Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Characterization of the orientation dependence of magnetization transfer measures in single and crossing-fiber white matter.

PURPOSE: To fully characterize the orientation dependence of magnetization transfer (MT) and inhomogeneous MT (ihMT) measures in the whole white matter (WM), for both single-fiber and crossing-fiber voxels. METHODS: A characterization method was developed using the fiber orientation obtained from diffusion MRI (dMRI) with diffusion tensor imaging (DTI) and constrained spherical deconvolution. This allowed for characterization of the orientation dependence of measures in all of WM, regardless of the number of fiber orientation in a voxel. Furthermore, the orientation dependence inside 31 different WM bundles was characterized to evaluate the homogeneity of the effect. Variation of the results within and between-subject was assessed from a 12-subject dataset. RESULTS: Previous results for single-fiber voxels were reproduced and a novel characterization was produced in voxels of crossing fibers, which seems to follow trends consistent with single-fiber results. Heterogeneity of the orientation dependence across bundles was observed, but homogeneity within similar bundles was also highlighted. Differences in behavior between MT and ihMT measures, as well as the ratio and saturation versions of these, were noted. CONCLUSION: Orientation dependence characterization was proven possible over the entirety of WM. The vast range of effects and subtleties of the orientation dependence on MT measures showed the need for, but also the challenges of, a correction method.

FIESTA: Autoencoders for accurate fiber segmentation in tractography.

White matter bundle segmentation is a cornerstone of modern tractography to study the brain's structural connectivity in domains such as neurological disorders, neurosurgery, and aging. In this study, we present FIESTA (FIbEr Segmentation in Tractography using Autoencoders), a reliable and robust, fully automated, and easily semi-automatically calibrated pipeline based on deep autoencoders that can dissect and fully populate white matter bundles. This pipeline is built upon previous works that demonstrated how autoencoders can be used successfully for streamline filtering, bundle segmentation, and streamline generation in tractography. Our proposed method improves bundle segmentation coverage by recovering hard-to-track bundles with generative sampling through the latent space seeding of the subject bundle and the atlas bundle. A latent space of streamlines is learned using autoencoder-based modeling combined with contrastive learning. Using an atlas of bundles in standard space (MNI), our proposed method segments new tractograms using the autoencoder latent distance between each tractogram streamline and its closest neighbor bundle in the atlas of bundles. Intra-subject bundle reliability is improved by recovering hard-to-track streamlines, using the autoencoder to generate new streamlines that increase the spatial coverage of each bundle while remaining anatomically correct. Results show that our method is more reliable than state-of-the-art automated virtual dissection methods such as RecoBundles, RecoBundlesX, TractSeg, White Matter Analysis and XTRACT. Our framework allows for the transition from one anatomical bundle definition to another with marginal calibration efforts. Overall, these results show that our framework improves the practicality and usability of current state-of-the-art bundle segmentation framework.

High-frequency longitudinal white matter diffusion- and myelin-based MRI database: Reliability and variability.

Assessing the consistency of quantitative MRI measurements is critical for inclusion in longitudinal studies and clinical trials. Intraclass coefficient correlation and coefficient of variation were used to evaluate the different consistency aspects of diffusion- and myelin-based MRI measures. Multi-shell diffusion and inhomogeneous magnetization transfer data sets were collected from 20 healthy adults at a high-frequency of five MRI sessions. The consistency was evaluated across whole bundles and the track-profile along the bundles. The impact of the fiber populations on the consistency was also evaluated using the number of fiber orientations map. For whole and profile bundles, moderate to high reliability of diffusion and myelin measures were observed. We report higher reliability of measures for multiple fiber populations than single. The overall portrait of the most consistent measurements and bundles drawn from a wide range of MRI techniques presented here will be particularly useful for identifying reliable biomarkers capable of detecting, monitoring and predicting white matter changes in clinical applications and has the potential to inform patient-specific treatment strategies.

Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by two major and interconnected hallmarks: inflammation and progressive neurodegeneration. OBJECTIVE: The aim of this work was to compare neurodegenerative processes, in the form of global and regional brain volume loss rates, in healthy controls (HCs) and in patients with relapsing MS (RMS) treated with ocrelizumab, which suppresses acute inflammation. METHODS: Whole brain, white matter, cortical gray matter, thalamic, and cerebellar volume loss rates were assessed in 44 HCs that were part of a substudy in the OPERA II randomized controlled trial (NCT01412333) and 59 patients with RMS enrolled in the same substudy as well as age- and sex-matched patients in OPERA I (NCT01247324) and II. Volume loss rates were computed using random coefficients models over a period of 2 years. RESULTS: Ocrelizumab-treated patients showed global and regional brain volume loss rates that were approaching that of HCs. CONCLUSION: These findings are consistent with an important role of inflammation on overall tissue loss and the role of ocrelizumab in reducing this phenomenon.

Intrathecal versus Peripheral Inflammatory Protein Profile in MS Patients at Diagnosis: A Comprehensive Investigation on Serum and CSF.

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected from 143 treatment-naïve MS patients at diagnosis. A customized panel of 61 inflammatory molecules was analyzed by a multiplex immunoassay. Correlations between serum and CSF expression levels for each molecule were performed by Spearman's method. The expression of sixteen CSF proteins correlated with their serum expression (p-value < 0.001): only five molecules (CXCL9, sTNFR2, IFNα2, Pentraxin-3, and TSLP) showed a Rho value >0.40, suggesting moderate CSF/serum correlation. No correlation between inflammatory serum patterns and Qalb was observed. Correlation analysis of serum expression levels of these sixteen proteins with clinical and MRI parameters pinpointed a subset of five molecules (CXCL9, sTNFR2, IFNα2, IFNß, and TSLP) negatively correlating with spinal cord lesion volume. However, following FDR correction, only the correlation of CXCL9 remained significant. Our data support the hypothesis that the intrathecal inflammation in MS only partially associates with the peripheral one, except for the expression of some immunomodulators that might have a key role in the initial MS immune response.

Regional Cerebellar Volume Loss Predicts Future Disability in Multiple Sclerosis Patients.

Cerebellar symptoms in multiple sclerosis (MS) are well described; however, the exact contribution of cerebellar damage to MS disability has not been fully explored. Longer-term observational periods are necessary to better understand the dynamics of pathological changes within the cerebellum and their clinical consequences. Cerebellar lobe and single lobule volumes were automatically segmented on 664 3D-T1-weighted MPRAGE scans (acquired at a single 1.5 T scanner) of 163 MS patients (111 women; mean age: 47.1 years; 125 relapsing-remitting (RR) and 38 secondary progressive (SP) MS, median EDSS: 3.0) imaged annually over 4 years. Clinical scores (EDSS, 9HPT, 25FWT, PASAT, SDMT) were determined per patient per year with a maximum clinical follow-up of 11 years. Linear mixed-effect models were applied to assess the association between cerebellar volumes and clinical scores and whether cerebellar atrophy measures may predict future disability progression. SPMS patients exhibited faster posterior superior lobe volume loss over time compared to RRMS, which was related to increase of EDSS over time. In RRMS, cerebellar volumes were significant predictors of motor scores (e.g. average EDSS, T25FWT and 9HPT) and SDMT. Atrophy of motor-associated lobules (IV-VI + VIII) was a significant predictor of future deterioration of the 9HPT of the non-dominant hand. In SPMS, the atrophy rate of the posterior superior lobe (VI + Crus I) was a significant predictor of future PASAT performance deterioration. Regional cerebellar volume reduction is associated with motor and cognitive disability in MS and may serve as a predictor for future disease progression, especially of dexterity and impaired processing speed.

Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS.

BACKGROUND: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections. OBJECTIVE: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNß1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570). METHODS: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model. RESULTS: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen's d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNß1a (p < 0.001) or placebo (p < 0.001). CONCLUSION: Ocrelizumab effectively reduced thalamic volume loss compared with IFNß1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance.

