The Role of Cerebellum and Basal Ganglia Functional Connectivity in Altered Voluntary Movement Execution in Essential Tremor.

Substantial evidence highlights the role of the cerebellum in the pathophysiology of tremor in essential tremor (ET), although its potential involvement in altered movement execution in this condition remains unclear. This study aims to explore potential correlations between the cerebellum and basal ganglia functional connectivity and voluntary movement execution abnormalities in ET, objectively assessed with kinematic techniques. A total of 20 patients diagnosed with ET and 18 healthy subjects were enrolled in this study. Tremor and repetitive finger tapping were recorded using an optoelectronic kinematic system. All participants underwent comprehensive 3T-MRI examinations, including 3D-T1 and blood-oxygen-level dependent (BOLD) sequences during resting state. Morphometric analysis was conducted on the 3D-T1 images, while a seed-based analysis was performed to investigate the resting-state functional connectivity (rsFC) of dorsal and ventral portions of the dentate nucleus and the external and internal segments of the globus pallidus. Finally, potential correlations between rsFC alterations in patients and clinical as well as kinematic scores were assessed. Finger tapping movements were slower in ET than in healthy subjects. Compared to healthy subjects, patients with ET exhibited altered FC of both dentate and globus pallidus with cerebellar, basal ganglia, and cortical areas. Interestingly, both dentate and pallidal FC exhibited positive correlations with movement velocity in patients, differently from that we observed in healthy subjects, indicating the higher the FC, the faster the finger tapping. The findings of this study indicate the possible role of both cerebellum and basal ganglia in the pathophysiology of altered voluntary movement execution in patients with ET.

Relationship between default mode network and resting-state electroencephalographic alpha rhythms in cognitively unimpaired seniors and patients with dementia due to Alzheimer's disease.

Here we tested the hypothesis of a relationship between the cortical default mode network (DMN) structural integrity and the resting-state electroencephalographic (rsEEG) rhythms in patients with Alzheimer's disease with dementia (ADD). Clinical and instrumental datasets in 45 ADD patients and 40 normal elderly (Nold) persons originated from the PDWAVES Consortium (www.pdwaves.eu). Individual rsEEG delta, theta, alpha, and fixed beta and gamma bands were considered. Freeware platforms served to derive (1) the (gray matter) volume of the DMN, dorsal attention (DAN), and sensorimotor (SMN) cortical networks and (2) the rsEEG cortical eLORETA source activities. We found a significant positive association between the DMN gray matter volume, the rsEEG alpha source activity estimated in the posterior DMN nodes (parietal and posterior cingulate cortex), and the global cognitive status in the Nold and ADD participants. Compared with the Nold, the ADD group showed lower DMN gray matter, lower rsEEG alpha source activity in those nodes, and lower global cognitive status. This effect was not observed in the DAN and SMN. These results suggest that the DMN structural integrity and the rsEEG alpha source activities in the DMN posterior hubs may be related and predict the global cognitive status in ADD and Nold persons.

Brain functional connectivity differences between responders and non-responders to sleeve gastrectomy.

PURPOSE: To compare resting-state functional connectivity (RSFC) of obese patients responders or non-responders to sleeve gastrectomy (SG) with a group of obese patients with no past medical history of metabolic or bariatric surgery. METHODS: MR images were acquired at 1.5 Tesla. Resting-state fMRI data were analyzed with statistical significance threshold set at p < 0.05, family-wise error (FWE) corrected. RESULTS: Sixty-two subjects were enrolled: 20 controls (age range 25-64; 14 females), 24 responders (excess weight loss > 50%; age range 23-68; 17 females), and 18 non-responders to sleeve gastrectomy (SG) (excess weight loss < 50%; age range 23-67; 13 females). About within-network RSFC, responders showed significantly lower RSFC with respect to both controls and non-responders in the default mode and frontoparietal networks, positively correlating with psychological scores. Non-responders showed significantly higher (p < 0.05, family-wise error (few) corrected) RSFC in regions of the lateral visual network as compared to controls. Regarding between-network RSFC, responders showed significantly higher anti-correlation between executive control and salience networks (p < 0.05, FWE corrected) with respect to both controls and non-responders. Significant positive correlation (Spearman rho = 0.48, p = 0.0012) was found between % of excess weight loss and executive control-salience network RSFC. CONCLUSION: There are differences in brain functional connectivity in either responders or non-responders patients to SG. The present results offer new insights into the neural correlates of outcome in patients who undergo SG and expand knowledge about neural mechanisms which may be related to surgical response.

