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Background: Previous MRI studies reported deep grey matter volume increases after electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). However, the clinical correlates of these changes are still unclear. It remains debated whether such volume changes are transient, and if they correlate with affective changes over time. We here investigated if ECT induces deep grey matter volume increases in MDD-patients; and, if so, whether volume changes persist over more than 9 months and whether they are related to the clinical outcome., Methods: We examined 16 MDD-patients with 3Tesla MRI before (baseline) and after an ECT-series and followed 12 of them up for 10-36 months. Patients' data were compared to 16 healthy controls. Affective scales were used to investigate the relationship between therapy-outcome and MRI changes., Results: At baseline, MDD-patients had lower values in global brain volume, white matter and peripheral grey matter compared to healthy controls, but we observed no significant differences in deep grey matter volumes. After ECT, the differences in peripheral grey matter disappeared, and patients demonstrated significant volume increases in the right hippocampus and both thalami, followed by subsequent decreases after 10-36 months, especially in ECT-responders. Controls did not show significant changes over time., Limitations: Beside the relatively small, yet carefully characterized cohort, we address the variability in time between the third scanning session and the baseline., Conclusions: ECT-induced deep grey matter volume increases are transient. Our results suggest that the thalamus might be a key region for the understanding of the mechanisms of ECT action., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Functional MRI is not routinely used for neurosurgical planning despite potential important advantages, due to difficulty of determining quality. We introduce a novel method for objective evaluation of fMRI scan quality, based on activation maps. A template matching analysis (TMA) is presented and tested on data from two clinical fMRI protocols, performed by healthy controls in seven clinical centers. Preliminary clinical utility is tested with data from low-grade glioma patients., Methods: Data were collected from 42 healthy subjects from seven centers, with standardized finger tapping (FT) and verb generation (VG) tasks. Copies of these "typical" data were deliberately analyzed incorrectly to assess feasibility of identifying them as "atypical." Analyses of the VG task administered to 32 tumor patients assessed sensitivity of the TMA method to anatomical abnormalities., Results: TMA identified all atypical activity maps for both tasks, at the cost of incorrectly classifying 3.6 (VG)-6.5% (FT) of typical maps as atypical. For patients, the average TMA was significantly higher than atypical healthy scans, despite localized anatomical abnormalities caused by a tumor., Conclusion: This study supports feasibility of TMA for objective identification of atypical activation patterns for motor and verb generation fMRI protocols. TMA can facilitate the use and evaluation of clinical fMRI in hospital settings that have limited access to fMRI experts. In a clinical setting, this method could be applied to automatically flag fMRI scans showing atypical activation patterns for further investigation to determine whether atypicality is caused by poor scan data quality or abnormal functional topography.

The triple-code model (TCM) of number processing suggests the involvement of distinct parietal cortex areas in arithmetic operations: the bilateral horizontal segment of the intraparietal sulcus (hIPS) for arithmetic operations that require the manipulation of numerical quantities (e.g., subtraction) and the left angular gyrus (AG) for arithmetic operations that require the retrieval of answers from long-term memory (e.g., multiplication). Although neuropsychological, neuroimaging, and brain stimulation studies suggest the dissociation of these operations into distinct parietal cortex areas, the role of strategy (online calculation vs. retrieval) is not yet fully established. In the present study, we further explored the causal involvement of the left AG for multiplication and left hIPS for subtraction using a neuronavigated repetitive transcranial magnetic stimulation (rTMS) paradigm. Stimulation sites were determined based on an fMRI experiment using the same tasks. To account for the effect of strategy, participants were asked whether they used retrieval or calculation for each individual problem. We predicted that the stimulation of the left AG would selectively disrupt the retrieval of the solution to multiplication problems. On the other hand, stimulation of the left hIPS should selectively disrupt subtraction. Our results revealed that left AG stimulation was detrimental to the retrieval and online calculation of solutions for multiplication problems, as well as, the retrieval (but not online calculation) of the solutions to subtraction problems. In contrast, left hIPS stimulation had no detrimental effect on both operations regardless of strategy., (Copyright © 2020 Fresnoza, Christova, Purgstaller, Jehna, Zaar, Hoffermann, Mahdy Ali, Körner, Gallasch, von Campe and Ischebeck.)

