Search

Objective: Executive functioning (EF) can be one of the earliest, despite under-detected, impaired cognitive domains in patients with multiple sclerosis (pwMS). However, it is still not clear the role of EF on verbal fluency tests given the presence of information processing speed (IPS) deficits in pwMS. Method: Performance of a group of 43 pwMS without IPS impairment as measured with the Symbol Digit Modalities Test (SDMT) and a group of 32 healthy controls (HC) was compared on the Phonemic and Semantic Fluency Tests. For each group, we scored the number of words generated (i) in the early time interval (i.e., first 15 sec, semi-automatic process) and (ii) in the late time interval (i.e., from 15 to 60 sec, controlled process). Results: Globally, pwMS produced significantly fewer words than HC on the Phonemic but not on the Semantic Fluency Test. Crucially, in the Phonemic Fluency Test pwMS generated significantly fewer words than HC in the late time interval, whereas no significant difference between the two groups emerged in the early time interval. Conclusions: These findings suggest that executive dysfunction is the core element on the Phonemic Fluency Test also in pwMS and it deserves attention in both research and clinical practice.

Background: The cerebrospinal fluid (CSF) molecular milieu is a marker of diffuse intrathecal inflammation in the meninges that, in turn, targets the grey matter (GM) in multiple sclerosis (MS). Cognitive impairment (CI) is associated with brain damage in MS and is often present early in people with MS (pwMS). Objective: To investigate whether a specific CSF inflammatory profile is associated with different degrees of CI in newly diagnosed pwMS. Methods: Sixty-nine pwMS and 43 healthy controls (HCs) underwent neuropsychological testing. The presence and levels of 57 inflammatory mediators in the CSF were assessed. Results: Apparently cognitively normal (ACN) pwMS had impaired executive functioning compared to HCs but performed better than pwMS with mild and severe CI (mCI and sCI) in all tests. CSF mediators involving innate immunity and immune activation and recruitment, differentiate ACN from pwMS with mCI, while CSF mediators related to B- and T-cell immunity and chemotaxis differentiate both ACN and mCI from those with sCI. CXCL13 was the only molecule that differentiated sCI from mCI pwMS. Conclusion: Specific CSF molecular patterns, reflecting the involvement of both innate and adaptive immune responses, are associated with the severity of CI in newly diagnosed pwMS.

Objective:To further investigate objective measures of cognitive fatigue (CF), defined as the inability to sustain performance over time, in newly diagnosed multiple sclerosis (MS) patients, by conducting a performance analysis on the Paced Auditory Serial Addition Test (PASAT) based on the type of errors (omissions vs. incorrect responses) committed.Method:Sixty-two newly diagnosed patients with MS (pwMS) and 41 healthy controls (HC) completed the PASAT. Analysis of the change in performance during the test was performed by comparing the number of correct responses, incorrect responses, and omissions in the 1st versus the 3rd tertile of the PASAT.Results:A significant decline in accuracy over time was observed to be related to an increment in the number of omissions, significantly more pronounced in pwMS than in HC. No change in the number of incorrect responses throughout the PASAT was observed for either group.Conclusions:CF can be detected even in newly diagnosed pwMS and might objectively manifest as a progressive increase in omissions during a sustained highly demanding task (i.e., PASAT). This pattern may reflect slowed processing speed and increased fatigue in pwMS. Focusing on omissions on the PASAT instead of correct responses only may improve its specificity as an objective measure of CF.

