[Show abstract][Hide abstract] ABSTRACT: Background: Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis, but its pathophysiological mechanisms are poorly understood. It is in particular unclear whether and how fatigue relates to structural and functional brain changes. Objective: We aimed to analyse the association of fatigue severity with basal ganglia functional connectivity, basal ganglia volumes, white matter integrity and grey matter density. Methods: In 44 patients with relapsingremitting multiple sclerosis and 20 age- and gender-matched healthy controls, resting-state fMRI, diffusion tensor imaging and voxel-based morphometry was performed. Results: In comparison with healthy controls, patients showed alteration of grey matter density, white matter integrity, basal ganglia volumes and basal ganglia functional connectivity. No association of fatigue severity with grey matter density, white matter integrity and basal ganglia volumes was observed within patients. In contrast, fatigue severity was negatively correlated with functional connectivity of basal ganglia nuclei with medial prefrontal cortex, precuneus and posterior cingulate cortex in patients. Furthermore, fatigue severity was positively correlated with functional connectivity between caudate nucleus and motor cortex. Conclusion: Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.
Full-text · Article · Nov 2014 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: Objective To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). Methods We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n=16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. Results Optic radiation lesion volume was associated with thinning of the optic radiation (p<0.001), delayed VEP (p=0.031), and visual disability indicated by FACT (p=0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p<0.001), including patients without previous optic neuritis (p<0.001). Conclusions Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of
No preview · Article · Aug 2014 · European Radiology
[Show abstract][Hide abstract] ABSTRACT: The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities.
[Show abstract][Hide abstract] ABSTRACT: Background
We investigated the applicability and feasibility of perceptive computing assisted gait analysis in multiple sclerosis (MS) patients using Microsoft Kinect™. To detect the maximum walking speed and the degree of spatial sway, we established a computerized and observer-independent measure, which we named Short Maximum Speed Walk (SMSW), and compared it to established clinical measures of gait disability in MS, namely the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk (T25FW).
Cross-sectional study of 22 MS patients (age mean ± SD 43 ± 9 years, 13 female) and 22 age and gender matched healthy control subjects (HC) (age 37 ± 11 years, 13 female). The disability level of each MS patient was graded using the EDSS (median 3.0, range 0.0-6.0). All subjects then performed the SMSW and the Timed 25-Foot Walk (T25FW). The SMSW comprised five gait parameters, which together assessed average walking speed and gait stability in different dimensions (left/right, up/down and 3D deviation).
SMSW average walking speed was slower in MS patients (1.6 ± 0.3 m/sec) than in HC (1.8 ± 0.4 m/sec) (p = 0.005) and correlated well with EDSS (Spearman’s Rho 0.676, p < 0.001). Furthermore, SMSW revealed higher left/right deviation in MS patients compared to HC. SMSW showed high recognition quality and retest-reliability (covariance 0.13 m/sec, ICC 0.965, p < 0.001). There was a significant correlation between SMSW average walking speed and T25FW (Pearson’s R = -0.447, p = 0.042).
Our data suggest that ambulation tests using Microsoft Kinect™ are feasible, well tolerated and can detect clinical gait disturbances in patients with MS. The retest-reliability was on par with the T25FW.
Full-text · Article · May 2014 · Journal of NeuroEngineering and Rehabilitation
[Show abstract][Hide abstract] ABSTRACT: Objective:
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe and efficacious technique for treating various neuropsychiatric disorders, but its underlying mechanisms are poorly understood. A newly developed H-coil allows the stimulation of deeper brain regions. This study is the first to investigate the effects of deep high-frequency rTMS on brain-derived neurotrophic factor (BDNF) serum concentrations in healthy volunteers. We aimed to evaluate the short-term effect of deep rTMS on BDNF serum concentrations.