Background and Study Aims:  Language is characteristically human, and preserving it is critical when resecting tumors in language-eloquent brain areas. Navigated repetitive transcranial magnetic stimulation (nrTMS) has been used in recent years as a noninvasive technique to identify preoperatively the language-eloquent cortical areas in tumor patients. An important objective is to increase the sensitivity and specificity of nrTMS in detecting language-related areas and increase the positive correlation of its results to that of intraoperative direct cortical stimulation (DCS). Although the technical aspects of the procedure have received enormous interest, factors related to the targeted cortical area such as previous cortical history or activity have been neglected. Therefore, the present study explores the impact of previous cortical history or activity on the effectiveness of a subsequent nrTMS mapping paradigm., Materials and Methods:  Twelve right-handed patients with a left hemispheric glioma underwent presurgical nrTMS language mapping and intraoperative language mapping with DCS. nrTMS was performed using a continuous theta burst stimulation paradigm to inhibit possible language relevant areas in the vicinity of the tumor, determined anatomically or based on functional magnetic resonance imaging hotspots. The nrTMS was applied in two separate sessions. One of the sessions randomly included a priming paradigm to precondition the targeted cortical areas., Results:  Priming stimulation decreased the error detection of the subsequent nrTMS mapping paradigm. This effect was more robust on major types of errors such as speech arrest and hesitation., Conclusion:  Prior cortical activity as induced by the priming stimulation has a profound impact on the responsiveness to the nrTMS mapping paradigm. Our findings further showed that metaplasticity, a type of homeostatic plastic process, could be elicited even in cortical areas affected by a growing tumor., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

OBJECTIVE Cerebral damage in frontal, parietal, and temporal brain areas and, probably more importantly, their interconnections can lead to deficits in language. However, neural plasticity and repair allow the brain to partly compensate for neural injury, mediated by both functional and structural changes. In this study, the authors sought to systematically investigate the relationship between language performance in brain tumor patients and structural perisylvian pathways (i.e., the arcuate fasciculus [AF]) using probabilistic fiber tracking on diffusion tensor imaging. The authors used a previously proposed model in which the AF is divided into anterior, long, and posterior segments. The authors hypothesized that right-handed patients with gliomas in the language-dominant (left) hemisphere would benefit from a more symmetrical or right-lateralized language pathway in terms of better preservation of language abilities. Furthermore, they investigated to what extent specific tumor characteristics, including proximity to the AF, affect language outcome in such patients. METHODS Twenty-seven right-handed patients (12 males and 15 females; mean age 52 ± 16 years) with 11 low-grade and 16 high-grade gliomas of the left hemisphere underwent 3-T diffusion-weighted MRI (30 directions) and language assessment as part of presurgical planning. For a systematic quantitative evaluation of the AF, probabilistic fiber tracking with a 2 regions of interest approach was carried out. Volumes of the 3 segments of both hemispheric AFs were evaluated by quantifying normalized and thresholded pathways. Resulting values served to generate the laterality index of the AFs. RESULTS Patients without language deficits tended to have an AF that was symmetric or lateralized to the right, whereas patients with deficits in language significantly more often demonstrated a left-lateralized posterior segment of the AF. Patients with high-grade gliomas had more severe language deficits than those with low-grade gliomas. Backward logistic regression revealed the laterality index of the posterior AF segment and tumor grade as the only independent statistically significant predictors for language deficits in this cohort. CONCLUSIONS In addition to the well-known fact that tumor entity influences behavioral outcome, the authors' findings suggest that the right homologs of structural language-associated pathways could be supportive for language function and facilitate compensation mechanisms after brain damage in functionally eloquent areas. This further indicates that knowledge about preoperative functional redistribution (identified by neurofunctional imaging) increases the chance for total or near-total resections of tumors in eloquent areas. In the future, longitudinal studies with larger groups are mandatory to overcome the methodological limitations of this cross-sectional study and to map neuroplastic changes associated with language performance and rehabilitation in brain tumor patients.

Background: Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages., Objective: To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS., Methods: We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS ( n = 48), relapsing-remitting multiple sclerosis ( n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5-6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0-3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC)., Results: CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17-7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC., Conclusion: Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB.

