGE signal change is small at 3 T (around 1%) and accurate detection is hampered by motion. The intravenous D-glucose injection is associated with transient side effects that can indirectly generate subject movements. In this study, the aim was to study DGE arterial input functions (AIFs) in healthy volunteers at 3 T for different scanning protocols, as a step towards making the glucose chemical exchange saturation transfer (glucoCEST) protocol more robust. Two different infusion durations (1.5 and 4.0 min) and saturation frequency offsets (1.2 and 2.0 ppm) were used. The effect of subject motion on the DGE signal was studied by using motion estimates retrieved from standard retrospective motion correction to create pseudo-DGE maps, where the apparent DGE signal changes were entirely caused by motion. Furthermore, the DGE AIFs were compared with venous blood glucose levels. A significant difference (p = 0.03) between arterial baseline and postinfusion DGE signal was found after D-glucose infusion. The results indicate that the measured DGE AIF signal change depends on both motion and blood glucose concentration change, emphasizing the need for sufficient motion correction in glucoCEST imaging. Finally, we conclude that a longer infusion duration (e.g. 3-4 min) should preferably be used in glucoCEST experiments, because it can minimize the glucose infusion side effects without negatively affecting the DGE signal change.

Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus.

BACKGROUND: Neuronal damage in systemic lupus erythematosus (SLE) is common, but the extent and mechanisms are unclear. Neurofilament light (NfL) concentrations rise in plasma and cerebrospinal fluid (CSF) during neuronal damage in various neurological disorders. In this cross-sectional study, plasma and CSF concentrations of NfL were explored as a marker of neuronal damage in SLE. METHODS: Seventy-two consecutive SLE out-patients and 26 healthy controls, all female, aged < 55 years, underwent magnetic resonance imaging (MRI) and neurocognitive testing. NfL concentrations in plasma from all individuals and in CSF from 32 patients were measured with single-molecule array technology. Patients were assessed by a rheumatologist and neurologist to define neuropsychiatric involvement (NPSLE) according to three attribution models: SLICC A, SLICC B and ACR. RESULTS: Plasma and CSF NfL concentrations correlated strongly (r = 0.72, p < 0.001). Both NPSLE and non-NPSLE patients in all attribution models had higher plasma NfL concentrations compared with healthy controls (log-NfL, pg/ml, mean (SD); healthy controls (0.71 (0.17)); SLICC A model: NPSLE (0.87 (0.13), p = 0.003), non-NPSLE (0.83 (0.18), p = 0.005); SLICC B model: NPSLE (0.87 (0.14), p = 0.001), non-NPSLE (0.83 (0.18), p = 0.008); ACR model: NPSLE (0.86 (0.16), p < 0.001), non-NPSLE (0.81 (0.17), p = 0.044)). Plasma and CSF NfL concentrations did not differ between NPSLE and non-NPSLE patients. Higher plasma NfL concentrations correlated with larger CSF volumes on MRI (r = 0.34, p = 0.005), and was associated with poorer cognitive performance in the domains of simple attention, psychomotor speed and verbal memory. SLICC/ACR-Damage Index ≥1 was independently associated with higher plasma NfL concentrations (ß = 0.074, p = 0.038). Higher plasma creatinine concentrations, anti-dsDNA-positivity, low complement C3 levels, or a history of renal involvement were associated with higher plasma NfL concentrations (ß = 0.003, p = 0.009; ß = 0.072, p = 0.031; ß = 0.077, p = 0.027; ß = 0.069, p = 0.047, respectively). CONCLUSIONS: Higher plasma NfL concentrations in NPSLE and non-NPSLE patients may indicate a higher degree of neuronal damage in SLE in general, corresponding to cognitive impairment and organ damage development. Furthermore, our results may indicate a higher degree of neuronal breakdown in patients with active SLE, also without overt clinical symptoms. NfL may serve as an indicator of neuronal damage in SLE in further studies.

Diffusion tensor imaging in glioblastoma patients treated with volumetric modulated arc radiotherapy: a longitudinal study.

