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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5289_Библиотеки_им_академика_М_И_Перельмана
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been extremely fortunate in being given the opportunity to collaborate with top
professionalsfromseveralpartsofthewords:I’mindebtedtoallmycoworkers,coauthors,
and supervisors, particularly Dr. Patrizio Pasqualetti, my statistical guru, expert advisor
and good friend; Dr.Fini, Dr.Dal Forno, Dr. Pauri, Dr. Curcio, Dr. Fabrizio, Mr. Fusco,
ProfessorVernieri,ProfessorBabiloniand ProfessorMiniussiforsupportingmewhenthis
scientific adventure started; Professor Tononi, Professor Massimini and Professor Huber,
whoopenedmymind;Dr.Esser,Dr.Riedner,Dr.FerrarelliandDr.Goldstein,whohelped
me in the USA; M.Sc. Säisänen who helped me with this thesis, and Dr. Aronica, who
polishedandimprovedmypoorEnglish.
IalsothankmyclosefriendsEmma,Alberto,Davide,Federica,Liliana,Mara,Anna
andLuigiwhosustainedmeovertheseyearsintheinternationalresearchcommunityand
evenbefore,duringthehardschooltime.
Alovelythoughtgoes to all my relatives andparticularlytomyauntsAlessandra,
CettinaandMarilena,tomyuncleFranco,andtomysweetgrandmotherInes,whoalways
looksforwardtomyreturnfrommytripsallovertheworld.
I cannot expresssufficient gratitude andlove to myparents, Mina andDomenico,
whotaughttometoreachmyobjectives,howeverfarorarduous,stepbystepintheright
way withouttaking short cuts and to my little brotherEgidio, who is now learning the
samelessonandwillalwaysbeinmyheart.
This work would not have been possible without the patience, love and also
technical and technological support that my fiancée David has given me over the last
sixteen years. He has sacrified his wellbeing innumerable times in favour of my goals. I
hopeto be abletoreturn at least partofthis love inourfuturelife together. Mostofthe
workwasperformedathomeduringmanyhoursthatwouldotherwisehavebeendevoted
tohimandmyfamily.
Ifondlydedicate thisthesistomygrandfathersGiovanniandEgidio,wholookafter
me since many years and to Anna, Lorenzo, my aunt Angela and my grandmother
Florinda,whohadaglimpseofthebeginningofthiswaybutarenotwithusanymore.
Kuopio,September2011
FlorindaIne
sMariaFerreri
XI
Listoftheoriginalpublications
Thisthesisisbasedonthefollowingfiveoriginalpublications:
I. FerreriF,PauriF,PasqualettiP,FiniR,DalFornoG,RossiniPM.
Motor cortex excitability in Alzheimer Disease: a transcranial magnetic
stimulationstudy.
AnnNeurol53(1):102‐8,2003
II. FerreriF,CurcioG,PasqualettiP,DeGennaroL,FiniR,andRossiniPM.
Mobilephoneemissionandhumanbrainexcitability.
AnnNeurol60(2):188‐96,2006
III. Ferreri F,PasqualettiP, Määttä S,PonzoD, Ferrarelli F, TononiG,Mervaala E,
MiniussiC,andRossiniPM.
Humanbrainconnectivityduringsingleand paired pulse transcranial magnetic
stimulation.
Neuroimage1;54(1):90‐102,2011
IV. FerreriF,PasqualettiP,MäättäS,PonzoD,GuerraA,BressiF,ChiovendaP,Del
Duca M, Giambattistelli F, Ursini F, Tombini M, Vernieri F and Rossini PM.
Motor cortex excitability in Alzheimer’s disease: a Transcranial Magnetic
Stimulationfollow‐upstudy.
NeurosciLetters1;492(2):94‐8,2011
V. FerreriF,PonzoD,HukkanenT,MervaalaE,KönönenM,PasqualettiP,Rossini
PMandMäättäS.
Human brain cortical correlates of short‐latency afferent inhibition (SAI): a
combinedEEG‐TMSstudy.
Submitted
The publications were adapted with the permission of the copyright owners. Some
unpublishedresultsarealsopresented.
