Reduced neurite density in the brain and cervical spinal cord in relapsing-remitting multiple sclerosis: A NODDI study.

BACKGROUND: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). OBJECTIVE: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing-remitting MS (RRMS) patients. METHODS: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). RESULTS: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. CONCLUSION: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.

The Influence of Contrast-to-Noise Ratio on the Discrimination Between Cortical and Juxtacortical Lesions in Multiple Sclerosis.

OBJECTIVE: The objective of this study was to investigate the contrast-to-noise ratio (CNR) between cortical gray matter (GM) and subcortical white matter (WM) across the cortex in relation to the ability of 3-dimensional fluid attenuated inversion recovery and 3-dimensional double inversion recovery to distinguish between cortical lesions (CLs) and juxtacortical lesions (JCs). METHODS: A total of 38 multiple sclerosis patients underwent magnetic resonance imaging. Two neuroradiologists scored CLs and JCs on magnetic resonance imaging in 9 cerebral areas. Lesions were marked as nonclassifiable (NCs) when blurred WM-GM boundary leads to inaccuracy of their discrimination. The CNR between WM and GM (CNRWM-GM) was evaluated across the cortical areas. RESULTS: The CNRWM-GM varies across the cortex; the lower values were found in motor and sensorimotor areas where almost all NCs were localized. A strong negative correlation was found between CNRWM-GM and NCs. CONCLUSIONS: Discrimination between CLs and JCs is affected from the sharp visualization of the WM-GM boundary, which is directly related to CNRWM-GM.

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.

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.

Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board.

PURPOSE: To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging ( DTI diffusion-tensor imaging ) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis. MATERIALS AND METHODS: The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI diffusion-tensor imaging parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI diffusion-tensor imaging parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing. RESULTS: There were relevant differences between patients and healthy control subjects in postural sway and DTI diffusion-tensor imaging parameters (P < .05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = -0.381 to 0.401, P < .05). However, both clinical and DTI diffusion-tensor imaging changes did not persist beyond 12 weeks after training. CONCLUSION: Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelination-related processes, suggesting that high-intensity, task-oriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis.

Balance deficit with opened or closed eyes reveals involvement of different structures of the central nervous system in multiple sclerosis.

OBJECTIVE: To evaluate whether balance deficit in patients with multiple sclerosis (MS), as assessed with eyes opened (EO) and closed (EC), is associated with damage of different structures of the central nervous system (CNS). METHODS: Fifty patients with MS and 20 healthy controls (HCs) underwent static posturography to calculate the body's center of pressure displacement (COP path) with EO and EC. They were scanned using a 3.0T magnet to obtain PD/T2 and 3D-T1-weighted images of the brain and spinal cord. We determined the mid-sagittal cerebellum area (MSCA) and upper cervical cord cross-sectional area (UCCA). We also measured the patients' lesion volumes (T2-LVs) on the whole brain and at different infratentorial levels. RESULTS: MS patients had wider COP paths with both EO and EC (p < 0.001), and lower values in both MSCA (p = 0.01) and UCCA (p = 0.008) than HCs. The COP path with EO was associated with MSCA (Beta = -0.58; p = 0.004) and T2-LV on middle cerebellar peduncles (Beta = 0.59; p = 0.002). The COP path with EC was associated with UCCA (Beta= -22.74; p = 0.003) and brainstem T2-LV (Beta = 0.52; p = 0.01). CONCLUSIONS: Balance deficit in MS was related to atrophy of both the cerebellum and spinal cord, but the extent of COP path under the two different conditions (EO or EC) implied different patterns of damage in the CNS.

Multiple sclerosis: white and gray matter damage associated with balance deficit detected at static posturography.

PURPOSE: To combine two unbiased (ie, without any a priori hypothesis) magnetic resonance (MR) imaging processing approaches, tract-based spatial statistics and voxel-based morphometry, to investigate the relationship between white matter and gray matter damage and computer-based measures of balance impairment assessed at static posturography in patients with multiple sclerosis (MS). MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Forty-five ambulatory patients with MS (34 women, 11 men) and 25 sex- and age-matched healthy control subjects were assessed by using a force platform to compute the displacement (in millimeters) of the body center of pressure in 30 seconds. In a separate session, patients underwent MR imaging at 3 T, including a dual-echo fast spin-echo sequence, a T1-weighted volume sequence, and a diffusion-tensor imaging sequence. T2 lesion volumes were assessed by using a semiautomated technique. Tract-based spatial statistics and voxel-based morphometry were used for the white and gray matter analyses, respectively, to correlate force platform measures with diffusion-tensor imaging parameters and regional gray matter volumes, adjusting for the patients' sex, age, disease duration, and lesion volume. RESULTS: Patients with MS had worse postural stability, widespread alterations in most white matter bundles, and gray matter atrophy in several brain regions compared with control subjects. In patients with MS, balance impairment was correlated with worse diffusion-tensor imaging parameters along the cerebellar connections and supratentorial associative white matter bundles (P < .05, threshold-free cluster enhancement corrected). Gray matter atrophy of the superior lobules of the cerebellum (IV, V, VI), and lobules VIII also correlated with worse posturometric values (P < .05, family-wise error corrected). CONCLUSION: Imbalance due to MS appears to be related to the disconnection between the spinal cord, cerebellum, and cerebral cortex, which in turn produces atrophy of the sensory motor cerebellar regions that are functionally connected with specific cortical areas.

