Interleukin-1ß Alters Hebbian Synaptic Plasticity in Multiple Sclerosis.

In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1ß on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1ß were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1ß levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1ß levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1ß may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity.

Inflammation and Corticospinal Functioning in Multiple Sclerosis: A TMS Perspective.

Transcranial magnetic stimulation (TMS) has been employed in multiple sclerosis (MS) to assess the integrity of the corticospinal tract and the corpus callosum and to explore some physiological properties of the motor cortex. Specific alterations of TMS measures have been strongly associated to different pathophysiological mechanisms, particularly to demyelination and neuronal loss. Moreover, TMS has contributed to investigate the neurophysiological basis of MS symptoms, particularly those not completely explained by conventional structural damage, such as fatigue. However, variability existing between studies suggests that alternative mechanisms should be involved. Knowledge of MS pathophysiology has been enriched by experimental studies in animal models (i.e., experimental autoimmune encephalomyelitis) demonstrating that inflammation alters synaptic transmission, promoting hyperexcitability and neuronal damage. Accordingly, TMS studies have demonstrated an imbalance between cortical excitation and inhibition in MS. In particular, cerebrospinal fluid concentrations of different proinflammatory and anti-inflammatory molecules have been associated to corticospinal hyperexcitability, highlighting that inflammatory synaptopathy may represent a key pathophysiological mechanism in MS. In this perspective article, we discuss whether corticospinal excitability alterations assessed with TMS in MS patients could be useful to explain the pathophysiological correlates and their relationships with specific MS clinical characteristics and symptoms. Furthermore, we discuss evidence indicating that, in MS patients, inflammatory synaptopathy could be present since the early phases, could specifically characterize relapses, and could progressively increase during the disease course.

Practice-dependent motor cortex plasticity is reduced in non-disabled multiple sclerosis patients.

OBJECTIVES: Skill acquisition after motor training involves synaptic long-term potentiation (LTP) in primary motor cortex (M1). In multiple sclerosis (MS), LTP failure ensuing from neuroinflammation could contribute to worsen clinical recovery. We therefore addressed whether practice-dependent plasticity is altered in MS. METHODS: Eighteen relapsing-remitting (RR)-MS patients and eighteen healthy controls performed 600 fast abductions of index finger in 30 blocks of 20 movements. Before and after practice, transcranial magnetic stimulation (TMS) was delivered over the hot spot of the trained first dorsal interosseous muscle. Movements kinematics, measures of cortical excitability, and the input/output curves of motor evoked potentials (MEPs) were assessed. RESULTS: Kinematic variables of movement improved with practice in patients and controls to a similar extent, although patients showed lower MEPs amplitude increase after practice. Practice did not change the difference in resting motor threshold values observed between patients and controls, nor did modulate short-interval intracortical inhibition. Clinical/radiological characteristics were not associated to practice-dependent effects. CONCLUSIONS: Practice-induced reorganization of M1 is altered in non-disabled RR-MS patients, as shown by impaired MEPs modulation after motor learning. SIGNIFICANCE: These findings suggest that in RR-MS physiological mechanisms of practice-dependent plasticity are altered.

Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis.

Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results:In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients.