[Neuropsychological and MRI diagnostics in secondary progressive multiple sclerosis]. / Neuropsychologische und Magnetresonanztomographie(MRT)-Diagnostik bei sekundär progredienter Multipler Sklerose.

BACKGROUND: Multiple sclerosis is a disease continuum with an initial relapsing remitting course (RRMS) and secondary progression (SPMS) at later stages. Most of the hitherto approved treatments do not adequately control for the phase of secondary progression. Thus, early detection of SPMS conversion is a key issue to initiate SPMS-tailored treatment. In this context, assessment of cognitive functions and magnetic resonance imaging (MRI) both play an important role in the longitudinal follow-up of MS patients. OBJECTIVE: To elucidate the importance of cognitive testing and MRI for prediction and detection of SPMS conversion as well as to discuss strategies for disease monitoring and for optimizing treatment in standard clinical care, particularly in outpatient settings. MATERIAL AND METHODS: Review article based on a nonsystematic literature review. RESULTS: Standardized cognitive testing can support early diagnosis of SPMS and facilitate disease monitoring. Annual application of sensitive screening tests, such as the Symbol Digit Modalities Test (SDMT) and Brief Visual Memory Test-Revised (BVMT­R) or the entire Brief International Cognitive Assessment for MS (BICAMS) test battery are recommended in this context. The MRI evidence of persistent inflammatory activity within 3 years of diagnosis as well as evidence of cortical lesions are predictive for SPMS conversion. Standardized MRI monitoring for markers of progression can substantiate clinical and neurocognitive signs of SPMS conversion. CONCLUSION: Multidisciplinary patient care involving careful clinical examination, neuropsychological testing and MRI monitoring is of great significance for the prediction of SPMS conversion and diagnostics. This enables early treatment adaptation, since pharmacological interventions in SPMS differ from those in RRMS. Continuous clinical, neuropsychological and MRI vigilance enable stringent monitoring of treatment outcomes with respect to neuroinflammatory and neurodegenerative activity as well as treatment-related complications.

Shedding light on the clinical recognition process of transient global amnesia.

BACKGROUND AND PURPOSE: Diagnostic uncertainty is common in the emergency evaluation of neurological conditions such as acute confusional states, particularly for non-neurologists. We aimed to investigate the clinical recognition process of transient global amnesia (TGA) before arrival at the hospital and in the emergency department (ED). METHODS: In this retrospective observational study, medical records of 365 patients with TGA were analysed concerning mode of arrival, symptoms and suspected diagnosis made by pre-hospital medical care providers and the ED neurologist. RESULTS: More than half of the 248 patients who were evaluated before arrival at the hospital (N = 157, 63.3%) received a diagnosis of suspected stroke, whereas TGA was considered in only 16 patients (6.5%), with recognition of acute amnesia in 150 patients (60.5%) and disturbed orientation in 86 patients (34.7%). Repetitive questions by the patient were noted in 28 patients (11.3%). In contrast, in 355 patients (97.3%), TGA was considered the primary diagnosis by the ED neurologist. Diagnosis in the ED was achieved by documenting ongoing impairment of episodic verbal memory (100.0%), repetitive questions as a prominent ancillary finding (95.5%) and the lack of focal neurological symptoms (100.0%) or by carefully obtaining collateral history suggestive of anterograde memory disturbance (89.9%) and/or repetitive questions (85.7%). CONCLUSION: Recognizing TGA crucially depends on identifying isolated anterograde episodic long-term memory disturbance or its observable effects such as repetitive questions and actions.

What remains after transient global amnesia (TGA)? An ultra-high field 7 T magnetic resonance imaging study of the hippocampus.