XII
XIII
Contents
1 INTRODUCTION......................................................................................................................1
2 REVIEWOFTHELITERATURE:BASICPRINCIPLESOFHUMANBRAIN
EXCITABILITY,CONNECTIVITYANDPLASTICITY.....................................................3
2.1 BRAINEXCITABILITY,CONNECTIVITYANDPLASTICITY........................4
2.2 TYPESANDMECHANISMSOFPLASTICITY....................................................4
2.2.1 Functionalmechanismsforcorticalplasticity...........................................................5
2.2.1.1 Long‐TermPotentiationandDepotentiation............................................................5
2.2.1.2 Long‐TermDepression.................................................................................................6
2.2.1.3 SpikeTiming‐DependentPlasticity............................................................................7
2.2.1.4 Metaplasticity................................................................................................................7
2.2.1.5 PlasticityofGABAergiccellandcircuits...................................................................8
2.2.2 Structuralmechanismsforcorticalplasticity............................................................8
2.3 PRINCIPLESOFBRAINCONNECTIVITY...........................................................9
2.4 TOWARDSANINTEGRATEDMODELOFCORTICALEXCITABILITY,
CONNECTIVITYANDPLASTICITY...................................................................13
2.5 BASICPRINCIPLESOFTMSANDTMS‐EEGCO‐REGISTRATION..........14
2.5.1 TranscranialMagneticStimulation..........................................................................14
2.5.1.1 MagneticResonanceImaging‐GuidedStereotacticTMS......................................16
2.5.2 TranscranialMagneticStimulationParadigms......................................................17
2.5.3 EEG‐TMSco‐registration...........................................................................................19
2.5.3.1 UsefulnessofTMS‐EEGinstudyingcorticalexcitability,connectivityand
plasticity.......................................................................................................................21
3 AIMSOFTHEORIGINALSTUDIESONMOTORCORTEXEXCITABILITY,
CONNECTIVITYANDPLASTICITYINHEALTHYSUBJECTSAND
ALZHEIMER’SDISEASEPATIENTS..................................................................................23
3.1 SPECIFICAIMSOFSTUDIESI‐V.........................................................................24
4 SUBJECT,MATERIALSANDMETHODS.........................................................................26
4.1 SUBJECTS...................................................................................................................26
4.2 MATERIALSANDMETHODS..............................................................................26
4.2.1 TranscranialMagneticStimulationandrecordingsystems(EMGandEEG)....26
4.2.1.1 StudiesIandIV...........................................................................................................26
4.2.1.2 StudyII.........................................................................................................................27
XIV
4.2.1.3 StudyIII........................................................................................................................29
4.2.1.4 StudyV.........................................................................................................................30
4.2.2 DataAnalysis...............................................................................................................30
4.2.2.1 StudiesIandIV...........................................................................................................31
4.2.2.2 StudyII.........................................................................................................................32
4.2.2.3 StudyIII........................................................................................................................33
4.2.2.4 StudyV.........................................................................................................................36
5 RESULTS....................................................................................................................................38
5.1.1 StudiesIandIV...........................................................................................................38
5.1.2 StudyII.........................................................................................................................43
5.1.3 StudyIII........................................................................................................................46
5.1.3.1 Supra‐thresholdsinglepulseTMSevokedactivity...............................................48
5.1.3.2 ISI3andISI11.ISI3andISI11versussupra‐thresholdsinglepulse.ISI11