Functional connectivity alterations in migraineurs with Alice in Wonderland syndrome.

BACKGROUND AND PURPOSE: Alice in Wonderland syndrome (AIWS) is a neurological disorder characterized by erroneous perception of the body schema or surrounding space. Migraine is the primary cause of AIWS in adults. The pathophysiology of AIWS is largely unknown, especially regarding functional abnormalities. In this study, we compared resting-state functional connectivity (FC) of migraine patients experiencing AIWS, migraine patients with typical aura (MA) and healthy controls (HCs). METHODS: Twelve AIWS, 12 MA, and 24 HCs were enrolled and underwent 3 T MRI scanning. Independent component analysis was used to identify RSNs thought to be relevant for AIWS: visual, salience, basal ganglia, default mode, and executive control networks. Dual regression technique was used to detect between-group differences in RSNs. Finally, AIWS-specific FC alterations were correlated with clinical measures. RESULTS: With respect to HCs, AIWS and MA patients both showed significantly lower (p < 0.05, FDR corrected) FC in lateral and medial visual networks and higher FC in salience and default mode networks. AIWS patients alone showed higher FC in basal ganglia and executive control networks than HCs. When directly compared, AIWS patients showed lower FC in visual networks and higher FC in all other investigated RSNs than MA patients. Lastly, AIWS-specific FC alterations in the executive control network positively correlated with migraine frequency. CONCLUSIONS: AIWS and MA patients showed similar FC alterations in several RSNs, although to a different extent, suggesting common pathophysiological underpinnings. However, AIWS patients showed additional FC alterations, likely due to the complexity of AIWS symptoms involving high-order associative cortical areas.

Alice in Wonderland syndrome: a lesion mapping study.

BACKGROUND AND PURPOSE: Alice in Wonderland syndrome (AIWS) is a rare neurological disorder, characterized by an erroneous perception of the body schema or surrounding space. It may be caused by a variety of neurological disorders, but to date, there is no agreement on which brain areas are affected. The aim of this study was to identify brain areas involved in AIWS. METHODS: We conducted a literature search for AIWS cases following brain lesions. Patients were classified according to their symptoms as type A (somesthetic), type B (visual), or type C (somesthetic and visual). Using a lesion mapping approach, lesions were mapped onto a standard brain template and sites of overlap were identified. RESULTS: Of 30 lesions, maximum spatial overlap was present in six cases. Local maxima were identified in the right occipital lobe, specifically in the extrastriate visual cortices and white matter tracts, including the ventral occipital fasciculus, optic tract, and inferior fronto-occipital fasciculus. Overlap was primarily due to type B patients (the most prevalent type, n = 22), who shared an occipital site of brain damage. Type A (n = 5) and C patients (n = 3) were rarer, with lesions disparately located in the right hemisphere (thalamus, insula, frontal lobe, hippocampal/parahippocampal cortex). CONCLUSIONS: Lesion-associated AIWS in type B patients could be related to brain damage in visual pathways located preferentially, but not exclusively, in the right hemisphere. Conversely, the lesion location disparity in cases with somesthetic symptoms suggests underlying structural/functional disconnections requiring further evaluation.

Italian translation and validation of fatigue symptoms and impacts questionnaire in relapsing multiple sclerosis (FSIQ-RMS).

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS) and impacts on daily life. The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new 20-item tool that investigates the aspects of fatigue in MS. It concerns motor, cognitive, social, and emotional aspects of fatigue. We aim at validating the Italian version of FSIQ-RMS in an Italian population of MS patients and demonstrate its reliability and construct validity. METHODS: We included patients with diagnosis of MS, age between 18 and 70 years with ability to participate in a 90-min interview. Each patient completed the Italian version of FSIQ-RMS and Fatigue Severity Scale (FSS) at the same time. Construct validity was explored by the exploratory factor analysis; reliability was assessed with Cronbach's alpha; and test-retest stability was examined through intraclass correlation coefficient (ICC). Concurrent validity was calculated using Pearson's correlation. RESULTS: We enrolled 171 patients (126 female and 45 male), 83% with relapsing MS (RMS), and 17% with secondary progressive MS (SPMS). Italian FSIQ-RMS showed a Cronbach's alpha of 0.92; ICC was 0.96. Pearson's correlation coefficient between FSIQ-RMS and FSS total score was statistically significant (p < 0.01); FSIQ-RMS inversely correlated also with BMI and positively with EDSS. CONCLUSION: The Italian version of FSIQ-RMS has excellent psychometric properties and can be used in research and clinical setting to evaluate physical, cognitive, and social fatigue in both RMS and SPMS.