BACKGROUND AND PURPOSE: The aim was to study whether ultra-high field 7 T magnetic resonance imaging (MRI) can demonstrate chronic focal defects in the hippocampus corresponding to the former acute diffusion-weighted imaging (DWI) lesions and to assess chronic T2-hyperintense hippocampal lesion load in transient global amnesia (TGA) patients. METHODS: Follow-up of 7 T MRI of the hippocampus was performed in 13 patients with documented hippocampal DWI lesions (detected via 3 T MRI) after acute TGA. The location of the DWI lesions was transformed to 7 T T2 images after data co-registration. Additionally, the T2-hyperintense lesion load was estimated in each patient and compared with that of 13 healthy controls. RESULTS: Magnetic resonance imaging (7 T) was performed after a median of 4 months. No structural abnormality at the site of the previous TGA lesion was observed in any case. None of the controls showed DWI lesions. There was no significant difference between patients and controls concerning the number (P = 0.67) or volume (P = 0.45) of T2-hyperintense hippocampal lesions. CONCLUSIONS: Diffusion-weighted imaging lesions in patients with TGA do not provoke any visible sequelae and do not result in hippocampal cavities. The occurrence of incidental hippocampal T2 lesions after TGA is not more frequent than in controls.

The association between retinal nerve fibre layer thickness and N-acetyl aspartate levels in multiple sclerosis brain normal-appearing white matter: a longitudinal study using magnetic resonance spectroscopy and optical coherence tomography.

BACKGROUND AND PURPOSE: N-acetyl aspartate (NAA) assessed using proton magnetic resonance spectroscopy (1 H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness (RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis (MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter (NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. METHODS: Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) score, optical coherence tomography and magnetic resonance imaging including 1 H MRS at baseline and after 1 year. RESULTS: At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS (SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing-remitting MS and SPMS (99.8 ± 12.3 µm vs. 92.4 ± 12.8 µm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM (r = 0.42; P = 0.008) and T2 WM lesions (r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year (ρ = 0.43, P = 0.046). CONCLUSIONS: N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression.

Six-year follow-up of a case series with non-communicating syringomyelia in multiple sclerosis.

BACKGROUND: Non-communicating syringomyelia (NCS) has occasionally been described in case reports and small case series as an incidental finding of spinal cord (SC) pathology in patients with multiple sclerosis (MS), but only little is known on the clinical course and progression of NCS, and in more general terms on the prognosis of patients with MS and NCS. METHODS: Nine patients with MS with known NCS at baseline and a control group of 18 age-, sex- and disease course-matched patients with MS without NCS were recruited for a follow-up visit after 6 years. All 27 patients underwent clinical examination and brain magnetic resonance imaging (MRI), and 8/9 patients with NCS were additionally studied with MRI of the SC. MRI data were analysed for changes in length and maximal cross-sectional area of the NCS, lesion volumes of the brain and cord as well as for volumetric metrics of the whole brain (using SIENAX), the cerebellum and medulla oblongata (using ECCET). RESULTS: NCS did not significantly change in size when corrected for multiple comparisons. The clinical data (annual relapse rate, EDSS and disease duration) and MRI metrics (T2 and T1 lesion load; whole brain, cerebellar and medulla oblongata volumes as well as their percentage volume change per year) did not significantly differ between patients with MS with or without NCS. CONCLUSION: The stable findings regarding size and shape of the syrinx and lack of distinguishing MRI and clinical features support the assumption that NCS is not defining a prognostically or pathogenetically distinct subgroup of patients with MS.

A diagnostic support system based on pain drawings: binary and k-disease classification of EDS, GBS, FSHD, PROMM, and a control group with Pain2D.

BACKGROUND AND OBJECTIVE: The diagnosis of rare diseases (RDs) is often challenging due to their rarity, variability and the high number of individual RDs, resulting in a delay in diagnosis with adverse effects for patients and healthcare systems. The development of computer assisted diagnostic decision support systems could help to improve these problems by supporting differential diagnosis and by prompting physicians to initiate the right diagnostic tests. Towards this end, we developed, trained and tested a machine learning model implemented as part of the software called Pain2D to classify four rare diseases (EDS, GBS, FSHD and PROMM), as well as a control group of unspecific chronic pain, from pen-and-paper pain drawings filled in by patients. METHODS: Pain drawings (PDs) were collected from patients suffering from one of the four RDs, or from unspecific chronic pain. The latter PDs were used as an outgroup in order to test how Pain2D handles more common pain causes. A total of 262 (59 EDS, 29 GBS, 35 FSHD, 89 PROMM, 50 unspecific chronic pain) PDs were collected and used to generate disease specific pain profiles. PDs were then classified by Pain2D in a leave-one-out-cross-validation approach. RESULTS: Pain2D was able to classify the four rare diseases with an accuracy of 61-77% with its binary classifier. EDS, GBS and FSHD were classified correctly by the Pain2D k-disease classifier with sensitivities between 63 and 86% and specificities between 81 and 89%. For PROMM, the k-disease classifier achieved a sensitivity of 51% and specificity of 90%. CONCLUSIONS: Pain2D is a scalable, open-source tool that could potentially be trained for all diseases presenting with pain.