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2-weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion-load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between-structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion-load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body-fluid markers.

Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort.

BACKGROUND AND PURPOSE: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short-term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse-onset MS. METHODS: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing-remitting [RRMS] and 43 secondary-progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine-hole peg test and the timed 25-foot walk test. RESULTS: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy. CONCLUSION: This study demonstrates the capability of short-term MRI metrics to accurately predict future dynamics of disability progression in a real-world relapse-onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care.

Longitudinal patterns of cortical thinning in multiple sclerosis.

In multiple sclerosis (MS), cortical atrophy is correlated with clinical and neuropsychological measures. We aimed to examine the differences in the temporospatial evolution of cortical thickness (CTh) between MS-subtypes and to study the association of CTh with T2-weighted white matter lesions (T2LV) and clinical progression. Two hundred and forty-three MS patients (180 relapsing-remitting [RRMS], 51 secondary-progressive [SPMS], and 12 primary-progressive [PPMS]) underwent annual clinical (incl. expanded disability status scale [EDSS]) and MRI-examinations over 6 years. T2LV and CTh were measured. CTh did not differ between MS-subgroups. Higher total T2LV was associated with extended bilateral CTh-reduction on average, but did not correlate with CTh-changes over time. In RRMS, CTh- and EDSS-changes over time were negatively correlated in large bilateral prefrontal, frontal, parietal, temporal, and occipital areas. In SPMS, CTh was not associated with the EDSS. In PPMS, CTh- and EDSS-changes over time were correlated in small clusters predominantly in left parietal areas. Increase of brain lesion load does not lead to an immediate CTh-reduction. Although CTh did not differ between MS-subtypes, a dissociation in the correlation between CTh- and EDSS-changes over time between RRMS and progressive-MS was shown, possibly underlining the contribution of subcortical pathology to clinical progression in progressive-MS.

Clinical associations of T2-weighted lesion load and lesion location in small vessel disease: Insights from a large prospective cohort study.

BACKGROUND: Subcortical T2-weighted (T2w) lesions are very common in older adults and have been associated with dementia. However, little is known about the strategic lesion distribution and how lesion patterns relate to vascular risk factors and cognitive impairment. AIM: The aim of this study was to analyze the association between T2w lesion load and location, vascular risk factors, and cognitive impairment in a large cohort of older adults. METHODS: 1017 patients participating in a large prospective cohort study (INtervention project on cerebroVAscular disease and Dementia in the district of Ebersberg, INVADE II) were analyzed. Cerebral T2w white matter and deep grey matter lesions, the so-called white matter hyperintensities (WMHs), were outlined semi-automatically on fluid attenuated inversion recovery images and normalized to standard stereotaxic space (MNI152) by non-linear registration. Patients were assigned to either a low-risk or a high-risk group. The risk assessment considered ankle brachial index, intima media thickness, carotid artery stenosis, atrial fibrillation, previous cerebro-/cardiovascular events and peripheral artery disease as well as a score based on cholesterol levels, blood pressure and smoking. Separate lesion distributions were obtained for the two risk groups and compared using voxel-based lesion-symptom mapping. Moreover, we assessed the relation between lesion location and cognitive impairment (demographically adjusted z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery Plus, CERAD-NAB Plus) using voxel-based statistics (α = 0.05). RESULTS: A total of 878 out of 1017 subjects (86%) had evaluable MRI data and were included in the analyses (mean age: 68.2 ±â€¯7.6 years, female: 515). Patients in the high-risk group were characterized by a significantly higher age, a higher proportion of men, a higher lesion load (p < 0.001), and a worse performance in some of the cognitive subdomain scores (p < 0.05). Voxels with significant associations to the subjects' cerebrovascular risk profiles were mainly found at locations of the corpus callosum, superior corona radiata, superior longitudinal fasciculus, internal and external capsule, and putamen. While several cognitive domains have shown significant associations with the participants' total lesion burden (p < 0.05), no focal WMH locations were found to be associated with cognitive impairment. CONCLUSION: Age, gender, several cognitive scores, and WMH lesion load were shown to be significantly associated with vascular risk factors in a population of older, but cognitively preserved adults. Vascular risk factors seem to promote lesion formation most severely at well-defined locations. While lesion load showed weak associations to some cognitive scores, no focal locations causing specific cognitive disturbances were identified in this large cohort of older adults.