This was a double-blind, randomized deep high-frequency rTMS study using an H-coil on a cohort of 13 healthy volunteers (NCT01106365). The following stimulation protocols were applied: 18-Hz stimulation of the left dorsolateral prefrontal cortex (PFC), 5-Hz stimulation of the primary motor cortex (MC) and sham stimulation in random order. Blood samples were obtained before, 30 min after and 60 min after each treatment.
The BDNF serum concentration decreased significantly after MC and PFC stimulation, but not after sham stimulation. Furthermore, BDNF serum level changes were associated with changes in individual alertness.
Although BDNF serum concentrations do not necessarily correlate with BDNF levels in the cerebrospinal fluid or the brain, these results indicate an acute biological effect of deep rTMS on BDNF release, and demonstrate that this change correlates with alertness.
Full-text · Article · Mar 2014 · Neuropsychobiology
[Show abstract][Hide abstract] ABSTRACT: Cerebral magnetic resonance elastography (MRE) measures the viscoelastic properties of brain tissues in vivo. It was recently shown that brain viscoelasticity is reduced in patients with multiple sclerosis (MS), highlighting the potential of cerebral MRE to detect tissue pathology during neuroinflammation. To further investigate the relationship between inflammation and brain viscoelasticity, we applied MRE to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced and monitored by MRE in a 7-tesla animal MRI scanner over 4 weeks. At the peak of the disease (day 14 after immunization), we detected a significant decrease in both the storage modulus (G') and the loss modulus (G″), indicating that both the elasticity and the viscosity of the brain are reduced during acute inflammation. Interestingly, these parameters normalized at a later time point (day 28) corresponding to the clinical recovery phase. Consistent with this, we observed a clear correlation between viscoelastic tissue alteration and the magnitude of perivascular T cell infiltration at both day 14 and day 28. Hence, acute neuroinflammation is associated with reduced mechanical cohesion of brain tissues. Moreover, the reduction of brain viscoelasticity appears to be a reversible process, which is restored when inflammation resolves. For the first time, our study has demonstrated the applicability of cerebral MRE in EAE, and showed that this novel imaging technology is highly sensitive to early tissue alterations resulting from the inflammatory processes. Thus, MRE may serve to monitor early stages of perivascular immune infiltration during neuroinflammation.
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
Fatigue is one of the most frequent symptoms in multiple sclerosis (MS), affecting up to 90% of patients at onset or during the course of the disease. Repetitive transcranial magnetic stimulation (rTMS) has proven efficacious for treating depression.
Effects on brain-derived neurotrophic factor (BDNF) serum level were observed in both TMS verum arms, prefrontal cortex (PFC) and motor cortex (MC), but not in the sham group.
[Show abstract][Hide abstract] ABSTRACT: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study.
We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim.
In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p < 0.001). Cortical pathology was absent in NMOSDs. In our MS cohort, we detected 36 leukocortical, 8 intracortical, and 8 subpial cortical lesions in 7 of 18 patients.
The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Background:Damage to venules in multiple sclerosis was first described decades ago. Today, ultrahigh magnetic field strength T2*-weighted magnetic resonance imaging (MRI) techniques depict very small cerebral veins in vivo with great anatomical detail.Objective:We aimed to investigate alterations of periventricular small blood vessel appearance in relation to T2 lesion count and distribution in multiple sclerosis and clinically isolated syndrome in comparison with healthy control subjects at 7 Tesla MRI.Methods:We investigated 38 patients (including 16 with early multiple sclerosis and seven with clinically isolated syndrome) and 22 matched healthy controls at 7 Tesla. The protocol included T2*-weighted Fast Low Angle Shot, and T2-weighted Turbo Inversion Recovery Magnitude sequences. We quantified periventricular venous density by a novel region-of-interest-based algorithm, expressing the ratio of 'veins per region-of-interest' as well as of 'periventricular vascular area'.Results:Our study revealed significantly decreased venous density in multiple sclerosis patients compared with healthy controls. Venous alterations were already detectable in clinically isolated syndrome and early multiple sclerosis, although to a smaller extent. Venous density correlated inversely with periventricular and whole-brain T2 lesion count. Furthermore, we found no indication for cerebral venous congestion in multiple sclerosis.Conclusion:High spatially resolving anatomical T2*-weighted MRI revealed vascular alterations in early stages of multiple sclerosis, presumably as a part of widespread haemodynamic and metabolic alterations.
