Long-Term Paired Associative Stimulation for Restoration of Motor Function after Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition and consequent loss of motor control remains one of the main causes of disability. Motor recovery after SCI depends on the amount of spared and restored neural connections in the spinal cord. Most SCIs are incomplete and even neurologically complete injuries possess some spared neural connections. Damaged motor pathways can be reactivated by external stimulation. However, current treatment approaches are mainly palliative, such as assisting adaptation to impairments. Thus, there is a need for novel therapies to induce neuroplasticity in the spinal cord and strengthen weak and disrupted neural connections. In this thesis, paired associative stimulation (PAS) was applied as a long-term treatment for chronic incomplete SCI of traumatic origin. PAS is a non-invasive neuromodulation paradigm where descending volleys induced by transcranial magnetic stimulation (TMS) of the motor cortex are timed to coincide with antidromic volleys elicited by peripheral nerve electrical stimulation (PNS). The stimulation protocol was designed to coincide TMS- and PNS-induced volleys at the cortico-motoneuronal synapses in the spinal cord. Continuous pairing of TMS and PNS stimuli can change synaptic efficacy and produce long-term potentiation (LTP)-like plasticity in the corticospinal tract. Augmentation of synaptic strength at the spinal level has clear therapeutic value for SCI, as it can enhance motor control over paralyzed muscles. The aim of the thesis was to investigate the possible therapeutic effects of long-term PAS on hand and leg motor function in individuals with chronic incomplete SCI of traumatic origin. Study I explored long-term PAS therapeutic potential by providing long-term PAS until full recovery of hand muscle strength or until improvements ceased. The PAS protocol was designed to coincide TMS- and PNS-induced volleys in the cervical spinal cord, which is both the location of the stimulated lower motor neuron cell bodies and the site of the injury. Improvements up to normal values of hand muscle strength (Manual Muscle Test [MMT]) and increased amplitude of motor evoked potentials (MEPs) were obtained after more than 1-year stimulation in a participant with SCI. The participant regained almost complete self-care of the upper body. This was the first demonstration of restoring normal strength and range of movement of individual hand muscles by means of long-term PAS. The effect persisted over 6 months of follow up. Study II probed the effects of long-term PAS on leg muscle strength and walking in a group of five people with SCI. The PAS protocol was designed to coincide TMS- and PNS-induced volleys in the lumbar spinal cord but the site of the injury was in the cervical spinal cord. Long-term PAS delivered for 2 months significantly increased the total lower limb MMT score. This effect was stable over a 1-month follow up. Walking speed increased after 2 months of PAS in all participants. This study was the first demonstration that long-term PAS may significantly increase leg muscle strength and affect walking. The MMT score prior to the intervention was a good predictor of changes in walking speed. Study III developed a novel technique that enables probing neural excitability at the cervical spinal level by utilizing focal magnetic coil and anatomy-specific models for re-positioning of the coil. The technique enabled recording of highly reproducible MEPs and was suitable for accurate maintenance and retrieval of the focal coil position at the cervical level. In summary, this thesis contributes to the understanding of therapeutic efficacy of long-term PAS for restoration of motor control over hand and leg muscles after chronic SCI. This work challenges the view that chronic SCI is an irreversible pathologic condition and demonstrates the possibility of restoring neurological function many years postinjury when spontaneous recovery is extremely rare. The increased amplitude of MEPs, sustainable motor improvements, and the effects observed regardless of injury location indicate that PAS induces stable changes in the corticospinal pathways.Selkäydinvamma on ihmiseen