Simultaneous EEG-fMRI using pulse sequences with EPI and Spiral K-Space trajectories: Clinical application in Fixation-off epilepsy
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(3) !. ! ! ! !. A!quien!construye!mi!hogar,!ayer,!ahora!y!siempre.! To!who!builds!my!home,!yesterday,!now!and!forever.! ! ! ¡Ojalá!vivas!todos!! los!días!de!tu!vida!! Jonathan!Swift!! ! ! “Somewhere,!something!! incredible!is!waiting!! to!be!known.”! Carl!Sagan! !. ! ! !. !. !.
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(5) !. !. Agradecimientos! ! Dicen!que!el!hombre!es!el!animal!que!tropieza!dos!veces!en!la!misma!piedra…!yo! diría! que! en! mi! caso,! esta! es! la! tercera! vez! en! la! misma! piedra.! Otro! proyecto! académico! en! el! que! los! agradecimientos! se! dejan! para! el! final! y! te! resulta! muy! complicado! elegir! el! momento! idóneo! para! escribirlos.! Y,! ¿qué! es! lo! que! ocurre?! que! lo! haces! en! el! último! momento.! Para! más! información,! mañana! imprimo! la! tesis.!! Los!que!me!conocen!desde!siempre!o!al!menos!desde!que!era!joven,!;)!una!recién! graduada,!tal!vez!se!acuerden!que!he!seguido!una!metáfora!basada!en!las!estancias! de!una!casa!que!es!mi!hogar.!Porque!así!es!como!veo!yo!la!vida,!hay!personas!que! pasan!para!un!café!o!una!cerveza!y!marchan,!los!que!se!quedan!una!temporada!y! luego! te! visitan! de! vez! en! cuando! y! aquellos! que! están! siempre,! siempre,! contigo! aunque! no! sea! físicamente.! Y! yo! quiero! agradecer! a! todos,! primero,! porque! soy! quien!soy!gracias!o!por!culpa!de!ellos!y,!segundo,!porque!este!proyecto!de!tesis!lo! ha!vivido,!disfrutado,!reído,!llorado!mucha!gente.! En! primer! lugar,! me! voy! a! saltar! mis! propias! normas! de! no! mencionar! nombres! para! agradecer! a! mi! mami! que! me! quiera! con! locura,! que! me! entienda,! que! me! cuide,!que!me!apoye…!porque!yo!creo!que!no!se!puede!querer!más.!Gracias!mami.! Y!también!a!mi!yaya!que!siente!devoción!por!mi,!que!me!echa!muchísimo!de!menos! aunque!no!debería!porque!estoy!siempre!virtualmente!con!ellas.!Gracias!yayi.!No! os!pongáis!celosos!los!demás!que!somos!muchos!y!bastante!bien!avenidos,!porque! me! encanta! mi! familia! y! porque! cada! vez! somos! más! (aunque! sigamos! echando! mucho!de!menos!a!mi!otro!pilar),!gracias!por!seguir!siendo!mi!pasillo!central.!! Además! de! mi! pasillo! central,! me! considero! extremadamente! afortunada! de! conservar! lo! mejor! de! mi! salita! de! estar! de! Alcorcón! y! la! mayor! parte! del! gran! salón! comedor! con! tod@s! mis! chic@s! especiales! e! incluso! más! gracias! a! unos! jueves!especiales.!!. !. !.