Implementation of a piritramide based patient-controlled analgesia (PCA) as a standard of care for pain control in late abortion induction: A prospective cohort study from a patient perspective.

Objective: To assess whether the implementation of patient-controlled analgesia (PCA) with piritramide using an automatic pump system under routine conditions is effective to reduce pain in late abortion inductions. Study design: Prospective observational cohort study. Setting: Patients requiring medically indicated abortion induction from 14 weeks of pregnancy onwards between July 2019 and July 2020 at the department of Obstetrics and Prenatal Medicine of the Bonn University Hospital in Germany. Methods: Evaluation of pain management after implementation of a PCA system compared with previous nurse-controlled tramadol-based standard under routine conditions. Patients answered a validated pain questionnaire and requirement of rescue analgesics was assessed. Pain intensity and satisfaction were measured on a ten-point numeric rating scale. Main Outcome Measure Maximal pain intensity. Results: Forty patients were included. Patients using Piritramide-PCA complained of higher pain sores than those in the standard group (6.90 (± 2.34) vs. 4.83 (± 2.87), (p < 0.05)). In both groups the level of satisfaction with the analgesia received was comparable (8.00 (± 2.45) vs 7.67 (± 2.62), (p = 0.7)). Patients in the PCA group suffered more nausea (63.2 % vs 30 % respectively, OR 4.0, 95 % CI 1.05-15.20, p < 0.05) and expressed more the desire for more analgesic support compared to the control group (OR 5.7 (1-33.25), p = 0.05). Conclusion: Women with abortion induction after 14 weeks of gestation suffer from relevant severe pain, which requires adequate therapy. However, addition of PCA does not seem to bring any advantage in patients undergoing this procedure.

Multiple Sclerosis Severity Scale and whole-brain N-acetylaspartate concentration for patients' assessment.

BACKGROUND: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking. OBJECTIVE: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients' disease course. METHODS: The MSSS and average WBNAA loss rate (ΔWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined. Some 27 patients exhibited a 'benign' disease course, characterized by an Expanded Disability Status Scale score (EDSS) of 3.0 or less, and 34 were 'non-benign': EDSS score higher than 3.0. RESULTS: The two cohorts were indistinguishable in age and disease duration. Benign patients' EDSS and MSSS (2.1 ± 0.7, 1.15 ± 0.60) were significantly lower than non-benign (4.6 ± 1.0, 3.6 ± 1.2; both p < 10(-4)). Their respective average ΔWBNAA, 0.10 ± 0.16 and 0.11 ± 0.12 mM/year, however, were not significantly different (p > 0.7). While MSSS is both sensitive to (92.6%) and specific for (97.0%) benign MS, ΔWBNAA is only sensitive (92.6%) but not specific (2.9%). CONCLUSION: Since the WBNAA loss rate is similar in both phenotypes, the only difference between them is their clinical classification, characterized by MSSS and EDSS. This may indicate that 'benign' MS probably reflects fortuitous sparing of clinically eloquent brain regions and better utilization of brain plasticity.

Diffusion-weighted imaging for the differential diagnosis of disorders affecting the hippocampus.

