MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS. METHODS/DESIGN: This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses. DISCUSSION: Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials. TRIAL REGISTRATION: Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.

Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.

OBJECTIVES: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity. METHODS: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety. RESULTS: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time. CONCLUSIONS: MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found. CLASSIFICATION OF EVIDENCE: This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.

OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

Head motion parameters in fMRI differ between patients with mild cognitive impairment and Alzheimer disease versus elderly control subjects.

Motion artifacts are a well-known and frequent limitation during neuroimaging workup of cognitive decline. While head motion typically deteriorates image quality, we test the hypothesis that head motion differs systematically between healthy controls (HC), amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and consequently might contain diagnostic information. This prospective study was approved by the local ethics committee and includes 28 HC (age 71.0 ± 6.9 years, 18 females), 15 aMCI (age 67.7 ± 10.9 years, 9 females) and 20 AD (age 73.4 ± 6.8 years, 10 females). Functional magnetic resonance imaging (fMRI) at 3T included a 9 min echo-planar imaging sequence with 180 repetitions. Cumulative average head rotation and translation was estimated based on standard fMRI preprocessing and compared between groups using receiver operating characteristic statistics. Global cumulative head rotation discriminated aMCI from controls [p < 0.01, area under curve (AUC) 0.74] and AD from controls (p < 0.01, AUC 0.73). The ratio of rotation z versus y discriminated AD from controls (p < 0.05, AUC 0.71) and AD from aMCI (p < 0.05, AUC of 0.75). Head motion systematically differs between aMCI/AD and controls. Since motion is not random but convoluted with diagnosis, the higher amount of motion in aMCI and AD as compared to controls might be a potential confounding factor for fMRI group comparisons. Additionally, head motion not only deteriorates image quality, yet also contains useful discriminatory information and is available for free as a "side product" of fMRI data preprocessing.

Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years.

BACKGROUND: The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes. OBJECTIVE: The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years. METHODS: We examined 28 patients with clinically definite MS according to Poser's criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5. RESULTS: We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and ΔEDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91-2.22×therapy+0.079×age+0.057×s-EPT0 (Model 1, R (2)=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1. CONCLUSIONS: These results further support a role for combined EP-measures as predictors of long-term disability in MS.

Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients.

PURPOSE: To determine whether spinal cord atrophy differs among disease subtypes in multiple sclerosis (MS) and whether it offers diagnostic and clinical correlative information beyond that provided by other magnetic resonance (MR) imaging markers. MATERIALS AND METHODS: The institutional review board approved the study; all subjects gave written informed consent. Upper cervical cord cross-sectional area (UCCA), brain and spinal cord lesion loads, and brain atrophy were measured in 440 patients with MS (311 with relapsing-remitting [RR] MS, 92 with secondary-progressive [SP] MS, and 37 with primary-progressive [PP] MS) studied in two centers. Disability was scored with the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (TWT), and the nine-hole peg test. UCCA was compared between groups with the Mann-Whitney U test. Correlations were assessed with the Spearman ρ test. Multivariate associations between UCCA and clinical and other MR imaging parameters, including number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord, were assessed by using multiple linear regression, adjusted for study center site. RESULTS: The UCCA in patients with SP MS (median, 79 mm(2); interquartile range, 72.4-84.9 mm(2)) and PP MS (median, 77.3 mm(2); interquartile range, 69-82.5 mm(2)) was significantly smaller (P < .001) than that in patients with RR MS (median, 84 mm(2); interquartile range, 78.7-89.3 mm(2)). UCCA was inversely correlated with EDSS score, TWT, and nine-hole peg test findings (ρ ≤ -0.29, P < .001 for all comparisons). UCCA, number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord were found to be significant explanatory factors for clinical disability (R(2) = 0.564). The UCCA and the number of hypointense brain lesions on T1-weighted images were the strongest MR imaging parameters for explaining physical disability, as measured with the EDSS. CONCLUSION: Spinal cord abnormalities have a strong effect on clinical disability in MS. MR imaging-derived UCCA was found to be the most significant spinal cord parameter for explaining EDSS score.

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials.

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.

Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability.

BACKGROUND: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. OBJECTIVES: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. METHODS: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing-remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. RESULTS: Grey matter volume was lower in relapsing-remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing-remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. CONCLUSIONS: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing-remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.

Can cortical thickness asymmetry analysis contribute to detection of at-risk mental state and first-episode psychosis? A pilot study.

