Effects On Corticospinal Tract Homology Of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study Part 2
Aug 31, 2023
3.2. Relationships between MEP Shape Similarities Changes and Fatigue Amelioration
The changes in inter-body-side homology similarity did not show a significant correlation with the changes in mFIS (p >0.05, consistently).
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3.3. MEP Amplitude and Latency
No effect was observed in terms of MEP amplitudes and latencies either as differences between the two body sides or as an effect of Faremus treatment (Table 2).
4. Discussion
As a key result, Faremus induced a change in the physiological direction of the homology between the two corticospinal tracts, as estimated by the similarity of the MEP morphology via the Fréchet distance. Interestingly, the modifications induced by Faremus were more evident in the inter-side relationship than in dominant and non-dominant intrasides.
4.1. CST Asymmetries and Fatigue
Very recently, the anatomical CST correlation with fatigue in MS patients has been assessed via anatomical connectivity mapping (ACM) based on diffusion MRI tractography [45]. Unexpectedly, concerning healthy volunteers, MS patients bilaterally displayed altered higher ACM. In terms of the relationship with fatigue, while interhemispheric asymmetries outside the CST did not scale with individual symptoms, the higher the ACM values in the left relative to the right CST, the more severe the symptoms were. In agreement with higher CST morphological asymmetries in MS fatigue concerning healthy controls, our functional assessment evidenced much higher inter-body-side CST asymmetries with Fréchet distances ranging around double values than the distribution in healthy volunteers [53].
Similar behavior has also been observed in other neuropathological conditions. Three months of paretic arm robotic rehabilitation changed the inter-hemispheric coupling of somatosensory homologs [60], which distributed across a wide range before robotic rehabilitation but in a narrow range after treatment. The authors speculated that the interhemispheric connectivity found at the end of the rehabilitation program corresponded to a more functionally efficacious and "physiological" condition since patients reached a clear motor improvement through robotic rehabilitation. Similarly, in the present case, we can speculate that a better physiological condition consequent to an amelioration of fatigue induced by Faremus can reflect i more physiological state of the CST homology.
The asymmetries of the CST excitability in MS patients were recently evaluated in terms of TMS resting and active motor thresholds and intracortical inhibitory efficacy via the cortical silent period. Intracortical inhibition alterations and increased asymmetry of excitability were significantly correlated with more severe fatigue symptoms. Interestingly, altered inter-lateral asymmetries evidenced lost dominance concerning the non-dominant side [37]. Notably, in the present investigation, the smaller intra-side distance concerning the inter-side one previously observed in a healthy sample was lost pre-Faremus for the dominant CST (one-tailed tt-test t(9) = 1.201, p = 0.0130), Figure 4A) and regained this property post-Faremus (t(9) = 2.736, p = 0.011), Figure 4D). By the alterations with MS fatigue prominent in the dominant side, the dynamics of neuronal electrical activity, and eurodynamics, lost the physiological greater complexity in M1 compared with S1 in the dominant hemisphere [11].
4.2. CST Homology Modified by Faremus S1 Neuromodulation
Faremus personalized S1 neuromodulation, giving rise to a fatigue amelioration, changed the homology of the two CSTs.
The efficacy of Faremus is supported by two previous sham-controlled randomized trials [26,27]. Even in the present subgroup, the improvement in fatigue levels at 27% on average can be considered clinically significant, as typically 20% is indicated as the threshold to identify responders to a given intervention.
Concerning the speculation on the possible effects of Faremus intervention on CST homology, we integrate the present with previous observations that Faremus treatment considerably affected the neurodynamics that changed more strongly in S1, the target of the neuromodulation, than in M1. Nevertheless, in terms of functional connectivity, the changes were mostly evident in the connection between homolog left and right primary motor areas [11]. Here, we observed that Faremus changed in a physiological direction the similarity between the two homolog CSTs. These effects on the CSTs induced by Faremus S1 neuromodulation highlight how sensory and motor counterparts are the two sides of the same coin. A suggestive example of such an inextricable relationship can be found in a TMS study, where MEPs were simultaneously recorded from two hand muscles innervated by the same nerve, before and after the anesthetic block of the nerve supplying the somatosensory inflow from only one of the two, demonstrating that the muscle with sensory deprivation selectively lost part of its motor representation [61]. Extending the observation to behavioral effects, a paradigmatic example of the critical somatosensory role in motor execution comes from the selective perturbation of goal-directed reaching movements as a consequence of selectively blocking by genetic manipulation the sensory inflow from the forelimb [62].
4.3. Central More Than Peripheral Origin of MS Fatigue
In a group of MS patients suffering from a wide range of fatigue, we found that the alterations of the cortico-muscular coherence correlated with fatigue severity, while this was not the case for the behavioral alterations detectable in motor execution [63]. It is interesting to complement the Faremus-induced improvement of fatigue symptoms associated with changes in cortical neurodynamics and intracortical functional connectivities [11] with the lack of association with effects on the CST found here. These pieces of evidence strengthen the role of central mechanisms more than peripheral–behavioral ones at the origin of MS fatigue and lead us to speculate that the Faremus-induced changes observed in MEPs' shape similarity are a consequence of the changes of central mechanisms at the origin of fatigue.