(6) !. ! Sin! embargo,! seguimos! remodelando! la! azotea! para! dar! cabida! a! más! investigadores! biomédicos! que! se! merecen! una! mención! especial! porque! realmente!han!representado!mi!día!a!día!durante!los!últimos!4!años!y!con!los!que! he! trabajado! codo! con! codo,! compartido! mesa,! escáner,! despacho,! hemos! publicado!juntos,!e!incluso!vivido!juntos.!Aquí!voy!a!saltarme!de!nuevo!mi!política! antiCnombres!porque!cuatro!personas!han!leído,!corregido,!comentado!mi!tesis!de! forma! totalmente! desinteresada,! gracias! en! especial! a! Kenia,! pero! también! a! Ricardo! Bruña,! a! Eva! Manzanedo! y! a! mi! prima! Mamen.! En! este! punto,! también! quiero!agradecer!a!mis!tutores!de!tesis!su!apoyo,!su!disponibilidad!y!también!por! abrirme!muchísimas!puertas.!Gracias!Juan!Antonio.!Gracias!Paco.! Pero!quizá!lo!que!más!me!haya!enriquecido!y!moldeado!en!este!último!periodo!de! mi!vida!haya!sido!mi!apartamento!itinerante!(que!debe!ser!como!la!casa!de!globos! de! Up! porque! no! para! de! moverse! de! un! sitio! a! otro).! Empezó! en! Reino! Unido! pasando!por!Pittsburgh!y!lleva!instalado!en!Múnich!desde!hace!más!de!1!año,!sin! contar! con! la! multitud! de! miniCparadas! intermedias! de! exploración! del! mundo.! Gracias!también!a!las!conferencias!científicas.!En!los!últimos!años!he!conocido!más! gente!de!distintas!partes!del!mundo!que!en!todo!el!resto!de!mi!vida!y!es!fascinante.! Gracias!por!dejarme!conoceros,!quereros,!compartir!inquietudes,!aquí!o!allí.! I!would!like!to!also!write!this!last!part!of!my!acknowledgements!in!English.!I!want! to! highlight! that! what! it! has! enriched! and! shaped! me! more! these! last! years! has! been! my! foreign! experiences.! It! started! in! United! Kingdom,! it! makes! a! stop! at! Pittsburgh! and! it! has! been! settled! in! Munich! for! more! than! 1! year,! without! counting! all! the! multiple! miniCstops! to! explore! the! world.! Thanks! also! to! the! scientific!conferences.!In!these!last!years,!I!have!met!more!international!and!multiC cultural!people!than!in!all!the!rest!of!my!life!and!it!is!fascinating.!Thanks!for!let!me! know!you,!love!you,!share!way!of!living!and!curiosity,!here!or!there.! La!vida!continua.!Con!todos.!Gracias.! Live!continues.!With!all!of!you.!Thanks! ! ! !. !.
(7) !. !. Resumen* La!adquisición!de!electroencefalografía!(EEG)!durante!la!adquisición!de!imágenes! de! Resonancia! Magnética! funcional! (RMf)! proporciona,! de! forma! no! invasiva,! la! captura!simultánea!de!la!respuesta!hemodinámica!cerebral!al!mismo!tiempo!que!la! actividad!eléctrica!cerebral.!Esta!técnica!multimodal!proporciona!una!combinación! ideal! de! la! excelente! resolución! espacial! de! RMf! con! la! resolución! temporal! del! orden!del!milisegundo!del!EEG.! Sin! embargo,! esta! técnica! multimodal! se! enfrenta! a! cuatro! principales! retos! tecnológicos!que!han!de!ser!solventados!para!mejorar!la!combinación!simultánea! de!estas!dos!técnicas!de!neuroimagen:! o Instrumentación!EEG!y!seguridad!del!paciente.! o Calidad! de! la! señal! EEG! en! presencia! de! los! campos! magnéticos! variables! del!escáner!de!Resonancia!Magnética.! o SNR! y! CNR! de! las! imágenes! de! Resonancia! Magnética! en! función! de! la! secuencia!de!pulsos!de!RMf!utilizada.! o La! interrelación! de! ambas! señales! constituye! un! reto! ya! que! las! señales! medidas!por!cada!modalidad!provienen!de!un!fenómeno!fisiológico!distinto! cuyo!acoplamiento!no!se!conoce!totalmente!en!la!actualidad.! Desde!el!punto!de!vista!de!las!aplicaciones!clínicas!de!esta!técnica!multimodal,!una! de!las!más!interesantes!es!el!estudio!de!la!actividad!eléctrica!anormal!en!pacientes! con!epilepsia.!Este!tipo!de!adquisición!difiere!de!la!mayoría!de!las!aplicaciones!de! RMf!puesto!que!el!estímulo!se!genera!internamente,!de!forma,!a!menudo,!aleatoria! e! infrecuente.! El! estudio! de! la! respuesta! hemodinámica! de! esta! actividad! es,! por! tanto,!sólo!posible!si!se!captura!esta!actividad!con!EEG!de!forma!simultánea.!! En!este!proyecto!de!tesis,!se!tiene!como!primer!objetivo!el!desarrollo!de!un!setup! experimental! optimizado! para! registro! simultáneo! de! EEGYRMf! y! la! evaluación! cuantitativa! de! la! influencia! en! la! modificación! de! las! distintas! características! del! setup!bajo!estudio:!utilización!de!distintas!secuencias!de!pulsos!de!adquisición!con! distintos! esquemas! de! relleno! del! espacio! k! y! el! impacto! de! sincronización,!. !. i!.