PURPOSE: To investigate whether cortical thickness analysis in individuals with an at-risk mental state (ARMS) might contribute to early detection of psychosis. MATERIALS AND METHODS: Ethics committee approval and written informed consent were obtained. Cortical thickness was analyzed because early disease-related morphometric changes were expected to be most pronounced in the cerebral cortex. With the assumption of progressive change in cortical thickness from control subjects, to those with an ARMS, and then to those who have had a first episode (FE) of psychosis, the brain regions that substantially differ between those with FE psychosis and control subjects were identified. Whether these regions help discriminate between the ARMS group and control subjects was tested. Because normal interindividual variation of cortical thickness, even for control subjects, may exceed that expected with early disease-related changes, intraindividual cortical thickness asymmetry was analyzed. Twenty age- and sex-matched individuals for each group (ARMS group, FE group, and control subjects) were recruited within a prospective early-detection study. High-spatial-resolution magnetization-prepared rapid gradient-echo magnetic resonance (MR) brain images were acquired with a 1.5-T MR imager. Cortical thickness asymmetry was analyzed in 41 anatomic regions corresponding to the Talairach standard brain atlas. RESULTS: Direct cortical thickness analysis did not help distinguish between groups. Cortical thickness asymmetry analysis helped distinguish between groups (P = .007); variability increased from control subjects, to the ARMS group, and then to the FE group in seven anatomic regions (P < .0001). Cortical thickness asymmetry in these regions helped distinguish the FE group from control subjects (P = .0006; sensitivity, 70.0%; specificity, 85.0%) and showed a trend toward helping to distinguish the ARMS group from control subjects (P = .06; sensitivity, 75.0%; specificity, 65.0%). CONCLUSION: Cortical thickness asymmetry analysis is more accurate than direct cortical thickness measurement in distinguishing the control from the FE group and might contribute to early detection of an ARMS.

Neural activation associated with corrective saccades during tasks with fixation, pursuit and saccades.

Corrective saccades are small eye movements that redirect gaze whenever the actual eye position differs from the desired eye position. In contrast to various forms of saccades including pro-saccades, recentering-saccades or memory guided saccades, corrective saccades have been widely neglected so far. The fMRI correlates of corrective saccades were studied that spontaneously occurred during fixation, pursuit or saccadic tasks. Eyetracking was performed during the fMRI data acquisition with a fiber-optic device. Using a combined block and event-related design, we isolated the cortical activations associated with visually guided fixation, pursuit or saccadic tasks and compared these to the activation associated with the occurrence of corrective saccades. Neuronal activations in anterior inferior cingulate, bilateral middle and inferior frontal gyri, bilateral insula and cerebellum are most likely specifically associated with corrective saccades. Additionally, overlapping activations with the established pro-saccade and, to a lesser extent, pursuit network were present. The presented results imply that corrective saccades represent a potential systematic confound in eye-movement studies, in particular because the frequency of spontaneously occurring corrective saccades significantly differed between fixation, pursuit and pro-saccades.

Spatial and temporal analysis of fMRI data on word and sentence reading.

Written language comprehension at the word and the sentence level was analysed by the combination of spatial and temporal analysis of functional magnetic resonance imaging (fMRI). Spatial analysis was performed via general linear modelling (GLM). Concerning the temporal analysis, local differences in neurovascular coupling may confound a direct comparison of blood oxygenation level-dependent (BOLD) response estimates between regions. To avoid this problem, we parametrically varied linguistic task demands and compared only task-induced within-region BOLD response differences across areas. We reasoned that, in a hierarchical processing system, increasing task demands at lower processing levels induce delayed onset of higher-level processes in corresponding areas. The flow of activation is thus reflected in the size of task-induced delay increases. We estimated BOLD response delay and duration for each voxel and each participant by fitting a model function to the event-related average BOLD response. The GLM showed increasing activations with increasing linguistic demands dominantly in the left inferior frontal gyrus (IFG) and the left superior temporal gyrus (STG). The combination of spatial and temporal analysis allowed a functional differentiation of IFG subregions involved in written language comprehension. Ventral IFG region (BA 47) and STG subserve earlier processing stages than two dorsal IFG regions (BA 44 and 45). This is in accordance with the assumed early lexical semantic and late syntactic processing of these regions and illustrates the complementary information provided by spatial and temporal fMRI data analysis of the same data set.

Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF.

OBJECTIVE: We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS). METHODS: 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS. RESULTS: Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS. CONCLUSIONS: Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.

Mapping continuous neuronal activation without an ON-OFF paradigm: initial results of BOLD ceiling fMRI.