The aim of the study is to investigate the impact of coping strategies on Health-Related Quality of Life (HRQoL) and physical disability assessed with the Expanded Disability Status Scale (EDSS) of people with multiple sclerosis (pwMS). PwMS were asked to focus on “MS diagnosis” as the core stressor. One hundred eight pwMS completed the Coping Responses Inventory-Adult form (CRI-Adult), the Multiple Sclerosis Quality of Life-29 (MSQoL-29), and the Depression Anxiety Stress Scale-21 (DASS-21). Multiple regression analyses (first block: EDSS, disease duration, and DASS-21) revealed that physical MSQoL-29 was positively associated with Alternative Rewards and negatively with Resigned Acceptance of the CRI-Adult. The mental MSQoL-29 was positively associated with Problem-Solving and negatively with Emotional Discharge. The Expanded Disability Status Scale (EDSS; first block: disease duration and general distress) was negatively associated with Positive Reappraisal. The Analysis of covariance (ANCOVA) revealed that pwMS with lower physical disability showed higher scores in Positive Reappraisal and lower scores in Emotional Discharge than pwMS with a higher physical disability. Coping strategies can play a role on HRQoL and physical disability in pwMS above and beyond EDSS, disease duration, and general distress. Psychological interventions should be considered in pwMS since the time of diagnosis to promote engagement in adaptive coping strategies and contrast the maladaptive ones.

Although cognitive impairment (CI) is frequently observed in people with multiple sclerosis (pwMS), its pathogenesis is still controversial. Conflicting results emerged concerning the role of microstructural gray matter (GM) damage especially when involving the deep GM structures. In this study, we aimed at evaluating whether differences in cortical and deep GM structures between apparently cognitively normal (ACN) and CI pwMS (36 subjects in total) are present, using an extensive set of diffusion MRI (dMRI) indices and conventional morphometry measures. The results revealed increased anisotropy and restriction over several deep GM structures in CI compared with ACN pwMS, while no changes in volume were present in the same areas. Conversely, reduced anisotropy/restriction values were detected in cortical regions, mostly the pericalcarine cortex and precuneus, combined with reduced thickness of the superior frontal gyrus and insula. Most of the dMRI metrics but none of the morphometric indices correlated with the Symbol Digit Modality Test. These results suggest that deep GM microstructural damage can be a strong anatomical substrate of CI in pwMS and might allow identifying pwMS at higher risk of developing CI.

Social cognition (SC) can be impaired in multiple sclerosis (MS) patients; however, most studies have not controlled for generalized cognitive impairment (CI), nor have they examined the role of the amygdala using advanced structural neuroimaging. Whether deficits in SC occur in the disease even before the concomitant manifestation of CI, with a specific interest in the role of bilateral amygdala.In this study, we enrolled 31 RRMS patients and 38 healthy controls (HC). SC was examined with the Reading the Mind in the Eyes (RME), a task of facial affect recognition (FAR), and the empathy quotient (EQ). 3T MRI scans were obtained for all patients with special interest in quantifying amygdala lesions by cortical lesion volume (CLV) estimation.The results showed that the RRMS group did worse as compared to HC in the RME (p .001), the FAR task (p = .001), and the EQ (p = .022). Patients had mainly difficulties in recognition the negative emotions of fear (p .001) and anger (p = .036). Finally, CLV of bilateral amygdala was a significant predictor of RME (p .001) and FAR (p = .005).We conclude that SC can be impaired in several domains in RRMS patients even in the absence of CI and that it is related specifically to bilateral amygdala damage as measured by CLV.

Introduction In this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. Methods We studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. Results The mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 ± 1.0 vs 1.7 ± 1.0, p Conclusion Our findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage.

Social cognition (SC) has become a topic of widespread interest in the last decade. SC deficits were described in multiple sclerosis (MS) patients, in association with amygdala lesions, even in those without formal cognitive impairment. In this 3-year follow-up study, we aimed at longitudinally investigating the evolution of SC deficits and amygdala damage in a group of cognitive-normal MS patients, and the association between SC and psychological well-being. After 3 years (T3) from the baseline examination (T0), 26 relapsing-remitting MS patients (RRMS) were retested with a neuropsychological battery and SC tasks (theory of mind, facial emotion recognition, empathy). A SC composite score (SCcomp) was calculated for each patient. Emotional state, fatigue, and quality of life (QoL) were also evaluated. RRMS patients at T3 underwent a 3T-MRI as performed at T0, from which were calculated both volume and cortical lesion volume (CLV) of the amygdalae. Compared to T0, at T3 all RRMS patients were still cognitive-normal and remained stable in their global SC impaired performance. At T0, SCcomp correlated with amygdala CLV (p = 0.002) while, at T3, was more associated with amygdala volume (p = 0.035) rather than amygdala CLV (p = 0.043). SCcomp change T3-T0 correlated with global emotional state (p = 0.043), depression (p = 0.046), anxiety (p = 0.034), fatigue (p = 0.025), and QoL-social functioning (p = 0.033). We showed the longitudinal stability of SC deficits in cognitive-normal RRMS patients, mirroring the amygdala structural damage and the psychological well-being. These results highlight that SC exerts a key role in MS.