(8) !. ! principalmente.! El! primer! paso! para! la! consecución! de! ese! primer! objetivo! fue! el! desarrollo!de!una!secuencia!de!pulsos!para!RMf!de!relleno!en!espiral!del!espacio!k.! Por! otro! lado,! este! proyecto! de! tesis! doctoral! incluye! un! estudio! clínico! en! pacientes!epilépticos!haciendo!uso!de!un!setup!mejorado!y!un!proceso!de!análisis! optimizado.!De!esta!forma,!se!estudia!un!tipo!raro!de!síndrome!epiléptico!llamado! epilepsia! criptogénica! generalizada! por! sensibilidad! a! la! pérdida! de! fijación.! Este! síndrome! no! ha! sido! investigado! intensamente! debido! al! escaso! número! de! pacientes! de! este! tipo! en! el! mundo! y! por! las! limitaciones! de! otras! técnicas! de! imagen.!Sólo!existen!tres!trabajos!previos!usando!la!técnica!de!registro!simultáneo! EEGYRMf!en!pacientes!con!sensibilidad!a!la!fijación.!El!último!objetivo!de!esta!tesis! es! proporcionar! evidencia! sobre! el! beneficio! del! uso! de! la! técnica! de! registro! simultáneo! para! mejora! en! el! diagnóstico! de! estos! pacientes! y! el! conocimiento! sobre!el!síndrome.! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !. !. ii!.
(9) !. !. Abstract* ! Acquisition!of!electroencephalogram!(EEG)!during!functional!Magnetic!Resonance! Imaging! (fMRI)! provides,! nonYinvasively,! the! simultaneous! capture! of! cerebral! hemodynamic! response! as! well! as! the! registered! electric! cerebral! activity! on! the! scalp.! This! new! multimodal! technique! provides! an! ideal! combination! of! the! excellent! spatial! resolution! of! fMRI! with! the! millisecond! temporal! resolution! of! EEG.! However,! there! are! four! major! challenges! related! to! this! multimodal! technique,! which!must!be!addressed!to!improve!the!simultaneous!combination!of!these!two! neuroimaging!techniques:! o EEG!instrumentation!and!patient!safety.!! o EEG!signal!quality!preservation!because!the!simultaneous!acquisition!inside! the! MR! scanner! introduces! several! different! and! specific! types! of! EEG! artifacts,! among! them,! the! gradient! artifact! and! the! cardiac! pulseYrelated! artifact.! o MR! images! SNR! and! CNR! that! will! be! dependent! on! the! used! fMRI! pulse! sequence.!! o Interrelation! of! both! signals! is! challenging! because! the! electrical! signals! measured! by! the! EEG! system! and! hemodynamic! signals! measured! by! the! MR!scanner!come!from!different!physiological!events!whose!coupling!is!still! not!fully!understood.!! From! the! point! of! view! of! the! clinical! applications! of! this! multimodal! technique,! one!of!the!most!interesting!ones!is!the!study!of!the!abnormal!electrical!activity!in! patients! with! epilepsy.! This! work! differs! from! most! applications! of! fMRI! because! the!stimulus!is!internally!generated,!in!a!random!and!infrequent!way!in!most!of!the! cases.!! In! this! thesis! project,! it! is! aimed! to! develop! an! improved! experimental! setup! for! simultaneous! EEGYfMRI! and! test! the! influence! of! different! key! acquisition! !. iii!.
