Quantification of Thalamic Atrophy in MS: From the Multicenter Italian Neuroimaging Network Initiative Data Set to Clinical Application.

BACKGROUND AND PURPOSE: Thalamic atrophy occurs from the earliest phases of MS; however, this measure is not included in clinical practice. Our purpose was to obtain a reliable segmentation of the thalamus in MS by comparing existing automatic methods cross-sectionally and longitudinally. MATERIALS AND METHODS: MR images of 141 patients with relapsing-remitting MS (mean age, 38 years; range, 19-58 years; 95 women) and 69 healthy controls (mean age, 36 years; range, 22-69 years; 47 women) were retrieved from the Italian Neuroimaging Network Initiative repository: T1WI, T2WI, and DWI at baseline and after 1 year (136 patients, 31 healthy controls). Three segmentation software programs (FSL-FIRST, FSL-MIST, FreeSurfer) were compared. At baseline, agreement among pipelines, correlations with age, disease duration, clinical score, and T2-hyperintense lesion volume were evaluated. Effect sizes in differentiating patients and controls were assessed cross-sectionally and longitudinally. Variability of longitudinal changes in controls and sample sizes were assessed. False discovery rate-adjusted P < .05 was considered significant. RESULTS: At baseline, FSL-FIRST and FSL-MIST showed the highest agreement in the results of thalamic volume (R = 0.87, P < .001), with the highest effect size for FSL-MIST (Cohen d = 1.11); correlations with demographic and clinical variables were comparable for all software. Longitudinally, FSL-MIST showed the lowest variability in estimating thalamic volume changes for healthy controls (SD = 1.07%), the highest effect size (Cohen d = 0.44), and the smallest sample size at 80% power level (15 subjects per group). CONCLUSIONS: Multimodal segmentation by FSL-MIST increased the robustness of the results with better capability to detect small variations in thalamic volumes.

Expanding the spectrum of neonatal-onset AIFM1-associated disorders.

OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.

Altered Functional Connectivity of the Subthalamic Nucleus in Parkinson's Disease: Focus on Candidates for Deep Brain Stimulation.

BACKGROUND: The hypothesis that the effectiveness of deep brain stimulation (DBS) in Parkinson's disease (PD) would be related to connectivity dysfunctions between the site of stimulation and other brain regions is growing. OBJECTIVE: To investigate how the subthalamic nucleus (STN), the most frequently used DBS target for PD, is functionally linked to other brain regions in PD patients according to DBS eligibility. METHODS: Clinical data and resting-state functional MRI were acquired from 60 PD patients and 60 age- and sex-matched healthy subjects within an ongoing longitudinal project. PD patients were divided into 19 patients eligible for DBS and 41 non-candidates. Bilateral STN were selected as regions of interest and a seed-based functional MRI connectivity analysis was performed. RESULTS: A decreased functional connectivity between STN and sensorimotor cortex in both PD patient groups compared to controls was found. Whereas an increased functional connectivity between STN and thalamus was found in PD patient groups relative to controls. Candidates for DBS showed a decreased functional connectivity between bilateral STN and bilateral sensorimotor areas relative to non-candidates. In patients eligible for DBS, a weaker STN functional connectivity with left supramarginal and angular gyri was related with a more severe rigidity and bradykinesia whereas a higher connectivity between STN and cerebellum/pons was related to poorer tremor score. CONCLUSION: Our results suggest that functional connectivity of STN varies among PD patients eligible or not for DBS. Future studies would confirm whether DBS modulates and restores functional connectivity between STN and sensorimotor areas in treated patients.

Abnormal thalamic functional connectivity correlates with cardiorespiratory fitness and physical activity in progressive multiple sclerosis.