Objective: Slowing information processing speed (IPS) is a biomarker of neuronal damage in patients with multiple sclerosis (pwMS). A focus on IPS might be the ideal solution in the perspective of ...

BACKGROUND The mechanisms driving primary progressive and relapsing-remitting multiple sclerosis (PPMS/RRMS) phenotypes are unknown. Magnetic resonance imaging (MRI) studies support the involvement of gray matter (GM) in the degeneration, highlighting its damage as an early feature of both phenotypes. However, the role of GM microstructure is unclear, calling for new methods for its decryption. PURPOSE To investigate the morphometric and microstructural GM differences between PPMS and RRMS to characterize GM tissue degeneration using MRI. STUDY TYPE Prospective cross-sectional study. SUBJECTS Forty-five PPMS (26 females) and 45 RRMS (32 females) patients. FIELD STRENGTH/SEQUENCE 3T scanner. Three-dimensional (3D) fast field echo T1-weighted (T1-w), 3D turbo spin echo (TSE) T2-w, 3D TSE fluid-attenuated inversion recovery, and spin echo-echo planar imaging diffusion MRI (dMRI). ASSESSMENT T1-w and dMRI data were employed for providing information about morphometric and microstructural features, respectively. For dMRI, both diffusion tensor imaging and 3D simple harmonics oscillator based reconstruction and estimation models were used for feature extraction from a predefined set of regions. A support vector machine (SVM) was used to perform patients' classification relying on all these measures. STATISTICAL TESTS Differences between MS phenotypes were investigated using the analysis of covariance and statistical tests (P

Whether gray matter (GM) regions are differentially vulnerable in Relapsing-Remitting and Primary Progressive Multiple Sclerosis (RRMS and PPMS) is still unknown. The objective of this study was to evaluate morphometric and microstructural properties based on structural and diffusion magnetic resonance imaging (dMRI) data in these MS phenotypes, and verify if selective intra-pathological alterations characterise GM structures. Diffusion Tensor Imaging (DTI) and 3D Simple Harmonics Oscillator based Reconstruction and Estimation (3D-SHORE) models were used to fit the dMRI signals, and several features were subsequently extracted from the regional values distributions (e.g., mean, median, skewness). Statistical analyses were conducted to test for group differences and possible correlations with physical disability scores. Results highlighted 3D-SHORE sensitivity to microstructural differences in hippocampus, which was also significantly correlated to physical disability. Conversely, morphometric measurements did not reach any statistical significance. Our study emphasized the potential of dMRI, and in particular the importance of advanced models such as 3D-SHORE with respect to DTI in characterizing the two MS types. In addition, hippocampus has been revealed as particularly relevant in the distinction of RRMS from PPMS and calls for further investigation.

Introduction and methods In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS‐specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post‐mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf‐L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis. Results PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P

Pitch-height can be represented in a spatial format. Reaction times (RTs) to lower pitch-heights are faster when responses are executed in the lower side of space, whereas RTs to higher pitch-heights are faster when responses are executed in the upper side of space. This effect is called the Spatial-Music Association of Response Codes (SMARC) effect. We investigated how pitch-height and the brightness of a tone's timbre might contribute in eliciting the SMARC effect as a function of music expertise by comparing the results of 24 musicians with the results we gathered previously (Pitteri et al., 2017) with 24 non-musicians. Three experimental conditions were used: pitch-height varied, brightness varied; pitch-height varied, brightness fixed; pitch-height fixed, brightness varied. We found that the coherent modulation of both pitch-height and brightness elicited the strongest SMARC effect, independently of music expertise. These results add evidence to the hypothesis that the strongest SMARC effect does not belong to pitch-height or brightness, but to pitch-height and brightness together.

