Origins and perspectives

Inflammation is more pronounced in the acute stages of MS but can continue into the chronic stages. Peripheral immune cells found to infiltrate MS lesions include macrophages, T cells, B cells, and plasma cells. At later stages of the disease, these cells, along with activated CNS-resident microglia and astrocytes, promote atrophy of grey and white matter.^[3]

• Remyelination – the regenerative process of restoring nerve fiber myelin sheaths varies in MS. The extent of remyelination is heterogeneous both between individuals and during the disease course.^[2][8] This variability can depend on several factors including a patient’s age, presence of oligodendrocyte^† precursors, axonal integrity, and location of lesions.^[2]
• Brain plasticity, including reorganisation of synaptic connections. Brain plasticity functionally compensates for a loss of synaptic inputs. This may be driven by inflammatory mediators at the synapse through long-term potentiation (LTP) and long-term depression (LTD).^[9][10][11]

_{*Reestablishing or rearranging neural connections.
†Cell type that creates myelin in the CNS.}

• GABAergic and glutamatergic system balance. CNS inflammation in MS causes a marked imbalance between GABAergic and glutamatergic transmission, and a loss of synapses, all of which leads to a diffuse ‘synaptopathy’. Altered synaptic transmission can occur early in MS, independently of demyelination and axonal loss, and subsequently causes excitotoxic damage (and ultimately neurodegeneration).^[12]
• Upregulation of sphingosine-1-phosphate (S1P) receptors. S1P receptors are expressed throughout the body and have been shown to be upregulated in the CNS in MS.^[13][14][15] S1P receptors have been correlated with a wide range of physiological processes, such as vascular development, CNS homeostasis, lymphocyte egress from the lymphatic organs and lymphocyte organs, and lymphocyte chemotaxis. S1P signalling has also been shown to inhibit axon guidance by causing growth cone* collapse and neurite retraction. Upregulation of S1P signalling in MS has also been linked to astrocyte activation during MS inflammation. Preclinical studies have shown that these processes may be critical for CNS remodelling, and thus the inhibition of these processes may limit repair.^{[16][17][18][19][20][21]}

_{*Specialised end of an axon that determines and guides the direction of growth.}

• Decreased overall efficiency. Studies of patients living with MS have shown decreased nodal (regional) efficiency in many regions of the brain and an increased 'average path length' (a measure of the reorganisation of tracts between affected brain regions) also indicating degenerated efficiency.^[22][23][24]
• Cortical reorganisation. Cortical reorganisation has been demonstrated to occur in the brains of patients with early relapsing-remitting multiple sclerosis (RRMS). These reorganisational changes have been observed to occur both in people with or without disease activity as defined by NEDA-3.*^[25]

_{*In a 1-year longitudinal study, patients with early RRMS meeting criteria for no evidence of disease activity (NEDA-3; n = 56) and those with evidence of disease activity (n = 36) showed increases in local cortical connections. This change was not observed in healthy controls (n = 101) over the same period.^[25]}

Altered functional connectivity has been associated with changes in MS symptoms. Cognitive and motor performance as well as other neurologic dysfunctions (e.g. fatigue, visual problems, depression, and sleep disturbance) are often associated with alterations in functional connectivity or change in network coherence.^[22]