Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis

Journal of Neurology - Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress...     

Reduced subjective response to acute ethanol administration among young men with a broad bipolar phenotype

Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8?g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects ('feel high': F=14.2, p=0.001; 'feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.     

Cerebellar activation during copying geometrical shapes

We studied functional MRI activation in the cerebellum during copying 9 geometrical shapes (equilateral triangle, isosceles triangle, square, diamond, vertical trapezoid, pentagon, hexagon, circle, and vertical lemniscate). Twenty subjects were imaged during 3 consecutive 45-s periods (rest, visual presentation, and copying). First, there was a positive relation between cerebellar activation and the peak speed of individual movements. This effect was strongest in the lateral and posterior ipsilateral cerebellum but it was also present in the paramedian zones of both cerebellar hemispheres and in the vermis. A finer grain analysis of the relations between the time course of the blood oxygenation level-dependent activation and movement parameters revealed a significant relation to hand position and speed but not to acceleration. Second, there was a significant relation between the intensity of voxel activation during visual presentation and the speed of the upcoming movement. The spatial distribution of these voxels was very similar to that of the voxels activated during copying, indicating that the cerebellum might be involved in motor rehearsal, in addition to its role during movement execution. Finally, a factor analysis of the intensity of activated voxels in the ipsilateral cerebellum during copying (adjusted for the speed effect) extracted 3 shape factors. Factor 1 reflected "roundness," factor 2 "upward pointing," and factor 3 "pointing (up or down) and elongation." These results link cerebellar activation to more global, spatial aspects of copying.     

Cerebral cortical mechanisms of copying geometrical shapes: a multidimensional scaling analysis of fMRI patterns of activation

We used multidimensional scaling (MDS) to characterize the integrative neural mechanisms during viewing and subsequently copying nine geometrical shapes. Human subjects initially looked at a central fixation point (“rest” period), then looked at a geometrical shape (“visual” period) which they copied without visual feedback (“copying” period). BOLD signal was recorded from voxels in 28 cortical areas (14 from each hemisphere) using a 4 Tesla magnet. For each voxel, signal ratios of “Visual versus Rest” (VR), and “Copy versus Visual” (CV) were calculated and used to construct two sets of Euclidean distance dissimilarity matrices for the nine shapes, with separate matrices defined for each region of interest (ROI) across subjects. The relations of perceptual and motor aspects of the shapes to MDS dimensions and specific ROIs were assessed using stepwise multiple regressions. The optimal individually scaled (INDSCAL) solutions were 2-dimensional. For the VR condition, MDS dimensions were significantly associated with the presence of crossing in a shape (Dimension 1), and with perimeter, height, cycles, peak segment speed, and horizontal symmetry (Dimension 2). ROIs most prominently associated with these dimensions essentially comprised the medial frontal lobe bilaterally, the inferior frontal gyrus bilaterally, and the left intraparietal sulcus (Dimension 1), and visual areas, including the calcarine sulcus and cuneus bilaterally (Dimension 2). These results document the expected involvement of visual areas and support the hypothesis advanced on the basis of previous findings (Lewis et al. 2003a) that a motor rehearsal of the upcoming shape copying is occurring during this visual presentation period. For the CV condition, practically one motor feature (number of segments drawn) dominated both dimensions, with a secondary engagement of horizontal symmetry in Dimension 1. The right postcentral gyrus, right intraparietal sulcus, right superior parietal lobule and right inferior parietal lobule contributed mostly to Dimension 1; the superior frontal gyrus bilaterally, right middle frontal gyrus, left postcentral gyrus, left inferior parietal lobule contributed mostly to Dimension 2; and the left superior parietal lobule and left intraparietal sulcus contributed to both dimensions approximately equally. CV BOLD activation of ROIs contributing to Dimension 1 (or to both dimensions) was significantly associated with the number of shape segments drawn. Since the direction of movement differs in successively drawn shape segments, the number of segments (minus one) equals the number of changes in the direction of movement. We conclude that this fundamental spatial motor aspect of drawing geometrical shapes is the critical variable, independent of the particular shape drawn, that dominates cortical activation during copying.     