Background Memory impairment is one of the most frequently and early detected impairment in multiple sclerosis (MS) patients. Several authors have argued that when a failure occurs in the retrieval of lexical information, this might be due to a reduction of the lexical pool, related to semantic memory. Here we further investigated memory alteration in MS patients, by focusing on memory distortions (i.e., false memories) for semantically-related material. Methods A group of 40 consecutive relapsing remitting MS (RRMS) patients and a matched control group of 40 healthy controls performed the Deese-Roediger-McDermott (DRM), a false memory task for lists of associated words. Results At recall, RRMS patients reported a reduced number of false recalls for semantically-related but non-presented items (i.e., critical false recalls) compared to HCs; at recognition, RRMS patients showed a reduced level of confidence for false recognitions of critical items. Conclusion We found a reduced susceptibility to false memories in RRMS patients compared to HCs. The potential mechanisms underlying this effect are discussed in light of the alterations in the structure of semantic memory.

Verbal learning and memory deficits are among the most frequent in people with multiple sclerosis (pwMS) and have been shown to be affected by deficits in other cognitive domains, such as information processing speed and executive functioning (EF). In the present study, we aimed to further investigate the differential impact that EF may exert on verbal learning and memory on both behavioural and neural levels. Seventy pwMS were assessed with a comprehensive battery of neuropsychological tests, including tests of verbal memory (Selective Reminding Test; SRT) and EF (Stroop test; Phonemic and Alternate Verbal Fluency; Modified Five-Point Test). Structural 3Tesla magnetic resonance imaging (MRI) scans were available for 68 patients; cortical thickness of several frontal, pre-frontal, and hippocampal regions was calculated. Multivariable linear regression analysis showed that patients' performance on Alternate Fluency Test predicted both their immediate (SRT-LTS: R2 = .38; p

OBJECTIVE Spatial neglect (SN) constitutes a substantial barrier to functional recovery after acquired brain injury. However, because of its multimodal nature, no single test can capture all the signs of SN. To provide a clinically feasible solution, we used conventional neuropsychological tests as well as the Catherine Bergego Scale (CBS) via the Kessler Foundation Neglect Assessment Process (KF-NAP). The goal was to add evidence that a global approach should detect better even subtle signs of SN. METHOD Fourteen individuals with lesions located in the right cerebral hemisphere participated in the study. Participants were assessed with a comprehensive battery of neuropsychological tests, comprising a set of visuospatial tests to evaluate several spatial domains. In addition, patients underwent functional assessment with the Barthel Index, the Functional Independence Measure (FIM), and the CBS via KF-NAP. RESULTS The CBS via KF-NAP was associated with the visuospatial paper-based tests (p = .004) as well as the Motor FIM (p = .003), and was more sensitive than the Behavioral Inattention Test-Conventional in detecting SN (p = .014). CONCLUSIONS We showed that the CBS via KF-NAP was able: (a) to detect functional impairment, especially motor, related to SN; (b) to selectively measures spatial rather than nonspatial dysfunctions; and (c) to be highly sensitive in detecting SN signs especially in those patients with mild severity, covering several aspects of SN manifestations. The patient's SN diagnosis based on the CBS via KF-NAP is clinically important and directly relevant to care planning and goal setting. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The mechanism of action of fingolimod within the central nervous system and its efficacy in reducing/preventing both focal and diffuse grey matter (GM) damage in active multiple sclerosis (MS) are not completely understood. In this longitudinal, 2-year prospective, phase IV, single-blind study, 40 MS patients treated with fingolimod and 39 untreated age, gender, and disability-matched MS patients were enrolled. Each patient underwent a neurological examination every 6 months and a 3T MRI at the beginning of the treatment and after 24 months. The accumulation of new cortical lesions (CLs) and the progression of regional GM atrophy were compared between the two groups. At the end of the study (T24), the percentage of patients with new CLs (13.5 vs. 89%, p

Objective Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course? Methods To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. Results Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. Interpretation A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739-755.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti-inflammatory effect and/or to a direct effect on neuronal cells.In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS.Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect.