BACKGROUND: The human hippocampus can be affected in a large variety of very different neurological diseases, of which acute ischemic stroke, transient global amnesia, epilepsy, and limbic encephalitis are the most common. Less frequent etiologies include various infections and encephalopathy of different origins. Clinical presentation notably comprises confusional state, altered vigilance, memory deficits of various extent and seizures. While in hypoxic or hypoglycemic encephalopathy, clinical presentation and surrounding circumstances provide some clues to reach the correct diagnosis, in the above-listed more common disorders, signs and symptoms might overlap, making the differential diagnosis difficult. This review presents recent studies using the diffusion-weighted imaging (DWI) technique in diseases involving the hippocampus. METHODS: References for the review were identified through searches of PubMed from 1965 to January 2011. Only papers published in English were reviewed. Full articles were obtained and references were checked for additional material where appropriate. RESULTS: All pathologies affecting the hippocampus are associated with distinct lesion patterns on magnetic resonance imaging, and especially DWI has the ability to demonstrate even minute and transient hippocampal lesions. In acute ischemic stroke in the posterior cerebral artery territory, involvement of the hippocampal formation occurs in four distinct patterns on DWI that can be easily differentiated and correspond to the known vascular anatomy of the hippocampus. In the subacute phase after transient global amnesia (TGA), dot-like hyperintense lesions are regularly found in the lateral aspect of the hippocampus on DWI. The DWI lesions described after prolonged seizures or status epilepticus include unilateral or bilateral hippocampal, thalamic, and cortical lesions of various extent, not restricted to vascular territories. In limbic encephalitis, DWI lesions are only infrequently found and usually affect the hippocampus, uncus and amygdala. Furthermore, in some rare cases DWI lesions of different etiology may coexist. CONCLUSION: In patients with diseases affecting the hippocampus, DWI appears to be useful in differentiating between underlying pathologies and may facilitate a definite diagnosis conducive to an optimal treatment. With a careful clinical examination, experience with the interpretation of DWI findings and knowledge of associated phenomena, it is indeed possible to differentiate between ischemic, ictal, metabolic, and TGA-associated findings.

Brain imaging in patients with transient ischemic attack: a comparison of computed tomography and magnetic resonance imaging.

BACKGROUND: Brain imaging in stroke aims at the detection of the relevant ischemic tissue pathology. Cranial computed tomography (CT) is frequently used in patients with transient ischemic attack (TIA) but no data is available on how it directly compares to magnetic resonance imaging (MRI). METHODS: We compared detection of acute ischemic lesions on CT and MRI in 215 consecutive TIA patients who underwent brain imaging with either CT (n = 161) or MRI (n = 54). An MRI was performed within 24 h in all patients who had CT initially. RESULTS: An initial assessment with CT revealed no acute pathology in 154 (95.7%) and possible acute infarction in 7 (4.3%) patients. The acute infarct on CT was confirmed by diffusion-weighted imaging (DWI) in only 2 cases (28.6%). DWI detected an acute infarct in 50 of the 154 patients with normal baseline CT (32.5%). Among 54 patients without baseline CT, DWI showed acute ischemic lesions in 19 (35.2%). The ischemic lesions had a median volume of 0.87 cm(3) (range: 0.08-15.61), and the lesion pattern provided clues to the underlying etiology in 13.7%. CONCLUSION: Acute MRI is advantageous over CT to confirm the probable ischemic nature and to identify the etiology in TIA patients.

Thrombolysis in posterior circulation stroke: stroke subtypes and patterns, complications and outcome.

BACKGROUND: Patients with posterior circulation stroke (PCS) were underrepresented in or even excluded from the large clinical trials investigating acute therapy with thrombolysis. Therefore, the knowledge about potential benefits and risks of thrombolysis in PCS is sparse. METHODS: From July 2004 until June 2007, 237 stroke patients were treated with thrombolysis within 3 h after onset of symptoms in our stroke unit. Baseline characteristics, etiology, CT/MRI stroke patterns, clinical outcome, and complications of patients with PCS were compared to those with anterior circulation stroke (ACS). RESULTS: There were 30 patients in the PCS group; 198 had ACS. In the PCS group, less patients had a history of prior stroke (0/30 vs. 31/198 (15.7%), p = 0.02) and less were treated with platelet inhibitors (6/30 (20.0%) vs. 83/198 (41.9%), p = 0.02). Onset to treatment time was higher in the PCS group (156.2 ± 23.2 vs. 141.1 ± 30.7, p = 0.01). Small vessel disease occurred more often in PCS patients (10/30 (33.3%) vs. 12/198 (6.1%), p < 0.001), whereas stroke of undetermined cause was less frequent (5/30 (16.7%) vs. 75/198 (37.9%), p = 0.02). Correspondingly, PCS patients had more lacunar (13/30 (43.3%) vs. 15/198 (7.3%), p < 0.001) strokes on CT/MRI. Patients with PCS had significantly lower median NIHSS scores after 2 and 24 h, whereas the median NIHSS and mRS scores at discharge as well as the mRS score at the 3-month follow-up, although still lower, did not differ significantly between both groups. Outcome was similar with regard to complications and mortality. CONCLUSIONS: Patients with PCS have a higher rate of small vessel disease and lacunar stroke. In terms of potential benefits and risks of thrombolysis, we could demonstrate no significant differences between PCS and ACS. Acute PCS patients should be diagnosed and treated with the same elaborateness as ACS patients.