The authors who studied the corticospinal excitability by TMS and peripheral electric stimulation before and after a fatiguing task arrived at similar conclusions in people with MS, reporting a more central than peripheral origin of behavioral fatigue mechanisms [64].
A possible reason for the lack of relationships with clinical changes can derive from the non-ecologic TMS. The TMS implies supra-physiological synchronizations, which are excellent in assessing the circuit propagation velocities and fiber impairments—relevant for clinical evaluation in many pathological conditions including MS, carpal tunnel syndrome, etc.—but less sensitive to neuronal networking alterations subtending symptoms not secondary to major damages and tissue degeneration.
4.4. MEP Shape vs. Amplitude
We found that the assessment—via Fréchet distance– of the MEP morphology was sensitive to Faremus-related changes. Instead, the MEP amplitudes did not change by the treatment. We previously observed that in MS patients, the evoked activity morphology is sensitive to subtle changes induced in the central circuitry more than the response amplitude [10]. More recently, we found that the somatosensory evoked potential morphology can be exploited to enhance the monitoring sensitivity to cerebral blood flow reduction over the SEP amplitude [47]. With remarkable relevance, the morphology of MEPs sensitive to homology features that do not emerge from MEP amplitudes appeared in addition to pathological conditions even in healthy states [53].
4.5. Limitations of the Present Work
The present exploratory work presents limitations that can be addressed through future research.
The CST homology was observed after the treatment, and a longitudinal assessment of its behavior along with the re-emergence of fatigue would be interesting.
Data in healthy individuals were provided in previous work [53] in a consistent group of people of similar age but collected in a different laboratory in the frame of an independent experiment that collected data of the first dorsal interosseous muscle.
The CST homology investigation, ancillary to Faremus clinical trials, was executed in a subgroup of patients undergoing only the real treatment. It would be advisable to carry out the same investigation in a larger group of MS subjects with a sample size comparable to that of the two Faremus RCTs and perform a direct comparison with a double-blind, sham-controlled, crossover design.
We analyzed the CST comparing the dominant vs. non-dominant hemi bodies without relating with the handedness level, as assessed, for example, by the scoring of the Edinburgh Inventory. Our analysis strategy is based on the concept that left-handers, in addition to being about 10% of the population, do not invert brain organization concerning right-handers, and handedness-dependent dominance brain asymmetries are more pronounced in right-handed than in left-handed people. Nevertheless, enrolling larger samples of people would be interesting to take this variability into account. Notably, the commutative property holds, as for every distance measure, for the Fréchet distance, so that evaluations do not depend on which side is the dominant one.
5. Conclusions
The present data strengthen the knowledge of the relevance of sensorimotor feedback for brain physiology since S1 neuromodulation, which ameliorated fatigue symptoms, changed the homology between the dominant and non-dominant CSTs. The present results support also a central more than peripheral–behavioral mechanism as the origin of MS fatigue. All in all, the results discussed here are in line with the emergence of new measures that, sensitive to network characteristics, provide new insights into the mechanisms of neuronal organization underlying relevant symptoms.
Author Contributions: Conceptualization, F.T.; methodology, F.T. and F.C.; software, F.C., A.T., and S.P.; validation, P.P.; formal analysis, F.T. and P.P.; investigation, C.C., and A.C.; resources, F.T., K.A., L.C., F.M., and F.B.; data curation, F.T., F.C., A.T., S.P., and M.B.; writing—original draft preparation, F.T. and M.B.; writing—review and editing, F.T., M.B., E.G., J.G., and T.L.; visualization, M.B., and E.G.; supervision, F.T., F.M., and F.B.; project administration, F.T. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by: (1) FISM–Fondazione Italiana Sclerosi Multipla-Cod.2014/R [Faremus CuNeH], (2) POR FESR LAZIO 2014–2020, Prog. 28,109, Digital Helpers per e-Communities in Sanitá [DHelp4H], finanziato da Lazio Innova per conto della Regione Lazio (prot. Gecoweb A0320–2019–28,109), AvvisoPubblico della Regione Lazio “Progetti Strategici”, anno 2019, cup B89C20001430002).
Institutional Review Board Statement: All methods were carried out in the Declaration of Helsinki. The Ethics Committee Lazio1—San Camillo Forlanini approved the experimental protocols (023/CE Lazio1,11 January 2016).
Informed Consent Statement: All patients signed the informed consent form before their enrollment.
Data Availability Statement: The data presented in this study are available on request from the corresponding author.
Acknowledgments: In addition to all people with MS who gave their time and collaboration, the authors wish to thank Vittorio Pizzella, Paolo M Rossini, Maria Maddalena Filippi, Silvana Zannino, Domenico Lupoi, Anna Ghazaryan, Massimiliano Mirabella, Arianna Pizzichino, Daniele Spizzichino, and Massimiliano Marconi for their technical contributions.
Conflicts of Interest: The authors declare no conflict of interest.
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