(10) !. ! strategies:! the! influence! of! using! different! kYspace! trajectories! fMRI! pulse! sequences! and! the! impact! of! synchronization.! The! first! necessary! step! for! these! aims!consisted!of!the!development!of!a!modified!spiral!EPI!pulse!sequence!from!its! basic!form!in!order!to!improve!the!quality!of!both!signals:!EEG!and!fMRI.!! On! the! other! hand,! and! in! a! more! practical! part! of! this! PhD! thesis,! the! use! of! an! improved!simultaneous!EEGYfMRI!experimental!setup!and!a!proper!preprocessing! and!analysis!of!both!kinds!of!data!was!applied!in!a!clinical!study.!A!rare!epileptic! syndrome! known! as! FixationYoff! Sensitivity! (FoS)! Cryptogenic! Generalized! Epilepsy!(CGE)!was!examined.!This!syndrome!has!not!been!intensively!studied!due! to! scarce! number! of! cases! and! limitations! of! other! techniques;! in! fact,! there! are! only!three!previous!works!in!the!literature!where!FoS!discharges!were!examined! with!simultaneous!EEGYfMRI.!This!thesis!project!aims!to!obtain!novel!results!in!the! study!of!FixationYOff!CGE!patients!using!simultaneous!EEGYfMRI.!! ! ! ! ! ! ! ! ! ! ! ! ! ! !. ! iv!.
(11) !. !. TABLE&OF&CONTENTS* SECTION A: BASIC CONCEPTS AND THESIS PLAN Resumen!. i!. Abstract!. iii!. TABLE!OF!CONTENTS!. v!. LIST!OF!FIGURES!. ix!. LIST!OF!TABLES!. xv!. I.! INTRODUCTION!. 1!. II.! PRELIMINARY!CONCEPTS!. 7!. 1.! ELECTROENCEPHALOGRAPHY!. 7!. 2.! FUNCTIONAL!MAGNETIC!RESONANCE!IMAGING!. 13!. 3.! PULSE!SEQUENCE!DEVELOPMENT!. 18!. 4.! EPILEPSY!. 25!. III.! STATE!OF!THE!ART!. 33!. 1.! THE!MULTIMODAL!TECHNIQUE!OF!SIMULTANEOUS!EEGYfMRI!. 33!. 2.! APPLICATIONS!OF!SIMULTANEOUS!EEGYFMRI!IN!SPONTANEOUS! ACTIVITY!. 77!. 3.! NEUROIMAGING!TECHNIQUES!IN!FIXATIONYOFF!SENSITIVITY!EPILEPSY!!! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!85!! IV.! THESIS!PLAN!. 89!. SECTION*B:*EXPERIMENTAL*SETUP*AND*RESULTS* V. INTRODUCTION!TO!SECTION!B!. 93. VI.. 95. MATERIALS!AND!METHODS!. 1. Spiral!pseudo!Real!Time:!SpRETI. 95. 2. TESTING!DIFFERENT!SIMULTANEOUS!EEGYfMRI!EXPERIMENTAL!SETUPS:! IMPACT!OF!DIFFERENT!PULSE!SEQUENCES!AND!SYNCHRONIZATION! 111 VII.. RESULTS. 129. 1. Spiral!pseudo!REal!TIme:!SpRETI !. v!. 129.
(12) !. ! 2. TESTING!DIFFERENT!SIMULTANEOUS!EEGYfMRI!EXPERIMENTAL!SETUPS:! IMPACT!OF!DIFFERENT!PULSE!SEQUENCES!AND!SYNCHRONIZATION! 149 VIII.. DISCUSSION. 169. 1. MODIFIED!PULSE!SEQUENCE:!SpRETI. 169. !!!!!!!!!2. SYNCHRONIZATION!AND!USE!OF!DIFFERENT!PULSE!SEQUENCES!IN!!! !!!!!!!!!SIMULTANEOUS!EEGYfMRI 174 SECTION*C:*CLINICAL*VALIDATION* IX. INTRODUCTION!TO!SECTION!C!. 181. X. MATERIALS!AND!METHODS. 185. 1. PARTICIPANTS. 185. 2. ACQUISITION!HARDWARE. 186. 3. DATA!ACQUISITION. 187. 4. DATA!PREPROCESSING. 189. 5. DATA!ANALYSES. 190. XI. RESULTS. 197. 1. HEALTHY!SUBJECTS!PROFILE!AS!‘GOLD!STANDARD’. 197. 2. DISRUPTED!PROFILES!FOR!TWO!FoS!CGE!PATIENTS. 205. XII.. DISCUSSION. 217. 1. COMPARISON!PATIENTS!VERSUS!CONSTROLS!AND!PATIENTS!BETWEEN! THEM 218 2. COMPARISON!WITH!PREVIOUS!FoS!LITERATURE. 220. 3. METHODOLOGICAL!CONSIDERATIONS. 221. SECTION*D:*CONCLUSIONS* XIII.. 229. 1. LINK!BETWEEN!EXPERIMENTAL!IMPROVEMENTS!AND!CLINICAL! APPLICATION!OF!THIS!PhD!THESIS. 229. 2. CONCLUSIONS. 231. XIV.. !. CONCLUSIONS. FUTURE!WORK. 235. REFERENCES. 239. ACRONYMS. 261 vi!.