Short-term adaptation to a simple motor task: a physiological process preserved in multiple sclerosis.

Short-term adaptation indicates the attenuation of the functional MRI (fMRI) response during repeated task execution. It is considered to be a physiological process, but it is unknown whether short-term adaptation changes significantly in patients with brain disorders, such as multiple sclerosis (MS). In order to investigate short-term adaptation during a repeated right-hand tapping task in both controls and in patients with MS, we analyzed the fMRI data collected in a large cohort of controls and MS patients who were recruited into a multi-centre European fMRI study. Four fMRI runs were acquired for each of the 55 controls and 56 MS patients at baseline and 33 controls and 26 MS patients at 1-year follow-up. The externally cued (1 Hz) right hand tapping movement was limited to 3 cm amplitude by using at all sites (7 at baseline and 6 at follow-up) identically manufactured wooden frames. No significant differences in cerebral activation were found between sites. Furthermore, our results showed linear response adaptation (i.e. reduced activation) from run 1 to run 4 (over a 25 minute period) in the primary motor area (contralateral more than ipsilateral), in the supplementary motor area and in the primary sensory cortex, sensory-motor cortex and cerebellum, bilaterally. This linear activation decay was the same in both control and patient groups, did not change between baseline and 1-year follow-up and was not influenced by the modest disease progression observed over 1 year. These findings confirm that the short-term adaptation to a simple motor task is a physiological process which is preserved in MS.

Risk of symptomatic intracerebral hemorrhage in patients treated with intra-arterial thrombolysis.

BACKGROUND: In intra-arterial (IA) thrombolysis trials, higher rates of symptomatic intracerebral haemorrhage (sICH) were found than in trials with intravenous (IV) recombinant tissue plasminogen activator (tPA); this observation could have been due to the inclusion of more severely affected patients in IA thrombolysis trials. In the present study, we investigated the rate of sICH in IA and combined IV + IA thrombolysis versus IV thrombolysis after adjusting for differences in clinical and MRI parameters. METHODS: In this multicenter study, we systematically analyzed data from 645 patients with anterior-circulation strokes treated with either IV or IA thrombolysis within 6 h following symptom onset. Thrombolytic regimens included (1) IV tPA treatment (n = 536) and (2) IA treatment with either tPA or urokinase (n = 74) or (3) combined IV + IA treatment with either tPA or urokinase (n = 35). RESULTS: 44 (6.8%) patients developed sICH. sICH patients had significantly higher scores on the National Institutes of Health Stroke Scale (NIHSS) at admission and pretreatment DWI lesions. The sICH risk was 5.2% (n = 28) in IV thrombolysis, which is significantly lower than in IA (12.5%, n = 9) or IV + IA thrombolysis (20%, n = 7). In a binary logistic regression analysis including age, NIHSS score, time to thrombolysis, initial diffusion weighted imaging lesion size, mode of thrombolytic treatment and thrombolytic agent, the mode of thrombolytic treatment remained an independent predictor for sICH. The odds ratio for IA or IV + IA versus IV treatment was 3.466 (1.19-10.01, 95% CI, p < 0.05). CONCLUSION: In this series, IA and IV + IA thrombolysis is associated with an increased sICH risk as compared to IV thrombolysis, and this risk is independent of differences in baseline parameters such as age, initial NIHSS score or pretreatment lesion size.