Introduction Among disease-modifying treatments for multiple sclerosis, natalizumab (NTZ) is highly effective, well tolerated and generally safe. Major concerns regard the risk of developing progressive multifocal leukoencephalopathy (PML), and the occurrence of rebounds or disease activity after its discontinuation. The aim of this study was to explore the efficacy of dimethyl fumarate (DMF) in preventing disease reactivation after NTZ discontinuation. Methods Thirty-nine patients with relapsing remitting multiple sclerosis, at high risk of PML, were switched from NTZ to DMF and underwent neurological and 3T MRI monitoring for 2 years. Clinical and MRI data regarding the 2-year period preceding NTZ treatment, the 2 years of NTZ treatment and the 2 years of DMF were collected. Results During the DMF phase, among the 39 patients, one or more relapses occurred in five patients (12.8%), increased disability progression in 4 (10.3%) and MRI activity in 8 (20.5%). Post-NTZ rebound effect was observed only in one patient. Overall, only two dropouts (one rebound activity and one gastrointestinal side effect) were registered and almost 80% of the patients have still no evidence of disease activity at the end of DMF treatment. The multiple linear regression model revealed that the number of relapses and MRI parameters before DMF treatment were good predictors of disease activity during treatment with DMF. Discussion DMF appeared generally safe and no carryover PML among investigated cases was observed. Although DMF did not eliminate the possibility of disease reactivation, it seems anyway a promising drug for those patients who shall discontinue NTZ. The clinical and radiological activity preceding the DMF treatment might be used as a prognostic marker of therapy response.

Purpose: Spatial neglect (SN) impedes rehabilitation success and leaves long-term consequences. We asked experts to provide their opinions in addressing SN by scenario (ideal vs. reality) and by recovery phase (earliest, acute, subacute, and chronic). Experts were individuals who have assessed or treated patients with SN clinically. Materials and methods: This study was conducted using an anonymous survey on the Internet with 189 responders over 3 months. Located in 23 different countries, 127 experts of seven disciplines were included (occupational therapy, physical therapy, nursing, speech and language pathology or therapy, neurology, physical medicine and rehabilitation, and psychology or neuropsychology). Results: Comparing the two scenarios, more treatments were selected in the ideal than in the reality scenario for all recovery phases except for the chronic phase. In both scenarios, (1) more treatments were selected in acute and subacute phases than in earliest or chronic phases, (2) less experienced experts selected diverse treatment options more often, and (3) highly experienced experts were more likely to provide their reasons of treatment selection, suggestions of treatment delivery methods, and other insights. Finally, 83.7% reported obstacles in treating SN. Conclusions: Experts’ treatment selections are consistent with current evidence and practice guidelines. Recognizing the limitation of evidence, their opinions may help generate ideas in various topics (e.g., dosing, integrative intervention, and treatment implementation) to be examined in future studies.Implications for RehabilitationClinicians with experience in treating people with spatial neglect (i.e., experts as defined in the present study) recognized the limitation of evidence but nonetheless suggested specific treatments by recovery phase.In both the reality and ideal scenarios, experts included visual scanning, active limb activation, and sustained attention training in the top-five selections. Prism adaptation was in the top-five selections in the ideal scenario, while in the reality scenario, it was in the top-five in all phases except for the earliest phase where it was the sixth most selected.They also shared their valuable opinions in when to use which treatment to address spatial neglect and how to deliver certain interventions, which may help to generate ideas in various topics (e.g., dosing, integrative intervention, knowledge dissemination, and treatment implementation) that can be examined in future studies.We suggest that (1) clinicians consider collective expert opinions reported here to enhance their clinical judgment and practices, (2) researchers develop studies focused on treatments with limited evidence but selected here by experts, and (3) funding agencies provide the means to research and implementation projects that will generate rich information for improving practice guidelines and rehabilitation outcomes for patients with spatial neglect.The majority of the experts reported some obstacles in providing treatment for spatial neglect, and time and equipment shortages were the most common barriers, which should be addressed at the system level to determine whether removing those barriers have long-term beneficial impacts on both patients and healthcare systems. Clinicians with experience in treating people with spatial neglect (i.e., experts as defined in the present study) recognized the limitation of evidence but nonetheless suggested specific treatments by recovery phase. In both the reality and ideal scenarios, experts included visual scanning, active limb activation, and sustained attention training in the top-five selections. Prism adaptation was in the top-five selections in the ideal scenario, while in the reality scenario, it was in the top-five in all phases except for the earliest phase where it was the sixth most selected. They also shared their valuable opinions in when to use which treatment to address spatial neglect and how to deliver certain interventions, which may help to generate ideas in various topics (e.g., dosing, integrative intervention, knowledge dissemination, and treatment implementation) that can be examined in future studies. We suggest that (1) clinicians consider collective expert opinions reported here to enhance their clinical judgment and practices, (2) researchers develop studies focused on treatments with limited evidence but selected here by experts, and (3) funding agencies provide the means to research and implementation projects that will generate rich information for improving practice guidelines and rehabilitation outcomes for patients with spatial neglect. The majority of the experts reported some obstacles in providing treatment for spatial neglect, and time and equipment shortages were the most common barriers, which should be addressed at the system level to determine whether removing those barriers have long-term beneficial impacts on both patients and healthcare systems.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping–hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

