Neurophysiological and behavioural correlates of ocrelizumab therapy on manual dexterity in patients with primary progressive multiple sclerosis

Abstract

Background Hand dexterity impairment is a key feature of disability in people with primary progressive multiple sclerosis (PPMS). So far, ocrelizumab, a recombinant humanized monoclonal antibody that selectively depletes CD20-expressing B cells, is the only therapy approved for PPMS and recent analysis reported its ability to reduce the risk of upper limb disability progression. However, the neural mechanisms underlying hand impairment in PPMS and the brain networks behind the effect of ocrelizumab on manual dexterity are not fully understood. Objective Main aims of our study were: (i) to investigate neurophysiological and behavioural correlates of hand function impairment in subjects with PPMS, and (ii) to use neurophysiologic and behavioural measures to track the effects of ocrelizumab therapy on manual dexterity. Methods Seventeen PPMS patients and 17 healthy-controls underwent routine neurophysiological protocols assessing the integrity of cortico-spinal and somatosensory pathways and advanced transcranial magnetic stimulation (TMS) protocols evaluating inhibitory (short and long interval intracortical inhibition, short-latency afferent inhibition) and facilitatory (motor thresholds, intracortical facilitation, short-interval intracortical facilitation) circuits in the primary motor cortex. All subjects also underwent behavioural analysis of hand dexterity by means of nine-hole peg test and finger movement analysis, and hand strength with handgrip and three-point pinch test. Neurophysiological and clinical assessments of hand functionality were also performed after 1 year of ocrelizumab therapy. Results At baseline PPMS patients displayed a significant impairment of hand dexterity and strength compared to healthy controls (all p < 0.03). Neurophysiological study disclosed prolonged latencies of standard somatosensory and motor evoked potentials (all p < 0.025) and an overall reduction of intracortical excitability at TMS protocols, involving both excitatory and inhibitory circuits. Importantly, hand dexterity impairment, indexed by delayed 9HPT, correlated with TMS protocols investigating cortical sensorimotor integration (short-latency afferent inhibition, SAI), p = 0.009. Both parameters, 9HPT (p = 0.01) and SAI (p = 0.01), displayed a significant improvement after 1 year of therapy with ocrelizumab. Conclusion Intracortical sensorimotor networks are involved in hand dexterity dysfunction of PPMS. Ocrelizumab therapy displays a beneficial effect on hand dexterity impairment most likely through intracortical networks implicated in fast sensorimotor integration.

Short‐latency afferent inhibition is reduced in people with multiple sclerosis during fatiguing muscle contractions

“…In the current study, there were no group differences detected for SSEP measurements. An absence of SSEP deficits opposes several previous MS studies (Chiappa, 1980;Comi et al, 1999;Dubbioso et al, 2022;Trojaborg & Petersen, 1979; Walsh et al, 2005), where SSEP abnormality rates occurred in $60%-80% (Chiappa, 1980;Trojaborg & Petersen, 1979) of MS individuals. As there were no differences in the ascending SSEP in the current study, MS-related SAI differences were most likely associated with central integration of the sensory and motor signal.…”

“…Although this is the first study to reveal that fatiguing contractions suppress SAI, there are several previous reports that SAI is affected in people with MS while in a resting state (Cucurachi et al, 2008; Dubbioso et al, 2022; Mango et al, 2019; Topkan et al, 2022) or when administered pharmacological interventions known to improve motor function (Dubbioso et al, 2022; Nicoletti et al, 2019). The neurotransmitters that are implicated in SAI include acetylcholine and GABA, where SAI is enhanced by cholinergic transmission (Di Lazzaro et al, 2000, 2005; Fujiki et al, 2006) and reduced by GABAergic transmission (Di Lazzaro et al, 2007; Teo et al, 2009).…”

Non-invasive brain stimulation therapy on neurological symptoms in patients with multiple sclerosis: A network meta analysis

“…The underlying etiology of fatigue, cognitive impairment, and pain in MS may be similar, and the overlap may be a result of lesions in MS occurring in highly interconnected deep gray matter, whereby their ripple effects may affect a variety of other brain circuits ( 59 ). It has been proposed that PwMS with impairment of hand performance may be correlated with cortico-cortical disconnections due to demyelination or a strict disruption of the motor network caused by neurodegenerative processes ( 60 ). Since NIBS has been widely used as rehabilitation treatments for neurological diseases and various mechanisms based on neuroplasticity, neural protection and/or regeneration induced by NIBS are being explored, adaptation of NIBS protocols according to different stages of brain damage and degeneration await further research ( 61 ).…”

Multiple Sclerosis in the Digital Health Age: Challenges and Opportunities - A Systematic Review

“…In the same vein, the second most frequently investigated evoked potential in EEG is MEP, whose latency, amplitude and any detected abnormalities have extensively been analysed and investigated 14,20,21,25,31,32,[38][39][40][41][42][43][44][45] . Interestingly, SSEPs 10,17,20,21,28,35,36,43,[46][47][48] and AEPs 8,16,17,28 were less common and frequently used in the reviewed studies, but still offer, when combined with other evoked potentials, solid composite scores. Similarly, authors in 49,50 investigated and analysed evoked related potential (ERP) responses in MS patients by using the two-tone oddball paradigm.…”