BACKGROUND: Altered thalamic volumes and resting state (RS) functional connectivity (FC) might be associated with physical activity (PA) and cardiorespiratory fitness (CRF) in people with progressive multiple sclerosis (PMS). OBJECTIVES: To assess thalamic structural and functional alterations and investigate their correlations with PA/CRF levels in people with PMS. METHODS: Seven-day accelerometry and cardiopulmonary exercise testing were used to assess PA/CRF levels in 91 persons with PMS. They underwent 3.0 T structural and RS fMRI acquisition with 37 age/sex-matched healthy controls (HC). Between-group comparisons of MRI measures and their correlations with PA/CRF variables were assessed. RESULTS: PMS people had lower volumes compared to HC (all p < 0.001). At corrected threshold, PMS showed decreased intra- and inter-thalamic RS FC, and increased RS FC between the thalamus and the hippocampus, bilaterally. At uncorrected threshold, decreased thalamic RS FC with caudate nucleus, cerebellum and anterior cingulate cortex (ACC), as well as increased thalamic RS FC with occipital regions, were also detected. Lower CRF, measured as peak oxygen consumption (VO2peak), correlated with lower white matter volume (r = 0.31, p = 0.03). Moreover, lower levels of light PA correlated with increased thalamic RS FC with the right hippocampus (r = - 0.3, p = 0.05). DISCUSSION: People with PMS showed widespread brain atrophy, as well as pronounced intra-thalamic and thalamo-hippocampal RS FC abnormalities. White matter atrophy correlated with CRF, while increased thalamo-hippocampal RS FC was associated to worse PA levels. Thalamic RS FC might be used to monitor physical impairment and efficacy of rehabilitative and disease-modifying treatments in future studies.

Biomarkers of Migraine and Cluster Headache: Differences and Similarities.

OBJECTIVE: This study was undertaken to identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared. METHODS: Clinical, functional, and structural MRI data were obtained from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Support vector machine algorithms and a stepwise removal process were used to discriminate headache patients from controls, and subgroups of patients. Regional between-group differences and association between imaging features and patients' clinical characteristics were also investigated. RESULTS: The accuracy for classifying headache patients from controls was 80%. The classification accuracy for discrimination between migraine and controls was 89%, and for cluster headache and controls it was 98%. For distinguishing cluster headache from migraine patients, the MRI classifier yielded an accuracy of 78%, whereas MRI-clinical combined classification model achieved an accuracy of 99%. Bilateral hypothalamic and periaqueductal gray (PAG) functional networks were the most important MRI features in classifying migraine and cluster headache patients from controls. The left thalamic network was the most discriminative MRI feature in classifying migraine from cluster headache patients. Compared to migraine, cluster headache patients showed decreased functional interaction between the left thalamus and cortical areas mediating interoception and sensory integration. The presence of restlessness was the most important clinical feature in discriminating the two groups of patients. INTERPRETATION: Functional biomarkers, including the hypothalamic and PAG networks, are shared by migraine and cluster headache patients. The thalamocortical pathway may be the neural substrate that differentiates migraine from cluster headache attacks with their distinct clinical features. ANN NEUROL 2023;93:729-742.

Exploring the Association of HLA Genetic Risk Burden on Thalamic and Hippocampal Atrophy in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a complex disease of the central nervous system for which human leukocyte antigen (HLA) alleles are major contributors to susceptibility. Several investigations have focused on the relationship between HLA and clinical parameters, while few studies have evaluated its correlation with brain magnetic resonance imaging (MRI) measures. We investigated the association between the HLA genetic burden (HLAGB), originating from the most updated HLA alleles associated with MS, and neuroimaging endophenotypes, with a specific focus on brain atrophy metrics. A monocentric Italian cohort of 334 MS patients with imputed HLA alleles and cross-sectional volumetric measures of white matter (WM), gray matter (GM), hippocampus, thalamus and T2-hyperintense lesions was investigated. Linear regression models with covariate adjustment were fitted for each metric. We detected no effect of HLAGB on WM and GM volumes. Interestingly, we found a marginal correlation between higher HLAGB and lower hippocampal volume (ß = -0.142, p = 0.063) and a nominal association between higher HLAGB and lower thalamic volume (ß = -0.299, p = 0.047). No association was found with T2 lesion volumes. The putative impact of higher HLAGB on hippocampus and thalamus suggests, if replicated in independent cohorts, a possible cumulative contribution of HLA risk loci on brain volumetric traits linked to clinical deficits in MS.

Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

Clinical correlates of hypothalamic functional changes in migraine patients.