Evaluation of Disability Progression in Multiple Sclerosis via Magnetic-Resonance-Based Deep Learning Techniques.

Short-term disability progression was predicted from a baseline evaluation in patients with multiple sclerosis (MS) using their three-dimensional T1-weighted (3DT1) magnetic resonance images (MRI). One-hundred-and-eighty-one subjects diagnosed with MS underwent 3T-MRI and were followed up for two to six years at two sites, with disability progression defined according to the expanded-disability-status-scale (EDSS) increment at the follow-up. The patients' 3DT1 images were bias-corrected, brain-extracted, registered onto MNI space, and divided into slices along coronal, sagittal, and axial projections. Deep learning image classification models were applied on slices and devised as ResNet50 fine-tuned adaptations at first on a large independent dataset and secondly on the study sample. The final classifiers' performance was evaluated via the area under the curve (AUC) of the false versus true positive diagram. Each model was also tested against its null model, obtained by reshuffling patients' labels in the training set. Informative areas were found by intersecting slices corresponding to models fulfilling the disability progression prediction criteria. At follow-up, 34% of patients had disability progression. Five coronal and five sagittal slices had one classifier surviving the AUC evaluation and null test and predicted disability progression (AUC > 0.72 and AUC > 0.81, respectively). Likewise, fifteen combinations of classifiers and axial slices predicted disability progression in patients (AUC > 0.69). Informative areas were the frontal areas, mainly within the grey matter. Briefly, 3DT1 images may give hints on disability progression in MS patients, exploiting the information hidden in the MRI of specific areas of the brain.

Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis.

BACKGROUND: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability. OBJECTIVE: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS). METHODS: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I-V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach. RESULTS: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results. CONCLUSION: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.

No evidence of iron deposition in essential tremor: a susceptibility-weighted imaging study.

OBJECTIVE: To evaluate the role of iron deposition in subcortical nuclei of patients with essential tremor (ET). METHODS: Twenty-three patients with ET underwent a standardized 3T-MRI protocol. We specifically assessed iron deposition using susceptibility-weighted angiography (SWAN) images in seven specific regions of interest (ROIs): the thalamus, putamen, globus pallidus, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus. Tremor in ET patients was clinically assessed using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). ET patient data were compared with data obtained from 23 Parkinson's disease (PD) patients and 14 healthy subjects (HS). RESULTS: No differences in iron deposition in the seven ROIs were found between ET patients and HS. Conversely, PD patients showed increased iron deposition in the substantia nigra in comparison with both ET patients and HS. CONCLUSIONS: Our results indicate the absence of iron deposition in subcortical nuclei of ET patients, which is generally considered a marker of neurodegeneration.

Deep grey matter involvement and altered sensory gating in multiple sclerosis.

BACKGROUND: Somatosensory temporal discrimination threshold (STDT) is altered in multiple sclerosis (MS). In healthy subjects (HS), voluntary movement modulates the STDT through mechanisms of subcortical sensory gating. OBJECTIVE: With neurophysiological and magnetic resonance imaging (MRI) techniques, we investigated sensory gating and sensorimotor integration in MS. METHODS: We recruited 38 relapsing-remitting multiple sclerosis (RR-MS) patients with no-to-mild disability and 33 HS. We tested STDT at rest and during index finger abductions and recorded the movement kinematics. Participants underwent a 3T MRI protocol. RESULTS: Patients exhibited higher STDT values and performed slower finger movements than HS. During voluntary movement, STDT values increased in both groups, albeit to a lesser extent in patients, while the mean angular velocity of finger movements decreased in patients alone. Patients had a smaller volume of the thalamus, pallidum and caudate nucleus, and displayed higher mean diffusivity in the putamen, pallidum and thalamus. STDT correlated with thalamic volume while mean angular velocity correlated with putaminal volume. Changes in mean angular velocity during sensorimotor integration inversely correlated with mean diffusivity in the thalamus and pallidum. Changes in STDT and velocity were associated with fatigue score. CONCLUSION: Altered STDT and sensorimotor integration are related to structural damage in the thalamus and basal ganglia in MS and likely to affect motor performance.