Idiopathic Intracranial Hypertension Papillopathy due to Hormonal Changes during Pregnancy.

Background: The underlying mechanisms of papilledema associated with intracranial hypertension remain unclear. A case of bilateral papillary edema in a patient with chronic idiopathic intracranial hypertension who was asymptomatic during her two pregnancies is reported. Case Presentation. A 19-year-old Caucasian female, in her third month of pregnancy, complained of difficulties with close reading. The patient's visual acuity was 20/20 on the Snellen chart and improved with a 0.50 D correction in both eyes. Near vision and slit lamp examinations revealed normal findings bilaterally. However, a fundus examination showed bilateral papillary edema without evidence of hemorrhages or neovascularization. Blood tests were unremarkable, except for a slight increase in C-reactive protein levels. The patient had a prepregnancy weight of 63 kilograms, with a BMI of 24.91 kg/m2. Magnetic resonance imaging of the brain revealed features consistent with chronic idiopathic intracranial hypertension, which resolved after delivery. Two and a half years later, during a subsequent pregnancy, the patient experienced a recurrence of bilateral papillary edema due to the IIH. It was managed similarly as the first occurrence, resulting in bilateral anatomical and functional recovery. Recent research revealed that, during pregnancy, hormones interact with the central nervous system, leading to an increase in the size of neurons which could potentially result in intracranial hypertension. Conclusions: The influence of hormonal fluctuations during pregnancy on the development of transient central nervous system abnormalities in individuals with chronic intracranial hypertension, leading to papillary edema, remains a matter of debate.

Impaired cortical deactivation during hand movement in the relapsing phase of multiple sclerosis: a cross-sectional and longitudinal fMRI study.

BACKGROUND: Little is known about the cortical activation changes during clinical relapses in multiple sclerosis (MS). OBJECTIVE: To assess cross-sectional and longitudinal differences in functional magnetic resonance imaging (fMRI) cortical patterns between the relapsing and stable phases of MS. METHODS: We studied 32 patients with relapsing-remitting MS with mild disability: 19 within 48 h of symptom onset of a new relapse (G1) and 13 in the stable phase, relapse-free for at least 6 months (G2). All patients underwent fMRI twice, upon entry (time 1) and 30-50 days later (time 2), during right-hand movement. RESULTS: No between-group differences were observed in age, disability or T2 lesion load. Between-group analysis showed a significant difference in the ipsilateral precentral gyrus (IPG) activation at time 1. Activity differences in the IPG expressed reduced deactivation in G1 compared with G2. Longitudinal changes in brain activity in the IPG were significantly greater in G1 than G2. G1 patients with a slow clinical recovery (n = 8) showed different activity at baseline and greater activity changes over time in the IPG than patients with a fast recovery (n = 11). CONCLUSION: This study shows that the relapsing phase is associated with reduced brain deactivation in the IPG, which is more marked in patients with a slow clinical recovery. Increased cortical excitability associated with inflammation may determine functional modifications within the ipsilateral motor area.

Neuroimaging in Sickle Cell Disease: A Review.

Sickle cell disease is the most common hereditary hemoglobinopathy, which results in abnormally shaped and rigid red blood cells. These sickle-shaped red blood cells cause vaso-occlusion and ischemic phenomena that can affect any organ in the body. As a common cause of disability, the neurological manifestations of sickle cell disease are particularly important. Neuroimaging has a crucial role in the diagnosis, management, and prevention of the complications of sickle cell disease. These complications can affect the brain parenchyma, vasculature, and skull and can be ascribed directly or indirectly to a vasculopathy of small and large vessels. Vaso-occlusion can cause ischemic stroke. Ischemic damage in the absence of an acute neurological deficit, and therefore only apparent on neuroimaging, is termed silent cerebral ischemia. Weakening of the arterial walls can cause aneurysms. In its most severe form, a vasculopathy of the terminal internal carotid arteries can progress to moyamoya syndrome, characterized by steno-occlusive disease and the formation of friable collateral arteries. Rupture of aneurysms or friable collateral arteries is a potential cause of intracranial hemorrhage. The skull and vertebrae may be affected by extra-medullary hematopoiesis, due to severe anemia, or iron deposition, due to chronic red blood cell transfusion. Impaired blood supply to bone is associated with osteomyelitis and osteonecrosis. Fat embolization syndrome is a rare complication of osteonecrosis, which may cause devastating neurological impairment. Awareness and early recognition of the diverse manifestations of sickle cell disease on neuroimaging is crucial to ensure optimal treatment in a complex patient cohort.

Cerebral microhaemorrhage in COVID-19: a critical illness related phenomenon?

