Modulation of human corticospinal excitability by paired associative stimulation

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments

Effects of low-frequency whole-body vibration on motor-evoked potentials in healthy men.

addresses: Sport and Exercise Science Research Centre, Faculty of Engineering, Science and The Built Environment, London South Bank University, 103 Borough Road, London SE1 0AA, UK. [email protected] is the author's post-print version of an article published in Experimental Physiology, 2009, Vol. 94, Issue 1, pp. 103 - 116 Copyright © 2009 Wiley-Blackwell /The Physiological Society. The definitive version is available at www3.interscience.wiley.comThe aim of this study was to determine whether low-frequency whole-body vibration (WBV) modulates the excitability of the corticospinal and intracortical pathways related to tibialis anterior (TA) muscle activity, thus contributing to the observed changes in neuromuscular function during and after WBV exercise. Motor-evoked potentials (MEPs) elicited in response to transcranial magnetic stimulation (TMS) of the leg area of the motor cortex were recorded in TA and soleus (SOL) muscles of seven healthy male subjects whilst performing 330 s continuous static squat exercise. Each subject completed two conditions: control (no WBV) and WBV (30 Hz, 1.5 mm vibration applied from 111 to 220 s). Five single suprathreshold and five paired TMS were delivered during each squat period lasting 110 s (pre-, during and post-WBV). Two interstimulus intervals (ISIs) between the conditioning and the testing stimuli were employed in order to study the effects of WBV on short-interval intracortical inhibition (SICI, ISI = 3 ms) and intracortical facilitation (ICF, ISI = 13 ms). During vibration relative to squat exercise alone, single-pulse TMS provoked significantly higher TA MEP amplitude (56 +/- 14%, P = 0.003) and total area (71 +/- 19%, P = 0.04), and paired TMS with ISI = 13 ms provoked smaller MEP amplitude (-21 +/- 4%, P = 0.01) but not in SOL. Paired-pulse TMS with ISI = 3 ms elicited significantly lower MEP amplitude (TA, -19 +/- 4%, P = 0.009; and SOL, -13 +/- 4%, P = 0.03) and total area (SOL, -17 +/- 6%, P = 0.02) during vibration relative to squat exercise alone in both muscles. Tibialis anterior MEP facilitation in response to single-pulse TMS suggests that WBV increased corticospinal pathway excitability. Increased TA and SOL SICI and decreased TA ICF in response to paired-pulse TMS during WBV indicate vibration-induced alteration of the intracortical processes as well

Neural adaptive mechanisms in respiratory regulation : theory and experiments

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2002.Includes bibliographical references (p. 195-215).The respiratory regulatory system is an example of a complex biological control system. The principle goal of the regulator is to preserve the chemical balance of 02, CO2 and pH in the body. Although much is known about the visceral aspects of the respiratory control system, such as lung anatomy, gas exchange, and the mechanics of breathing, considerably less is understood about the neural centers in the brainstem that give rise to known varied respiratory responses. A more complete understanding of respiratory regulation necessitates better knowledge of these underling brain mechanisms. While the task of breathing may seem straightforward, the respiratory system faces many challenges that threaten to perturb homeostasis. It has been shown that the respiratory system adapts itself to better meet changing conditions, for example to meet the stresses of high altitude or increased airway resistance. The question remains then: what neural processes in the brainstem controller participate to engender such sophisticated autonomic regulation? The primary aim of this thesis was to uncover and characterize the central adaptive mechanisms involved in modulating respiratory output. A series of in-vivo animal studies is presented that were designed to elucidate the organizational and functional principles of neural adaptation intrinsic to the respiratory control centers. In these open-loop experimental studies, afferent feedback from vagal slowly-adapting receptors and/or carotid chemoreceptors was electrically activated.(cont.) The dynamic respiratory control response was assessed by measuring the efferent activity of the phrenic nerve. Administration of pharmacological agents was used to determine the contribution of NMDA receptors to the observed responses. The roles of certain brainstem nuclei were assessed by electrical lesions. The experimental results revealed dynamic and temporal filtering properties produced by adaptation and phase-locked gating respectively in the respiratory controller. These responses demonstrated novel neural differential and integral computations specific to expiratory and inspiratory control circuits. Moreover, mechanical and chemical feedbacks were shown to adaptively modulate each other's neural transfer functions in an associative manner. Modeling and computational studies were used to assess the significance that these processes may have for stability and compensatory responses during certain physiologic states and diseases. It is suggested that these neural processes may participate in the adaptive optimal control of breathing.by Young, Daniel L. Young.Ph.D

