Mõjud on kortikospinaal trakti homoloogia faremus isikupärastatud neuromodulatsioon leevendamine väsimus mitu skleroos : A kontseptsiooni tõestamine uuring osa 1
Aug 31, 2023
Abstraktne: Objectives: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. Methods: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. Results: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. Conclusions: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.
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【For more info:george.deng@wecistanche.com / WhatsApp:8613632399501}】
Märksõnad: transkraniaalne alalisvool stimulatsioon (tDCS); transkraniaalne elektriline stimulatsioon (tES); transkraniaalne magnetiline stimulatsioon (TMS); kortikospinaal trakti; mitmekordne skleroos (MS); täppis meditsiin
1. Introduction
1.1. MS väsimus
Multiple sclerosis (MS) is a chronic neurodegenerative disease, mainly driven by inflammatory processes, resulting in demyelinating lesions detectable in the white and gray matter throughout the central nervous system [1]. The onset of the disease typically ranges from 20 to 40 years of age and, in its most common clinical manifestation known as relapsing–remitting MS (RRMS), occurs with acute reversible neurological deficits lasting several days or weeks, while in a minority of patients, there is a gradual progression of the disease known as primary progressive MS (PPMS). Whatever the clinical manifestation and stage of the disease, chronic fatigue represents one of the most troubling symptoms impairing the daily life of up to 80% of the patients [2]. Defined as "the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors" [3,4], fatigue poses a challenge both for its diagnostic assessment and for its treatment, which is still limited to drugs, with little evidence of effectiveness while also showing unpleasant side effects [5].
1.2. Miks Rakendamine Ergastav Neuromodulatsioon Üle S1 In Ravi MS Väsimus
Considering the functional neural features of MS fatigue [6], there is consensus in the literature concerning a widespread alteration of neuronal electrical activity at the level of the sensorimotor network [7]. In particular, MS fatigue patients display depleted excitability of primary somatosensory and post-central networks [8–11] in contrast to hyperactivation and excessive excitability observed in frontal areas [12] and primary motor cortices (M1) both at rest and during motor execution [13–15]. Therefore, chronic fatigue, together with a plethora of diseases and symptoms stemming from an altered neuronal electrical activity, stands out as a suitable target for therapeutic interventions using electroceuticals [16,17], a new emerging class of devices that treat ailments through the supply of electrical currents also via invasive or non-invasive neuromodulations. Among the non-invasive ones, transcranial direct-current stimulation (tDCS) is capable of modulating the membrane excitability of neurons belonging to wide cortical networks by delivering weak electric currents through electrodes positioned on the scalp, ultimately inducing a change in cortical excitability when delivered for sufficient time [18–21]. tDCS has been extensively used to treat MS fatigue [22,23], proving its appropriateness in dealing with functional alterations underlying this symptom concerning other neurophysiological techniques with more focal mechanisms of action, such as repetitive transcranial magnetic stimulation (rTMS), that have been proven to be of limited application in this condition [24].
In line koos the eelmainitud kirjandus on aju elektriline aktiivsus omadused of MS väsimus tulemuseks in an impaired parietaalne-frontaalne funktsionaalne ühenduvus, me kohandatud a tDCS skeem et oli juba saavutatud an enhancement of resistance to fatigue in healthy people [25] implementing an electroceutical intervention against fatigue in MS called Faremus (väsimus leevendamine in multiple sclerosis) [23,26–28].
Faremus is a a isikupärastatud 5-day anodal tDCS (1.5 mA, 15 min per day) et sihtmärgid kogukeha primaarne somatosensoorne ala (S1) via a dokumenteeritud protseduur of shaping the anodal elektrood (35 cm2 ) based on MRI-tuletatud individuaalne kortikaalne voltimine of the central sulcus to leave the primary motor cortex (M1) and pre-central areas unstimulated [29–31]. The catode over bilateral occipital sites is a double-area electrode (7 % c3� 10 cm2 ) to avoid inhibitory effects on visual cortices.