(13) !. ! ANNEX!1:!FROM!SPIRAL.e!Y>!SpRETI.e. 265. ANNEX!2:!RECONSTRUCTION!PROGRAMS. 275. ANNEX!3:!SpRETI!PARAMETER!TESTING. 295. ANNEX!4:!GE!–!EPI!AND!GE!–!SPEP!CODE!CHANGES. 307. ANNEX!5:!INFLUENCE!OF!CAP!AND!STABILIZATION!OF!EDDYYCURRENTS. 309. ANNEX!6:!SYNCHRONIZATION!VS.!NO!SYNCHRONIZATION!IN!OTHER!EEG! CHANNELS 313. ! ! ! ! ! ! ! ! ! ! ! ! ! ! !. !. ANNEX!7:!ALL!PULSE!SEQUENCES!EFFECT!IN!OTHER!EEG!CHANNELS. 315. ANNEX!8:!EEG!ANALYSIS. 317. ANNEX!9:!PATENT!Y!P2001400342. 323!. !. vii!.
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(15) !. !. * LIST%OF%FIGURES* Figure!1.! EEG!signal!generation!schema!from!the!electric!currents!generated! inside!one!pyramidal!neuron!to!the!typical!oscillations!seen!in!an!ambulatory! EEG.!!!!!! 9! Figure!2.! Topographical!spatial!maps!generated!by!the!activation!of!a!group!of! neurons!in!the!vertex!of!the!brain!located!tangential!to!the!scalp!(left)!and! perpendicular!to!the!scalp!(right).! 10! Figure!3.! International!10Y20!system!electrode!placement!for!35!EEG!channels.11! Figure!4.! Example!of!an!Event!Related!Potential!(ERP),!more!especifically,!a! Visual!Evoked!Potential!(VEP)!. 13!. Figure!5.! Balloon!model:!Schema!of!the!key!factors!that!generate!the! hemodynamic!response!cascade!to!a!stimulus!that!generates!the!BOLD!signal!! (Source:!Faro!et!al.![22])! 15! Figure!6.! RestingYstate!networks!identifying!the!brain!function!they!support! (Source:!Martinez!et!al.![33])!!!! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!17! Figure!7.! Example!of!a!pulse!sequence!including!a!tagging!preparation!module,! excitation,!echo!generation!and!encoding,!and!correction!gradients.!The! schema!also!shows!how!the!excitation!can!be!repeated!in!time!for!encoding! purposes.! 18! Figure!8.! Pulse!sequence!functional!modules!for:!(Top)!one!type!of!fMRI!psd;! (Center)!second!type!of!fMRI!psd!where!the!excitation!and!the!preparation!are! combined;!and,!(Bottom)!an!example!of!a!typical!dwMRI!psd.! 19! Figure!9.! Saturation!pulse!previous!to!excitation!pulse!. 19!. Figure!10.! GradientYecho!generation!scheme!. 23!. Figure!11.! Example!of!a!nonYconvulsive!generalized!crisis!in!the!left!(absence)! and!a!partial!crisis!in!the!right!(occipital!epilepsy)!(Source:!Blum!et!al.![42])!27! Figure!12.! Axial!CT!brain!image!in!the!left!and!coronal!view!of!a!MRI!brain!image! in!the!right.! 30! Figure!13.! Twisting!electrode!leads!minimize!the!area!loop!reducing!the!induced! voltage!generated!by!emf!and!captured!by!the!EEG!system.! 37! Figure!14.! Main!two!EEG!artifacts!in!simultaneous!EEGYfMRI.!Gradient!or!imaging! artifact!in!green;!and!pulseYrelated!artifact!in!red.! 40! Figure!15.! Diagram!of!Stepping!Stone!Sequence,!EPIS.! !. ix!. 43!.
