Remodeling Functional Connectivity in Multiple Sclerosis: A Challenging Therapeutic Approach

Mario Stampanoni Bassi, Luana Gilio, Fabio Buttari, Pierpaolo Maffei, Girolama A Marfia, Domenico A Restivo, Diego Centonze, Ennio Iezzi, Mario Stampanoni Bassi, Luana Gilio, Fabio Buttari, Pierpaolo Maffei, Girolama A Marfia, Domenico A Restivo, Diego Centonze, Ennio Iezzi

Abstract

Neurons in the central nervous system are organized in functional units interconnected to form complex networks. Acute and chronic brain damage disrupts brain connectivity producing neurological signs and/or symptoms. In several neurological diseases, particularly in Multiple Sclerosis (MS), structural imaging studies cannot always demonstrate a clear association between lesion site and clinical disability, originating the "clinico-radiological paradox." The discrepancy between structural damage and disability can be explained by a complex network perspective. Both brain networks architecture and synaptic plasticity may play important roles in modulating brain networks efficiency after brain damage. In particular, long-term potentiation (LTP) may occur in surviving neurons to compensate network disconnection. In MS, inflammatory cytokines dramatically interfere with synaptic transmission and plasticity. Importantly, in addition to acute and chronic structural damage, inflammation could contribute to reduce brain networks efficiency in MS leading to worse clinical recovery after a relapse and worse disease progression. These evidence suggest that removing inflammation should represent the main therapeutic target in MS; moreover, as synaptic plasticity is particularly altered by inflammation, specific strategies aimed at promoting LTP mechanisms could be effective for enhancing clinical recovery. Modulation of plasticity with different non-invasive brain stimulation (NIBS) techniques has been used to promote recovery of MS symptoms. Better knowledge of features inducing brain disconnection in MS is crucial to design specific strategies to promote recovery and use NIBS with an increasingly tailored approach.

Keywords: brain networks; functional connectivity; inflammation; multiple sclerosis; non-invasive brain stimulation; synaptic plasticity.

Figures

Figure 1
Figure 1
Results of the main studies investigating interhemispheric connections in MS. Red coils and arrows represent CS, black coils and arrows depict TS. AMT, active motor threshold; CC, corpus callosum; CMCT, central motor conduction time; CS, conditioning stimulus; EDSS, expanded disability status scale; fMRI, functional magnetic resonance imaging; HC, healthy controls; IHI, interhemispheric inhibition; iM1, ipsilateral primary motor cortex; ISI, interstimulus interval; iSP, ipsilateral silent period; M1, primary motor cortex; PMd, dorsal premotor cortex; PP-MS, primary progressive multiple sclerosis; RMT, resting motor threshold; RR-MS, relapsing-remitting multiple sclerosis; SDMT, symbol digit modality test; T1-LL, T1 lesion load; TS, test stimulus.

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