Väsimus in MS on olnud sihitud poolt a sort of intervention protokollid kasutamine tDCS, koos erinev stimulatsioon parameetrid ja kortikaalne sihtmärgid [32,33]. Hulgas need, the dorsolateral prefrontal cortex, M1, and S1 represent the most investigated. Siiski, erinevused ting to heterogeensus in the number of sessions, current intensity and duration, sample size, and result measures do not allow disambiguating what tDCS parameetrid on eelistatud. Sellegipoolest, the tulemused a hiljutine kvantitatiivne ja metaanalüüs ülevaade by Gianni et al. [23] fookus on klass 1 RCTs kaasamine tDCS sekkumised vastu sümptomid peamiselt seotud to neuronaalne elektriline tasakaalustamatus paljastatud see Faremus kahepoolne S1 anodaalne stimulatsioon järjepidevalt näitas kliiniline efektiivsus in konkreetselt leevendav väsimus [23,26–28].
1.3. tasakaal vahemik poolpool homoloogid is kriitiline for funktsionaalne võime
Healthy brain functioning relies on the balance between hemispheric homologous areas, enabled by the core cerebral mechanism of inter-hemispheric inhibition, a ubiquitous feature of brain functioning implemented by crossed facilitation projections affecting surround/lateral inhibition networks aimed at supporting contrast-enhancing and integrative functions through the balancing of the activity of the two hemispheres [34]. The interplay between the activity of homologous hemispheric areas can thus be seen as a ubiquitous structural–functional mechanism that supports the plastic adaptation and learning processes of the brain [35,36] entering the regulation of inhibition and excitation mechanisms that support the functionality of the body segment they control.
As previously observed, MS fatigue patients display an electrophysiological profile compatible with local alterations of physiological excitatory–inhibitory mechanisms [7,13–15], secondary or giving rise to fatigue itself, that also reflect into the imbalances of the interhemispheric functional relationship between sensorimotor regions both at rest [37] and during movement execution [38–40]. These pieces of evidence pairing increased fatigue symptoms with an altered dynamic interplay between homologous cortical areas, in the absence of structural parenchymal changes, further support the primarily functional alteration of the sensorimotor system in MS fatigue. Notably, the somatosensory areas involved in the genesis and treatment of fatigue using Faremus are part of the origin of the CSTs. About 60% of the fibers that make up the CST come from the pre-central gyrus [41] and about 30% from the primary somatosensory areas [42] and parietal operculum [43]. Moreover, a previous study on the mechanisms of action of Faremus treatment [11] had shown that the reduction in fatigue levels was associated with a rebalancing of the functional connectivity within the key nodes of the sensorimotor network (bilateral S1 and M1), resulting in a main reinforcement of the interplay between the two homologous M1 areas.
On these bases, it is conceivable to expect that the effects of Faremus S1 neuromodulation, targeted at normalizing the activation patterns within the primary sensorimotor system, can be detectable along the whole central–-peripheral CST pathways as expressed by TSM-indutseeritud MEP features [44,45].
1.4. Kortikospinaal traktid ja MEP morfoloogia
Üksikimpulss ülelävi TMS üle M1 on laialdaselt kasutatav to hindamine funktsionaalsus of the CST as a tulemus of pulss levimine piki seljaaju juhe tuvastatud at kontralateraalne lihas tase koos pind elektroodid as motoorne potentsiaal (MEP) [46].
Sees meie eesmärk of hindamine inter-side (domineeriv vs. mitte-domineeriv) homoloogia, me tuletatud mõõt as sarnasus of ahel värbamine mustrid as meie tegi somatosensoorne esilekutsutud potentsiaalid (SEPid) [47] ja väljad (SEF-id) [48,49] via morfoloogiad of the evoked response, MEPs in the present investigation. Analoogselt, ja in leping koos hiljutine suuremahuline hinnangud of MEP morfoloogia [50], siin, me eesmärk kvantifitseerida kuidas Faremus ravi modifies the balance of the CST värbamine vahel domineeriv ja mitte-domineeriv keha küljed as hinnatud by morfoloogia sarnasus of vasak- ja parem-käsi lihas MEPid. To this end, we used the measure of similarity between two curves, the Fréchet distance [51,52], as we already Did in terved vabatahtlikud [53].