Cognitive functioning in multiple sclerosis (MS) patients is usually related to the classic, dichotomic classification of impaired vs. unimpaired cognition. However, this approach is far from mirroring the real efficiency of cognitive functioning. Applying a different approach in which cognitive functioning is considered as a continuous variable, we aimed at showing that even newly diagnosed relapsing&ndash, remitting MS (RRMS) patients might suffer from reduced cognitive functioning with respect to a matched group of neurologically healthy controls (HCs), even if they were classified as having no cognitive impairment (CI). Fifty newly diagnosed RRMS patients and 36 HCs were tested with an extensive battery of neuropsychological tests. By using Z-scores applied to the whole group of RRMS and HCs together, a measure of cognitive functioning (Z-score index) was calculated. Among the 50 RRMS patients tested, 36 were classified as cognitively normal (CN). Even though classified as CN, RRMS patients performed worse than HCs at a global level (p = 0.004) and, more specifically, in the domains of memory (p = 0.005) and executive functioning (p = 0.006). These results highlight that reduced cognitive functioning can be present early in the disease course, even in patients without an evident CI. The current classification criteria of CI in MS should be considered with caution.

OBJECTIVE Intrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. METHODS We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing-remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. RESULTS Forty-one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p

Growing evidence suggests that mental calculation might involve movements of attention along a spatial representation of numerical magnitude. Addition and subtraction on nonsymbolic numbers (numerosities) seem to induce a “momentum” effect, and have been linked to distinct patterns of neural activity in cortical regions subserving attention and eye movements. We investigated whether mental arithmetic on symbolic numbers, a cornerstone of abstract mathematical reasoning, can be affected by the manipulation of overt spatial attention induced by optokinetic stimulation (OKS). Participants performed additions or subtractions of auditory two-digit numbers during horizontal (experiment 1) or vertical OKS (experiment 2), and eye movements were concurrently recorded. In both experiments, the results of addition problems were underestimated, whereas results of subtractions were overestimated (a pattern that is opposite to the classic Operational Momentum effect). While this tendency was unaffected by OKS, vertical OKS modulated the occurrence of decade errors during subtractions (i.e., fewer during downward OKS and more frequent during upward OKS). Eye movements, on top of the classic effect induced by OKS, were affected by the type of operation during the calculation phase, with subtraction consistently leading to a downward shift of gaze position and addition leading to an upward shift. These results highlight the pervasive nature of spatial processing in mental arithmetic. Furthermore, the preeminent effect of vertical OKS is in line with the hypothesis that the vertical dimension of space–number associations is grounded in universal (physical) constraints and, thereby, more robust than situated and culture-dependent associations with the horizontal dimension. Electronic supplementary material The online version of this article (10.1007/s00426-018-1053-0) contains supplementary material, which is available to authorized users.