Multi-scale resting state functional reorganization in response to multiple sclerosis damage.

PURPOSE: In multiple sclerosis (MS), how brain functional changes relate to clinical conditions is still a matter of debate. The aim of this study was to investigate how functional connectivity (FC) reorganization at three different scales, ranging from local to whole brain, is related to tissue damage and disability. METHODS: One-hundred-nineteen patients with MS were clinically evaluated with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite. Patients and 42 healthy controls underwent a multimodal 3 T MRI, including resting-state functional MRI. RESULTS: We identified 16 resting-state networks via independent component analysis and measured within-network, between-network, and whole-brain (global efficiency and degree centrality) FC. Within-network FC was higher in patients than in controls in default mode, frontoparietal, and executive-control networks, and corresponded to low clinical impairment (default mode network versus Expanded Disability Status Scale r = - 0.31, p < 0.01; right frontoparietal network versus Paced Auditory Serial Addition Test r = 0.33, p < 0.01). All measures of between-network and whole-brain FC, except default mode network global efficiency, were lower in patients than in controls, and corresponded to high disability (i.e., basal ganglia global efficiency versus Timed 25-Foot Walk r = - 0.25, p < 0.03; default mode global efficiency versus Expanded Disability Status Scale r = - 0.44, p < 0.001). Altered measures of within-network, between-network, and whole-brain FC were combined in functional indices that were linearly related to disease duration, Paced Auditory Serial Addition Test and lesion load and non-linearly related to Expanded Disability Status Scale. CONCLUSION: We suggest that the combined evaluation of functional alterations occurring at different levels, from local to whole brain, could exhaustively describe neuroplastic changes in MS, while increased within-network FC likely represents adaptive compensatory processes, decreased between-network and whole-brain FC likely represent loss of functional network integration consequent to structural disruption.

Abnormal Cerebellar Connectivity Patterns in Patients with Parkinson's Disease and Freezing of Gait.

In this study, we aimed to evaluate the importance of cerebellum in freezing of gait (FOG) pathophysiology. Due to the fundamental role of the cerebellum in posture and gait control, we examined cerebellar structural and functional connectivity (FC) in patients with PD and FOG. We recruited 15 PD with FOG (PD-FOG), 16 PD without FOG (PD-nFOG) patients, and 16 healthy subjects (HS). The FOG Questionnaire (FOG-Q) assessed FOG severity. Three tesla-MRI study included resting-state functional MRI, diffusion tensor imaging (DTI), and 3D T1-w images. We located seed regions in the cerebellar locomotor region, fastigial, and dentate nucleus to evaluate their FC. DTI parameters were obtained on the superior, middle, and inferior cerebellar peduncles. Global and lobular cerebellum volumes were also calculated. Cerebellar locomotor and fastigial FC was higher in cerebellar and posterior cortical areas in PD-FOG than in HS. FC of the cerebellar locomotor region with cerebellar areas positively correlated with FOG-Q. Dentate FC was lower in the prefrontal and parieto-occipital cortices in PD-FOG than in HS and in the brainstem, right basal ganglia, and frontal and parieto-occipital cortices than in PD-nFOG. DTI parameters in superior and middle cerebellar peduncles were altered in PD-FOG compared with PD-nFOG and significantly correlated with FOG-Q. There were no differences in cerebellar volumes between PD-FOG and either PD-nFOG or HS. Our results suggest that altered connectivity of the cerebellum contributes to the pathophysiology of FOG. FC of the cerebellar locomotor region and white matter (WM) properties of cerebellar peduncles correlate with FOG severity, supporting the hypothesis that abnormal cerebellar function underlies FOG in PD.

White matter rather than gray matter damage characterizes essential tremor.