BACKGROUND: Chemo- and radiotherapy (RT) is standard treatment for patients with high-grade glioma, but may cause side-effects on the patient's cognitive function. AIM: Use of diffusion tensor imaging (DTI) to investigate the longitudinal changes in normal-appearing brain tissue in glioblastoma patients undergoing modern arc-based RT with volumetric modulated arc therapy (VMAT) or helical tomotherapy. MATERIALS AND METHODS: The study included 27 patients newly diagnosed with glioblastoma and planned for VMAT or tomotherapy. All subjects underwent magnetic resonance imaging at the start of RT and at week 3, 6, 15, and 26. Fourteen subjects were additionally imaged at week 52. The DTI data were co-registered to the dose distribution maps. Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were assessed in the corpus callosum, the centrum semiovale, the hippocampus, and the amygdala. RESULTS: Significant longitudinal changes in FA, MD, and RD were mainly found in the corpus callosum. In the other examined brain structures, only sparse and transient changes were seen. No consistent correlations were found between biodose, age, or gender and changes in DTI parameters. CONCLUSION: Longitudinal changes in MD, FA, and RD were observed but only in a limited number of brain structures and the changes were smaller than expected from literature. The results suggest that modern, arc-based RT may have less negative effect on normal-appearing parts of the brain tissue up to 12 months after radiotherapy.

Tensor-valued diffusion MRI in under 3 minutes: an initial survey of microscopic anisotropy and tissue heterogeneity in intracranial tumors.

PURPOSE: To evaluate the feasibility of a 3-minutes protocol for assessment of the microscopic anisotropy and tissue heterogeneity based on tensor-valued diffusion MRI in a wide range of intracranial tumors. METHODS: B-tensor encoding was performed in 42 patients with intracranial tumors (gliomas, meningiomas, adenomas, and metastases). Microscopic anisotropy and tissue heterogeneity were evaluated by estimating the anisotropic kurtosis (MKA ) and isotropic kurtosis (MKI ), respectively. An extensive imaging protocol was compared with a 3-minutes protocol. RESULTS: The fast imaging protocol yielded parameters with characteristics in terms of bias and precision similar to the full protocol. Glioblastomas had lower microscopic anisotropy than meningiomas (MKA = 0.29 ± 0.06 vs. 0.45 ± 0.08, P = 0.003). Metastases had higher tissue heterogeneity (MKI = 0.57 ± 0.07) than both the glioblastomas (0.44 ± 0.06, P < 0.001) and meningiomas (0.46 ± 0.06, P = 0.03). CONCLUSION: Evaluation of the microscopic anisotropy and tissue heterogeneity in intracranial tumor patients is feasible in clinically relevant times frames.

Longitudinal study of cognitive function in glioma patients treated with modern radiotherapy techniques and standard chemotherapy.

Introduction: Cognitive function is an important outcome measure in patients with brain tumor, providing information about the patient's clinical situation, treatment effects and possible progressive disease. The aim of this longitudinal study was to evaluate effects of the currently used radiation and chemotherapy treatment on cognitive function and to investigate associations between cognitive function at baseline and progression as well as overall survival.Methods: 32 patients newly diagnosed with malignant glioma were evaluated at baseline with CNS Vital Signs (CNS-VS), a computerized standardized neuropsychological test battery, prior to arc-based radiotherapy and concomitant chemotherapy with Temozolomide. CNS-VS measures the cognitive functions known to be affected in patients with brain tumor, covering nine cognitive domains. Follow-up cognitive evaluations were performed in 26 patients after 3.5 months and in 13 patients 1 year after treatment start.Results: Overall cognitive scores were lower in the studied patient cohort at baseline compared to standardized domain scores. At 3.5 months follow-up cognitive functioning was slightly decreased, but only in 1/9 cognitive domains - visual memory - where significant changes were found compared to baseline test results. Similarly, at 12 months follow-up no significant changes in cognitive test results were seen compared to baseline examination, except for a decrease in the visual memory domain. In relation to early progression, the most significant cognitive deficits were dysfunctional visual memory and low executive functioning at baseline. Low executive function at baseline correlated most significantly with shorter overall survival.Conclusion: The present study suggests that the currently used arc-based radiotherapy and chemotherapy might affect cognitive function less negatively than previously described during treatment and in the first year after treatment in malignant glioma patients. In general, a high cognitive test score at baseline was associated with longer time to progression and with longer survival.