Background Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. Case presentation We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. Conclusions Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution.

Transcoding numerals containing zero is more problematic than transcoding numbers formed by non-zero digits. However, it is currently unknown whether this is due to zeros requiring brain areas other than those traditionally associated with number representation. Here we hypothesize that transcoding zeros entails visuo-spatial and integrative processes typically associated with the right hemisphere. The investigation involved 22 right-brain-damaged patients and 20 healthy controls who completed tests of reading and writing Arabic numbers. As expected, the most significant deficit among patients involved a failure to cope with zeros. Moreover, a voxel-based lesion-symptom mapping (VLSM) analysis showed that the most common zero-errors were maximally associated to the right insula which was previously related to sensorimotor integration, attention, and response selection, yet for the first time linked to transcoding processes. Error categories involving other digits corresponded to the so-called Neglect errors, which however, constituted only about 10% of the total reading and 3% of the writing mistakes made by the patients. We argue that damage to the right hemisphere impairs the mechanism of parsing, and the ability to set-up empty-slot structures required for processing zeros in complex numbers; moreover, we suggest that the brain areas located in proximity to the right insula play a role in the integration of the information resulting from the temporary application of transcoding procedures.

OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.

Pitch-height is often labeled spatially (i.e., low or high) as a function of the fundamental frequency of the tone. This correspondence is highlighted by the so-called Spatial-Musical Association of Response Codes (SMARC) effect. However, the literature suggests that the brightness of the tone's timbre might contribute to this spatial association. We investigated the SMARC effect in a group of non-musicians by disentangling the role of pitch-height and the role of tone-brightness. In three experimental conditions, participants were asked to judge whether the tone they were listening to was (or was not) modulated in amplitude (i.e., vibrato). Participants were required to make their response in both the horizontal and the vertical axes. In a first condition, tones varied coherently in pitch (i.e., manipulation of the tone's F0) and brightness (i.e., manipulation of the tone's spectral centroid); in a second condition, pitch-height varied whereas brightness was fixed; in a third condition, pitch-height was fixed whereas brightness varied. We found the SMARC effect only in the first condition and only in the vertical axis. In contrast, we did not observe the effect in any of the remaining conditions. The present results suggest that, in non-musicians, the SMARC effect is not due to the manipulation of the pitch-height alone, but arises because of a coherent change of pitch-height and brightness; this effect emerges along the vertical axis only.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Although cognitive impairment (CI) affects a large proportion of MS patients, only few data are available about its prognostic value associated with advanced magnetic resonance imaging (MRI) metrics. Objectives: We aimed at investigating the relationship between the early CI and the disease progression over 8-year follow-up in MS patients. Methods: We conducted a retrospective 8-year longitudinal study involving 78 patients with relapsing-remitting MS, who completed neuropsychological examination and structural MRI at the time of diagnosis. Each patient was clinically evaluated every 6 months, and cortical thickness was quantified at baseline and at the end of the follow-up. Patients were classified as having normal cognition and mild or severe CI. Results: The results show that CI at the time of diagnosis is a good predictor of conversion to definite MS ( p Conclusion: We confirmed and extended the evidence that early CI might be helpful in the identification of MS patients at high risk of disability progression and poor clinical outcome and should be considered as a marker of most aggressive pathology.

Background: Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. Objectives: To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. Methods: A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. Results: Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS ( p< 0.05 for all comparisons). Conclusions: Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.