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging-based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Awake craniotomy is a well-established procedure in surgery of intracranial tumors in eloquent areas. However, sufficiently standardized instruments for the assessment of sensory-motor function before, during and after the operation are currently lacking, despite their importance for evaluation of operative outcome., Patients and Methods: To address this issue, we designed a standardized assessment tool (the "sensory-motor profile awake scale"; SMP-a). The final scale consists of three motor sections (face, arm and leg) assessing both gross and fine motor skills and one sensory section. It differentiates between six grades of impairment and its tasks are applicable for intraoperative continuous monitoring of sensory-motor functions and supporting processes. We analyzed the data of 17 patients with intracranial tumors eligible for awake craniotomy who were preoperatively assessed with the SMP-a. In addition, we present an exemplary case., Results: Our data support the assumption that the SMP-a is feasible in patients eligible for awake craniotomy, even in patients with symptoms of mild aphasia or more severe sensory-motor deficits caused by tumor recurrence. The exemplary case demonstrates the feasibility of repeated measures with the SMP-a in a tumor patient, including the adaption of tasks to the individual requirements of an intraoperative setting., Conclusion: This exploratory study suggests that the SMP-a might be a feasible rating scale in patients with intracranial tumors. The flexibility of the scale enables individual adaption, but preserves the standardized scoring system to allow comparison between assessment dates, patients and, hopefully in the future, institutions. However, future studies are mandatory to provide data on the instrument's diagnostic properties with respect to feasibility, objectivity, validity and reliability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We present the first case report describing a craniotomy for a glioblastoma in a patient with hemihydranencephaly (HHE). Ten years ago our patient had average cognitive and language functions, indicating very good adaption of his single right hemisphere. Due to the tumour he developed a deceleration, deficits in language functions and mild impairments of basic cognitive functions. Further neuroplastic reorganisations of his right hemisphere in response to the tumour growth are discussed. The favourable postoperative outcome supported the decision for careful tumour resection in this patient with HHE.

Objective: It has been suggested recently that cortical pathology in multiple sclerosis (MS) may, at least partly, be caused by factors in cerebrospinal fluid (CSF). We thus hypothesized that MS-related tissue changes in compartments close to the CSF, such as periventricular lesions, might correlate with cortical pathology., Methods: We investigated a cohort of 160 patients, comprising 91 with a clinically isolated syndrome (CIS) and 69 with relapsing-remitting MS (RRMS; mean age: CIS: 31.4 ± 9.0; RRMS: 33.0 ± 8.7 years; mean disease duration: CIS: 7.2 ± 15 months; RRMS: 8.0 ± 6.5 years, Expanded Disability Status Scale (median, min-max): CIS: 1, 0-3.5; RRMS: 1.25, 0-4) with 3.0T magnetic resonance imaging. MS lesions were segmented semiautomatically on fluid-attenuated inversion recovery images. To quantify periventricular lesion load (PV-LL), we generated ventricle masks and dilated them by a voxel factor of 3. Lesions within the dilated ventricle margin were classified as periventricular. Cortical thinning was assessed by cortical mean thickness (CMT) and compared to data from 58 healthy controls (HCs; mean age: 29.1 ± 7.4 years)., Results: Compared to HC, CIS and (even more so) RRMS patients demonstrated significantly reduced CMT. Even after controlling for ventricular volume and total lesion load, increased periventricular lesion occupancy (percentage of PV-LL) significantly correlated with decreased CMT in RRMS (r = -0.295; p = 0.015), but not in CIS (r = 0.032; p = 0.768) patients., Interpretation: The correlation between increased periventricular lesion burden and decreased CMT indicative of subpial cortical pathology supports the concept that common CSF-mediated factors might play a role in the accumulation of damage to gray and white matter in MS., (© 2015 American Neurological Association.)

