Multiple sclerosis (MS) is commonly seen as a chronic, inflammatory, demyelinating, and neurodegenerative progressive disease of the central nervous system (CNS).
Primary progressive multiple sclerosis (PPMS) is characterized by a gradual, continuous worsening of neurological function from disease onset, without a clearly defined relapsing phase. Secondary progressive multiple sclerosis (SPMS) develops after an initial relapsing-remitting phase, during which patients experience relapses followed by partial or complete recovery. Over time, relapses become less prominent or cease, while disability progression continues independently, driven primarily by neurodegenerative processes such as ongoing axonal loss.
Recent research demonstrates that progression independent of relapse activity (PIRA) is common in the relapsing remitting phase of the disease and can be a major driver of disability accumulation. At the cellular level the highest rate of axonal loss, the pathological substrate for permanent neurological disability, occurs very early on in the disease evolution.
At one point it becomes the only driver of disability progression and one is deemed to have entered the secondary progressive phase of MS.
The unmet challenge lies in identifying effective strategies to slow or modify this progression once the inflammatory mechanisms underlying relapse activity has waned.
MS Disease Progression – Potential Mechanisms of Action
Several possible mechanisms of disability progression in patients with progressive MS have been suggested such as compartmentalized inflammation, mitochondrial toxicity etc (Giovannoni G. et al 2022 and Absinta M. et al 2020). Inflammation as measured by conventional MRI metrics has however shown very modest correlation with clinical progression. (Barkhof 2002). Chronic disability progression in patients with MS once established, appears also unaffected by the currently available immunomodulatory treatments (Cree et al., 2021).
Recent studies with a new class of medications called the BTKi’s, such as tolebrutinib have shown only a very modest reduction in the progression of multiple sclerosis symptoms. Serum neurofilament light levels (sNFl), an excellent biomarker of axonal loss secondary to inflammatory activity, has been unable to accurately reflect disability progression unrelated to relapse activity in MS patients (Barro et al 2022 and Bridel et al 2021). These observations all raise the important question as to whether there exist mechanisms of physical disability progression in MS that does not directly involve inflammation nor neurodegeneration with axonal and/or neuronal loss.
If one takes a new perspective, seeing the brain as a large-scale neural network (i.e. a connectome). Within such a perspective, disease mechanisms are explained from the loss of structural and functional connections between distant brain regions rather than the result of focal lesions. MS can thus be seen as a disconnection syndrome. Disconnection leads to focal atrophy. Volume measures of highly interconnected areas (i.e. hubs), such as the thalamus, have shown better correlations with clinical presentation (Azevedo et al. 2018).
Progressive structural disconnection within a network can eventually reach a critical level of network efficiency loss and lead to relatively rapid network collapse with accompanying accelerated clinical progression (Schoonheim et al. 2015). Structural and functional connectivity are interdependent. The topology of the structural network will shape and limit the functional network that originates from it. Initially in MS, functional connectivity is increased possibly to compensate for the structural damage, but eventually neural network hubs become overloaded and rigid as shown by a reduction in the dynamic fluctuations between different neural network activation and eventually fail (Schoonheim et al. 2022).
Brain Oscillations and Network Synchrony: The Neurophysiological Basis of rTMS
Rhythmic electrical activity, ubiquitous in the brain, has been linked with a plethora of brain functions ranging from attention, sensory processing to memory. Such oscillations, or rhythms, are easily recorded by electroencephalography (EEG). The emergence of synchronous activity is highly sensitive to network structure, and thus dependent on the numerous plastic mechanisms that alter the network properties in a continuous fashion. RTMS can induce and entrain topographic oscillations in focal and distal functionally connected cortical areas. It is postulated that post-lesionally established, but maladaptive network oscillations could be modulated by rTMS and, by restoring normal synchrony, alleviate clinical disability. (Thut and Miniussi 2009)
Brain oscillations demonstrate how nervous tissue has intrinsic resonance properties that shape its susceptibility and responsiveness to neuromodulation, especially to periodic signals such as those used in rTMS. This emergent feature of brain networks represents a novel opportunity to better understand and influence functional neuronal network connectivity.
rTMS for Multiple Sclerosis Patients: Impacts on Disability and Disease Progression
rTMS is a form of non-invasive neuromodulation that has been shown to improve MS patients’ symptomatology. Several studies using different stimulation modalities and durations were able to demonstrate a significant reduction in spasticity (Korzhova et al. 2019; Şan, Yılmaz, and Kesikburun 2019; Centonze et al. 2007; Boutiere et al. 2017).
One study demonstrated that the improvement in spasticity was accompanied by improvement in resting-state functional connectivity (Boutiere et al. 2017). Other studies have shown improvement in cognition and, in one study, that improvement was accompanied by a reduction in frontal lobe hyper activation and an improvement in functional connectivity (Hulst et al. 2017). Studies have shown improvement in hand dexterity (Elzamarany et al. 2016) gait, bladder control and neurogenic pain (Palm et al. 2014; Iodice, Manganelli, and Dubbioso 2017). A recent update to the evidence-based guidelines for rTMS gave a B level of evidence for intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis (Lefaucheur et al. 2020). The mechanisms by which rTMS may enable recovery is speculated to involve improved functional neural network connectivity, increased activity dependent remyelination, and improved neural network synchrony.
Evaluating rTMS for Gait Impairment and Symptom Control in Multiple Sclerosis
At CNO we have initiated a sham-controlled study of rTMS in patients with multiple sclerosis related walking disability. The clinical trial will test the hypothesis that our rTMS protocol can improve the walking speed and distance of people with MS induced spastic paraparesis. The study will also evaluate the impact of rTMS on other MS symptoms such as pain, spasticity, bladder control and will describe and correlate the changes in brain oscillation parameters induced by the rTMS treatment.
This study includes individuals with primary progressive MS as well as those with secondary progressive MS, two disease subtypes in which walking impairment and spastic paraparesis are common and often poorly responsive to existing disease-modifying therapies. By examining both clinical outcomes and rTMS-induced changes in brain network oscillations, this trial aims to better understand whether targeted neuromodulation may influence future disability progression. This work contributes to the growing field of multiple sclerosis clinical trials exploring complementary approaches to symptom management and functional recovery beyond pharmacological treatment alone.
Challenge the Assumption of Inevitable Decline – Help us Make Wheelchairs a Thing of the Past
This research is part of our broader efforts to rise to the unmet challenges in current MS treatment. It is our hope that targeted neuromodulation will prove to be a viable method of influencing future disability progression and support functional recovery to improve walking ability and help make wheelchairs obsolete. If you are interested in learning more about this study or exploring whether it may be suitable for you or a loved one, please feel free to contact the clinic. Our team will be happy to provide further details and answer your questions.