Logarithmic transformation for high-field BOLD fMRI data

Parametric statistical analyses of BOLD fMRI data often assume that the data are normally distributed, the variance is independent of the mean, and the effects are additive. We evaluated the fulfilment of these conditions on BOLD fMRI data acquired at 4 T from the whole brain while 15 subjects fixated a spot, looked at a geometrical shape, and copied it using a joystick. We performed a detailed analysis of the data to assess (a) their frequency distribution (i.e. how close it was to a normal distribution), (b) the dependence of the standard deviation (SD) on the mean, and (c) the dependence of the response on the preceding baseline. The data showed a strong departure from normality (being skewed to the right and hyperkurtotic), a strong linear dependence of the SD on the mean, and a proportional response over the baseline. These results suggest the need for a logarithmic transformation. Indeed, the log transformation reduced the skewness and kurtosis of the distribution, stabilized the variance, and made the effect additive, i.e. independent of the baseline. We conclude that high-field BOLD fMRI data need to be log-transformed before parametric statistical analyses are applied.     

Reduced Subjective Response to Acute Ethanol Administration Among Young Men with a Broad Bipolar Phenotype

Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects (‘feel high'': F=14.2, p=0.001; ‘feel effects'': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.     

Efficacy of inpatient personalized multidisciplinary rehabilitation in multiple sclerosis: behavioural and functional imaging results

Journal of Neurology - Although multidisciplinary rehabilitation programs are commonly used in clinical practice for patients with multiple sclerosis (MS), they are currently underexamined. This...     

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2‐weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion‐load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between‐structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion‐load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body‐fluid markers.     

Longitudinal patterns of cortical thinning in multiple sclerosis

In multiple sclerosis (MS), cortical atrophy is correlated with clinical and neuropsychological measures. We aimed to examine the differences in the temporospatial evolution of cortical thickness (CTh) between MS‐subtypes and to study the association of CTh with T2‐weighted white matter lesions (T2LV) and clinical progression. Two hundred and forty‐three MS patients (180 relapsing–remitting [RRMS], 51 secondary‐progressive [SPMS], and 12 primary‐progressive [PPMS]) underwent annual clinical (incl. expanded disability status scale [EDSS]) and MRI‐examinations over 6 years. T2LV and CTh were measured. CTh did not differ between MS‐subgroups. Higher total T2LV was associated with extended bilateral CTh‐reduction on average, but did not correlate with CTh‐changes over time. In RRMS, CTh‐ and EDSS‐changes over time were negatively correlated in large bilateral prefrontal, frontal, parietal, temporal, and occipital areas. In SPMS, CTh was not associated with the EDSS. In PPMS, CTh‐ and EDSS‐changes over time were correlated in small clusters predominantly in left parietal areas. Increase of brain lesion load does not lead to an immediate CTh‐reduction. Although CTh did not differ between MS‐subtypes, a dissociation in the correlation between CTh‐ and EDSS‐changes over time between RRMS and progressive‐MS was shown, possibly underlining the contribution of subcortical pathology to clinical progression in progressive‐MS.     

Reliable and fast volumetry of the lumbar spinal cord using cord image analyser (Cordial)

Objective

To validate the precision and accuracy of the semi-automated cord image analyser (Cordial) for lumbar spinal cord (SC) volumetry in 3D T1w MRI data of healthy controls (HC).

Materials and methods

40 3D T1w images of 10 HC (w/m: 6/4; age range: 18–41 years) were acquired at one 3T-scanner in two MRI sessions (time interval 14.9±6.1 days). Each subject was scanned twice per session, allowing determination of test-retest reliability both in back-to-back (intra-session) and scan-rescan images (inter-session). Cordial was applied for lumbar cord segmentation twice per image by two raters, allowing for assessment of intra- and inter-rater reliability, and compared to a manual gold standard.

Results

While manually segmented volumes were larger (mean: 2028±245 mm³ vs. Cordial: 1636±300 mm³, p<0.001), accuracy assessments between manually and semi-automatically segmented images showed a mean Dice-coefficient of 0.88±0.05. Calculation of within-subject coefficients of variation (COV) demonstrated high intra-session (1.22–1.86%), inter-session (1.26–1.84%), as well as intra-rater (1.73–1.83%) reproducibility. No significant difference was shown between intra- and inter-session reproducibility or between intra-rater reliabilities. Although inter-rater reproducibility (COV: 2.87%) was slightly lower compared to all other reproducibility measures, between rater consistency was very strong (intraclass correlation coefficient: 0.974).

Conclusion

While under-estimating the lumbar SCV, Cordial still provides excellent inter- and intra-session reproducibility showing high potential for application in longitudinal trials.

Key Points

? Lumbar spinal cord segmentation using the semi-automated cord image analyser (Cordial) is feasible.? Lumbar spinal cord is 40-mm cord segment 60 mm above conus medullaris.? Cordial provides excellent inter- and intra-session reproducibility in lumbar spinal cord region.? Cordial shows high potential for application in longitudinal trials.