Continuous resting-state (RS) functional magnetic resonance imaging (fMRI) has become particularly useful to identify changes in functional connectivity (FC) in CNS disorders. Fair et al. proposed a method of volume extraction to emulate RS fMRI from block-design experiments. Whether the validity of this approach holds true in multiple sclerosis (MS) patients has not been tested formally so far. Twelve MS patients and 18 controls underwent conventional RS fMRI and a cognitive block-design fMRI. The total amount of volumes as well as the truncated set of volumes of both functional datasets was separately analyzed using a seed-based approach. Overall, seed-based analyses of FC from the anterior cingulated cortex allowed identification of the same key-network constituents using different analytical approaches, whereas higher-level within-group analyses of emulated RS versus continuous RS also revealed significant distinct differences in FC networks. Using the emulated RS approach, a general identification of connectivity networks similar to those obtained using conventional RS data also appears feasible in diseased brains. Higher-level contrasts, however, yielded different results attesting to a significant impact of employed methodology.

Although age-related gait changes have been well characterized, little is known regarding potential functional changes in central motor control of distal lower limb movements with age. We hypothesized that there are age-related changes in brain activity associated with the control of repetitive ankle movements, an element of gait feasible for study with functional magnetic resonance imaging. We analyzed standardized functional magnetic resonance imaging data from 102 right-foot dominant healthy participants aged 20-83 years for age-associated effects using FSL and a meta-analysis using coordinate-based activation likelihood estimation. For the first time, we have confirmed age-related changes in brain activity with this gait-related movement of the lower limb in a large population. Increasing age correlated strongly with increased movement-associated activity in the cerebellum and precuneus. Given that task performance did not vary with age, we interpret these changes as potentially compensatory for other age-related changes in the sensorimotor network responsible for control of limb function., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology., Methods: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability., Results: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance., Conclusions: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.

Readout-segmented echo planar imaging with 2D navigator-based reacquisition is an uprising technique enabling the sampling of high-resolution diffusion images with reduced susceptibility artifacts. However, low signal from the small voxels and long scan times hamper the clinical applicability. Therefore, we introduce a regularization algorithm based on total variation that is applied directly on the entire diffusion tensor. The spatially varying regularization parameter is determined automatically dependent on spatial variations in signal-to-noise ratio thus, avoiding over- or under-regularization. Information about the noise distribution in the diffusion tensor is extracted from the diffusion weighted images by means of complex independent component analysis. Moreover, the combination of those features enables processing of the diffusion data absolutely user independent. Tractography from in vivo data and from a software phantom demonstrate the advantage of the spatially varying regularization compared to un-regularized data with respect to parameters relevant for fiber-tracking such as Mean Fiber Length, Track Count, Volume and Voxel Count. Specifically, for in vivo data findings suggest that tractography results from the regularized diffusion tensor based on one measurement (16 min) generates results comparable to the un-regularized data with three averages (48 min). This significant reduction in scan time renders high resolution (1 × 1 × 2.5 mm(3)) diffusion tensor imaging of the entire brain applicable in a clinical context.

Purpose: To apply quantitative susceptibility mapping (QSM) in the basal ganglia of patients with multiple sclerosis (MS) and relate the findings to R2* mapping with regard to the sensitivity for clinical and morphologic measures of disease severity., Materials and Methods: The local ethics committee approved this study, and all subjects gave written informed consent. Sixty-eight patients (26 with clinically isolated syndrome, 42 with relapsing-remitting MS) and 23 control subjects underwent 3-T magnetic resonance (MR) imaging. Susceptibility and R2* maps were reconstructed from the same three-dimensional multiecho spoiled gradient-echo sequence. Mean susceptibilities and R2* rates were measured in the basal ganglia and were compared between different phenotypes of the disease (clinically isolated syndrome, MS) and the control subjects by using analysis of variance, and regressing analysis was used to identify independent predictors., Results: Compared with control subjects, patients with MS and clinically isolated syndrome had increased (more paramagnetic) magnetic susceptibilities in the basal ganglia. R2* mapping proved less sensitive than QSM regarding group differences. The strongest predictor of magnetic susceptibility was age. Susceptibilities were higher with increasing neurologic deficits (r = 0.34, P < .01) and lower with normalized volumes of gray matter (r = -0.35, P < .005) and the cortex (r = -0.35, P < .005)., Conclusion: QSM provides superior sensitivity over R2* mapping in the detection of MS-related tissue changes in the basal ganglia. With QSM but not with R2* mapping, changes were already observed in patients with clinically isolated syndrome, which suggests that QSM can serve as a sensitive measure at the earliest stage of the disease., (© RSNA, 2013.)

