Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE).

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P < 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

Cortical thickness following electroconvulsive therapy in patients with depression: a longitudinal MRI study.

OBJECTIVE: Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome. METHOD: Using 3 Tesla MRI scanner, we obtained T1-weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes. RESULTS: We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6-month follow-up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects. CONCLUSION: The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.

White matter maturation during 12 months in individuals at ultra-high-risk for psychosis.

OBJECTIVE: The neurodevelopmental hypothesis of psychosis suggests that disrupted white matter (WM) maturation underlies disease onset. In this longitudinal study, we investigated WM connectivity and compared WM changes between individuals at ultra-high-risk for psychosis (UHR) and healthy controls (HCs). METHOD: Thirty UHR individuals and 23 HCs underwent MR diffusion tensor imaging before and after 12 months of non-manualized standard care. Positive and negative symptoms and level of functioning were assessed. Tract-based spatial statistics were employed. RESULTS: During 12 months, none of the UHR individuals transitioned to psychosis. Both UHR individuals and HCs increased significantly in fractional anisotropy (FA). UHR individuals showed significant FA increases predominantly in the left superior longitudinal fasciculus (SLF) (P = 0.01), and HCs showed significant FA increases in the left uncinate fasciculus (P = 0.03). Within UHR individuals, a significant positive correlation between FA change and age was observed predominantly in the left SLF (P = 0.02). Within HCs, no significant correlation between FA change and age was observed. No significant correlations between baseline FA and clinical outcomes were observed; however, FA changes were significantly positively correlated to changes in negative symptoms (P = 0.04). CONCLUSION: As normal brain maturation occurs in a posterior to frontal direction, our findings could suggest disturbed WM maturation in UHR individuals.

Patterns of white matter microstructure in individuals at ultra-high-risk for psychosis: associations to level of functioning and clinical symptoms.

BACKGROUND: Individuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals. METHODS: Forty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method. RESULTS: PLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD. CONCLUSIONS: UHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

No abnormalities of intrinsic brain connectivity in the interictal phase of migraine with aura.

BACKGROUND AND PURPOSE: Functional neuroimaging studies have shown hyperresponsiveness of cortical areas to visual stimuli in migraine patients with aura outside of attacks. This may be a key feature in the initiation of aura episodes and possibly also migraine headache attacks. It is unknown if cortical dysfunction is present at rest, i.e. in the absence of any external stimuli. Functional magnetic resonance imaging is a powerful technique for evaluating resting state functional connectivity, i.e. coherence of brain activity across cerebral areas. The objective of this study was to investigate resting-state functional brain connectivity in migraineurs with aura outside of attacks using functional magnetic resonance imaging. METHODS: Forty patients suffering from migraine with visual aura and 40 individually age and gender matched healthy controls with no history or family history of migraine were investigated. Following advanced denoising, the data were analyzed both in a hypothesis-driven fashion, testing for abnormalities involving 27 different brain areas of potential relevance to migraine with aura including the cortical visual areas, the amygdala and peri-aqueductal grey matter, and in a data-driven exploratory fashion (dual regression) in order to reveal any possible between-group differences of resting state networks. Age, gender, attack frequency and disease duration were included as nuisance variables. RESULTS: No differences of functional connectivity were found between patients and controls. CONCLUSIONS: The previously reported increased cortical hyperresponsivity in the interictal phase of migraine with aura is unlikely to be caused by abnormalities of intrinsic brain connectivity. The interictal migraine aura brain may be abnormally functioning only during exposure to external stimuli.

Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: a randomized study using FDG PET imaging.