Previous studies have shown that number processing can induce spatial biases in perception and action and can trigger the orienting of visuospatial attention. Few studies, however, have investigated how spatial processing and visuospatial attention influences number processing. In the present study, we used the optokinetic stimulation (OKS) technique to trigger eye movements and thus overt orienting of visuospatial attention. Participants were asked to stare at OKS, while performing parity judgements (Experiment 1) or number comparison (Experiment 2), two numerical tasks that differ in terms of demands on magnitude processing. Numerical stimuli were acoustically presented, and participants responded orally. We examined the effects of OKS direction (leftward or rightward) on number processing. The results showed that rightward OKS abolished the classic number size effect (i.e., faster reaction times for small than large numbers) in the comparison task, whereas the parity task was unaffected by OKS direction. The effect of OKS highlights a link between visuospatial orienting and processing of number magnitude that is complementary to the more established link between numerical and visuospatial processing. We suggest that the bidirectional link between numbers and space is embodied in the mechanisms subserving sensorimotor transformations for the control of eye movements and spatial attention.

Arabic numerals are diffused and language-free representations of number magnitude. To be effectively processed, the digits composing Arabic numerals must be spatially arranged along a left-to-right axis. We studied one patient (AK) to show that left neglect, after right hemisphere damage, can selectively impair the computation of the spatial frames underpinning recognition and understanding of Arabic numerals, without impairing the spatial frames for coding alphabetic strings or for coding environmental spatial information. The presence in our brain of these specific and precise spatial frames must be rooted in the paramount importance of Arabic numerals processing in our everyday activities.

Background Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet. The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years. Methods This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients. Forty consecutive OCB-negative (OCB−) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB− MS, 11 OCB+ MS and 10 patients with other neurological conditions. Results Increased number of CLs was found in OCB+ compared to OCB− patients (p

Unilateral Spatial Neglect, the most dramatic manifestation of contralesional space unawareness, is a highly heterogeneous syndrome. The presence of neglect is related to core spatially lateralized deficits, but its severity is also modulated by several domain-general factors (such as alertness or sustained attention) and by task demands. We previously showed that a computer-based dual-task paradigm exploiting both lateralized and non-lateralized factors (i.e., attentional load/multitasking) better captures this complex scenario and exacerbates deficits for the contralesional space after right hemisphere damage. Here we asked whether multitasking would reveal contralesional spatial disorders in chronic left-hemisphere damaged (LHD) stroke patients, a population in which impaired spatial processing is thought to be uncommon. Ten consecutive LHD patients with no signs of right-sided neglect at standard neuropsychological testing performed a computerized spatial monitoring task with and without concurrent secondary tasks (i.e., multitasking). Severe contralesional (right) space unawareness emerged in most patients under attentional load in both the visual and auditory modalities. Multitasking affected the detection of contralesional stimuli both when presented concurrently with an ipsilesional one (i.e., extinction for bilateral targets) and when presented in isolation (i.e., left neglect for right-sided targets). No spatial bias emerged in a control group of healthy elderly participants, who performed at ceiling, as well as in a second control group composed of patients with Mild Cognitive Impairment. We conclude that the pathological spatial asymmetry in LHD patients cannot be attributed to a global reduction of cognitive resources but it is the consequence of unilateral brain damage. Clinical and theoretical implications of the load-dependent lack of awareness for contralesional hemispace following LHD are discussed.

Objective Time is an elusive phenomenon that is difficult to grasp with our senses. Recent work has shown how spatial representations often lie beneath temporal ones, as shown by a family of spatiotemporal congruency effects. For instance, individuals who have been exposed to left-to-right orthographic systems are better at judging short durations with their left effector and long durations with their right effector than vice versa, a phenomenon known as the spatial-temporal association of response codes (STEARC) effect. In the present neuropsychological study, we aimed to provide evidence that spatial attention mechanisms play a crucial role in generating this spatially organized mental time line. Method A group of 13 patients suffering from right hemisphere lesions with different degrees of spatial neglect signs and a control group of 15 age- and education-matched neurologically healthy participants were administered a unimanual version of a spatiotemporal compatibility task (STEARC task). Results The main results showed that the more a patient suffered from spatial neglect signs, the smaller the accuracy difference was between the left and right side responses for short durations. Conclusions These findings corroborate the hypothesis that the presence of disorders in spatial attention affects the left-to-right mental time line representation, especially in its leftward segment, proportionally with the amount of deficit. This study therefore suggests the critical role of spatial attention for the emergence of a spatial representation of time durations.