Bradykinesia-the cardinal symptom in Parkinson's disease (PD)-affects both upper and lower limbs. While several functional imaging studies investigated the impact of levodopa on movement-related neural activity in Parkinson's disease during upper limb movements, analogue studies on lower limb movements are rare. We studied 20 patients with PD (mean age 66.8 ± 7.2 years) after at least 12 h drug withdrawal (OFF-state) and a second time approximately 40 min after oral administration of 200 mg levodopa (ON-state) behaviourally and by functional magnetic resonance imaging (fMRI) at 3 T during externally cued active ankle movements of the more affected foot at fixed rate. Results were compared with that obtained in ten healthy controls (HC) to separate pure pharmacological from disease-related levodopa-induced effects and to allow for interaction analyses. Behaviourally, all patients improved by at least 20 % regarding the motor score of the Unified Parkinson's disease rating scale after levodopa-challenge (mean scores OFF-state: 38.4 ± 10.1; ON-state: 25.5 ± 8.1). On fMRI, levodopa application elicited increased activity in subcortical structures (contralateral putamen and thalamus) in the patients. In contrast, no significant levodopa-induced activation changes were found in HC. The interaction between "PD/HC group factor" and "levodopa OFF/ON" did not show significant results. Given the levodopa-induced activation increases in the putamen and thalamus with unilateral ankle movements in patients with PD but not in HC, we speculate that these regions show the most prominent response to levodopa within the cortico-subcortical motor-circuit in the context of nigrostriatal dysfunction.

Multiple sclerosis (MS) is a chronic inflammatory central nervous system disorder with a neurodegenerative component. While in the past, MS has been predominantly viewed as a white matter (WM) disease, gray matter (GM) pathology receives increasing attention in MS research. In this study, we tested hypothesis-free for a possible spatial relationship between cortical volume changes and disturbed integrity of projecting WM tracts. We used voxel-based morphometry (VBM), lesion probability maps (LPM), and probabilistic tractography to compare brain magnetic resonance imaging (MRI) scans obtained at 3 Tesla of 15 low disabled MS patients with 15 matched healthy controls (HCs). Areas of decreased cortical volume in the patients identified by VBM were used as seeds for tractography. Volume in two cortical areas in the left inferior frontal gyrus (IFG) and the left lateral occipital cortex (LOC) was reduced in patients compared to HCs. Starting from the IFG-region, tractography suggested impaired connections between left and right portions of the frontal lobe in the patients. Using the LOC as a seed, in patients, the left inferior longitudinal and fronto-occipital pathways appeared disintegrated compared to HCs. Swapping the seeds to homologous contralateral areas showed similar results for frontal, but different results for occipital brain areas. This at least partly could be explained by differential interference with WM lesions. These findings suggest a regional dependence between cortical GM and WM tract alterations in MS patients. While confirmation in larger and more heterogenic samples is needed, this study indicates that combining several MRI methods (VBM, LPM, and Probabilistic Tractography) may provide important insights into interacting processes related to the fiber tract and GM changes in MS.

Objectives: Resting state (RS) functional MRI recently identified default network abnormalities related to cognitive impairment in MS. fMRI can also be used to map functional connectivity (FC) while the brain is at rest and not adhered to a specific task. Given the importance of the anterior cingulate cortex (ACC) for higher executive functioning in MS, we here used the ACC as seed-point to test for differences and similarities in RS-FC related to sustained attention between MS patients and controls., Design: Block-design rest phases of 3 Tesla fMRI data were analyzed to assess RS-FC in 31 patients (10 clinically isolated syndromes, 16 relapsing-remitting, 5 secondary progressive MS) and 31 age- and gender matched healthy controls (HC). Participants underwent extensive cognitive testing., Observations: In both groups, signal changes in several brain areas demonstrated significant correlation with RS-activity in the ACC. These comprised the posterior cingulate cortex (PCC), insular cortices, the right caudate, right middle temporal gyrus, angular gyri, the right hippocampus, and the cerebellum. Compared to HC, patients showed increased FC between the ACC and the left angular gyrus, left PCC, and right postcentral gyrus. Better cognitive performance in the patients was associated with increased FC to the cerebellum, middle temporal gyrus, occipital pole, and the angular gyrus., Conclusion: We provide evidence for adaptive changes in RS-FC in MS patients compared to HC in a sustained attention network. These results extend and partly mirror findings of task-related fMRI, suggesting FC may increase our understanding of cognitive dysfunction in MS.

