Doriana Landi

Intra-cortical connectivity in multiple sclerosis: a neurophysiological approach

Multiple sclerosis is an autoimmune disease predominantly affecting the white matter of the CNS, causing--among functional sequelae-cortico--cortical partial or total disconnection. Since functional connectivity linking cerebral regions is reliably reflected by synchronization of their neuronal firing, in this study an electrophysiological parameter measured by magnetoencephalography was used to quantify an intra-cortical connectivity (ICC) index focused on the primary somatosensory cortical areas (S1). Twenty-one patients affected by mild (Extended Disability Scale Score, median 1,5) relapsing-remitting (RR) multiple sclerosis in the remitting phase without clinically evident sensory impairment were evaluated. Three dimensional MRI was used to quantify the lesion load, discriminating black hole and non-black hole portions, normalized by individual brain volumes. When matched with a control population, multiple sclerosis patients showed a reduced ICC combined with the complete loss of the finger-dependent functional specialization in S1 cortex of the dominant hemisphere. No association was found between ICC impairment and disease duration, or prolongation of the central sensory conduction time, presence of spinal cord lesions and ongoing disease modifying therapy. The ICC index slightly correlated with the lesion load. A local index of ICC in a circumscribed brain primary area was altered in mildly disabled RR-multiple sclerosis patients, also in absence of any impairment of central sensory conduction. In conclusion, the diffuse damage influencing the multi-nodal network subtending complex cerebral functions also affects intrinsic cortical connectivity. The S1 ICC index is proposed as a highly sensitive and simple-to-test functional measure for the evaluation of intra-cortical synchronization mechanisms in RR-multiple sclerosis.

fMRI-vs-MEG evaluation of post-stroke interhemispheric asymmetries in primary sensorimotor hand areas

Growing evidence emphasizes a positive role of brain ipsilesional (IL) reorganization in stroke patients with partial recovery. Ten patients affected by a monohemispheric stroke in the middle cerebral artery territory underwent functional magnetic resonance (fMRI) and magnetoencephalography (MEG) evaluation of the primary sensory (S1) activation via the same paradigm (median nerve galvanic stimulation). Four patients did not present S1 fMRI activation [Rossini, P.M., Altamura, C., Ferretti, A., Vernieri, F., Zappasodi, F., Caulo, M., Pizzella, V., Del Gratta, C., Romani, G.L., Tecchio, F., 2004. Does cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics? Brain 127, 99-110], although inclusion criteria required bilateral identifiable MEG responses. Mean Euclidean distance between fMRI and MEG S1 activation Talairach coordinates was 10.1+/-2.9 mm, with a 3D intra-class correlation (ICC) coefficient of 0.986. Interhemispheric asymmetries, evaluated by an MEG procedure independent of Talairach transformation, were outside or at the boundaries of reference ranges in 6 patients. In 3 of them, the IL activation presented medial or lateral shift with respect to the omega-shaped post-rolandic area while in the other 3, IL areas were outside the peri-rolandic region. In conclusion, despite dissociated intensity, the MEG and fMRI activations displayed good spatial consistency in stroke patients, thus confirming excessive interhemispheric asymmetries as a suitable indicator of unusual recruitments in the ipsilesional hemisphere, within or outside the peri-rolandic region.

Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis

OBJECTIVE Fingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5mg/day. METHODS Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5ms) and intracortical facilitation (at 7, 9, 11 and 13ms) were estimated at T0 and T1. RESULTS Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. CONCLUSIONS Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. SIGNIFICANCE This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models.

Cortical ischemic lesion burden measured by DIR is related to carotid artery disease severity.

Background: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. Methods: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). Results: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). Conclusions: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored.

Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol

Background: Cognitive dysfunction affects 40%–65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). Objective: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing-remitting multiple sclerosis (RRMS) patients without cognitive impairment. Methods: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). Results: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. Conclusion: Our results showed a primary deficit in executive control processes involved in the task-switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis

BackgroundIn the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS.MethodsAt the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up.ResultsCSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system.ConclusionsOur results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis

Objective To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. Methods An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. Results From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. Conclusions Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

TRPV1 polymorphisms and risk of interferon β-induced flu-like syndrome in patients with relapsing-remitting multiple sclerosis.

Interferon-β (IFN-β) is often discontinued in RRMS patients due to its most common side effect, the flu-like syndrome (FLS). The mechanisms underlying IFN β-induced FLS symptoms are still unclear. The endocannabinoid system (ECS) is a key regulator of pain and inflammation. Thus we tested the hypothesis that the ECS could be involved in FLS severity by exploring the effect of genetic polymorphisms with functional impact on the ECS, on patient-reported FLS symptoms. GG-carriers of the transient-receptor-potential-vanilloid-1 (TRPV1) single nucleotide polymorphism rs222747 reported greater pain and weakness during FLS. This study suggests that the TRPV1 channel is involved in FLS severity.

P17.11 Neuroanatomic and functional profile of fatigue in multiple sclerosis: an integrated morphofunctional study

E. Cases Rodríguez1, J. Miró Lladó2, M. Veciana De Las Heras1, I. Moreno Gómez1, J.P. Pérez1, M.A. Macau2, S. Fernández Fernández2, M.M. Santurino Plaza2, J. Mora Salvadó3, S. Castañer Llanes4, M. Falip Centellas2 1Neurophysiology department. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 2Epilepsy Unit. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 3Spect Unit. Nuclear Medicine Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 4IDI: Image Diagnostic Institute. Hospital Universitari de Bellvitge, Barcelona, Spain

P17.12 Inter-hemispheric connectivity in multiple sclerosis: an integrative electrophysiological-structural study

E. Cases Rodríguez1, J. Miró Lladó2, M. Veciana De Las Heras1, I. Moreno Gómez1, J.P. Pérez1, M.A. Macau2, S. Fernández Fernández2, M.M. Santurino Plaza2, J. Mora Salvadó3, S. Castañer Llanes4, M. Falip Centellas2 1Neurophysiology department. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 2Epilepsy Unit. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 3Spect Unit. Nuclear Medicine Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 4IDI: Image Diagnostic Institute. Hospital Universitari de Bellvitge, Barcelona, Spain