(16) !. ! Figure!16.! Effects!of!Helium!Pump!inside!a!General!Electric!3T!HDx!MR!scanner.* The!midYblue!line!is!after!gradient!artifact!removal,!the!green!line!is!after!the! sequence!has!finished,!but!with!the!helium!pump!on,!the!red!line!is!with!the! helium!pump!switched!off!and!the!dark!blue!line!is!in!outside!the!scanner.! (Courtesy:!Judith!Nottage,!IoP!KCL,!London!)! 46! Figure!17.! Diagram!of!Average!Artifact!Subtraction!algorithm!(Source:!Allen!at!al.!! [49])! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!47! Figure!18.! Schema!of!the!pulseYrelated!artifact!removal!based!of!Average!Artifact! Subtraction!(Source:!Allen!et!al.![48])! 52! Figure!19.! Global!field!power!(GFP)!analysis!of!pulseYrelated!artifact.!(A)! Comparison!between!outside!the!scanner!(pink)!and!inside!1.5!T!MRI!scanner! (green),!expressed!as!standard!deviation!(STD)!over!time,!with!0!ms!denoting! the!onset!of!the!ECG!R!wave.!(B)!The!same!as!A!but!comparing!1.5!T!(green)! and!3T!(blue)! 55! Figure!20.! Position!of!electrodes!can!be!detected!by!local!distortions!generated! by!the!EEG!electrodes!and!conductive!gel!interfaces!(orange).!The!artifact! caused!by!the!longer!EOG!lead!is!highlighted!in!red.! 57! Figure!21.! Gradient!–!Echo!Blipped!EPI!pulse!sequence!profile!(top)!and!kYspace! trajectory!(bottom)! 61! Figure!22.! GradientYecho!spiralYout!EPI!pulse!sequence!profile!(top)!and!kYspace! trajectory!(bottom)! 67! Figure!23.! GradientYecho!spiralYinYout!EPI!pulse!sequence!profile!(left)!and!kY space!trajectory!(right)! 69! Figure!24.! The!steps!for!an!EEGYinformed!fMRI!approach!for!interictal! epileptiform!activity!are!depicted.!a)!Epileptic!events!are!identified!and! marked!from!the!filtered!EEG!signal.!b)!A!boxcar!function!is!generated!using! the!onset!and!the!duration!of!the!EEG!events.!c)!The!boxcar!function!is! convolved!with!the!hemodynamic!response!function!(HRF).!This!signal!will!be! used!in!the!GLM!used!to!analyze!the!fMRI!signal.! 73! Figure!25.! Schematic!of!dataYdriven!symmetric!fusion!using!ICA:!a)!joint!ICA!and! b)!parallel!ICA.! 77! Figure!26.! Spiral!reconstruction!schematic!in!four!stages!using!gridding!. 100. Figure!27.! (a)!The!logYscale!inverse!Fourier!transform!of!a!Hamming!window.!(b)! The!convolution!rollYoff!correction!for!the!image.!(c)!The!effective!inverse! Fourier!transform!after!multiplying!by!the!rollYoff!correction!(Source:!Jackson!et! al.![127]!)! 102 Figure!28.! Example!of!different!sensitivity!profiles!per!channel!coil!in!a!6Ychannel! brain!coil! 103 Figure!29.! Examples!of!the!images!that!are!used!for!the!visual!task!paradigm! 109 !. x!.