versusISI3...................................................................................................................52
5.1.3.3 ppTMS‐evokedEEGresponseslatencymodulation.............................................54
5.1.3.4 CorrelationbetweenEMGandEEGmeasuresinsingleandppTMS.................54
5.1.4 StudyV.........................................................................................................................58
5.1.4.1 Event‐relatedspectralperturbationandintertrialcoherence..............................62
5.1.4.2 CorrelationbetweenEEGmodulationandMEPmodulation.............................63
6 DISCUSSION............................................................................................................................64
6.1 SINGLESTUDYDISCUSSION.............................................................................64
6.1.1 StudiesIandIV...........................................................................................................64
6.1.2 StudyII.........................................................................................................................65
6.1.3 StudyIII........................................................................................................................65
6.1.4 StudyV.........................................................................................................................66
6.2 GENERALDISCUSSION........................................................................................67
7 SUMMARYANDCONCLUSION........................................................................................71
8 REFERENCES............................................................................................................................72
APPENDIX:ORIGINALPUBLICATIONS
XV
Abbreviations
μV
microVolt
GMFP
GlobalMean‐FieldPower
ACh
Acetylcholine
Hz
Hertz
AChEIs
AcetylcholinesteraseInibitors
IADL
InstrumentalActivitiesof
DailyLiving
AD
Alzheimer’sDisease
ICF
IntracorticalFacilitation
ADM
AbductorDigitiMinimi
IFCN
InternationalFederationof
ClinicalNeurophysiology
AMPA
α‐Amino‐3‐Hydroxy‐5‐Methyl‐
4‐IsoxazolePropionicAcid
ISIs
Inter‐StimulusIntervals
ANOVA
AnalysisofVariance
ITC
IntertrialCoherence
Aβ
β‐amyloid
kHz
kiloHertz
c/s
cicle/second
kΩ
kiloOhm
CB1
Cannabinoidtype1receptor
LTD
Long‐TermDepression
CDR
ClinicalDementiaRating
LTP
Long‐TermPotentiation
CoG
CenterofGravity
M1
PrimaryMotorCortex
CSP
CorticalSilentPeriod
MANOVA
MultivariateAnalysisof
Variance
dB
decibel
MEG
Magnetoencephalography
DTI
DiffusionTensorImaging
MEP
MotorEvokedPotential
ECD
ExtensorDigitorumCommunis
mGluR
metabotropicGlutamate
Receptor
EEG
Electroencephalography
mm
millimetre
EMF
ElectromagneticField
MMSE
MiniMentalStateExamination
EMG
Electromyography
MR
MagneticResonance
EOG
Electro‐oculogram
MRI
MagneticResonanceImaging
ERD
Event‐Related
Desynchronization
ms
millisecond
ERS
Event‐RelatedSynchronization
MT
MotorThreshold
ERSP
Event‐RelatedSpectral
Perturbation
mV
milliVolt
fEPSPs
fastExcitatoryPostsynaptic
Potentials
N20
NegativeSEPdeflections
fIPSPs
fastInhibitoryPostsynaptic
Potentials
N7,N18,N44
,
N100,N280
NegativeTMS‐evokedEEG
deflections
fMRI
functionalMagneticResonance
Imaging
NMDA
N‐Methyl‐D‐Aspartato
GABA
Gamma‐AminobutyricAcid
OP
OpponentPollicis
GEE
GeneralEstimatingEquation
P13
,
P30
,
P60
P180
PositiveTMS‐evokedEEG
deflections
XVI
ppTMS
pairedpulseTranscranial
MagneticStimulation
rMT
restingMotorThreshold
rTMS
repetitiveTranscranial
MagneticStimulation
SAI
Short‐latencyAfferent
Inhibition
SD
StandardDeviation
sEPSPs
slowExcitatoryPostsynaptic
Potentials
SICI
Short‐IntervalIntracortical
Inhibtion
sIPSPs
slowInhibitoryPostsynaptic
Potentials
SnPM
StatisticalnonParametric
Mapping
STDP
SpikeTiming‐Dependent
Plasticity
T
Tesla
TES
TranscranialElectrical
Stimulation
TMS
TranscranialMagnetic
Stimulation
TNF
Tumor‐NecrosisFactor
1 Introduction
Itisnowwellknownthatoneofthemostimportantcapabilitiesofthehumanbrainis
changingitsorganizationstructurallyand/orfunctionally throughout life in order tocope
with normal and abnormal experiences and inputs from the surrounding world. This
capacity,namedneuroplasticity,hasbeenextensivelyinvestigatedinthelast few decades
notonlybecauseitsupportsseveralbrainfunctionsincludingcognitiveprocesses,butalso
because of its potential therapeutic applications in neuropsychiatric disorders. The
examinationofneuroplasticitywasinitiallypossibleonlyonanimalpreparationswhilethe
recent development ofadvanced technologiesallows nowadays non‐invasive exploration
on the living human brains. Among the tools currently available to neuroscientists
TranscranialMagneticStimulation(TMS)isanon‐invasiveandpainlesstechniquethathas
opened up completely new and fascinating avenues to study, induce or manipulate the
mechanismsunderlyingplasticityofthehumanbrain.
Firstly, TMS can be used to investigate the functional state of the cerebral cortex
(KobayashiandPascual‐Leone,2003;RossiniandRossi,2007)andtheresponsivenessofthe
neuronalpopulationtoincomingsignals,thatistheneuronalexcitability,detectingchanges
whichmayhaveoccurredthroughprocesses such as learning or recoveryfromanervous
system lesion. Secondly,TMScan interfere withthe brain activity,inducingshort‐lasting
‘virtual lesions’ which may directly test ‘in vivo’ the functional relevance and the
connectivityofseveralbraincortices(Oliverietal.,1999;Oliverietal.,2000a;Oliverietal.,
2000b; Friston et al., 2003; Ziemann et al., 2008).Thirdly, TMS can manipulate the brain
plasticity, inducing by itself changes in excitability and connectivity of the stimulated
cortex which might be used therapeutically in neurological and psychiatric diseases
(Rothwell, 2010; PlatzandRothwell, 2010). AllPublications (I‐V) inthis thesis usedTMS
mostofallasaprobeofcorticalexcitability.
InTMStheexcitationofneuronsindeepgreymattercanbeeitherdirectorindirect
throughvolleysfromsuperficialneurons(Barkeretal.,1985).Adequatestimulationofthe
primarymotor cortex(M1)evokesindirectexcitationofpyramidalneuronsvialocalinter‐
neurons with higher probability than direct excitation (Amassian and Cracco, 1987). The
volley along the corticospinal pathway can elicit electromyographic (EMG) responses,
termedmotorevokedpotentials(MEPs),inthe target muscles contra‐lateral to the side of
the stimulation (Hallett, 2000). Even though MEPs are used routinely in research and
sometimes in clinical settings to study the motor cortex excitability, a proper evaluation
should clearly differentiate between the indices of the overall excitability of the
corticospinal system (corticospinal excitability), and those directly and specifically
reflectingtheexcitabilityofthemotorcortex(corticalexcitability).Indeedtheproblemwith
EMGingeneral,andwithMEPsinparticular,isthattheyareaffectedbyacombinationof
cortical,subcortical,andspinal‐cordmechanisms,whichusuallycoincideintime,making
their separation very difficult. Amplitudes and latencies of MEPs are in fact parameters
resulting from a combinationof excitatory and i
nhibitory events occurring in a complex
2
synapticnetworkatdifferent neurallevelsalongthemotorpathway(Rossini etal.,1987a;
Rothwelletal.,1987; Hallett, 2011;Hallett,2007;RossiniandRossi,2007),and the relative
contributionoftheseeventsisfarfromfullyelucidated(Baumeretal.,2003;Rothwell,2010)
TMScanbedeliveredinseveralparadigmssuchassinglepulse,paired‐pulseorrepetitive
and each of these paradigms has contributed to clarify some aspects of the corticospinal
physiopathology(Ziemann,1999).Theresultsof StudiesI‐II‐IVofthisthesiscomplement
these findings clearly demonstrating the role of some TMS paradigms (that is TMS
mappingandpaired pulse TMS (ppTMS))intheevaluationofcorticospinalexcitabilityin
healthyandpathologicalsubjects.However,aspreviouslymentioned,ifdrawnexclusively
onMEPrecordings,conclusionsaboutcorticalpathologiesoringeneralaboutinvolvement
of M1 in a given process might be uncertain. Recently, a technical device has been
introducedthatallows therecordingelectroencephalographic(EEG) responsestodifferent
TMSparadigmswithmillisecondresolutionlikelywithoutspinalandmuscularinfluences.
CombiningTMSofagivenscalpsitewithEEGenablesanon‐invasive,finallydirect,
methodtostudy corticalexcitability,connectivityandplasticity(Ilmoniemietal.,1997). A
networkof neuronal connections is infactengagedwhenTMS‐evokedactivation extends
fromastimulationsitetootherpartsofthebrain,andthesummationofsynapticpotentials
producesdeflectionsinscalpEEGsignals,startingfewmillisecondsafterthestimulusand
lasting about 300 ms,first in the form ofrapid oscillations and then as lower‐frequency
waves (Ilmoniemi et al., 1997). The amplitude, latency, and scalp topography of single
pulse TMS‐evoked EEG responses have been clearly described (Komssiet al.,2004). The
characteristics of theseresponsesare thoughttodepend onthe stimulation intensityand
functional state ofthe stimulatedcortex as well as theoverall brain(Komssi et al., 2004;
Siebneretal.,2009). IthasbeensuggestedthattheveryfirstpartoftheTMS evokedEEG
responsereflectstheexcitability‐thatisthefunctionalstate‐ofthestimulatedcortexwhile
itsspatio‐temporal distribution over thescalpreflectsthespread of activation‐thatis the
effectiveconnectivityofthestimulatedarea(Leeetal.,2003;KomssiandKähkönen,2006)‐
toothercortical areas‐viaintraandinter‐hemisphericcortico‐cortical connections‐aswell
astosub‐corticalstructuresandspinalcordviaprojectionfibres.TheresultsofStudiesIII
and V of this thesis compleme
nt these findings by adding new insight into previously
delineatedfunctionalbehaviourofhumanbrainasinvestigatedbyEEGoscillationsevoked
by TMS on M1. In fact, two further early responses‐N7 and P13‐ were observed and
characterized in more details; moreover the dependence of the EEG evoked activity on
somediffer
entTMSparadigms(thatis ppTMS andshortlatencyafferentinhibition(SAI))
wasdescribedandcorrelatewiththeMEPsvariabilityinducedbythesameparadigms.