OBJECTIVE: To elucidate the hypothalamic involvement in episodic migraine and investigate the association between hypothalamic resting state functional connectivity changes and migraine patients' clinical characteristics and disease progression over the years. METHODS: Ninety-one patients with episodic migraine and 73 controls underwent interictal resting state functional magnetic resonance imaging. Twenty-three patients and controls were re-examined after a median of 4.5 years. Hypothalamic resting state functional connectivity changes were investigated using a seed-based correlation approach. RESULTS: At baseline, a decreased functional interaction between the hypothalamus and the parahippocampus, cerebellum, temporal, lingual and orbitofrontal gyrus was found in migraine patients versus controls. Increased resting state functional connectivity between the hypothalamus and bilateral orbitofrontal gyrus was demonstrated in migraine patients at follow-up versus baseline. Migraine patients also experienced decreased right hypothalamic resting state functional connectivity with ipsilateral lingual gyrus. A higher migraine attack frequency was associated with decreased hypothalamic-lingual gyrus resting state functional connectivity at baseline, while greater headache impact at follow-up correlated with decreased hypothalamic-orbitofrontal gyrus resting state functional connectivity at baseline. At follow-up, a lower frequency of migraine attacks was associated with higher hypothalamic-orbitofrontal gyrus resting state functional connectivity. CONCLUSIONS: During the interictal phase, the hypothalamus modulates the activity of pain and visual processing areas in episodic migraine patients. The hypothalamic-cortical interplay changes dynamically over time according to patients' clinical features.

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.

Clinical predictivity of thalamic sub-regional connectivity in clinically isolated syndrome: a 7-year study.

Here, we explored trajectories of sub-regional thalamic resting state (RS) functional connectivity (FC) modifications occurring in clinically isolated syndrome (CIS) patients early after their first clinical episode, and assessed their relationship with disability over 7 years. RS fMRI and clinical data were prospectively acquired from 59 CIS patients and 13 healthy controls (HC) over 2 years. A clinical re-assessment was performed in 53 (89%) patients after 7 years. Using a structural connectivity-based atlas, five thalamic sub-regions (frontal, motor, postcentral, occipital, and temporal) were used for seed-based RS FC. Thalamic RS FC abnormalities and their longitudinal changes were correlated with disability. Thirty-nine (66.1%) patients suffered a second clinical relapse, but the median EDSS remained stable over time. At baseline, CIS patients vs HC showed reduced RS FC (p < 0.001, uncorrected) with: (1) frontal cortices, for the whole thalamus, occipital, postcentral, and temporal thalamic sub-regions, (2) occipital cortices, for the occipital thalamic sub-region. In CIS, the longitudinal analysis revealed at year 2 vs baseline: (1) no significant whole-thalamic RS FC changes; (2) reduction of motor, postcentral, and temporal sub-regional RS FC with occipital cortices (p < 0.05, corrected); (3) an increase (p < 0.001, uncorrected) of postcentral and occipital sub-regional thalamic RS FC with frontal cortices, left putamen, and ipsi- and contralateral thalamus, this latter correlating with less severe clinical disability at year 7. Thalamo-cortical disconnections were present in CIS mainly in thalamic sub-regions closer to the third ventricle early after the demyelinating event, evolved in the subsequent 2 years, and were associated with long-term clinical disability.

Regional changes in thalamic shape and volume are related to cognitive performance in multiple sclerosis.

BACKGROUND: The relationship between cognitive performance and regional thalamic atrophy in multiple sclerosis (MS) has been investigated in recent studies. OBJECTIVE AND METHODS: To further assess this relationship, 118 relapsing-remitting MS patients and 52 healthy controls underwent a neuropsychological assessment and a 3T-MRI (3-Tesla magnetic resonance imaging). Cognitive performances were correlated with thalamic shape changes by using Vertex Analysis. RESULTS: Information processing speed performance correlated with atrophy of frontal/motor-connected thalamic sub-regions. Inhibitory control performance correlated with atrophy of all thalamic sub-regions. Global cognitive status correlated with atrophy of frontal/temporal-connected sub-regions. CONCLUSIONS: These findings support the hypothesis that, within the thalamus, the damage of the anterior regions is most relevant for cognitive dysfunction.