Microstructural white matter alterations associated to neurocognitive deficits in childhood leukemia survivors treated with cranial radiotherapy - a diffusional kurtosis study.

Background: Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL). Diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI) are MRI techniques that quantify microstructural changes in brain white matter (WM) and DKI is regarded as the more sensitive of them. Our aim was to more thoroughly understand the nature of cognitive deficits after cranial radiotherapy (CRT) in adulthood after childhood ALL. Material and methods: Thirty-eight (21 women) ALL survivors, median age 38 (27-46) years, were investigated at median 34 years after diagnosis. All had been treated with a CRT dose of 24 Gy and with 11 years of complete hormone supplementation. DTI and DKI parameters were determined and neurocognitive tests were performed in ALL survivors and 29 matched controls. Results: ALL survivors scored lower than controls in neurocognitive tests of vocabulary, memory, learning capacity, spatial ability, executive functions, and attention (p < .001). The survivors had altered DTI parameters in the fornix, uncinate fasciculus, and ventral cingulum (all p < .05) and altered DKI parameters in the fornix, uncinate fasciculus, and dorsal and ventral cingulum (p < .05). Altered DTI parameters in the fornix were associated with impaired episodic verbal memory (r = -0.40, p < .04). The left and right uncinate fasciculus (r = 0.6, p < .001), (r = -0.5, p < .02) as well as the right ventral cingulum (r = 0.5, p < .007) were associated with impaired episodic visual memory. Altered DKI parameters in the fornix, right uncinate fasciculus (r = 0.3, r = 0.05, p = .02), and ventral cingulum (r = 0.3, p = .02) were associated with impaired results of episodic visual memory. Conclusion: ALL survivors with cognitive deficits demonstrated microstructural damage in several WM tracts that were more extensive with DKI as compared to DTI; this might be a marker of radiation and chemotherapy neurotoxicity underlying cognitive dysfunction.

Evaluation of reproducibility in MRI quantitative volumetric assessment and its role in the prediction of overall survival and progression-free survival in glioblastoma.

BACKGROUND: Residual tumor volume (RTV) and extent of resection (EOR) have previously been shown to affect survival in glioblastoma (GB) patients. Quantitative radiological assessment (QRA) of these factors could potentially affect clinical decision-making in the postoperative period. PURPOSE: The first aim was to evaluate the reproducibility of different volume estimation methods of RTV and EOR by comparing QRA with subjective visual estimation and with objective volume estimations. The second aim was to clarify whether QRA of RTV and EOR would provide accuracy in predicting progression-free survival (PFS) and overall survival (OS) in GB patients. MATERIAL AND METHODS: Seventy GB patients were studied retrospectively. Reproducibility of QRA was compared to conventional visual analysis. Intra-rater agreement between two repeated measurements of 25 patients was calculated. QRA for RTV and EOR was made for the entire study population. Survival analysis was performed by multivariate cox-regression analysis. RESULTS: QRA of RTV and EOR gave superior intra-rater agreement compared to subjective evaluation. Multivariate survival analysis showed prognostic significance on 18 months PFS (hazard ratio [HR] = 0.44, P = 0.003) and OS (HR = 0.42, P = 0.012) at RTV < 1.6 mL and with EOR > 96% on PFS (HR = 2.152, P = 0.005) but not on OS (HR = 1.92, P = 0.053). CONCLUSION: QRA of tumor volumes is more robust compared to standard evaluation methods. Since EOR and RTV are correlated to the prognosis in GB, quantitative analysis of tumor volumes could aid decision-making and patient management postoperatively.

Imaging brain tumour microstructure.

Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called 'microstructure imaging'. The promise of microstructure imaging is one of 'virtual biopsy' with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging.

Neurite density imaging versus imaging of microscopic anisotropy in diffusion MRI: A model comparison using spherical tensor encoding.