Physical exercise increases peripheral insulin sensitivity, but regional differences are poorly elucidated in humans. We investigated the effect of aerobic exercise training on insulin-stimulated glucose uptake in five individual femoral muscle groups and four different adipose tissue regions, using dynamic (femoral region) and static (abdominal region) 2-deoxy-2-[¹8F]fluoro-d-glucose (FDG) PET/CT methodology during steady-state insulin infusion (40 mU·m⁻²·min⁻¹). Body composition was measured by dual X-ray absorptiometry and MRI. Sixty-one healthy, sedentary [V(O2max) 36(5) ml·kg⁻¹·min⁻¹; mean(SD)], moderately overweight [BMI 28.1(1.8) kg/m²], young [age: 30(6) yr] men were randomized to sedentary living (CON; n = 17 completers) or moderate (MOD; 300 kcal/day, n = 18) or high (HIGH; 600 kcal/day, n = 18) dose physical exercise for 11 wk. At baseline, insulin-stimulated glucose uptake was highest in femoral skeletal muscle followed by intraperitoneal visceral adipose tissue (VAT), retroperitoneal VAT, abdominal (anterior + posterior) subcutaneous adipose tissue (SAT), and femoral SAT (P < 0.0001 between tissues). Metabolic rate of glucose increased similarly (~30%) in the two exercise groups in femoral skeletal muscle (MOD 24[9, 39] µmol·kg⁻¹·min⁻¹, P = 0.004; HIGH 22[9, 35] µmol·kg⁻¹·min⁻¹, P = 0.003) (mean[95% CI]) and in five individual femoral muscle groups but not in femoral SAT. Standardized uptake value of FDG decreased ~24% in anterior abdominal SAT and ~20% in posterior abdominal SAT compared with CON but not in either intra- or retroperitoneal VAT. Total adipose tissue mass decreased in both exercise groups, and the decrease was distributed equally among subcutaneous and intra-abdominal depots. In conclusion, aerobic exercise training increases insulin-stimulated glucose uptake in skeletal muscle but not in adipose tissue, which demonstrates some interregional differences.

The spatial distribution of age-related white matter changes as a function of vascular risk factors--results from the LADIS study.

White matter hyperintensities (WMH) are a frequent finding on brain MRI of elderly subjects, and have been associated with various risk factors, as well as with development of cognitive and functional impairment. While an overall association between WMH load and risk factors is well described, possible spatially restricted vulnerability remains to be established. The aim of this study was to investigate the spatial distribution of WMH in normally functioning elderly subjects. We introduce a voxel-based approach in which lesion probability is mapped as a function of clinical risk factors using logistic regression, and validate the method using simulated datasets. The method was then applied in a total of 605 participants of the LADIS study (age 74 ± 5 years, all with WMH), and the location of manually delineated WMH was investigated after spatial normalisation. Particularly strong and widespread associations were found for age, gender and hypertension. Different distribution patterns were found for men and women. Further, increased probability was found in association with self-reported alcohol and tobacco consumption, as well as in those with a history of migraine. It is concluded that the location of WMH is dependent on the risk factors involved pointing towards a regionally different pathogenesis and/or vulnerability of the white matter.

Cognitive deficits in multiple sclerosis: correlations with T2 changes in normal appearing brain tissue.

OBJECTIVES: Although disease load in multiple sclerosis (MS) often is based on T2 lesion volumes, the changes in T2 of normal appearing brain tissue (NABT) are rarely considered. By means of magnetic resonance, (MR) we retrospectively investigated whether T2 changes in NABT explain part of the cognitive impairment seen in MS and constitute a supplement to traditional measurement of T2 lesion volume. MATERIALS AND METHODS: Fifty patients with clinically definite MS were included (38 women, 12 men). Patients were MR scanned, neuropsychologically tested, and evaluated clinically with the Kurtzke Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Impairment Scale (MSIS). Voxel-wise T2 estimates and total T2 lesion volume were tested for correlations with eight cognitive domains, a general cognitive dysfunction factor (CDF), and the two clinical scales. RESULTS: We found distinct clusters of voxels with T2 estimates correlating with CDF, mental processing speed, complex motor speed, verbal fluency, and MSIS. A significant negative correlation was found between total lesion volume and CDF (r = -0.34, P = 0.02), verbal intelligence (r = -0.40, P = 0.005), mental processing speed (r = -0.34, P = 0.03), visual problem solving (r = -0.40, P = 0.01), and complex motor speed (r = -0.39, P = 0.01). No significant correlation was detected between total lesion load and the clinical measures EDSS and MSIS. CONCLUSION: Our results suggest that even in the NABT MR detects changes likely to be associated with an underlying pathology and possibly contributes to the cognitive impairment in MS.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months.