In vivo gradients of thalamic damage in paediatric multiple sclerosis: a window into pathology.

The thalamus represents one of the first structures affected by neurodegenerative processes in multiple sclerosis. A greater thalamic volume reduction over time, on its CSF side, has been described in paediatric multiple sclerosis patients. However, its determinants and the underlying pathological changes, likely occurring before this phenomenon becomes measurable, have never been explored. Using a multiparametric magnetic resonance approach, we quantified, in vivo, the different processes that can involve the thalamus in terms of focal lesions, microstructural damage and atrophy in paediatric multiple sclerosis patients and their distribution according to the distance from CSF/thalamus interface and thalamus/white matter interface. In 70 paediatric multiple sclerosis patients and 26 age- and sex-matched healthy controls, we tested for differences in thalamic volume and quantitative MRI metrics-including fractional anisotropy, mean diffusivity and T1/T2-weighted ratio-in the whole thalamus and in thalamic white matter, globally and within concentric bands originating from CSF/thalamus interface. In paediatric multiple sclerosis patients, the relationship of thalamic abnormalities with cortical thickness and white matter lesions was also investigated. Compared to healthy controls, patients had significantly increased fractional anisotropy in whole thalamus (f2 = 0.145; P = 0.03), reduced fractional anisotropy (f2 = 0.219; P = 0.006) and increased mean diffusivity (f2 = 0.178; P = 0.009) in thalamic white matter and a trend towards a reduced thalamic volume (f2 = 0.027; P = 0.058). By segmenting the whole thalamus and thalamic white matter into concentric bands, in paediatric multiple sclerosis we detected significant fractional anisotropy abnormalities in bands nearest to CSF (f2 = 0.208; P = 0.002) and in those closest to white matter (f2 range = 0.183-0.369; P range = 0.010-0.046), while we found significant mean diffusivity (f2 range = 0.101-0.369; P range = 0.018-0.042) and T1/T2-weighted ratio (f2 = 0.773; P = 0.001) abnormalities in thalamic bands closest to CSF. The increase in fractional anisotropy and decrease in mean diffusivity detected at the CSF/thalamus interface correlated with cortical thickness reduction (r range = -0.27-0.34; P range = 0.004-0.028), whereas the increase in fractional anisotropy detected at the thalamus/white matter interface correlated with white matter lesion volumes (r range = 0.24-0.27; P range = 0.006-0.050). Globally, our results support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from white matter lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. Assessing thalamic microstructural changes using a multiparametric magnetic resonance approach may represent a target to monitor the efficacy of neuroprotective strategies early in the disease course.

Mesial temporal lobe and subcortical grey matter volumes differentially predict memory across stages of multiple sclerosis.

BACKGROUND/OBJECTIVE: Memory deficits due to multiple sclerosis (MS) have been variably linked to lower subcortical grey matter (SCGM) and mesial temporal lobe (MTL) volumes. We investigated which is the better predictor and whether this changes across disease stages. METHODS/RESULTS: Memory was assessed in 315 patients. Magnetic resonance imaging (MRI) measured volumes of total brain, grey matter, white matter, MTL (hippocampus, amygdala) and SCGM (thalamus, caudate). MTL predicted memory in the total sample and in patients with earlier (<10 years) or later (⩾10 years) relapsing disease. SCGM (specifically thalamus) predicted memory in progressive patients. CONCLUSIONS: Neuroanatomical correlates of memory deficits differ across disease stages.

Structural connectivity-defined thalamic subregions have different functional connectivity abnormalities in multiple sclerosis patients: Implications for clinical correlations.