Design and construction of an innovative brain phantom prototype for MRI.

PURPOSE: The purpose of this project was to construct a physical brain phantom for MRI, mimicking structure and T1 relaxation properties of white matter (WM) and gray matter (GM). METHODS: The phantom design comprised 2 compartments, 1 resembling the WM and 1 resembling the GM. Their T1 relaxation times, as assessed using an inversion recovery turbo spin echo sequence, were reproduced using an agar gel doped with contrast agent (CA) and their folding patterns were simulated through a molding-casting procedure using 3D-printed casts and flexible silicone molds. Three versions of the assembling procedure were adopted to build: Phantom1 without any separation; Phantom2 with a varnish layer; and Phantom3 with a thin wax layer between the compartments. RESULTS: Phantom1 was characterized by an immediate diffusion of CA between the 2 compartments. Phantom2 and Phantom3, instead, showed relaxation times and shape comparable with the target ones identified in a healthy control subject (WM: 754 ± 40 ms; GM: 1277 ± 96 ms). Moreover, both compartments revealed intact gyri and sulci. However, the diffusion of CA made Phantom2 stable only for a short period of time. Phantom3 showed stability within a time window of several days but the wax layer between the WM and GM was visible in the MRI. CONCLUSION: Structural and intensity properties of the constructed phantoms are useful in evaluating and validating steps from image acquisition to image processing. Moreover, the described constructing procedure and its modular design make it adjustable to a variety of applications.

Attack-related damage of thalamic nuclei in neuromyelitis optica spectrum disorders.

OBJECTIVES: In neuromyelitis optica spectrum disorders (NMOSD) thalamic damage is controversial, but thalamic nuclei were never studied separately. We aimed at assessing volume loss of thalamic nuclei in NMOSD. We hypothesised that only specific nuclei are damaged, by attacks affecting structures from which they receive afferences: the lateral geniculate nucleus (LGN), due to optic neuritis (ON) and the ventral posterior nucleus (VPN), due to myelitis. METHODS: Thirty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 50.1±14.1 years, 36 women, 25 with prior ON, 36 with prior myelitis) and 37 healthy controls (age: 47.8 ± 12.5 years, 32 women) were included in this cross-sectional study. Thalamic nuclei were assessed in magnetic resonance images, using a multi-atlas-based approach of automated segmentation. Retinal optical coherence tomography was also performed. RESULTS: Patients with ON showed smaller LGN volumes (181.6±44.2 mm3) compared with controls (198.3±49.4 mm3; B=-16.97, p=0.004) and to patients without ON (206.1±50 mm3 ; B=-23.74, p=0.001). LGN volume was associated with number of ON episodes (Rho=-0.536, p<0.001), peripapillary retinal nerve fibre layer thickness (B=0.70, p<0.001) and visual function (B=-0.01, p=0.002). Although VPN was not smaller in patients with myelitis (674.3±67.5 mm3) than controls (679.7±68.33; B=-7.36, p=0.594), we found reduced volumes in five patients with combined myelitis and brainstem attacks (B=-76.18, p=0.017). Volumes of entire thalamus and other nuclei were not smaller in patients than controls. CONCLUSION: These findings suggest attack-related anterograde degeneration rather than diffuse thalamic damage in NMOSD. They also support a potential role of LGN volume as an imaging marker of structural brain damage in these patients.

Preferential spinal cord volume loss in primary progressive multiple sclerosis.