BACKGROUND: Cerebral glutamate and gamma-aminobutyric acid (GABA) levels might predict clinical outcome in individuals at ultrahigh risk (UHR) for psychosis but have previously primarily been investigated in smaller cohorts. We aimed to study whether baseline levels of glutamate and GABA in anterior cingulate cortex (ACC) and glutamate in thalamus could predict remission status and whether baseline metabolites differed in the remission versus the nonremission group. We also investigated the relationship between baseline metabolite levels and severity of clinical symptoms, functional outcome, and cognitive deficits at follow-up. METHODS: About 124 UHR individuals were recruited at baseline. In this, 74 UHR individuals were clinically and cognitively assessed after 12 months, while remission status was available for 81 (25 remission/56 nonremission). Glutamate and GABA levels were assessed at baseline using 3 T proton magnetic resonance spectroscopy. Psychopathology, symptom severity, and remission were assessed with the Comprehensive Assessment of At-Risk Mental States and Clinical Global Impression and functional outcome with the Social and Occupational Functioning Assessment Scale. Cognitive function was estimated with the Cambridge Neuropsychological Test Automated Battery. RESULTS: There were no differences between baseline glutamate and GABA levels in subjects in the nonremission group compared with the remission group, and baseline metabolites could not predict remission status. However, higher baseline levels of GABA in ACC were associated with clinical global improvement (r = -0.34, N = 51, p = 0.01) in an explorative analysis. CONCLUSIONS: The variety in findings across studies suggests a probable multifactorial influence on clinical outcome in UHR individuals. Future studies should combine multimodal approaches to attempt prediction of long-term outcome.

Acute MRI changes in progressive ischemic stroke.

BACKGROUND AND PURPOSE: Neurological deterioration following acute stroke is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanisms are not fully understood, and it is difficult to predict which patients are at risk of deterioration. Our study aimed to assess if acute MRI findings could be used for the prediction of stroke in progression (SIP). METHODS: Prospectively 41 patients, 13 with lacunar infarcts and 28 with territorial infarcts, were admitted to an acute stroke unit within 24 h of stroke onset (median 11 h, range 3- 22). Diffusion-weighted imaging (DWI), perfusion-weighted imaging and magnetic resonance angiography were performed 3 times, immediately after clinical evaluation, on day 7 and after 3 months. Clinical neurological assessments were performed every 2 h during the first 24 h and once daily from day 2 to 7. SIP was defined as a permanent decrease of >or=3 Scandinavian Stroke Scale (SSS) points for speech or >or=2 SSS points for consciousness or >or=2 SSS points for limb strength, when assessed at baseline compared to the day after admission and daily during the following week. Patients were followed up on day 90 and assessed using the modified Rankin Scale, Barthel Index and SSS score. Patients with and without SIP were compared using both clinical and MRI data obtained on admission, on day 7 and after 3 months. RESULTS: Fifteen patients (37%) developed SIP. Increased DWI lesion volume on day 7 in all strokes was associated with SIP (chi(2), p = 0.005). All lacunar infarcts with a DWI volume >1.5 cm(3) at baseline (4 patients) developed SIP (p < 0.005). Patients with territorial infarcts and SIP had lower baseline SSS scores with severer symptoms than non-SIP patients (p

Cerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensities.

BACKGROUND AND PURPOSE: There is growing evidence that white matter hyperintensities (WMH) should not be considered as benign age-dependent changes on MR images but indicate pathological changes with clinical consequences. Previous studies comparing subjects with WMH to normal controls have reported global reductions in cerebral blood flow (CBF) and cerebral vascular reactivity. In this study, we examined localized hemodynamic status to compare WMH to normal appearing white matter (NAWM). METHODS: A group of 21 normal 85-year-old subjects were studied using dynamic contrast-enhanced MRI together with administration of acetazolamide. From a combination of anatomic images with different signal weighting, regions of interest were generated corresponding to gray and white matter and WMH. Localized measurements of CBF and cerebral blood volume (CBV) and mean transit time were obtained directly within WMH and NAWM. RESULTS: When comparing WMH to NAWM, measurements showed significantly lower CBF (P=0.004) and longer mean transit time (P< 0.001) in WMH but no significant difference in CBV (P=0.846). The increases in CBF and CBV induced by acetazolamide were significantly smaller in WMH than in NAWM (P=0.026, P<0.001). CONCLUSION: These results show that a change in the hemodynamic status is present within the WMH, making these areas more likely to be exposed to transient ischemia inducing myelin rarefaction. In the future, MRI may be used to examine the effect of therapeutic strategies designed to prevent or normalize vascular changes.

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: II. Normal values and gray matter blood flow response to visual activation.