The ability to recognize emotional facial expressions is crucial to adequate social behavior. Previous studies have suggested deficits in emotion recognition in multiple sclerosis (MS). These deficits were accompanied by several confounders including cognitive or visual impairments, disease duration, and depression. In our study we used functional MRI (fMRI) to test for potential early adaptive changes in only mildly disabled MS patients performing an emotion recognition task including the facial expressions of the emotions anger, fear and disgust. Fifteen relapsing-remitting MS patients with a median Expanded Disability Status Scale (EDSS) score of 2 (range: 0-3.5) and 15 healthy controls (HC) matched for age, gender, and education underwent behavioral (BERT: behavioral emotion recognition test; BRB-N: Brief Repeatable Battery for neuropsychological tests, WCST: Wisconsin Card Sorting Test) and clinical assessments (BDI: Beck Depression Inventory). Conventional MRI at 3.0T served to assess whole-brain volume, white matter, gray matter, cerebrospinal fluid, and T2-lesion load; during fMRI, participants were confronted with neutral, scrambled, angry, disgusted, and fearful faces, and houses. In the absence of differences in cognitive performance and in the ability to accurately recognize distinct emotional facial expressions, MS patients demonstrated excess fMRI activations during facial recognition compared to HC. These differences concerned the posterior cingulate cortex (PCC) and precuneus for anger and disgust contrasted to neutral faces, and the occipital fusiform gyri and the anterior CC for neutral faces versus houses. This study provides first evidence for excess activation during processing of higher order visual stimuli of emotional content in the absence of emotional, visual or cognitive behavior abnormalities already in earlier stages of MS.

Objectives: Abnormal high cerebral iron deposition may be implicated in chronic neurologic disorders, including multiple sclerosis (MS). R2* relaxometry has been recently validated in a postmortem study to indicate brain iron accumulation in a quantitative manner. We used this technique to assess brain iron levels in different stages of MS and healthy controls (HC) and determined their relation with demographic, clinical, neuropsychological, and other imaging variables., Methods: We studied 113 consecutive patients (35 clinically isolated syndrome [CIS], 78 MS) and 35 HC with 3 T MRI and clinical and neuropsychological examination. Iron deposition in subcortical gray matter structures was assessed by automated, regional calculation of R2* rates., Results: Basal ganglia (BG) R2* levels were significantly increased in MS compared to CIS (p < 0.001) and HC (p < 0.005). They were correlated with age (r = 0.5, p < 0.001), disease duration (r = 0.5, p < 0.001), Expanded Disability Status Scale (r = 0.3, p < 0.005), and the z values of mental processing speed (r = -0.3, p < 0.01). Stepwise linear regression analysis revealed gray matter atrophy as the strongest independent predictor of BG R2* levels (p < 0.001), followed by age (p < 0.001) and T2 lesion load (p < 0.005)., Conclusion: BG iron accumulation in MS occurs with advancing disease and is related to the extent of morphologic brain damage, which argues for iron deposition as an epiphenomenon. The absence of increased iron levels in patients with CIS indicates that iron accumulation does not precede the development of MS.

Background: Lesion dissemination in time and space represents a key feature and diagnostic marker of multiple sclerosis (MS). The correlation between magnetic resonance imaging (MRI) lesion load and disability is only modest, however. Strategic lesion location might at least partially account for this 'clinico-radiologic paradox'., Objectives: Here we used a non-parametric permutation-based approach to map lesion location probability based on MS lesions identified on T2-weighted MRI. We studied 121 patients with clinically isolated syndrome, relapsing-remitting or secondary progressive MS and correlated these maps to assessments of neurologic and cognitive functions., Results: The Expanded Disability Status Scale correlated with bilateral periventricular lesion location (LL), and sensory and coordination functional system deficits correlated with lesion accumulation in distinct anatomically plausible regions, i.e. thalamus and middle cerebellar peduncule. Regarding cognitive performance, decreased verbal fluency correlated with left parietal LL comprising the putative superior longitudinal fascicle. Delayed spatial recall correlated with &#95;amygdalar, &#95;left frontal and parietal LL. Delayed selective reminding correlated with bilateral frontal and temporal LL. However, only part of the spectrum of cognitive and neurological problems encountered in our cohort could be explained by specific lesion location., Conclusions: Lesion probability mapping supports the association of specific lesion locations with symptom development in MS, but only to limited extent.