ThenthepresentthesisprovidesevidencesonthefeasibilityofTMSandTMS‐EEGfor
the evaluation of M1 excitability and connectivity, addressing some crucial issues for a
better elucidation of themechanisms underlying brain neuroplasticity in human healthy
andpathologicalsubjects.
3
2 Review of the literature: basic principles of human
brainexcitability,connectivityandplasticity
A rising body of evidence from animal models and neuroimaging and
neurophysiologicstudiesin humansprovidesevidenceforplastic changesandadaptation
incentralnervoussystemthroughoutlife(Pascual‐Leoneetal.,1998;Hallett,1999;Siebner
andRothwell,2003;Pascual‐Leoneet al., 2005; Ziemann et al.,2008).inordertocopewith
experiencesandinputs from the surrounding aswell asfromthe‘interior’environments
.
While the developing nervous system seems more capable of modifications, dynamic
plasticchangescanbe documentedintheadultnervoussystemas well. The adultcentral
nervous system is indeed emerging as a dynamically adapting and changing system in
whichmodificationsaredrivenbyafferentinput,efferentdemandandenvironmentaland
behaviouralinfluencesoffunctionalsignificance(Pascual‐Leoneetal.,1998).Ononehand,
neuralnetworksexhibitmodularityandcarryoutspecificfunctions,andontheotherthey
retainthecapacitytodeviatefromtheirusualfunctionsandtoreo
rganizethemselves.The
term‘neuroplasticity’encompassesthecapacityofsynapses,neurons,neuronalcircuitsand
networks in the brain to perceive, adapt and respond to new information, sensory
stimulation, development, damage or dysfunction, allowing short‐term to long‐lasting
changes in their connections and behaviour (Pascual‐Leone et al., 1998; Rossini and Dal
Forno, 2004; Rossini et al., 2003; Pascual‐Leone et al., 2005). Neuroplasticity takes place
mainlyduring development whenneuronsin the youngbrainsprout branches andform
synapses.Whenthebraininitiatestoprocesssensory information,someofthesesynapses
reinforce,somedeteriorateandothers, if unused, areevencompletelyremoved,aprocess
named ‘synaptic pruning’ (Pascual‐Leone et al., 1998). Further forms of neuroplasticity
workduringthelife‐spanunderdifferentcircumstanceseventhoughsometimesonlytoa
limited extent, underlying theacquisition of new skills, learning, memory, adaptation to
newcontextsandevenrecoveryoffunctionafternervoussysteminjury(Rossinietal.,2010;
Rossini et al., 2011) when the brain attempts to compensate for lost activity leading to
positivebut also negativeoraberrant reorganization. Neocortexisa particularly relevant
region for plasticity because it accomplishes sensory, motor, and cognitive tasks with
stronglearningcomponents.
Investigatorshavemadeseveralimportantimprovementstowardsunderstandingthe
molecular underpinnings ofthesefundamental plasticityprocesses and towardsdefining
the learning rules that manage their induction (Buonomano, 1999). Since the 1970s
neuroplasticity has gained wide acceptance throughout the scientific community as a
essentialpropertyofthebrain andplasticchangesofsynapses,neurons,neuronalcircuits
and netwo
rks have been even directly observed thanks to the development of modern
molecular, imaging and electrophysiological techniques which can reach as far as the
cellularlevel
.
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