Standard functional magnetic resonance imaging (fMRI) requires alternations between activation (ON) and baseline (OFF) periods to map the haemodynamic response to neuronal activation. Consequently, standard fMRI cannot map continuous activations in conditions like tinnitus without an ON-OFF paradigm. We present a novel approach to fMRI that allows mapping of continuous neuronal activation. Compared with standard fMRI, we introduced the application of CO(2) as potent vasodilator. CO(2) induces a 'global' blood oxygenation level-dependent (BOLD) response. The neurovascular coupling in conjunction with the limited cerebral vasodilation implies a limitation or ceiling of the BOLD response. We hypothesize that active areas exhibit a reduced CO(2)-induced DeltaBOLD due to pre-existing 'local' task-induced BOLD response. This putative reduction in DeltaBOLD might be exploited for mapping of continuous neuronal activation. BOLD ceiling fMRI was tested in the auditory system. Six healthy subjects performed three runs: only continuous monaural auditory; only 10% CO(2); simultaneous auditory and CO(2) stimulation. First, we demonstrated the ceiling of DeltaBOLD during continuous auditory activation. According to the known predominantly contralateral auditory processing, monaural auditory stimulation reduced predominantly contralateral (0.41 +/- 0.13%; P < 0.00001) and significantly less (P < 0.0001) ipsilateral DeltaBOLD (0.33 +/- 0.17%; P < 0.00001). The non-auditory area was not affected. Second, this BOLD ceiling was exploited to generate an initial activation map of continuous auditory activation (ON period). In contrast to standard fMRI, an OFF period without neuronal activation was not required. BOLD ceiling fMRI is proposed as a complement to standard fMRI for those conditions where ON-OFF paradigms are impossible.

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

BACKGROUND: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis. METHODS: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses. RESULTS: A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second. CONCLUSIONS: In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].).

Effect of fMRI acoustic noise on non-auditory working memory task: comparison between continuous and pulsed sound emitting EPI.

Conventional blood oxygenation level-dependent (BOLD) based functional magnetic resonance imaging (fMRI) is accompanied by substantial acoustic gradient noise. This noise can influence the performance as well as neuronal activations. Conventional fMRI typically has a pulsed noise component, which is a particularly efficient auditory stimulus. We investigated whether the elimination of this pulsed noise component in a recent modification of continuous-sound fMRI modifies neuronal activations in a cognitively demanding non-auditory working memory task. Sixteen normal subjects performed a letter variant n-back task. Brain activity and psychomotor performance was examined during fMRI with continuous-sound fMRI and conventional fMRI. We found greater BOLD responses in bilateral medial frontal gyrus, left middle frontal gyrus, left middle temporal gyrus, left hippocampus, right superior frontal gyrus, right precuneus and right cingulate gyrus with continuous-sound compared to conventional fMRI. Conversely, BOLD responses were greater in bilateral cingulate gyrus, left middle and superior frontal gyrus and right lingual gyrus with conventional compared to continuous-sound fMRI. There were no differences in psychomotor performance between both scanning protocols. Although behavioral performance was not affected, acoustic gradient noise interferes with neuronal activations in non-auditory cognitive tasks and represents a putative systematic confound.

Characteristics of ultrasmall superparamagnetic iron oxides in patients with brain tumors.

OBJECTIVE: The aim of this study was to evaluate the characteristics of an ultrasmall superparamagnetic iron oxides (USPIO) agent in patients with brain tumors and to correlate changes on MRI with histopathologic data collected systematically in all patients. SUBJECTS AND METHODS: Nine patients with brain tumors were imaged before and 24 hr after administration of a USPIO at a dose of 2.6 mg Fe/kg. Analysis of MR images included qualitative and quantitative comparison of the USPIO and gadolinium enhancement of brain tumors. Brain surgery was performed 25-112 hr after administration of the USPIO. The histopathologic workup included iron histochemistry with diaminobenzidine (DAB)-enhanced Perls stain. RESULTS: In seven of nine patients, USPIO-related changes of signal intensity were observed in gadolinium-enhancing brain tumors on T1- and T2*-weighted sequences. The difference in signal intensity on T1-weighted USPIO series was 40.1% +/- 26.7% (mean +/- SD). On T2*-weighted USPIO series, the difference in signal intensity was -33.1% +/- 18.4% in solid tumor parts. Areas of suspected radiation necrosis did not enhance in three patients with prior radiation therapy. Iron histochemistry revealed the presence of iron deposits in macrophages in two patients. CONCLUSION: USPIO agents will not replace gadolinium in the workup of patients with brain tumors. Our findings suggest that USPIO agents seem to offer complementary information and may help to differentiate between brain tumors and areas of radiation necrosis. Signal intensity changes on T2*-weighted images might be related to the blood pool properties of the agent, possibly reflecting steady-state susceptibility effects.