In spite of the well-known importance of thalami in multiple sclerosis (MS), only limited data on whole and subregional thalamic functional connectivity (FC) changes are available. Using diffusion tensor imaging, we performed a structural connectivity based thalamic parcellation and investigated subregional thalamic resting-state (RS) FC alterations and their relationship with clinical/cognitive measures in MS. MRI data from a reference set of healthy controls (HC) were used to parcellate the thalami into five subregions, according to their structural connectivity. For each thalamic subregion, a seed-based RS FC analysis was performed in 187 MS patients and 94 HC. Correlations between thalamic RS FC and clinical/cognitive variables were assessed. Compared to HC, MS patients showed increased intra- and inter-thalamic RS FC for almost all thalamic subregions, and increased RS FC between all thalamic subregions and the left insula. Frontal and motor thalamic subregions also showed reduced RS FC with the caudate nucleus. For the temporal thalamic subregion, we observed reduced RS FC with the ipsilateral thalamus, anterior and middle cingulate cortex, and cerebellum. Compared to cognitively preserved, cognitively impaired MS patients had higher thalamic RS FC with several temporal areas. In MS patients, lower RS FC between thalamic subregions and the caudate and cingulate cortex correlated with worse motor performance, whereas higher RS FC with the insula correlated with better motor performance. The main thalamic subregions have different RS-FC abnormalities in MS patients. Increased thalamic RS FC with the insula may have a compensatory role, whereas increased RS FC with temporal areas, observed in patients with cognitive impairment may reflect maladaptive mechanisms. Hum Brain Mapp 38:6005-6018, 2017. © 2017 Wiley Periodicals, Inc.

MRI substrates of sustained attention system and cognitive impairment in pediatric MS patients.

OBJECTIVE: To explore the structural and functional integrity of the sustained attention system in patients with pediatric multiple sclerosis (MS) and its effect on cognitive impairment. METHODS: We enrolled 57 patients with pediatric MS and 14 age- and sex-matched healthy controls (HCs). Patients with >3 abnormal tests at neuropsychological evaluation were classified as cognitively impaired (CI). Sustained attention system activity was studied with fMRI during the Conners Continuous Performance Test (CCPT). Structural integrity of attention network connections was quantified with diffusion tensor (DT) MRI. RESULTS: Within-group analysis showed similar patterns of recruitment of the attention network in HCs and patients with pediatric MS. Diffuse network DT MRI structural abnormalities were found in patients with MS. During CCPT, with increasing task demand, patients with pediatric MS showed increased activation of the left thalamus, anterior insula, and anterior cingulate cortex (ACC) and decreased recruitment of the right precuneus compared to HCs. Thirteen patients (23%) were classified as CI. Compared to cognitively preserved patients, CI patients with pediatric MS had decreased recruitment of several areas located mainly in parietal and occipital lobes and cerebellum and increased deactivation of the ACC, combined with more severe structural damage of white matter tracts connecting these regions. CONCLUSIONS: Our results suggest that the age-expected level of sustained attention system functional competence is achieved in patients with pediatric MS. Inefficient regulation of the functional interaction between different areas of this system, due to abnormal white matter integrity, may result in global cognitive impairment in these patients.

Correlates of Executive Functions in Multiple Sclerosis Based on Structural and Functional MR Imaging: Insights from a Multicenter Study.

Purpose To study the concomitant use of structural and functional magnetic resonance (MR) imaging correlates to explain information processing speed (IPS) and executive function (EF) in multiple sclerosis (MS). Materials and Methods Local ethics committee approval was obtained at all sites for this prospective, multicenter study. All subjects provided written informed consent. Twenty-six patients with relapsing-remitting MS and 32 healthy control subjects from four centers underwent structural and functional MR imaging, including a go/no-go task and neuropsychological assessment. Subtests of the Brief Repeatable Battery of Neuropsychological Tests, the Wisconsin Card Sorting Test, and the performance with the functional MR imaging paradigm were used as estimates of IPS and EF. Activation of the thalamus and the inferior frontal gyrus (pars triangularis), thalamic volume, T2 lesion load, and age were used to explain IPS and EF in regression models. Results Compared with control subjects, patients showed increased activation in a frontoparietal network, including both thalami, during the execution of the go/no-go task. Patients had decreased thalamic volume (P < .001). Among tested variables, thalamic volume (ß = 0.606, P = .001), together with thalamic activation (ß = -0.410, P = .022), were the best predictors of IPS and EF and helped explain 52.7% of the variance in IPS and EF. Conclusion This study highlights the potential of the combined use of functional and morphologic parameters to explain IPS and EF in patients with relapsing-remitting MS and confirms the central role of the thalamus as a relay station in executive functioning. (©) RSNA, 2016.