Recognition and processing of emotional facial expression are crucial for social behavior and employ higher-order cognitive and visual working processes. In neuropsychiatric disorders, impaired emotion recognition most frequently concerned three specific emotions, i.e., anger, fear, and disgust. As incorrect processing of (neutral) facial stimuli per se might also underlie deficits in the recognition of emotional facial expressions, we aimed to assess all these aspects in one experiment. We therefore report here a functional magnetic resonance imaging (fMRI) paradigm for parallel assessment of the neural correlates of both the recognition of neutral faces and the three clinically most relevant emotions for future use in patients with neuropsychiatric disorders. FMRI analyses were expanded through comparisons of the emotional conditions with each other. The differential insights resulting from these two analyses strategies are compared and discussed. 30 healthy participants (21 F/9 M; age 36.3 ± 14.3, 17-66 years) underwent fMRI and behavioral testing for non-emotional and emotional face recognition. Recognition of neutral faces elicited activation in the fusiform gyri. Processing angry faces led to activation in left middle and superior frontal gyri and the anterior cingulate cortex. There was considerable heterogeneity regarding the fear versus neutral contrast, resulting in null effects for this contrast. Upon recognition of disgust, activation was noted in bilateral occipital, in the fronto-orbital cortex and in the insula. Analyzing contrasts between emotional conditions showed similar results (to those of contrasting with reference conditions) for separated emotional network patterns. We demonstrate here that our paradigm reproduces single aspects of separate previous studies across a cohort of healthy subjects, irrespective of age. Our approach might prove useful in future studies of patients with neurologic disorders with potential effect on emotion recognition., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Bradykinesia represents one of the cardinal and most incapacitating features of Parkinson's disease (PD). In this context, investigating the cerebral control mechanisms for limb movements and defining the associated functional neuroanatomy is important for understanding the impaired motor activity in PD. So far, most studies have focused on motor control of upper limb movements in PD. Ankle movement functional MRI (fMRI) paradigms have been used to non-invasively investigate supraspinal control mechanisms relevant for lower limb movements in healthy subjects, patients with Multiple sclerosis, and stroke. Using such an active and passive paradigm in 20 PD patients off medication (mean age 66.8 ± 7.2 years) and 20 healthy controls (HC; mean age 62.3 ± 6.9 years), we here wished to probe for possible activation differences between PD and HC and define functional correlates of lower limb function in PD. Active ankle movement versus rest was associated with a robust activation pattern in expected somatotopy involving key motor areas both in PD and HC. However, contrasting activation patterns in patients versus controls revealed excess activation in the patients in frontal regions comprising pre-supplementary motor areas (pre-SMA) and SMA proper. The extent of SMA activation did not correlate with behavioural parameters related to gait or motor function, and no differences were seen with the passive paradigm. This finding might be indicative of higher demand and increased effort in PD patients to ensure adequate motor function despite existing deficits. The missing correlation with behavioural variables and lack of differences with the passive paradigm suggests that this excess activation is not exclusively compensatory and also not hard-wired.