1.5. Uuring eesmärk
Läbi the present proof-of-concept study, we pose the working hypothesis that Faremus will modify in the physiological direction the homology between the two CSTs. We will also elate the relationship of the inter-side MEP morphology similarity with the intra-side for both the dominant and non-dominant CSTs. For simplicity, we will refer to the dominant CST, i.e.e. , from the left hemisphere to the right hand, as DxDx and, analogously, SnSn and DxSn for the intra-side non-dominant and inter-side CSTs, vastavalt.
In the case of changes between pre-and post-Faremus, we will test kas seal on a korrelatsioon vahel muutused indutseeritud poolt Faremus ravi ja paranemine of väsimus sümptomid.
2. Meetodid
Kõik meetodid olid läbi viidud välja poolt the Deklaratsioon of Helsingi. The Ethics Committee Lazio1—San Camillo Forlanini approved the experimental protocols (023/CE Lazio1, 11 January 2016). Kõik patsiendid allkirjastatud the informeeritud nõusolek vorm enne nende registreerumine.
2.1. Uuring disain
praegune kontseptsiooni tõestamine uuring keskendub - mehhanismid tegevus of Faremus,�% a0 samas selle efektiivsus testitud via kaks sõltumatu topeltpime, võlts kontrollitud, crossover randomiseeritud kontrollitud uuringud (RCT) on olnud juba avaldatud [26 - 2 c27 % 5d. The RCT result was the fatigue level reduction as measured by the modified fatigue impact scale (IFIS), a valideeritud küsimustik koos 21 esemed hindamine krooniline väsimus koos füüsiline, kognitiivne, ja psühhosotsiaalsed dimensioonid [54].
olevik uuring, ancillary to the main RCTs on the efficacy of Faremus in relieving MS fatigue, assesses the effects of Faremus on the CST homology (Joonis 1). We estimated the similarity of left and right MEP morphologies before and after Faremus.
The TMS protocol was executed in baseline (T{{{0}}; pre-Faremus, the day of the first tDCS application and before the stimulation) and post-Faremus (T1; in 8 patients, TMS was executed on the fifth day, waiting 4 h after the last tDCS stimulatsioon, and in 2 patients, it was executed on the following Monday, i.e., 7 days after T0). Each patsient läbitud kogu the TMS-indutseeritud parlamendiliikmed alates kaks keha küljed (vt joonised 1 ja 2).
Patsiendid olid värvatud kui diagnoositud koos retsidiivs–remitting MS vastavalt to Mc-Donald's kriteeriumid [55] ja täidetud koos abikõlblikkus kriteeriumid as järgneb.
kaasamine kriteeriumid olid as järgmine:
• Absence of clinical or radiological evidence of disease activity (NEDA) for at least 3 months preceding the study;
• madal aste puue as hinnanguline by laiendatud puue staatus skaala (EDSS, Kurtzke 1983) < 2.5;
• väsimus as hinnanguline by mFIS > 30.
%e2%80%a2+Exclusion+Criteria+were+as+follows%3a%c2%a0
• praegune või eelnev (sees vähem kui 12 nädal enne registreerumine) ekspositsioon psühhotroopne ravim(id) (antidepressant, anksiolüütiline, antipsühhootikumid, krambivastased ained, ja müolaksant ravimid);
• kooseksisteerimine muu haigus(ed) potentsiaalselt seotud koos väsimus (st, aneemia ja rasedus);
• praegune või eelnev (sees vähem kui 4 nädal enne registreerumine) kokkupuude väsimusevastane tooted;
• ajalugu of epilepsia
neuroloog kogutud the kliiniline ajalugu see kaasatud haigus kestus ja aastane retsidiiv määr, EDSS, ja Beck Depressioon inventuur (BDI).
Faremus Ravi (5-Day Anodal tDCS with Isikupärastatud S1 Elektrood)
As detailne in [26,27], an individualiseeritud elektrood (piirkondlik isikupärastatud elektrood, RePE) oli kujuline alates aju anatoomiline MRI iga patsient to fit the central sulcus and target the whole-body somatosensory representation areas (Joonis 1). For 5 järjestikused päevad, a RePE anood oli korralikult positsioneeritud via neuronavigation [SofTaxic Neuronavigation System ver.2.0 (www.softaxic.com, E.M.S. , Bologna, Itaalia)] üle the central sulcus (5 mm eesmisel, 15 mm posteriorly), and tDCS was applied for 15 min per day, delivering 1,5 mA current across the RePE anood (35 cm2 ) and a ristkülikukujuline kuklaluu katood tsentreeritud on the Oz of the electroencephalographic international system, with the long side on the longitudinal direction (10 × 7 cm2 ).