Reproducibility of fMRI in the clinical setting: implications for trial designs.

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

MRI characteristics of atypical idiopathic inflammatory demyelinating lesions of the brain : A review of reported findings.

BACKGROUND: Idiopathic inflammatory demyelinating lesions (IIDL) of the brain usually present with a morphologic pattern characteristic of multiple sclerosis (MS). Atypical appearances of IIDLs also exist, however, and can pose significant diagnostic problems and uncertainty regarding prognosis and adequate therapy. We attempted to improve upon this situation by reviewing the literature. METHODS: We performed a PubMed search from January 1984 through December 2004 for articles in English reporting on IIDLs which had been considered as morphologically atypical (66 articles; 270 cases reported). From these publications 69 individual patient reports allowed the extraction of adequate information on magnetic resonance imaging (MRI) and associated disease characteristics. RESULTS: Reported atypical IIDLs most frequently manifested as large ring-like lesions (n = 27) which are now considered quite suggestive of an antibodymediated form of MS. Truly atypical IIDLs were less common and exhibited appearances which we termed megacystic (n = 8), Balolike (n = 11) and diffusely infiltrating (n = 11). Despite limitations imposed by the absence of original data the inter-rater agreement in defining these subtypes of atypical IIDLs was moderate to substantial (kappa 0.48-0.68) and we noted trends for their association with certain demographic, clinical and paraclinical variables. INTERPRETATION: We suggest that IIDLs reported as atypical in the literature can be segregated into several distinct subtypes based on their MRI appearance. The recognition of these patterns may be useful for the differential diagnosis and for a future classification. Because of the limitations inherent in our review this will have to be confirmed by a prospective registry.

Relating functional changes during hand movement to clinical parameters in patients with multiple sclerosis in a multi-centre fMRI study.

We performed a prospective multi-centre study using functional magnetic resonance imaging (fMRI) to better characterize the relationships between clinical expression and brain function in patients with multiple sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls). Patients showed greater task-related activation bilaterally in brain regions including the pre- and post-central, inferior and superior frontal, cingulate and superior temporal gyri and insula (P < 0.05, all statistics corrected for multiple comparisons). Both patients and healthy controls showed greater brain activation with increasing age in the ipsilateral pre-central and inferior frontal gyri (P < 0.05). Patients, but not controls, showed greater brain activation in the anterior cingulate gyrus and the bilateral ventral striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found. This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater cognitive 'resource allocation' and suggests age-related differences in brain responses to the disease. These observations add to evidence that brain functional responses (including potentially adaptive brain plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.

Impairment of movement-associated brain deactivation in multiple sclerosis: further evidence for a functional pathology of interhemispheric neuronal inhibition.

Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

Diffusion MR imaging in multiple sclerosis: technical aspects and challenges.

SUMMARY: Diffusion tensor (DT) MR imaging has frequently been applied in multiple sclerosis (MS) because of its ability to detect and quantify disease-related changes of the tissue microstructure within and outside T2-visible lesions. DT MR imaging data collection places high demands on scanner hardware and, though the acquisition and postprocessing can be relatively straightforward, numerous challenges remain in improving the reproducibility of this technique. Although there are some issues concerning image quality, echo-planar imaging is the most widely used acquisition scheme for diffusion imaging studies. Once the DT is estimated, indexes conveying the size, shape, and orientation of the DT can be calculated and further analyzed by using either histogram- or region-of-interest-based analyses. Because the orientation of the DT reflects the orientation of the axonal fibers of the brain, the pathways of the major white matter tracts can also be visualized. The DT model of diffusion, however, is not sufficient to characterize the diffusion properties of the brain when complex populations of fibers are present in a single voxel, and new ways to address this issue have been proposed. Two developments have enabled considerable improvements in the application of DT MR imaging: high magnetic field strengths and multicoil receiver arrays with parallel imaging. This review critically discusses models, acquisition, and postprocessing approaches that are currently available for DT MR imaging, as well as their limitations and possible improvements, to provide a better understanding of the strengths and weaknesses of this technique and a background for designing diffusion studies in MS.