Objectives: Cognitive dysfunction (CD) is frequent in multiple sclerosis (MS) and can occur at early stages. Whereas functional reorganization with disease progression has been described for the motor system in MS using fMRI, no such studies exist for cognition. We attempted to assess the concept of functional reorganization concerning cognition using a simple "Go/No-go" fMRI paradigm., Methods: Patients with a clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS) (n = 10), or secondary progressive MS (SPMS) (n = 10), and 28 healthy controls (HC), underwent a comprehensive neuropsychological test battery, clinical examination, structural imaging, and an fMRI Go/No-go discrimination task at 3 T., Results: Patients performed worse than HC regarding memory, sustained attention and concentration, and information processing. These differences were driven by patients with SPMS. The fMRI task elicited activation in a widespread network including bilateral mesial and dorsolateral frontal, parietal, insular, basal ganglia, and cerebellar regions. Task performance was similar between phenotypes, but deviation from the activation pattern observed in HC and patients with CIS increased with disease progression. Patients with RRMS showed increased brain activation in the precuneus, both superior parietal lobes, and the right fusiform gyrus, and recruited the hippocampus with increasing demands. Patients with SPMS demonstrated the most abnormal network function, including recruitment of pre-SMA, bilateral superior and inferior parietal, dorsolateral prefrontal, right precentral, bilateral postcentral, and right temporal brain areas., Conclusion: Using a cognitive fMRI paradigm, we were able to confirm adaptive changes of neuronal activation with progressing MS and to provide strong evidence for their compensatory nature, at least partially.

Background: Cognitive deficits are frequent in multiple sclerosis (MS) and have been associated with morphologic brain changes. Less information exists on their extent and relation to MRI findings in clinically isolated syndrome (CIS). It is also unclear if structural changes as detected by magnetization transfer (MT) imaging may provide an additional explanation for cognitive dysfunction., Objective: To analyse the extent of cognitive deficits and their relation to MRI metrics including MT imaging in CIS compared to relapsing-remitting MS (RRMS)., Methods: Forty-four CIS and 80 RRMS patients underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and a 3 T MRI scan., Results: BRB-N subtests revealed similar results in CIS and RRMS. Impaired mental processing speed was most prevalent in both groups (CIS 13.6%; RRMS 16.3%) and thus served for correlation with MRI metrics. Using stepwise linear regression analyses, the strongest predictor for decreased mental processing speed was normalized cortex volume (p < 0.001) followed by T₂-lesion load (p < 0.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (p < 0.005)., Conclusion: Cognitive dysfunction occurs in CIS in a pattern similar to RRMS, with impaired mental processing speed being most prevalent. Cortical MT-ratio changes may be an early sign for tissue changes related to impaired mental processing speed in CIS while this association shifts to increased signs of cortical atrophy and lesion load in RRMS.

Objectives: Multiple sclerosis (MS) is a chronic multifocal CNS disorder which can affect higher order cognitive processes. Whereas cognitive disturbances in MS are increasingly better characterised, emotional facial expression (EFE) has rarely been tested, despite its importance for adequate social behaviour., Patients and Methods: We tested 20 patients with a clinically isolated syndrome suggestive of MS (CIS) or MS and 23 healthy controls (HC) for the ability to differ between emotional facial stimuli, controlling for the influence of depressive mood (ADS-L). We screened for cognitive dysfunction using The Faces Symbol Test (FST)., Results: The patients demonstrated significant decreased reaction-times regarding emotion recognition tests compared to HC. However, the results also suggested worse cognitive abilities in the patients. Emotional and cognitive test results were correlated., Conclusion: This exploratory pilot study suggests that emotion recognition deficits might be prevalent in MS. However, future studies will be needed to overcome the limitations of this study., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Increased iron deposition has been implicated in the pathophysiology of multiple sclerosis (MS), based on visual analysis of signal reduction on T(2)-weighted images. R(2)* relaxometry allows to assess brain iron accumulation quantitatively., Objective: To investigate regional brain iron deposition in patients with a clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) and its associations with demographical, clinical, and conventional magnetic resonance imaging (MRI) parameters., Methods: We studied 69 patients (CIS, n = 32; RRMS, n = 37) with 3T MRI and analyzed regional R(2)* relaxation rates and their correlations with age, disease duration, disability, T(2) lesion load, and normalized brain volumes., Results: Basal ganglia R(2)* relaxation rates increased in parallel with age (r = 0.3-0.6; P < 0.01) and were significantly higher in RRMS than in CIS (P < 0.05). Using multivariate linear regression analysis, the rate of putaminal iron deposition was independently predicted by the patients' age, disease duration, and gray matter atrophy., Conclusions: Quantitative assessment by R(2)* relaxometry suggests increased iron deposition in the basal ganglia of MS patients, which is associated with disease duration and brain atrophy. This technique together with long-term follow-up thus appears suited to clarify whether regional iron accumulation contributes to MS morbidity or merely reflects an epiphenomenon.