BACKGROUND: Little is known on longer term changes of spinal cord volume (SCV) in primary progressive multiple sclerosis (PPMS). OBJECTIVE: Longitudinal evaluation of SCV loss in PPMS and its correlation to clinical outcomes, compared to relapse-onset multiple sclerosis (MS) subtypes. METHODS: A total of 60 MS age-, sex- and disease duration-matched patients (12 PPMS, each 24 relapsing-remitting (RRMS) and secondary progressive MS (SPMS)) were analysed annually over 6 years of follow-up. The upper cervical SCV was measured on 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images using a semi-automatic software (CORDIAL), along with the total brain volume (TBV), brain T2 lesion volume (T2LV) and Expanded Disability Status Scale (EDSS). RESULTS: PPMS showed faster SCV loss over time than RRMS ( p < 0.01) and by trend ( p = 0.066) compared with SPMS. In contrast to relapse-onset MS, in PPMS SCV loss progressed independent of TBV and T2LV changes. Moreover, in PPMS, SCV was the only magnetic resonance imaging (MRI) measurement associated with EDSS increase over time ( p < 0.01), as opposed to RRMS and SPMS. CONCLUSION: SCV loss is a strong predictor of clinical outcomes in PPMS and has shown to be faster and independent of brain MRI metrics compared to relapse-onset MS.

Cortical abnormalities in episodic migraine: A multi-center 3T MRI study.

BACKGROUND: Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of most previous studies may partially explain these inconsistencies. OBJECTIVE: To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort. METHODS: Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures. RESULTS: Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate. CONCLUSION: These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.

Cortical Thickness Alterations in Chronic Pain Disorder: An Exploratory MRI Study.

OBJECTIVE: Chronic pain disorder (CPD) has been associated with brain changes, especially in limbic circuits. However, in most patients with chronic pain, depression or anxiety is a common comorbidity. In this exploratory and naturalistic study, we investigated brain cortical thickness (CTh) differences between patients with CPD and healthy controls, with consideration of concurrent psychiatric symptoms. METHODS: Twenty-three patients with CPD and 23 age- and sex-matched healthy volunteers were included in this study. CTh was estimated using Freesurfer on high-resolution three-dimensional T1-weighted images acquired with a 3T scanner. Group differences were investigated using an analysis of covariance model that included age, sex, and Beck Depression Inventory I and Trait Anxiety Inventory scores as covariates. The relationship between CTh and Toronto Alexithymia Scale (TAS-20) scores was also investigated in patients. Data were corrected for multiplicity using the False Discovery Rate approach (q < .05). RESULTS: The comparison between groups using demographics and Beck Depression Inventory I scores as covariates showed thinner cortex in patients compared with controls, after correction for multiplicity in the left precentral (F(1,42) = 21.9, p < .05) and postcentral gyri (F(1,42) = 26.9, p < .05) and in the left inferior temporal sulcus (F(1,42) = 19.6, p < .05). Moreover, using the Trait Anxiety Inventory as covariate, a trend toward significance (p < .001 uncorrected) was seen for the left precentral gyrus (F(1,42) = 13.8), right middle frontal (F(1,42) = 14.3) and inferior parietal gyri (F(1,42) = 13.4), and right anterior temporal pole (F(1,42) = 15.9). CONCLUSIONS: The results indicate that brain morphological differences between patients with chronic pain disorder and healthy controls are localized to regions that correspond to sensory as well as affective dimensions of pain processing.

Altered thalamic connectivity during spontaneous attacks of migraine without aura: A resting-state fMRI study.

