Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study.

To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo-cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far.

Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.

BACKGROUND: Cognitive problems frequently occur in patients with multiple sclerosis (MS) and profoundly affect their quality of life. So far, the best cognitive treatment options for MS patients are a matter of debate. Therefore, this study aims to investigate the effectiveness of two promising non-pharmacological treatments: cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT). Furthermore, this study aims to gain additional knowledge about the aetiology of cognitive problems among MS patients, since this may help to develop and guide effective cognitive treatments. METHODS/DESIGN: In a dual-centre, single-blind randomised controlled trial (RCT), 120 MS patients will be randomised into one of three parallel groups: CRT, MBCT or enhanced treatment as usual (ETAU). Both CRT and MBCT consist of a structured 9-week program. ETAU consists of one appointment with an MS specialist nurse. Measurements will be performed at baseline, post-intervention and 6 months after the interventions. The primary outcome measure is the level of subjective cognitive complaints. Secondary outcome measures are objective cognitive function, functional brain network measures (using magnetoencephalography), psychological symptoms, well-being, quality of life and daily life functioning. DISCUSSION: To our knowledge, this will be the first RCT that investigates the effect of MBCT on cognitive function among MS patients. In addition, studying the effect of CRT on cognitive function may provide direction to the contradictory evidence that is currently available. This study will also provide information on changes in functional brain networks in relation to cognitive function. To conclude, this study may help to understand and treat cognitive problems among MS patients. TRIAL REGISTRATION: This trial was prospectively registered at the Dutch Trial Registration (number NTR6459 , registered on 31 May 2017).

Thalamus structure and function determine severity of cognitive impairment in multiple sclerosis.

OBJECTIVE: This study investigates whether changes in functional connectivity, diffusivity, and volume of the thalamus can explain different severities of cognitive impairment in multiple sclerosis (MS). METHODS: An inception cohort of 157 patients with MS (104 women, mean age 41 years), 6 years postdiagnosis, was divided into 3 groups: cognitively preserved (CP, n = 108), mildly cognitively impaired (MCI, n = 22), and more severely cognitively impaired (SCI, n = 27). These groups were matched to 47 healthy controls (HC, 28 women, mean age 41 years). Thalamic volume, thalamic skeleton diffusivity (fractional anisotropy [FA] and mean diffusivity [MD]), and thalamic resting-state functional connectivity (FC) were compared between groups. RESULTS: Thalamic volume was significantly lower in all patient groups compared to controls, with lowest volumes in patients with SCI, and no difference between CP and MCI. Thalamic skeleton FA was decreased in SCI compared to HC only; MD was increased in SCI compared to all other groups. Thalamic FC was increased in SCI with a total of 15 regions, mainly sensorimotor, frontal, and occipital parts of the brain. Thalamic volume, FC, and MD remained independent predictors in a linear regression model (R(2) = 0.46), together with male sex and a lower level of education. Lesion and whole-brain volumes were not significant predictors. CONCLUSIONS: These findings indicate that thalamic changes in structure and function are highly informative regarding overall cognitive performance in MS. Increased thalamic FC only became apparent in SCI, possibly as a sign of maladaption.

Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study.

Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were performed in 86 MS patients and 21 healthy subjects. We computed cortical functional networks for fMRI and MEG by respectively the Pearson's correlation coefficient and the phase lag index using the same automated anatomical labeling atlas for both modalities. Thalamo-cortical functional connectivity was only estimated using fMRI. We computed conventional network metrics such as clustering coefficient and path length and analyzed the minimum spanning tree (MST), a subnetwork and backbone of the original network. MS patients showed reduced thalamic volumes and increased thalamo-cortical connectivity. MEG cortical functional networks showed a lower level of integration in MS in terms of the MST, whereas fMRI cortical networks did not differ between groups. Lower integration of MEG cortical functional networks was both related to thalamic atrophy as well as to increased thalamo-cortical functional connectivity in fMRI and to worse cognitive and clinical status. This study demonstrated for the first time that thalamic atrophy is associated with global disruption of cortical functional networks in MS and this global disruption of network activity was related to worse cognitive and clinical function in MS. Hum Brain Mapp 36:603-618, 2015. © 2014 Wiley Periodicals, Inc.

Subcortical atrophy and cognition: sex effects in multiple sclerosis.

OBJECTIVES: Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS. METHODS: Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group. RESULTS: Most deep GM volumes were reduced in patients, with larger effects on average in men (-11%) than in women (-6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R(2) = 0.31), while lesion volume was not a significant predictor in the model. CONCLUSIONS: Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS.