In diffusion MRI (dMRI), microscopic diffusion anisotropy can be obscured by orientation dispersion. Separation of these properties is of high importance, since it could allow dMRI to non-invasively probe elongated structures such as neurites (axons and dendrites). However, conventional dMRI, based on single diffusion encoding (SDE), entangles microscopic anisotropy and orientation dispersion with intra-voxel variance in isotropic diffusivity. SDE-based methods for estimating microscopic anisotropy, such as the neurite orientation dispersion and density imaging (NODDI) method, must thus rely on model assumptions to disentangle these features. An alternative approach is to directly quantify microscopic anisotropy by the use of variable shape of the b-tensor. Along those lines, we here present the 'constrained diffusional variance decomposition' (CODIVIDE) method, which jointly analyzes data acquired with diffusion encoding applied in a single direction at a time (linear tensor encoding, LTE) and in all directions (spherical tensor encoding, STE). We then contrast the two approaches by comparing neurite density estimated using NODDI with microscopic anisotropy estimated using CODIVIDE. Data were acquired in healthy volunteers and in glioma patients. NODDI and CODIVIDE differed the most in gray matter and in gliomas, where NODDI detected a neurite fraction higher than expected from the level of microscopic diffusion anisotropy found with CODIVIDE. The discrepancies could be explained by the NODDI tortuosity assumption, which enforces a connection between the neurite density and the mean diffusivity of tissue. Our results suggest that this assumption is invalid, which leads to a NODDI neurite density that is inconsistent between LTE and STE data. Using simulations, we demonstrate that the NODDI assumptions result in parameter bias that precludes the use of NODDI to map neurite density. With CODIVIDE, we found high levels of microscopic anisotropy in white matter, intermediate levels in structures such as the thalamus and the putamen, and low levels in the cortex and in gliomas. We conclude that accurate mapping of microscopic anisotropy requires data acquired with variable shape of the b-tensor.

The effects of uterine artery embolization with a new degradable microsphere in an experimental study.

Background Transarterial particle embolization is a common treatment of uterine fibroids, aiming to obtain ischemia resulting in shrinking of the fibroid with preservation of normal uterine tissue. Embolization with non-degradable microspheres is established, but causes permanent occlusion of the arteries, affecting both the uterus as well as the fibroids. Purpose To evaluate in vivo degradation, local tissue effects, and possible recanalization following intra-arterial deposition of the new, degradable starch microspheres (DSM), in a short-term experimental pilot study. Material and Methods Under general anesthesia, unilateral transarterial embolization of the uterine artery (UA) with DSM 500-700 µm was performed in five female sheep. The animals underwent renewed angiography at different intervals after embolization (19-65 h) and were subsequently sacrificed. Histological examination was performed. Results Embolization with absent flow in the UA could be completed in five of six animals. At final angiographic evaluation, recanalization of the embolized arteries was evident in three sheep. At the gross postmortem examination, edema and discoloration indicating ischemia of the uterus at the embolized side, was observed in all the sheep. At histopathological examination, different stages of DSM degradation in the arterial branches were observed in both endometrium and myometrium. Mild-to-moderate vasculitis and mild-to-extensive ischemic changes were present along with degeneration of the uterine glands. Conclusion This short-term pilot study proved efficacy of embolization with DSM causing ischemic changes in the embolized organ, but also degradation of the DSM with subsequent recanalization of the embolized arteries.

The link between diffusion MRI and tumor heterogeneity: Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE).

The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MKT), and DIVIDE was used to decompose MKT into components caused by microscopic anisotropy (MKA) and isotropic heterogeneity (MKI). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (µFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MKA correlated with cell eccentricity (r=0.95, p<10-7) and MKI with the cell density variance (r=0.83, p<10-3). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r=0.80, p<10-3) and microscopic scale (µFA, r=0.93, p<10-6). A multiple regression analysis showed that the conventional MKT parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MKA was associated only to cell eccentricity, and MKI only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean±s.d.) MKA=1.11±0.33 vs MKI=0.44±0.20 (p<10-3), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MKI=0.57±0.30 vs MKA=0.26±0.11 (p<0.05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale.

Intraventricular Extension of Supratentorial Intracerebral Hemorrhage: The Modified Graeb Scale Improves Outcome Prediction in Lund Stroke Register.

