Neurophysiological brain function predicts response to cognitive rehabilitation and mindfulness in multiple sclerosis: a randomized trial.

BACKGROUND: Cognitive treatment response varies highly in people with multiple sclerosis (PwMS). Identification of mechanisms is essential for predicting response. OBJECTIVES: This study aimed to investigate whether brain network function predicts response to cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT). METHODS: PwMS with cognitive complaints completed CRT, MBCT, or enhanced treatment as usual (ETAU) and performed three measurements (baseline, post-treatment, 6-month follow-up). Baseline magnetoencephalography (MEG) measures were used to predict treatment effects on cognitive complaints, personalized cognitive goals, and information processing speed (IPS) using mixed models (secondary analysis REMIND-MS study). RESULTS: We included 105 PwMS (96 included in prediction analyses; 32 CRT, 31 MBCT, 33 ETAU), and 56 healthy controls with baseline MEG. MEG did not predict reductions in complaints. Higher connectivity predicted better goal achievement after MBCT (p = 0.010) and CRT (p = 0.018). Lower gamma power (p = 0.006) and higher connectivity (p = 0.020) predicted larger IPS benefits after MBCT. These MEG predictors indicated worse brain function compared to healthy controls (p < 0.05). CONCLUSIONS: Brain network function predicted better cognitive goal achievement after MBCT and CRT, and IPS improvements after MBCT. PwMS with neuronal slowing and hyperconnectivity were most prone to show treatment response, making network function a promising tool for personalized treatment recommendations. TRIAL REGISTRATION: The REMIND-MS study was prospectively registered in the Dutch Trial registry (NL6285; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6459 ).

Cognitive rehabilitation and mindfulness reduce cognitive complaints in multiple sclerosis (REMIND-MS): A randomized controlled trial.

BACKGROUND: Cognitive problems, both complaints and objective impairments, are frequent and disabling in patients with multiple sclerosis (MS) and profoundly affect daily living. However, intervention studies that focus on cognitive problems that patients experience in their daily lives are limited. This study therefore aimed to investigate the effectiveness of cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT) on patient-reported cognitive complaints in MS. METHODS: In this randomized-controlled trial, MS patients with cognitive complaints completed questionnaires and underwent neuropsychological assessments at baseline, post-treatment and 6-month follow-up. Patient-reported cognitive complaints were primarily investigated. Secondary outcomes included personalized cognitive goals and objective cognitive function. CRT and MBCT were compared to enhanced treatment as usual (ETAU) using linear mixed models. RESULTS: Patients were randomized into CRT (n = 37), MBCT (n = 36) or ETAU (n = 37), of whom 100 completed the study. Both CRT and MBCT positively affected patient-reported cognitive complaints compared to ETAU at post-treatment (p<.05), but not 6 months later. At 6-month follow-up, CRT had a positive effect on personalized cognitive goals (p=.028) and MBCT on processing speed (p=.027). Patients with less cognitive complaints at baseline benefited more from CRT on the Cognitive Failures Questionnaire (i.e. primary outcome measuring cognitive complaints) at post-treatment (p=.012-.040), and those with better processing speed at baseline benefited more from MBCT (p=.016). CONCLUSION: Both CRT and MBCT alleviated cognitive complaints in MS patients immediately after treatment completion, but these benefits did not persist. In the long term, CRT showed benefits on personalized cognitive goals and MBCT on processing speed. These results thereby provide insight in the specific contributions of available cognitive treatments for MS patients.

Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy.

BACKGROUND: Thalamic atrophy is proposed to be a major predictor of disability progression in multiple sclerosis (MS), while thalamic function remains understudied. OBJECTIVES: To study how thalamic functional connectivity (FC) is related to disability and thalamic or cortical network atrophy in two large MS cohorts. METHODS: Structural and resting-state functional magnetic resonance imaging (fMRI) was obtained in 673 subjects from Amsterdam (MS: N = 332, healthy controls (HC): N = 96) and Graz (MS: N = 180, HC: N = 65) with comparable protocols, including disability measurements in MS (Expanded Disability Status Scale, EDSS). Atrophy was measured for the thalamus and seven well-recognized resting-state networks. Static and dynamic thalamic FC with these networks was correlated with disability. Significant correlates were included in a backward multivariate regression model. RESULTS: Disability was most strongly related (adjusted R2 = 0.57, p < 0.001) to higher age, a progressive phenotype, thalamic atrophy and increased static thalamic FC with the sensorimotor network (SMN). Static thalamus-SMN FC was significantly higher in patients with high disability (EDSS ⩾ 4) and related to network atrophy but not thalamic atrophy or lesion volumes. CONCLUSION: The severity of disability in MS was related to increased static thalamic FC with the SMN. Thalamic FC changes were only related to cortical network atrophy, but not to thalamic atrophy.

Development and evaluation of a manual segmentation protocol for deep grey matter in multiple sclerosis: Towards accelerated semi-automated references.

BACKGROUND: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods. OBJECTIVES: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF). METHODS: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially. RESULTS: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92. CONCLUSIONS: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload.

Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study.

BACKGROUND AND RATIONALE: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. METHODS: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. RESULTS: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings. CONCLUSION: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.

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.

Bright light treatment in elderly patients with nonseasonal major depressive disorder: a randomized placebo-controlled trial.