kokonaisvaltaisesti vaikuttava tila, ja motorinen heikkous on yksi tärkeimmistä tekijöistä, jotka aiheuttavat rajoituksia päivittäiseen elämään. - Nykyiset hoitomenetelmät pääasiassa lievittävät oireita. Ne helpottavat kivun ja spastisuuden hallintaa ja sopeutumista vammaan sekä estävät sekundaarisia komplikaatioita. Keskushermosto voi kuitenkin järjestyä uudelleen sopeutuakseen heikentyneeseen toimintaan, ja tätä muovautuvuutta voidaan käyttää terapeuttisena mahdollisuutena. Vaurioituneet hermoradat voidaan aktivoida uudelleen ulkoisella stimulaatiolla. Toipuminen selkäydinvamman jälkeen riippuu niistä selkäytimen hermoyhteyksistä, jotka ovat säästyneet ja jotka on onnistuttu palauttamaan. Usein selkäydinvammat ovat osittaisia, ja neurologisesti täydellisissäkin vammoissa on joitakin säästyneitä hermoyhteyksiä. Uusilla hoitomenetelmillä voidaan aktivoida selkäytimen neuroplastisuutta ja vahvistaa heikkoja ja katkenneita hermoyhteyksiä. Tässä väitöskirjassa kaksoisstimulaatiota (PAS) käytettiin pitkäaikaisena hoitona potilailla, joilla oli krooninen, traumaattinen osittainen selkäydinvamma. PAS on neuromodulaatiomenetelmä, jossa aivokuoren transkraniaalinen magneettistimulaatio (TMS) synkronoidaan perifeeristen hermojen sähköstimulaatioon (PNS). Stimulaatioprotokolla suunniteltiin niin että TMS: n ja PNS: n synnyttämät aktivaatiot kohtaavat selkäytimen synapseissa. Jatkuva TMS:n ja PNS:n aikaansaamien ärsykkeiden kohtaaminen selkäydintasolla voi voimistaa synapsien tehokkuutta ja tuottaa pitkäaikaisen synaptisen potentiaation (long-term potentiation, LTP) selkäytimessä. Synaptisen tehokkuuden kasvu selkäytimessä todennäköisesti parantaa lihasten tahdonalaista hallintaa. Väitöskirjan päätavoitteena on ollut tutkia pitkäaikaisen kaksoisstimulaation (PAS) mahdollisia terapeuttisia vaikutuksia käden ja jalkojen tahdonalaiseen lihasaktiivisuuteen henkilöillä, joilla on traumaattinen krooninen osittainen selkäydinvamma. Tutkimuksessa I selvitin pitkäaikaista PASin terapeuttista potentiaalia antamalla PAS-hoitoa niin kauan kunnes käden lihasten voima palautui kokonaan, tai voimassa ei tapahtunut enää kasvua. Yli vuoden kestäneen stimulaation jälkeen käsien lihasvoimat kohenivat normaaliarvoihin (Manuaalinen lihastesti, MMT) osallistujalla, jolla oli krooninen osittainen neliraajahalvaus. Sen lisäksi herätevastet (motor-evoked potentials) kasvoivat. Koehenkilön ylävartalon lihashallinta palautui lähes täydellisesti. Tämä on ensimmäinen osoitus yksittäisten käsilihasten normaalin voiman ja liikeratojen palautumisesta pitkäaikaisen PAS:n avulla selkäydinvammapotilaalla. Vaikutus säilyi 6 kuukauden seurannassa. Tutkimuksessa II tutkittiin pitkäaikaisen PAS: n vaikutuksia alaraajalihasten voimaan ja kävelyyn viidellä henkilöllä, joilla on krooninen tetraplegia. Kahden kuukauden ajan annettu pitkäaikainen PAS lisäsi merkittävästi alaraajojen MMT-pistemäärää keskimäärin yhdellä pisteellä lihasta kohden. Tämä tulos säilyi kuukauden seurannassa. Kaikkien osallistujien kävelynopeus kasvoi PAS-hoitojakson jälkeen. Tutkimus on ensimmäinen osoitus siitä, että pitkäaikainen PAS voi lisätä merkittävästi alaraajojen lihasvoimaa. MMT-pistemäärä ennen interventiota ennusti hyvin kävelynopeuden muutoksia. Tutkimuksessa III kehitettiin uusi tekniikka, joka mahdollistaa magneettistimulaation selkäydinalueella käyttäen fokaalista magneettikelaa ja pään anatomisia malleja magneettikelan toistettuun kohdentamiseen. Menetelmä mahdollisti toistettavien MEP-signaalien mittaamisen sekä kelan sijainnin tarkan, toistettavan paikannuksen ja kohdentamisen niskan alueella. Yhteenvetona voidaan todeta, että väitöskirja lisää ymmärrystä pitkäaikaisen PAS: n terapeuttisesta tehosta ylä- ja alaraajalihasten hallinnan palauttamisessa ja omatoimisuuden lisäämisessä kroonisen selkäydinvamman jälkeen. Väitöskirja haastaa käsityksen kroonisen selkäydinvamman aiheuttamien toimintahäiriöiden pysyvästä luonteesta. Sen lisäksi väitöskirja osoittaa mahdollisuuden palauttaa lihasaktiivisuutta nimenomaan kroonisessa selkäydinvammassa, jossa spontaani koheneminen on erittäin harvinaista. Voimistuneet lihasvasteet ja pysyvä lihashallinnan parannus vamman sijainnista riippumatta osoittavat, että PAS oikein käytettynä muokkaa liikejärjestelmää hyödyllisellä tavalla