No preview · Article · Jun 2012 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis is the most common chronic autoimmune disease of the central nervous system which preferentially affects females at childbearing age. For this reason, patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth. Preventive and personalized treatment approaches are considered, because topics as heredity, risk of congenital malformations, influence of pregnancy on MS and aspects of drug therapy during the period of conception, pregnancy, puerperium and lactation have to be discussed. Here, we provide an overview about the current state of knowledge regarding these issues.
Full-text · Article · Jun 2012 · EPMA Journal, The
[Show abstract][Hide abstract] ABSTRACT: The association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak, a phenomenon known as the clinico-radiological paradox. Here, we investigated to which degree it is possible to predict individual disease profiles from conventional magnetic resonance imaging (MRI) using multivariate analysis algorithms. Specifically, we conducted cross-validated canonical correlation analyses to investigate the predictive information contained in conventional MRI data of 40 MS patients for the following clinical parameters: disease duration, motor disability (9-Hole Peg Test, Timed 25-Foot Walk Test), cognitive dysfunction (Paced Auditory Serial Addition Test), and the expanded disability status scale (EDSS). It turned out that the information in the spatial patterning of MRI data predicted the clinical scores with correlations of up to 0.80 (p < 10(-9)). Maximal predictive information for disease duration was identified in the precuneus and somatosensory cortex. Areas in the precuneus and precentral gyrus were maximally informative for motor disability. Cognitive dysfunction could best be predicted using data from the angular gyrus and superior parietal lobe. For EDSS, the inferior frontal gyrus was maximally informative. In conclusion, conventional MRI is highly predictive of clinical disability in MS when pattern-based algorithms are used for prediction. Thus, the so-called clinico-radiological paradox is not apparent when using suitable analysis techniques.
No preview · Article · Mar 2012 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: In current clinical practice, T2-weighted magnetic resonance imaging (MRI) is commonly applied to quantify the accumulated multiple sclerosis (MS)lesion load, whereas T1-weighted sequences are used to differentiate edema, blood-brain barrier breakdown by contrast enhancement, and irreversible brain tissue damage(commonly called “black holes” owing to the loss of signal intensity in T1-weighted sequences). Black holes are histopathologically associated with axonal loss and severe tissue destruction. In addition, double inversion recovery techniques were developed to improve the sensitivity to cortical lesions.
To demonstrate the potential of ultrahigh-field 3-dimensional T1-weighted imaging using magnetization-prepared rapid acquisition and multiple gradient echoes(MPRAGE) to detect and characterize white and gray matter pathology in MS.
The patients with MS were recruited from the outpatient clinics of the Neuro Cure Clinical Research Center and underwent 7-T brain MRI at the Berlin Ultrahigh Field Facility, both of which are in Berlin, Germany.
Twenty patients with relapsing-remitting MS and 14 healthy controls underwent 7-T brain MRI, using a 24-channel receive head coil, and a subgroup of 18 patients with relapsing-remitting MS also underwent 1.5-T brain MRI. The imaging protocol included 2-dimensional T2-weighted fast low-angle shot (FLASH) and turbo inversion recovery magnitude (TIRM) sequences. For 3-dimensional T1-weighted imaging, the MPRAGE sequence was used. Each sequence was initially examined independently in separate analyses by an investigator blinded to all other data. In a second study, all detected lesions were retrospectively analyzed in a side-by-side comparison of all sequences.