What is different about a radiologist's brain?

PURPOSE: To investigate neuronal activations during processing of radiologic and nonradiologic images by experienced radiologists and nonradiologist subjects by using event-related functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: Study was approved by local ethics committee, and informed consent was obtained. Radiologic and control images were presented to 12 experienced radiologists (mean age, 35.8 years +/- 3.6 [standard deviation]) and 12 nonradiologist subjects (mean age, 33.0 years +/- 6.9). Half of the images were artificially manipulated-that is, for example, a local shadow was introduced. Subjects had to indicate whether a visually presented image was original or manipulated, while neuronal activity was assessed by using event-related functional MR imaging. Analysis was performed on the basis of fixed-effects general linear models with correction for multiple comparisons (false discovery rate). RESULTS: Radiologic images, when compared with control images, evoked stronger activations exclusively in the group of radiologists, notably in the bilateral middle and inferior temporal gyrus, bilateral medial and middle frontal gyrus, and left superior and inferior frontal gyrus (P < .001, corrected). Additionally, visual processing of control images (ie, nonradiologic images) differed significantly between experienced radiologists and nonradiologist subjects (P < .001, corrected). Radiologists showed strongest activation in the left-dominant more posterior superior and inferior parietal lobule, while nonradiologist subjects showed strongest activation in the right-dominant more anterior superior and inferior parietal lobule and postcentral gyrus. CONCLUSION: With radiologic experience, there is selective enhancement of brain activation with radiologic images, and the visual system is modified in general.

Differential sex-independent amygdala response to infant crying and laughing in parents versus nonparents.

BACKGROUND: Animal and human studies implicate forebrain neural circuits in maternal behavior. Here, we hypothesized that human brain response to emotional stimuli relevant for social interactions between infants and adults are modulated by sex- and experience-dependent factors. METHODS: We used functional magnetic resonance imaging and examined brain response to infant crying and laughing in mothers and fathers of young children and in women and men without children. RESULTS: Women but not men, independent of their parental status, showed neural deactivation in the anterior cingulate cortex, as indexed by decreased blood oxygenation level-dependent signal, in response to both infant crying and laughing. The response pattern changed fundamentally with parental experience: in the amygdala and interconnected limbic regions, parents (independent of sex) showed stronger activation from crying, whereas nonparents showed stronger activation from laughing. CONCLUSIONS: Our data show sex- and experience-dependent modulation of brain response to infant vocalizations. Successful recognition and evaluation of infant vocalizations can be critical for bonding mechanisms and for offspring well-being and survival. Thus, the modulation of responses by experience seems to represent an adaptive mechanism that can be related to reproductive fitness.

Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis.

BACKGROUND: Atrophy is recognized as a measure of destructive changes in multiple sclerosis (MS). The time course and pathologic mechanisms of atrophy development are not well understood. Significant atrophy was reported to occur within 9 to 12 months in relapsing remitting MS. OBJECTIVES: To test whether atrophy can be detected over short time intervals, and to evaluate its relationship to inflammation. DESIGN AND METHODS: Prior to randomization to a treatment trial, 138 untreated patients with relapsing remitting MS had 3 magnetic resonance imaging scans within a mean +/- SD follow-up of 76 +/- 20.2 days. Brain parenchymal fraction (BPF), a normalized measure of whole brain volume, the proportion of active (gadolinium-enhancing) scans, and the volume of T1-weighted gadolinium-enhancing and T2-weighted hyperintense lesions were determined at all time points. An annualized atrophy rate was estimated by calculating a regression slope. RESULTS: The median Expanded Disability Status Scale score was 3.5, the mean disease duration was 7.6, and the mean age was 38.5 years. The BPF decreased significantly by -0.229% from scan 1 to scan 3, while the proportion of active scans remained high (65%, 63%, and 67%). The BPF change was only weakly correlated to the volume of T1-weighted gadolinium-enhancing lesions in scan 1 (r = -0.185). The estimated annualized atrophy rate was -1.06% (95% confidence interval, -1.50% to -0.62%). CONCLUSIONS: The annualized atrophy rate found in this study is comparable with rates reported previously. Measurements of BPF allow detection of atrophy over short time intervals in active disease. The short-term relationship of inflammation to atrophy development was weak. Brain parenchymal fraction might be a promising measure in future phase 2 studies of agents, with an expected effect on tissue-destructive pathologic mechanisms of MS.