Guideline for Selection of Systems, Structures and Components to be considered in Ageing PSA

The guideline intends to provide a practical approach and to recommend the methods to be used in selection/prioritization of components, systems and structures (SSC) sensitive to ageing and important from risk point of view in operating nuclear power plants. The approach intends to ensure that the selection process will be carried out and documented in a uniform and consistent manner. The methods suitable for selection are briefly presented, and their advantages and disadvantages are specified. A list of generic ageing mechanisms, the factors favorable for their occurrence and some sensitive materials are provided in appendices. In the appendices are presented also the specific approaches and criteria used for SSC prioritization and selection in case studies performed in the frame of Ageing PSA task 3 activities. The guideline was developed in the frame of EC JRC Ageing PSA Network (APSA) activities.JRC.DDG.F.5-Safety of present nuclear reactor

Terms of Reference for APSA European Network on Use of PSA for Evaluation of Ageing Effects to the Safety of Energy Facilities. Revision 2

The Terms of Reference specifies the background, objectives, scope, main tasks and organization of European Network on Use of Probabilistic Safety Assessment (PSA) for Evaluation of Ageing Effects to the Safety of Energy Facilities (EC JRC IE APSA Network). The Network was initiated under the JRC FP6/ 7 Institutional Action "Analysis and Management of Nuclear Accidents" (AMA) and is now operated within the framework of the JRC-IE Institutional project "Plant Operation Safety" POS no. 52103. This document updates the JRC-IE report EUR 22645 EN, issued in 2007. The document is prepared in accordance with the requirements of JRC QA Work Instruction "Management of Partnerships and Networks" W400 1.JRC.DDG.F.5-Safety of present nuclear reactor

Analysis of Data related to Ageing of VVER-440 NPP Components

The aim of case study was to demonstrate the applicability of methods for reliability parameters estimation, presented in the guideline (EUR 23954 EN), using the operational data from VVER-440 plants. Two types of calculations were performed, using Excel functions and WINBUGS scripts, to identify the possible trends of data. The study results are useful in revealing the problematic issues connected with use of data guideline (EUR 23954 EN) and for improvement of decision making process based on calculation results. Practical insights, recommendations and limitations are also discussed. The report was prepared by the Nuclear & Radiation Safety Center (NRSC), Yerevan, Armenia in cooperation with the Institute for Energy, EC Joint Research Centre, Petten, Netherlands, in the framework of the EC JRC Ageing PSA Network Task 4 activities.JRC.DDG.F.5-Safety of present nuclear reactor

Effects of Long-Term Paired Associative Stimulation on Strength of Leg Muscles and Walking in Chronic Tetraplegia : A Proof-of-Concept Pilot Study

Recovery of lower-limb function after spinal cord injury (SCI) is dependent on the extent of remaining neural transmission in the corticospinal pathway. The aim of this proof-of-concept pilot study was to explore the effects of long-term paired associative stimulation (PAS) on leg muscle strength and walking in people with SCI. Five individuals with traumatic incomplete chronic tetraplegia (>34 months post-injury, motor incomplete, 3 females, mean age 60 years) with no contraindications to transcranial magnetic stimulation (TMS) received PAS to one or both legs for 2 months (28 sessions in total, 5 times a week for the first 2 weeks and 3 times a week thereafter). The participants were evaluated with the Manual Muscle Test (MMT), AIS motor and sensory examination, Modified Asworth Scale (MAS), and the Spinal Cord Independence Measure (SCIM) prior to the intervention, after 1 and 2 months of PAS, and after a 1-month follow-up. The study was registered at (NCT03459885). During the intervention, MMT scores and AIS motor scores increased significantly (p = 0.014 and p = 0.033, respectively). Improvements were stable in follow-up. AIS sensory scores, MAS, and SCIM were not modified significantly. MMT score prior to intervention was a good predictor of changes in walking speed (Radj2 = 0.962). The results of this proof-of-concept pilot study justify a larger trial on the effect of long-term PAS on leg muscle strength and walking in people with chronic incomplete SCI.Peer reviewe

Practical Issues in Component Aging Analysis

This paper examines practical issues in the statistical analysis of component aging data. These issues center on the stochastic process chosen to model component failures. The two stochastic processes examined are repair same as new, leading to a renewal process, and repair same as old, leading to a nonhomogeneous Poisson process. Under the first assumption, times between failures can treated as statistically independent observations from a stationary process. The common distribution of the times between failures is called the renewal distribution. Under the second process, the times between failures will not be independently and identically distributed, and one cannot simply fit a renewal distribution to the cumulative failure times or the times between failures. The paper illustrates how the assumption made regarding the repair process is crucial to the analysis. Besides the choice of stochastic process, other issues that are discussed include qualitative graphical analysis and simple nonparametric hypothesis tests to help judge which process appears more appropriate. Numerical examples are presented to illustrate the issues discussed in the paper

Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed by Global Transcriptional Regulator NagR

Bifidobacterium longum subsp. infantis is a prevalent beneficial bacterium that colonizes the human neonatal gut and is uniquely adapted to efficiently use human milk oligosaccharides (HMOs) as a carbon and energy source. Multiple studies have focused on characterizing the elements of HMO utilization machinery in B. longum subsp. infantis; however, the regulatory mechanisms governing the expression of these catabolic pathways remain poorly understood. A bioinformatic regulon reconstruction approach used in this study implicated NagR, a transcription factor from the ROK family, as a negative global regulator of gene clusters encoding lacto-N-biose/galacto-N-biose (LNB/GNB), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT) utilization pathways in B. longum subsp. infantis. This conjecture was corroborated by transcriptome profiling upon nagR genetic inactivation and experimental assessment of binding of recombinant NagR to predicted DNA operators. The latter approach also implicated N-acetylglucosamine (GlcNAc), a universal intermediate of LNT and LNnT catabolism, and its phosphorylated derivatives as plausible NagR transcriptional effectors. Reconstruction of NagR regulons in various Bifidobacterium lineages revealed multiple potential regulon expansion events, suggesting evolution from a local regulator of GlcNAc catabolism in ancestral bifidobacteria to a global regulator controlling the utilization of mixtures of GlcNAc-containing host glycans in B. longum subsp. infantis and Bifidobacterium bifidum