One of the most limiting factors for the accurate quantification of physiologic parameters with positron emission tomography (PET) is the partial volume effect (PVE). To assess the magnitude of this contribution to the measurement of regional cerebral blood flow (rCBF), the authors have formulated four kinetic models each including a parameter defining the perfusable tissue fraction (PTF). The four kinetic models used were 2 one-tissue compartment models with (Model A) and without (Model B) a vascular term and 2 two-tissue compartment models with fixed (Model C) or variable (Model D) white matter flow. Furthermore, rCBF based on the autoradiographic method was measured. The goals of the study were to determine the following in normal humans: (1) the optimal model, (2) the optimal length of fit, (3) the model parameters and their reproducibility, and (4) the effects of data acquisition (2D or 3D). Furthermore, the authors wanted to measure the activation response in the occipital gray matter compartment, and in doing so test the stability of the PTF, during perturbations of rCBF induced by visual stimulation. Eight dynamic PET scans were acquired per subject (n = 8), each for a duration of 6 minutes after IV bolus injection of H2(15)O. Four of these scans were performed using 2D and four using 3D acquisition. Visual stimulation was presented in four scans, and four scans were during rest. Model C was found optimal based on Akaike's Information Criteria (AIC) and had the smallest coefficient of variance after a 6-minute length of fit. Using this model the average PVE corrected rCBF during rest in gray matter was 1.07 mL x min(-1) x g(-1) (0.11 SD), with an average coefficient of variance of 6%. Acquisition mode did not affect the estimated parameters, with the exception of a significant increase in the white matter rCBF using the autoradiographic method (2D: 0.17 mL x min(-1) x g(-1) (0.02 SD); 3D: 0.21 mL x min(-1) x g(-1) (0.02 SD)). At a 6-minute fit the average gray matter CBF using Models C and D were increased by 100% to 150% compared with Models A and B and the autoradiographic method. There were no significant changes in the perfusable tissue fraction by the activation induced rCBF increases. The largest activation response was found using Model C (median = 39.1%). The current study clearly demonstrates the importance of PVE correction in the quantitation of rCBF in normal humans. The potential use of this method is to cost-effectively deliver PVE corrected measures of rCBF and tissue volumes without reference to imaging modalities other than PET.

Monoaminergic systems in the brainstem and spinal cord of the turtle Pseudemys scripta elegans as revealed by antibodies against serotonin and tyrosine hydroxylase.

With the aim of gaining more insight into the monoaminergic regulation of spinal motor systems in the turtle, we have studied the distribution of 5-HT (5-HTir) and tyrosine hydroxylase immunoreactivity (THir) in the brainstem and spinal cord of Pseudemys scripta elegans. 5-HTir cell bodies were located in the midline in nucleus raphe inferior, nucleus raphe superior, and laterally in nuclei reticularis superior and inferior and nucleus reticularis isthmi. THir cell bodies were located in the commissural nucleus, nucleus tractus solitarii, the locus coeruleus-subcoeruleus complex, nuclei reticularis superior and inferior, the pretectal area, and substantia nigra. 5-HTir and THir tracts were found in lateral and ventral bundles superficially in the brainstem. 5-HTir fibers in the spinal cord were located in a large dorsolateral and a smaller ventrolateral tract. In the gray matter, a high concentration of 5-HTir fibers were observed in areas I-IV and in the lateral motor column of cervical and lumbar enlargements. Areas V-VIII and area X were less intensively innervated, with the lowest fibre concentration in areas VII-VIII and area X. Throughout the spinal cord, THir nerve fibres were located in the same areas but with a lower density. Small bipolar 5-HTir and THir cell bodies were found ventromedially to the central canal especially in cervical and lumbosacral segments. Large THir cells were found in area IX in the caudal sacral and coccygeal spinal cord. THir cerebrospinal fluid-contacting cells were also found in the most caudal part of the brainstem and the upper cervical spinal cord. The well developed spinal 5-HT system and the less developed THir system provides an anatomical explanation for the monoaminergic modulation of turtle motoneuron membrane properties, which has been observed in electrophysiological experiments.

Quantification of gadolinium-DTPA concentrations for different inversion times using an IR-turbo flash pulse sequence: a study on optimizing multislice perfusion imaging.

The purpose of this study was to optimize an inversion-recovery (IR) turbo fast low-angle shot (FLASH) for multislice imaging by evaluating the accuracy of calculated the relaxation-rate (R1) for different inversion times (TI). This is important for tracer kinetic modeling because it requires a system responding linearly to input. R1 are linearly related to changes in the concentration of gadolinium (Gd)-diethylenetriaminepentaacetic acid (DTPA), and R1 is a parameter that can be derived from the magnetic resonance (MR) signal. The accuracy of calculated R1 using an IR turbo fast low-angle shot was evaluated in phantoms and for increasing TIs using spectroscopically measured R1 values as reference. Signal curves, obtained in vivo after a bolus injection of Gd-DTPA, were used in an analytical computer program to study the effect of different TI-values on accurate calculation of R1. Results show that TIeff should be <200 ms to measure the bolus-passage of Gd-DTPA in blood accurately, whereas the myocardial response can be measured correctly for TIeff < 870 ms at 1.5 T. The initial slope of the myocardial signal enhancement curve becomes steeper for larger TI values, whereas the calculated R1 curves were similar, indicating that these curves, rather than signal curves, are more suitable even for qualitative perfusion evaluation. It is concluded that the results can be incorporated in a multislice IR turbo fast low-angle shot using the first slice (with a short TI) for assessment of both the arterial input function and the tissue response and the second slice in another position for assessment of the tissue response alone.