(17) !. ! Figure!30.! Simultaneous!EEGYfMRI!experimental!setup!. 113. Figure!31.! New!Braincap!EEG!cap!fitted!to!an!spherical!water!phantom!covered! with!electrolyte!paste.! 119 Figure!32.! Schematic!reconstruction!flow!chart!including!the!main!functions!used! in!each!step,!indicating!the!use!of!external!functions!into!the!customYbuilt! MATLAB!reconstruction!program.! 134 Figure!33.! Schema!of!the!most!relevant!steps!for!the!reconstruction!program!in! Matlab!for!an!example!in!one!volunteer.!A)!Key!parameters!of!the!raw!data,!B)! Simulated!Gradient!X!and!Gradient!Y,!C)!Kx!and!Ky!defined!by!the!gradients!in!B,! D)!kYspace!of!one!channel!of!one!slice!after!the!gridding,!E)!brain!image!after!the! Fourier!transform!and!reduction!of!FoV,!F)!Image!after!apodization,!G)!Phase! difference!combination!among!8!channels!for!the!B0!maps!volumes!and!H)!Sum! of!squares!combination!of!magnitude!image!using!8!channels.! 137 Figure!34.! One!channel!magnitude!and!phase!for!the!B0!map!calculation!and!whole! volume!for!fMRI!series!using!C!program!example.! 138 Figure!35.! Schematic!reconstruction!flow!chart!including!the!main!functions!used! in!each!step,!indicating!the!modification!made!in!the!code!from!the!UCSD!for!GEY SPEP!made! 139 Figure!36.! SpRETI!Parameter!testing!‘Test!1’!results:!(top!left)pulse!sequence! profile!for!RF!Magnitude,!RF!Phase,!Gradient!x,!Gradient!y!and!Gradient!z,! (bottom!left)!kYspace!trajectory,!(top!right)!one!volume!acquisition!with!GE! phantom!with!C!reconstruction!program!and!customYbuilt!Matlab!program,! (bottom!right)!Magnitude!and!phase!B0!map!reconstruction.! 143 Figure!37.! Motor!task!results!for!volunteer!1!and!volunteer!2.!Statistical!spatial! maps!(p<0.05,!FWE!corrected)!and!timecourse!in!peak!voxel!for!both! reconstruction!programs,!C!and!Matlab.! 144 Figure!38.! Comparison!of!the!motor!task!in!both!volunteers!using!GE!Y!EPI,!GE!Y! SPRLIO,!GE!Y!SPEP!(BOLD)!and!GE!Y!SpRETI.!!Overlapped!statistical!spatial!maps! results!(p<0.05,!FWE!corrected)!for!all!the!pulse!sequences!and!bar!plots!with! BOLD!contrast!and!peak!Z!maximum!and!minimum!values.! 145 Figure!39.! Visual!task!results!for!volunteer!1!and!volunteer!2.!Statistical!spatial! maps!(z<0.05,!FWE!corrected)!and!timecourse!in!peak!voxel!for!both! reconstruction!programs,!C!and!Matlab.! 147 Figure!40.! Comparison!of!the!visual!task!in!both!volunteers!using!GE!Y!SPRLIO,!GE!Y! SPEP!(BOLD)!and!GE!Y!SpRETI.!!Overlapped!statistical!spatial!maps!results! (p<0.05,!FWE!corrected)!for!all!the!pulse!sequences!and!bar!plots!with!BOLD! contrast!and!peak!Z!maximum!and!minimum!values.! 148 Figure!41.! EE!Gradient!artifact!in!6!different!EEG!channels!during:!A)!3!consecutive! volumes!when!running!GE!Y!EPI;!B)!12!consecutive!slices!when!running!GEYEPI;! and,!C)!3!consecutive!volumes!when!running!GE!Y!SPEP!(ASL–DualEcho)! 152 !. xi!.