By use of 7-T T2-weighted FLASH imaging, 604 cerebral lesions were detected in the patients with relapsing-remitting MS (mean, 30.2 lesions per patient[range, 2-107 lesions per patient]), but none were detected in healthy controls. Cortical pathology was visible in 10 patients (6 cortical lesions and 37 leukocortical lesions). Within the 7-T acquisitions, each lesion detected at T2-weighted sequences and/or double inversion recovery sequences was also clearly delineated on corresponding MPRAGE sequences in side-by-side analysis.However, at 1.5 T, the MPRAGE images depicted only 452 of 561 lesions visualized in T2-weighted sequences and/or double inversion recovery sequences. In contrast,when analyzing each sequence separately, we found that the 7-T MPRAGE depicted more lesions than the 7-TFLASH (728 lesions vs 584 lesions), and almost twice as many as the 1.5-T MPRAGE (399 lesions). The 7-TMPRAGE also improved the detection of cortical and leukocortical lesions (15 lesions vs 58 lesions).
At ultrahigh-field strength, T1-weighted MPRAGE is highly sensitive in detecting MS plaques within the white and the gray brain parenchyma. Our results indicate structural damage beyond demyelination in every lesion depicted, which is in accordance with postmortem histopathological studies. The 7-T MPRAGE clearly delineated every cortical lesion that was visualized by any other MRI sequence at 1.5 or 7 T.
No preview · Article · Feb 2012 · Archives of neurology
[Show abstract][Hide abstract] ABSTRACT: Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS.
We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS.
In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001).
Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is the most common chronic inflammatory disorder of the central nervous system (CNS) in young adults. The disease causes a wide range of symptoms depending on the localization and characteristics of the CNS pathology. In addition to drug-based immunomodulatory treatment, both drug-based and non-drug approaches are established as complementary strategies to alleviate existing symptoms and to prevent secondary diseases. In particular, physical therapy like exercise and physiotherapy can be customized to the individual patient's needs and has the potential to improve the individual outcome. However, high quality systematic data on physical therapy in MS are rare. This article summarizes the current knowledge on the influence of physical activity and exercise on disease-related symptoms and physical restrictions in MS patients. Other treatment strategies such as drug treatments or cognitive training were deliberately excluded for the purposes of this article.
Full-text · Article · Dec 2011 · EPMA Journal, The
[Show abstract][Hide abstract] ABSTRACT: Chronic cerebrospinal venous insufficiency (CCSVI) was proposed as the causal trigger for developing multiple sclerosis (MS). However, current data are contradictory and a gold standard for venous flow assessment is missing.
To compare structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS.
We enrolled 40 patients (44 ± 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0%-50%, 51%-80%, and >80%. ECCS analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position.
MRV identified 1 AV narrowing. IJV analysis yielded 12 patients for group 1 (30%), 19 patients for group 2 (48%), and 9 patients for group 3 (22%). By ECCS criteria, 4 patients (10%) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 ± 133 vs. 381 ± 213 mL/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 ± 172 vs. 231 ± 144 mL/min, p = 0.01), were different.
Our ECCS data contradict the postulated 100% prevalence of CCSVI criteria in MS. MRV seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings >80%. Our combined data argue against a causal relationship of venous narrowing and MS, favoring the rejection of the CCSVI hypothesis.
[Show abstract][Hide abstract] ABSTRACT: Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing-remitting type) in lesioned areas, areas of normal-appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques.
A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information.
Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10(-13)). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10(-7)). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10(-10)).
We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale.
[Show abstract][Hide abstract] ABSTRACT: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically.
To investigate the relationship between fatigue and sleep disorders in patients with MS.
Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n=26) and a non-fatigued MS subgroup (n=40).
Of the fatigued MS patients, 96% (n=25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n=24) (p=0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p<0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6-208; p=0.018).
Our results demonstrate a clear and significant relationship between fatigue and sleep disorders.
Full-text · Article · Jun 2011 · Multiple Sclerosis