OBJECTIVES: We investigated changes in gray matter (GM) and white matter (WM) in the whole brain, including both cortical and subcortical structures, and their relationship with tremor severity, psychiatric symptoms, and cognitive impairment in patients affected by essential tremor (ET). METHODS: We studied 19 ET patients and 15 healthy subjects (HS). All the subjects underwent a 3-T MRI study based on 3D-T1 and diffusion tensor images. For the GM analysis, cortical thickness was assessed by using the Computational Anatomy Tool, basal ganglia and thalamus volumes by using the FMRIB software library, and cerebellum lobular volumes by using the spatial unbiased atlas template. For the WM assessment, we performed a voxel-wise analysis by means of tract-based spatial statistics. Patients' tremor severity and psychiatric and cognitive disorders were evaluated by means of standard clinical scales. Neuroimaging data were correlated with clinical scores. RESULTS: We found significantly smaller right and left thalamic volumes in ET patients than in HS, which correlated with cognitive scores. We did not observe any significant differences either in cortical thickness or in cerebellar lobular volumes between patients and HS. WM abnormalities were detected in most hemisphere bundles, particularly in the corticospinal tract, cerebellar peduncles, and corpus callosum. The WM abnormalities significantly correlated with tremor severity, cognitive profile, and depression. CONCLUSION: Our study indicates that ET is characterized by several GM and WM changes of both infra- and supratentorial brain structures. The results may help to better understand mechanisms underlying tremor severity and psychiatric and cognitive impairment in ET. KEY POINTS: • We performed a comprehensive evaluation of gray and white matter in the same sample of patients with essential tremor using recently developed data analysis methods. • Essential tremor is characterized by widespread gray and white matter changes in both infra- and supratentorial brain structures. The results may help to better understand motor and non-motor symptoms in patients with essential tremor.

Erratum to "The Role of fMRI in the Assessment of Neuroplasticity in MS: A Systematic Review".

[This corrects the article DOI: 10.1155/2018/3419871.].

Role of Cerebellar Dentate Functional Connectivity in Balance Deficits in Patients with Multiple Sclerosis.

Purpose To prospectively investigate, by using resting-state functional magnetic resonance (MR) imaging, cerebellar dentate nuclei (DNs) functional connectivity abnormalities in multiple sclerosis (MS) to explore their impact on balance impairment in patients with MS, considering the role of DNs and their projections in maintaining balance, posture, and muscle tone, Materials and Methods All subjects provided written informed consent, and the protocol was approved by the university institutional review board. Twenty-five patients with relapsing-remitting MS and 20 healthy control subjects underwent a 3-T resting-state functional MR imaging and static posturography. The seed-based method was applied to identify the cerebellar DNs resting-state network; first-level and high-level analyses were performed by using software tools. Results Compared with control subjects, patients had worse postural stability and altered patterns of cerebellar DNs connectivity network, with decreased connectivity in caudate nuclei and thalami and increased connectivity in the cerebellum, pons, left amygdala, and orbitofrontal cortices (cluster level, family-wise error corrected, P < .05, z threshold > 2.3). In patients, the decreased connectivity in the left caudate nucleus was related with worse balance performance (cluster level, family-wise error corrected P < .05, z threshold > 1.96) regardless of age, lesion burden, and global clinical disability. Conclusion These results reveal abnormalities of corticocerebellar circuit connectivity in patients with MS as compared with control subjects and suggest that the decreased connectivity between the DN and the left caudate nucleus could play a role in balance impairment in MS. © RSNA, 2017.

Lesion symptom map of cognitive-postural interference in multiple sclerosis.

OBJECTIVE: To investigate the disease-altered structure-function relationship underlying the cognitive-postural interference (CPI) phenomenon in multiple sclerosis (MS). METHODS: We measured postural sway of 96 patients and 48 sex-/age-matched healthy controls by force platform in quiet standing (single-task (ST)) while performing the Stroop test (dual-task (DT)) to estimate the dual-task cost (DTC) of balance. In patient group, binary T2 and T1 lesion masks and their corresponding lesion volumes were obtained from magnetic resonance imaging (MRI) of brain. Normalized brain volume (NBV) was also estimated by SIENAX. Correlations between DTC and lesion location were determined by voxel-based lesion symptom mapping (VLSM) analyses. RESULTS: Patients had greater DTC than controls ( p < 0.001). Among whole brain MRI metrics, only T1 lesion volume correlated with DTC ( r = -0.27; p < 0.01). However, VLSM analysis did not reveal any association with DTC using T1 lesion masks. By contrast, we found clusters of T2 lesions in distinct anatomical regions (anterior and superior corona radiata, bilaterally) to be correlated with DTC ( p < 0.01 false discovery rate (FDR)-corrected). A multivariable stepwise regression model confirmed findings from VLSM analysis. NBV did not contribute to fit the model. CONCLUSION: Our findings suggest that the CPI phenomenon in MS can be explained by disconnection along specific areas implicated in task-switching abilities and divided attention.