Visual cortex reactivity in sedated children examined with perfusion MRI (FAIR).

Sleeping and sedated children can respond to visual stimulation with a decrease in blood oxygenation level dependent (BOLD) functional MRI signal response. The contribution of metabolic and hemodynamic parameters to this inverse signal response is incompletely understood. It has been hypothesized that it is caused by a relatively greater increase of oxygen consumption compared to rCBF (regional cerebral blood flow) increase. We studied the rCBF changes during visual stimulation in four sedated children, aged 4-71 months, and four alert adults, with an arterial water spin labeling technique (FAIR) and BOLD fMRI in a 1.5T MR scanner. In the children, FAIR signal decreased by a mean of 0.96% (range 0.77-1.05) of the baseline periods of the non-selective images, while BOLD signal decreased by 2.03% (range 1.99-2.93). In the adults, FAIR and BOLD signal increased by 0.88% (range 0.8-0.99) and 2.63% (range 1.99-2.93), respectively. Thus, in the children, an rCBF increase could not be detected by perfusion MRI, but indications of a FAIR signal decrease were found. An rCBF decrease in the primary visual cortex during stimulation has not been reported previously, but it is a possible explanation for the negative BOLD response. Future studies will have to address if this response pattern is a consequence of age or sleep/sedation.

A model system for perfusion quantification using FAIR.

Flow-sensitive experiments (FAIR) have been performed on a tube-flow phantom in order to validate quantitative perfusion measurements on humans. A straight-forward correspondence between perfusion and bulk-flow is found. It is shown that the flow phantom model only holds when the slice profiles of the involved RF pulses are taken into account. A small flow-independent off-set may be present in the data. The off-set is explained by the model. Based on the correspondence between the phantom and the in vivo models, it is shown that the lowest flow values that could be measured in the phantom correspond to perfusion values lower than the cortical perfusion in the brain. Thus, the experimental accuracy and the computational methods for quantitative perfusion measurements in vivo can be validated by a tube-flow phantom.

Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI.

OBJECTIVES: To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics. METHODS: Dynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls. RESULTS: Permeability measured as K(trans) was significantly higher in periventricular normal appearing white matter (NAWM) and thalamic gray matter in MS patients when compared to healthy controls, with periventricular NAWM showing the most pronounced difference. Recent relapse coincided with significantly higher permeability in periventricular NAWM, thalamic gray matter, and MS lesions. Immunomodulatory treatment and recent relapse were significant predictors of permeability in MS lesions and periventricular NAWM. Our results suggest that after an MS relapse permeability gradually decreases, possibly an effect of immunomodulatory treatment. CONCLUSIONS: Our results emphasize the importance of BBB pathology in MS, which we find to be most prominent in the periventricular NAWM, an area prone to development of MS lesions. Both the facts that recent relapse appears to cause widespread BBB disruption and that immunomodulatory treatment seems to attenuate this effect indicate that BBB permeability is intricately linked to the presence of MS relapse activity. This may reveal further insights into the pathophysiology of MS.

Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis.

Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.

Retinal atrophy correlates with fMRI response in patients with recovered optic neuritis.

OBJECTIVE: We wanted to investigate if retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) might be a good marker of acute and chronic changes in the afferent visual pathway following acute optic neuritis (ON). METHODS: We studied the relationship of optic nerve lesion length, optic nerve mean area, and RNFLT, quantified by OCT, with fMRI response to a visual paradigm in 40 patients with acute ON and 19 healthy controls in a prospective cohort study over a 6-month period. RESULTS: The main finding was a significant correlation of optic nerve lesion length and mean area with fMRI response in affected eyes in the acute phase and between RNFLT and fMRI response in affected eyes after recovery. CONCLUSION: RNFLT is a very good measure of damage to the afferent visual pathway in recovered patients with ON and should be included in future fMRI studies when looking for visual reorganization in recovered patients with ON.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.