B-cell depletion attenuates white and gray matter pathology in marmoset experimental autoimmune encephalomyelitis.

This study investigated the effect of CD20-positive B-cell depletion on central nervous system (CNS) white and gray matter pathology in experimental autoimmune encephalomyelitis in common marmosets, a relevant preclinical model of multiple sclerosis. Experimental autoimmune encephalomyelitis was induced in 14 marmosets by immunization with recombinant human myelin oligodendrocyte glycoprotein in complete Freund adjuvant. At 21 days after immunization, B-cell depletion was achieved by weekly intravenous injections of HuMab 7D8, a human-anti-human CD20 antibody that cross-reacts with marmoset CD20. In vivo magnetic resonance imaging showed widespread brain white matter demyelination in control marmosets that was absent in CD20 antibody-treated marmosets. High-contrast postmortem magnetic resonance imaging showed white matter lesions in 4of the 7 antibody-treated marmosets, but these were significantly smaller than those in controls. The same technique revealed gray matter lesions in 5 control marmosets, but none in antibody-treated marmosets. Histologic analysis confirmed that inflammation, demyelination, and axonal damage were substantially reduced in brain, spinal cord, and optic nerves of CD20 antibody-treated marmosets. In conclusion, CD20-postive B-cell depletion by HuMab 7D8 profoundly reduced the development of both white and gray matter lesions in the marmoset CNS. These data underline the central role of B cells in CNS inflammatory-demyelinating disease.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement.

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.

MR spectroscopic evidence for thalamic and hippocampal, but not cortical, damage in multiple sclerosis.

Gray matter (GM) damage is an important pathophysiological feature in Multiple Sclerosis (MS), and may be related to clinical, including cognitive, deficits. Quantitative single-voxel (1)H-Magnetic Resonance Spectroscopy (TR/TE 6000/20 ms) was performed in 33 MS patients (11 per disease subtype; mean age 48 years, 16 females) and 10 healthy controls (mean age 43 years, 7 females). No overall spectroscopic changes were found in MS cortex. In MS thalamus, a 9% decrease of N-acetyl aspartate (NAA; P=0.005) and a 31% increase of myo-inositol (Ins; P=0.002) were found. A 21% Ins increase was observed (P=0.02) in MS hippocampus. Reduced NAA and increased Ins concentrations are thought to reflect neuro-axonal damage or loss and gliosis, respectively. Significant correlations between Ins concentrations and total-brain T(2) lesion load were found for MS thalamus (r=0.65, P<0.001) and hippocampus (r=0.57, P=0.001). MS thalamic and hippocampal Ins concentrations also correlated with each other (r=0.68; P<0.001). Cortical Gln correlated with thalamic NAA (r=-0.38; P=0.03) in MS. Thalamic and hippocampal Ins increases were most prominent in secondary-progressive (SP) patients (37% and 34%, respectively), whereas the largest thalamic NAA decrease (14%) was found in primary-progressive (PP) patients. In conclusion, thalamic and hippocampal GM pathology are important features of (progressive) MS.

Quantitative 1H-MRS of healthy human cortex, hippocampus, and thalamus: metabolite concentrations, quantification precision, and reproducibility.

PURPOSE: To evaluate metabolite concentrations in cortical gray matter, hippocampus, and thalamus of healthy adults, and to investigate precision and reproducibility of quantitative proton magnetic resonance spectroscopy (1H-MRS) in these gray matter regions. MATERIALS AND METHODS: Quantitative single-voxel short echo-time spectra were obtained from healthy human cortex, hippocampus, and thalamus. Subjects were examined twice. Metabolite concentrations, quantification precision, and reproducibility were determined. RESULTS: There were no significant differences between test and retest measurements. Regional differences were observed with respect to metabolite concentrations, quantification precision, and reproducibility. Quantification precision and reproducibility of N-acetylaspartate and N-acetyl aspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline-containing compounds (Cho), and myo-inositol (myo-Ins), were better than those of glutamate (Glu) and glutamine (Gln). Generally, precision and reproducibility were better in cortex than in hippocampus or thalamus. The quantification precision was shown to correlate both with reproducibility and spectral linewidth. CONCLUSION: The reliability of quantitative MRS depends on the metabolite concerned, its concentration, and on the brain area studied. Moreover, the quantification precision of a metabolite in a single spectrum appears to be a reliable measure for its reproducibility in a longitudinal study.