2.2. MEP kogu ja analüüs
Stimulatsioon ja salvestamine seadistamine
uuritud subjekt lamamine on a mugav tugitool sisse a vaikne tuba. The lihas signaalid (elektromüogramm, EMG) of the oponent's pollicis (OP) of the right and left hands were sensed by two surface electrodes (2,5 cm apart) in a belly–tendon montage. We performed single-pulse TMS through a standard focal coil connected with a SuperRapid module (The Magstim Company Ltd., Whitland, UK). Sest each subject, we searched for the coil position evoking optimal MEP from the contralateral OP, and we assessed the motor resting threshold (RMT)—defined according to international standards as the intensity eliciting MEPs in the 50 microV amplituud scale in about 50% of 16 consecutive trials [56]. TMS was applied at an intensity adjusted to 120% of the RMT. TMS stiimulid olid esilekutsutud koos an interpulse intervall juhuslikult muutuv vahel 4 s ja 6 s kogumine umbes 20 kordused iga iga külg [57,58]. The available MEPid tulemuseks in an average of 18 per side.
2.3. MEP morfoloogia sarnasus
Me kasutasime the Fréchet distance estimate implement in Matlab [59]. The Fréchet distance estimates the minimum cord length sufficient to join two points traveling forward along two distinct curves, considering the rate of travel for either point is not tingimata uniform.
To estimate the individual similarity between the two CST hemi-bodies, we eassessed the Fréchet distances between each of the 18 right and 18 left OP MEPs, obtaining 324 DxSn MEP Fréchet distances. Similarly, the intra-sided estimates consisted of (n k ) with n=18 and k {= 2}, resulting in 153 Fréchet distances (for each DxDx and SnSn)
2.4. Statistiline analüüs
Antud the large number of values, we did not rely on the Shapiro–Wilk test for normality. By examinationing the distribution, we found huge numbers of outliers, and, for this reason, we transformed the original Fréchet distance values using the natural logarithmic function. The amelioration of Gaussian fitting was not satisfactory; seega, analyses were carried out by non-parametric Wilcoxon-matched paired signed-rank tests.
Me teatasime a tulemus for the olulisus of the effect at p < 0}.050.
To be consistent with the current literature, we also elatery and amplituud of MEPs on the two sides of the body and the inter-lateral difference, focusing eriti on the dispersance of intra- and inter-lateral amplituud, testing the hypothesis that Faremus will modify the homology between the two CSTs by modulating MEP similarity in a physiological direction.
Statistiline analüüs tehti tehti kasutati SPSS 27.
2.5. Andmed Saadavus
Parlamendiliikmed, Fréchet algoritmid, personal, ja kliiniline anonümiseeritud andmed will be available on on taotlus.
3. Tulemused
Kümme katsealused koos MS kannatused väsimus sisestatud the present study. The fatigue levels reduced after concerning before Faremus (Table 1, two-tailed t-test for paired samples, t(9)=2.556, p=0.031) with a 27% amelioration on average, as expressed by the mFIS percentage change, i.e., the difference between the mFIS scores before and after Faremus divided by the mFIS score before it ( Tabel 1).
3.1. Faremus Effects on MEP Morfoloogia Sarnasus As An Index of The Two CSTs' Homoloogia
The non-parametric Wilcoxon one-sided signed-ranks test (Pre > Post) indicated that the inter-side DxSn Fréchet distance before Faremus (mean rank=5.414) was higher than after Faremus (mean rank=5}.061, Z=1.886, p=0.032; Joonis 3A).
Intra-side comparisons did not show that the Fréchet distance before Faremus was higher than after Faremus, either in DxDx (Z= 1.478, p=0.080) or SnSn comparison (Z= 0}.255, p=0.423; Joonis 3B, C).
【For more info:george.deng@wecistanche.com / WhatsApp:8613632399501}】