BACKGROUND/AIMS: The modified Graeb Scale (mGS) is a semi-quantitative method to assess the extension of intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH). The mGS has been shown to prognosticate outcome after ICH in cohorts derived from convenience samples. We evaluated the external validity of mGS in supratentorial ICH-patients from an unselected cohort. METHODS: ICH-patients were included prospectively and consecutively in Lund Stroke Register. Follow-up survival status was obtained from the National Census Office; functional outcome was obtained from the Swedish Stroke Register or medical records. Using multivariate analyses, we examined if mGS was related to 30-day survival or poor functional outcome (modified Rankin Scale ≥4) at 90 days. RESULTS: Of 198 supratentorial ICH-patients, 86 (43%) had IVH (median mGS 12, range 1-28). In multivariate regression analyses, the mGS independently predicted 30-day mortality (per point; OR 1.16; 95% CI 1.06-1.27; p = 0.002) and poor functional outcome (OR 1.11; 95% CI 1.02-1.20; p = 0.011) after ICH. In receiver-operator characteristic analysis, the addition of mGS tended to be associated with a higher prognostic accuracy for survival (area under curve 0.886 vs. not including mGS 0.812; p = 0.053). CONCLUSIONS: The mGS improves outcome prediction after supratentorial ICH beyond other previously established factors in an unselected population.

Quantification of microscopic diffusion anisotropy disentangles effects of orientation dispersion from microstructure: applications in healthy volunteers and in brain tumors.

The anisotropy of water diffusion in brain tissue is affected by both disease and development. This change can be detected using diffusion MRI and is often quantified by the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Although FA is sensitive to anisotropic cell structures, such as axons, it is also sensitive to their orientation dispersion. This is a major limitation to the use of FA as a biomarker for "tissue integrity", especially in regions of complex microarchitecture. In this work, we seek to circumvent this limitation by disentangling the effects of microscopic diffusion anisotropy from the orientation dispersion. The microscopic fractional anisotropy (µFA) and the order parameter (OP) were calculated from the contrast between signal prepared with directional and isotropic diffusion encoding, where the latter was achieved by magic angle spinning of the q-vector (qMAS). These parameters were quantified in healthy volunteers and in two patients; one patient with meningioma and one with glioblastoma. Finally, we used simulations to elucidate the relation between FA and µFA in various micro-architectures. Generally, µFA was high in the white matter and low in the gray matter. In the white matter, the largest differences between µFA and FA were found in crossing white matter and in interfaces between large white matter tracts, where µFA was high while FA was low. Both tumor types exhibited a low FA, in contrast to the µFA which was high in the meningioma and low in the glioblastoma, indicating that the meningioma contained disordered anisotropic structures, while the glioblastoma did not. This interpretation was confirmed by histological examination. We conclude that FA from DTI reflects both the amount of diffusion anisotropy and orientation dispersion. We suggest that the µFA and OP may complement FA by independently quantifying the microscopic anisotropy and the level of orientation coherence.

Regional values of diffusional kurtosis estimates in the healthy brain.

PURPOSE: To provide estimates of the diffusional kurtosis in the healthy brain in anatomically defined areas and list these along previously reported values in pathologies. MATERIALS AND METHODS: Thirty-six volunteers (mean age = 33.1 years; range, 19-64 years) underwent diffusional kurtosis imaging. Mean kurtosis (MK), radial kurtosis (RK), mean diffusivity (MD), radial diffusivity (RD), and fractional anisotropy (FA) were determined in 26 anatomical structures. Parameter estimates were assessed regarding age dependence. RESULTS: MK varied from 1.38 in the splenium of the corpus callosum to 0.66 in the caudate head, MD varied from 0.68 to 0.62 µm(2) /ms and FA from 0.87 to 0.29. MK, and FA showed a strong positive correlation, RK and RD a strong negative correlation. Parameter estimates showed age correlation in some regions; also the average MK and RK for all WM and all GM areas, respectively, were negatively correlated with age. CONCLUSION: DKI parameter estimates MK and RK varied depending on the anatomical region and varied with age in pooled WM and GM data. MK estimates in the internal capsule, corpus callosum, and thalamus were consistent with previous studies. The range of values of MK and RK in healthy brain overlapped with that in pathologies.

Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.

BACKGROUND: Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment. METHODS: To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia. RESULTS: The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = -0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo. CONCLUSIONS: The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.