BACKGROUND: Cerebral microhaemorrhages are increasingly being recognised as a complication of COVID-19. This observational retrospective study aims to further investigate the potential pathophysiology through assessing the pattern of microhaemorrhage and clinical characteristics of patients with COVID-19 and microhaemorrhage. By comparing with similar patterns of microhaemorrhage in other non-COVID-19 disease, this study aims to propose possible common pathogenic mechanisms. METHODS: A retrospective observational case series was performed identifying all patients with COVID-19 complicated by cerebral microhaemorrhage on MRI. The distribution and number of microhaemorrhages were recorded using the microbleed anatomical scale, and patients' baseline characteristics and salient test results were also recorded. RESULTS: Cerebral microhaemorrhages were noted to have a predilection for the corpus callosum, the juxtacortical white matter and brainstem. All patients had a preceding period of critical illness with respiratory failure and severe hypoxia necessitating intubation and mechanical ventilation. DISCUSSION: This study demonstrates a pattern of cerebral microhaemorrhage that is similar to the pattern reported in patients with non-COVID-19 related critical illness and other causes of severe hypoxia. This raises questions regarding whether microhaemorrhage occurs from endothelial dysfunction due the direct effect of SARS-CoV-2 infection or from the secondary effects of critical illness and hypoxia.

Development of Autoimmune Thyroid Disease in Multiple Sclerosis Patients Post-Alemtuzumab Improves Treatment Response.

CONTEXT: Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20% and 40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect. OBJECTIVE: The objective of this work is to determine whether MS disease progression following alemtuzumab treatment differs in patients who develop AITD compared to those who do not. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 was conducted at a tertiary referral center. MAIN OUTCOME MEASURES: Thyroid status, new relapses, Expanded Disability Status Scale (EDSS) score change, and disability progression following alemtuzumab were evaluated. RESULTS: Twenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [interquartile range]; AITD: -0.25 [-1 to 0.5] vs non-AITD: 0 [1-0]. P = .007]. Multivariable regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (P = .011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (P = .023). There was no difference in the number of new focal T2 lesions and contrast-enhancing magnetic resonance imaging lesions developed following alemtuzumab between the 2 groups. CONCLUSION: Graves disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate.

COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.

OBJECTIVE: To describe a novel case of coronavirus disease 2019 (COVID-19)-associated acute necrotizing encephalopathy (ANE) in a patient with aplastic anemia where there was early brain stem-predominant involvement. METHODS: Evaluation of cause, clinical symptoms, and treatment response. RESULTS: A 59-year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness 10 days after the onset of subjective fever, cough, and headache. Nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was positive, and CT during admission demonstrated diffuse swelling of the brain stem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient's condition deteriorated, and MRI on day 6 demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. Appearances were consistent with hemorrhagic ANE with early brain stem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission. CONCLUSIONS: COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19-related neurologic disease.

Functional Connectivity Changes After Initial Treatment With Fingolimod in Multiple Sclerosis.

On the basis of recent functional MRI studies, Multiple Sclerosis (MS) has been interpreted as a multisystem disconnection syndrome. Compared to normal subjects, MS patients show alterations in functional connectivity (FC). However, the mechanisms underlying these alterations are still debated. The aim of the study is to investigate resting state (RS) FC changes after initial treatment with fingolimod, a proven anti-inflammatory and immunomodulating agent for MS. We studied 32 right-handed relapsing-remitting MS patients (median Expanded Disability Status Scale: 2.0, mean disease duration: 8.8 years) who underwent both functional and conventional MRI with a 3 Tesla magnet. All assessments were performed 3 weeks before starting fingolimod, then, at therapy-initiation stage and at month 6. Each imaging session included scans at baseline (run1) and after (run2) a 25-min, within-session, motor-practice task, consisting of a paced right-thumb flexion. FC was assessed using a seed on the left primary motor cortex to obtain parametric maps at run1 and task-induced FC change (run2-run1). Comparison between 3-week before- and fingolimod start sessions accounted for a test-retest effect. The main outcome was the changes in both baseline and task-induced changes in FC, between initiation and 6 months. MRI contrast enhancement was detected in 14 patients at initiation and only in 3 at month 6. There was a significant improvement (p < 0.05) in cognitive function, as measured by the Paced Auditory Serial Addition Task, at month 6 compared to initiation. After accounting for test-retest effect, baseline FC significantly decreased at month 6, with respect to initiation (p < 0.05, family-wise error corrected) in bilateral occipito-parietal areas and cerebellum. A task-induced change in FC at month 6 showed a significant increment in all examined sessions, involving not only areas of the sensorimotor network, but also posterior cortical areas (cuneus and precuneus) and areas of the prefrontal and temporal cortices (p < 0.05, family-wise error corrected). Cognitive improvement at month 6 was significantly (p < 0.05) related to baseline FC reduction in posterior cortical areas. This study shows significant changes in functional connectivity, both at baseline and after the execution of a simple motor task following 6 months of fingolimod therapy.