Background Functional connectivity of brain networks may be altered in migraine without aura patients. Functional magnetic resonance imaging (fMRI) studies have demonstrated changed activity in the thalamus, pons and cerebellum in migraineurs. Here, we investigated the thalamic, pontine and cerebellar network connectivity during spontaneous migraine attacks. Methods Seventeen patients with episodic migraine without aura underwent resting-state fMRI scan during and outside of a spontaneous migraine attack. Primary endpoint was a difference in functional connectivity between the attack and the headache-free days. Functional connectivity was assessed in four different networks using seed-based analysis. The chosen seeds were in the thalamus (MNI coordinates x,y,z: right, 22,-24,0 and left, -22,-28,6), pons (right, 8,-24,-32 and left, -8,-24,-32), cerebellum crus I (right, 46,-58,-30 and left, -46,-58,-30) and cerebellum lobule VI (right, 34,-42,-36 and left, -32,-42,-36). Results We found increased functional connectivity between the right thalamus and several contralateral brain regions (superior parietal lobule, insular cortex, primary motor cortex, supplementary motor area and orbitofrontal cortex). There was decreased functional connectivity between the right thalamus and three ipsilateral brain areas (primary somatosensory cortex and premotor cortex). We found no change in functional connectivity in the pontine or the cerebellar networks. Conclusions The study indicates that network connectivity between thalamus and pain modulating as well as pain encoding cortical areas are affected during spontaneous migraine attacks.

Association of clinical headache features with stroke location: An MRI voxel-based symptom lesion mapping study.

Background We have recently shown that the presence of headache in ischemic stroke is associated with lesions of the insular cortex. The aim of this post-hoc subgroup analysis was to investigate the association of specific headache features with stroke location in patients with acute ischemic stroke. Methods In this observational study, patients (mean age: 61.5, 58% males) with ischemic stroke and acute headache (n = 49) were investigated. Infarcts were manually outlined on 3D diffusion weighted magnetic resonance imaging (MRI) scans and transformed into standard stereotaxic space; lesions of the left hemisphere were mirrored in the x-axis to allow a voxel-wise group analysis of all patients. We analyzed the association of lesion location and the following phenotypical characteristics by voxel-based symptom lesion mapping: Headache intensity, different qualities of headache (pulsating, tension-type like and stabbing), and the presence of nausea, of cranial autonomic symptoms and of light or noise sensitivity. Results Headache intensity was associated with lesions of the posterior insula, the operculum and the cerebellum. "Pulsating" headache occurred with widespread cortical and subcortical strokes. The presence of "tension-like" and "stabbing" headache was not related to specific lesion patterns. Nausea was associated with lesions in the posterior circulation territory. Cranial-autonomic symptoms were related to lesions of the parietal lobe, the somatosensory cortex (SI) and the middle temporal cortex. The presence of noise sensitivity was associated with cerebellar lesions, whereas light sensitivity was not related to specific lesions in our sample. Conclusion Headache phenotype in ischemic stroke appears to be related to specific ischemic lesion patterns.

Clinical Correlations of Brain Lesion Location in Multiple Sclerosis: Voxel-Based Analysis of a Large Clinical Trial Dataset.

There is a limited correlation between white matter (WM) lesion load as determined by magnetic resonance imaging and disability in multiple sclerosis (MS). The reasons for this so-called clinico-radiological paradox are diverse and may, at least partly, relate to the fact that not just the overall lesion burden, but also the exact anatomical location of lesions predict the severity and type of disability. We aimed at studying the relationship between lesion distribution and disability using a voxel-based lesion probability mapping approach in a very large dataset of MS patients. T2-weighted lesion masks of 2348 relapsing-remitting MS patients were spatially normalized to standard stereotaxic space by non-linear registration. Relations between supratentorial WM lesion locations and disability measures were assessed using a non-parametric ANCOVA (Expanded Disability Status Scale [EDSS]; Multiple Sclerosis Functional Composite, and subscores; Modified Fatigue Impact Scale) or multinomial ordinal logistic regression (EDSS functional subscores). Data from 1907 (81%) patients were included in the analysis because of successful registration. The lesion mapping showed similar areas to be associated with the different disability scales: periventricular regions in temporal, frontal, and limbic lobes were predictive, mainly affecting the posterior thalamic radiation, the anterior, posterior, and superior parts of the corona radiata. In summary, significant associations between lesion location and clinical scores were found in periventricular areas. Such lesion clusters appear to be associated with impairment of different physical and cognitive abilities, probably because they affect commissural and long projection fibers, which are relevant WM pathways supporting many different brain functions.