Assessing the oscillatory properties of functional connections between sensory areas during crossmodal illusions: A correlational and causal investigation.

A comprehensive investigation on multisensory integration is presented whereby three complex studies investigating the role of neuro-oscillatory processes in tactile-visual and auditory-visual illusory tasks were conducted. Utilising EEG scanning we first replicated previous evidence of a correlation between individual alpha frequency and the auditory-induced Double Flash Illusion (DFI). We also provided evidence of a previously unreported correlation between individual beta frequency and the corresponding tactile-induced DFI. In two follow-up studies evidence is also provided of a causal relationship between beta processes and the tactile-induced DFI using a variant of paired associative TMS known as cortico-cortical Paired Associative Stimulation. Here we demonstrated by temporarily reducing occipital beta speed we can subsequently produce reliably predictable changes in the temporal profile of visuo-tactile multisensory processing. Using two control measures across two investigations we provided evidence suggesting that the stimulation that we utilised was both frequency specific and hemisphere specific. From this we concluded that multisensory processes are facilitated by the oscillatory properties of network-specific (auditory-to-visual or somatosensory-to-visual) neural connections favouring optimal, directional neural communication and integration between the senses

Motor learning and neuroplasticity in humans

The central nervous system is plastic, in that the number and strength of synaptic connections changes over time. In the adult the most important driver of such changes is experience, in the form of learning and memory. There are thought to be a number of rules, operating relatively local to each synapse that govern changes in strength and organisation. Some of these such as Hebbian plasticity or plasticity following repeated activation of a connection have been studied in detail in animal preparations. However, recent work with non-invasive methods of transcranial stimulation in human, such as transcranial magnetic stimulation, has opened the opportunity to study similar effects in the conscious human brain. In this thesis I use these methods to explore some of the presumed changes in synaptic connectivity in the motor cortex during different forms of motor learning. The experiments only concern learning in the healthy brain; however it seems likely that the same processes will be relevant to neurorehabilitation and disease of the nervous system. This thesis explores the link between neuroplasticity and motor learning in humans using non-invasive brain stimulation, pharmacological agents and psychomotor testing in 6 related studies. 1) Chapter 3 reports initial pharmacological investigations to confirm the idea that some of the long term effects of TMS are likely to involve LTP-like mechanisms. The study shows that NMDA agonism can affect the response to a repetitive form of TMS known as theta burst stimulation (TBS) 2) Following up on the initial evidence for the role of NMDA receptors in the long term effects of TBS, Chapter 4 explores the possible modulatory effects of dopaminergic drugs on TBS. 3) Chapter 5 takes the investigations to normal behaviours by examining how the NMDA dependent plasticity produced by TBS interacts with learning a simple motor task of rapid thumb abduction. The unexpected results force a careful examination of the possible mechanisms of motor learning in this task. 4) Chapter 6 expands on these effects by employing a battery of TMS methods as well as drug agents to examine the role of different intracortical circuits in ballistic motor learning. 5) Chapter 7 studies the plasticity of intracortical circuits involved in transcallosal inhibition. 6) Chapter 8 studies the interaction between synaptic plasticity invoked by TBS and sequence learning. The studies described in the thesis contribute to understanding of how motor learning and neuroplasticity interact, and possible strategies to enhance these phenomena for clinical application

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines

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