Dentate nucleus connectivity in adult patients with multiple sclerosis: functional changes at rest and correlation with clinical features.

BACKGROUND AND OBJECTIVE: The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates. MATERIALS AND METHODS: In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC. RESULTS: When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage. CONCLUSION: Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established.

The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence.

Brain plasticity is the basis for systems-level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25-minutes of task practice, were performed. Within-session between-run change in task-related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium-enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between-run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice-induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short-term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery-oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431-2445, 2016. © 2016 Wiley Periodicals, Inc.

Multiple Sclerosis: Changes in Thalamic Resting-State Functional Connectivity Induced by a Home-based Cognitive Rehabilitation Program.

Purpose To investigate thalamic connectivity changes after use of a video game-based cognitive rehabilitation program, as thalamic damage and alterations in thalamocortical functional connectivity (FC) are important factors in cognitive dysfunction in patients with multiple sclerosis (MS). Materials and Methods This prospective study was approved by the local ethical committee. Twenty-four patients with MS and cognitive impairment were randomly assigned to either an intervention or a wait-list group. Patients were evaluated with cognitive tests and 3-T resting-state functional magnetic resonance (MR) imaging at baseline and after an 8-week period. In addition, 11 healthy subjects underwent baseline resting-state functional MR imaging. Patients in the intervention group performed the video game-based cognitive rehabilitation program, while those in the wait-list group served as control subjects. Repeated measures analysis of variance was used to test efficacy of the intervention. The thalamic resting-state network was identified with a seed-based method; both first-level and high-level analyses were performed by using software tools. Results Patients showed lower baseline FC compared with healthy subjects. A significant improvement was seen in results of the Paced Auditory Serial Addition Test and the Stroop Test after 8 weeks of cognitive rehabilitation (F = 6.616, [P = .018] and F = 5.325 [P = .030], respectively). At follow-up, the intervention group had an increased FC in the cingulum, precuneus, and bilateral parietal cortex and a lower FC in the cerebellum and in left prefrontal cortex compared with the wait-list group (P < .05, family-wise error corrected); correlations were found between FC changes in these regions and cognitive improvement (P < .05, family-wise error corrected). Conclusion The results of this study show the relevance of thalamic regulation of the brain networks involved in cognition and suggest that changes in thalamic resting-state network connectivity may represent a functional substrate for cognitive improvement associated with a video game-based cognitive rehabilitation program. (©) RSNA, 2016.

Multiple sclerosis: altered thalamic resting-state functional connectivity and its effect on cognitive function.

PURPOSE: To investigate, by using resting-state (RS) functional magnetic resonance (MR) imaging, thalamocortical functional connectivity (FC) and its correlations with cognitive impairment in multiple sclerosis (MS). MATERIALS AND METHODS: All subjects provided written informed consent; the study protocol was approved by the university institutional review board for this HIPAA-compliant study. Forty-eight patients with relapsing-remitting MS and 24 control subjects underwent multimodal MR imaging, including diffusion-tensor imaging, three-dimensional (3D) T1-weighted imaging, and functional MR imaging at rest and a neuropsychological examination with the Paced Auditory Serial Addition Test (PASAT). Functional MR imaging data were analyzed with tools from FMRIB Software Library, by using the seed-based method to identify the thalamic RS network (RSN). RESULTS: When compared with control subjects, patients showed gray matter and white matter atrophy, as well as diffusion-tensor imaging abnormalities (P < .01). Patients displayed significantly greater synchronization than control subjects in the cerebellum; basal ganglia; hippocampus; cingulum; and temporo-occipital, insular, frontal, and parietal cortices. They also exhibited significantly lower synchronization in the thalamus; cerebellum; cingulum; and insular, prefrontal, and parieto-occipital cortices (cluster level, P < .05, corrected for familywise error [FWE]). In patients, the PASAT score at 3 seconds significantly inversely correlated with the thalamus, cerebellum, and some cortical areas in all cerebral lobes; the PASAT score at 2 seconds significantly correlated, even more strongly, with all the aforementioned regions and, in addition, with the cingulum and the left hippocampus (cluster level, P < .05, corrected for FWE). CONCLUSION: Thalamic RSN is disrupted in MS, and decreased performance in cognitive testing is associated with increased thalamocortical FC, thus suggesting that neuroplasticity changes are unable to compensate for tissue damage and to prevent cognitive dysfunction.