CONTEXT: Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD. OBJECTIVE: To determine the efficacy of BLT in elderly patients with MDD. DESIGN: Double-blind, placebo-controlled randomized clinical trial. SETTING: Home-based treatment in patients recruited from outpatient clinics and from case-finding using general practitioners' offices in the Amsterdam region. PARTICIPANTS: Eighty-nine outpatients 60 years or older who had MDD underwent assessment at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2). Intervention Three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux). MAIN OUTCOME MEASURES: Mean improvement in Hamilton Scale for Depression scores at T1 and T2 using parameters of sleep and cortisol and melatonin levels. RESULTS: Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%; 95% confidence interval, 4%-23%; P = .03) and from T0 to T2 (21%; 7%-31%; P = .001). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7% (P < .001), sleep efficiency increased by 2% (P = .01), and the steepness of the rise in evening melatonin levels increased by 81% (P = .03) compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% (P = .001) and the 24-hour urinary free cortisol level was 37% lower (P = .003) compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group (P = .02). CONCLUSIONS: In elderly patients with MDD, BLT improved mood, enhanced sleep efficiency, and increased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00332670.

Bright light in elderly subjects with nonseasonal major depressive disorder: a double blind randomised clinical trial using early morning bright blue light comparing dim red light treatment.

BACKGROUND: Depression frequently occurs in the elderly. Its cause is largely unknown, but several studies point to disturbances of biological rhythmicity. In both normal aging, and depression, the functioning of the suprachiasmatic nucleus (SCN) is impaired, as evidenced by an increased prevalence of day-night rhythm perturbations, such as sleeping disorders. Moreover, the inhibitory SCN neurons on the hypothalamus-pituitary adrenocortical axis (HPA-axis) have decreased activity and HPA-activity is enhanced, when compared to non-depressed elderly. Using bright light therapy (BLT) the SCN can be stimulated. In addition, the beneficial effects of BLT on seasonal depression are well accepted. BLT is a potentially safe, nonexpensive and well accepted treatment option. But the current literature on BLT for depression is inconclusive. METHODS/DESIGN: This study aims to show whether BLT can reduce non-seasonal major depression in elderly patients. Randomized double blind placebo controlled trial in 126 subjects of 60 years and older with a diagnosis of major depressive disorder (MDD, DSM-IV/SCID-I). Subjects are recruited through referrals of psychiatric outpatient clinics and from case finding from databases of general practitioners and old-people homes in the Amsterdam region. After inclusion subjects are randomly allocated to the active (bright blue light) vs. placebo (dim red light) condition using two Philips Bright Light Energy boxes type HF 3304 per subject, from which the light bulbs have been covered with bright blue- or dim red light- permitting filters. Patients will be stratified by use of antidepressants. Prior to treatment a one-week period without light treatment will be used. At three time points several endocrinological, psychophysiological, psychometrically, neuropsychological measures are performed: just before the start of light therapy, after completion of three weeks therapy period, and three weeks thereafter. DISCUSSION: If BLT reduces nonseasonal depression in elderly patients, then additional lighting may easily be implemented in the homes of patients to serve as add-on treatment to antidepressants or as a stand-alone treatment in elderly depressed patients. In addition, if our data support the role of a dysfunctional biological clock in depressed elderly subjects, such a finding may guide further development of novel chronobiological oriented treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00332670.

Accessory nerve to suprascapular nerve transfer to restore shoulder exorotation in otherwise spontaneously recovered obstetric brachial plexus lesions.

OBJECTIVE: A systematic follow-up of infants with an obstetric brachial plexus lesion of C5 and C6 or the superior trunk showing satisfactory spontaneous recovery of shoulder and arm function except for voluntary shoulder exorotation, who underwent an accessory to suprascapular nerve transfer to improve active shoulder exorotation, to evaluate for functional recovery, and to understand why other superior trunk functions spontaneously recover in contrast with exorotation. METHODS: In 54 children, an accessory to suprascapular nerve transfer was performed as a separate procedure at a mean age of 21.7 months. Follow-up examinations were conducted before and at 4, 8, 12, 24, and 36 months after operation and included scoring of shoulder exorotation and abduction. Intraoperative reactivity of spinatus muscles and additional needle electromyographic responses were registered after electrostimulation of suprascapular nerves. Histological examination of suprascapular nerves was performed. Trophy of spinatus muscles was followed by magnetic resonance imaging scanning. The influence of perinatal variables and results of ancillary investigations on outcome were evaluated. RESULTS: Exorotation improved from 70 degrees to functional levels exceeding 0 degrees, except in two patients. Abduction improved in 27 patients, with results of 90 degrees or more in 49 patients. Electromyography at 4 months did not show signs of denervation in 39 out of 40 patients. Intraoperative electrostimulation of suprascapular nerves elicited spinatus muscle reaction in 44 out of 48 patients. Histology of suprascapular nerves was normal. Preoperative magnetic resonance imaging scans showed only minor wasting of spinatus muscles in contrast with major wasting after successful operations. CONCLUSION: An accessory to suprascapular nerve transfer is effective to restore active exorotation when performed as the primary or a separate secondary procedure in children older than 10 months of age. Contradictory spontaneous recovery of other superior trunk functions and integrity of suprascapular nerves, as well as absence of spinatus muscle wasting direct to central nervous changes are possible main causes for the lack of exorotation.

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.

Cannabinoids in multiple sclerosis: do they have a therapeutic role?

This is an exciting time for cannabinoid research. Evidence suggests that cannabis (marijuana) can alleviate symptoms like muscle spasticity and pain in patients with multiple sclerosis (MS). Interest in the field of cannabinoids has been strengthened by the identification and cloning of cannabinoid receptors located in the central nervous system and the peripheral immune organs, and by the discovery of the endogenous cannabinoid ligands. Cannabinoids are also efficacious in animal models of MS. However, there have been only ten published clinical reports on the use of cannabis in MS, involving 78 individuals worldwide, and the results have been equivocal. Researchers encounter a number of difficulties in designing clinical studies that use cannabinoids. From the studies reporting the use of cannabinoids in MS patients with spasticity, the somewhat better designed studies failed to demonstrate objective improvement. Therefore, convincing evidence that cannabinoids are effective in MS is still lacking.