(18) !. ! Figure!42.! (A)!GE!–!EPI,!(B)!GE!–!SPRLIO!(spiral!inYout),!(C)!GE!–!SPRLIO!(spiral! out),!(D)!GE!–!SPEP!(BOLD),!(E)!GE!–!SPEP!(ASLYDualEcho)!and!(F)!GE!Y!SpRETI! pulse!sequence!profile!for!RF!pulse!and!X,!Y!and!Z!gradients!and!its! corresponding!average!gradient!artifact!in!EEG!channel!C3!for!one!slice! acquisition!time.! 155 Figure!43.! Head!view!of!oneYslice!gradient!artifact!waveforms!for!all!of!the!EEG! channels.! 156 Figure!44.! Frequency!voltage!density!spectrum!for:!(i)!GE!–!EPI,!(ii)!GE!–!SPRLIO! (spiral!out),!(iii)!GE!–!SPRLIO!(spiral!in_out),!(iv)!GE!–!SpRETI,!(v)!GE!–!SPEP! (BOLD)!and!(v)!GE!–!SPEP!(ASL!DualEcho)! 158 Figure!45.! Average!and!standard!deviation!of!gradient!artifact!of!one!slice!for!(i)! GEYEPI!without!synchronization!after!realignment!of!volumes,!(ii)!for!GEYEPI! with!synchronization,!(iii)!for!GE!Y!SPRLIO!without!synchronization!after! realignment!of!volumes!and,!(iv)!for!GE!Y!SPRLIO!with!synchronization.! 159 Figure!46.! Voltage!density!for!Welch!spectral!estimation!for!PHANTOM!DATA:!(i)! background!noise,!in!the!absence!of!pulse!sequence;!(ii)!GEYEPI!before!applying! AAS;!(iii)!GE!Y!SPRLIO!before!applying!AAS;!(iv)!GE!Y!EPI!without! synchronization!after!AAS;!(v)!GE!Y!SPRLIO!without!synchronization!after!AAS;! (vi)!GE!Y!EPI!with!synchronization!after!AAS;!(vii)!GE!Y!SPRLIO!with! synchronization!after!AAS.! 160 Figure!47.! PHANTOM!DATA:!Attenuation!of!signal!amplitude!(Y 20log10[corrected/uncorrected])!after!AAS!for!GE!Y!EPI!(top)!and!GE!Y!SPRLIO! (bottom)!compared!with!the!background!noise!(Y 20log10[background/uncorrected])!at!the!slice!frequency!(12.5!Hz)!and! harmonics.! 161 Figure!48.! PHANTOM!DATA:!Gain!of!signal!amplitude! (20log10[corrected/background])!after!AAS!for!GE!Y!EPI!and!GE!Y!SPRLIO!at!the! slice!frequency!(12.5!Hz)!and!harmonics!(1Hz!bandwidth).! 162 Figure!49.! PHANTOM!DATA:!Gain!of!signal!amplitude! (20log10[corrected/background])!after!AAS!for!GE!Y!EPI,!GE!Y!SPRLIO,!GE!–! SPEP!and!GE!Y!SpRETI!at!the!slice!frequency!(12.5!Hz)!and!harmonics!(1Hz! bandwidth)!in!the!worst!case!electrode!F3.! 164 Figure!50.! Comparison!between!the!spectra!of!the!worst!case!EEG!electrode!(F3)!of! 6!minutes!simultaneous!EEGYfMRI:!in!the!absent!of!sequence,!GE!Y!EPI,!GE!Y! SPRLIO!inYout,!GE!Y!SPRLIO!out,!GE!Y!SPEP!(BOLD),!GE!Y!SPEP!(ASLYDualEcho)! and!GE!Y!SpRETI!after!AAS.! 165 Figure!51.! HUMAN!DATA:!(i)!in!the!absence!of!sequences!after!PA,!(ii)!GE!Y!EPI!with! synchronization!after!AAS!and!PA!and!(iii)!GE!Y!SPRLIO!with!synchronization! after!AAS!and!PA.! 166 Figure!52.! HUMAN!DATA:!Gain!of!signal!amplitude! (20log10[corrected/background])!after!AAS!for!GE!Y!EPI!and!GE!Y!SPRLIO!at!the! !. xii!.
(19) !. ! slice!frequency!(12.5!Hz)!and!harmonics!(1Hz!bandwidth)!in!electrode!C3.!167 Figure!53.! VEP!and!ERSP!of!two!subjects!during!three!conditions:!outside!the!MR! scanner,!during!GE!Y!EPI!and!during!GE!Y!SPRLIO,!both!with!synchronization.168 Figure!54.! Real!spiral!trajectory!in!the!scanner!versus!ideal!spiral!trajectory! defined!by!the!pulse!sequence!(Source:!Montesinos,!P.![260])! 172! Figure!55. BlockYdesign!openedYclosed!eyes!paradigm!captured!outside!the! scanner.!Three!cycles!of!20!seconds!with!opened!eyes!and!20!seconds!with! closed!eyes. 187 Figure!56. BlockYdesign!openedYclosed!eyes!paradigm.!Five!cycles!of!20!seconds! with!opened!eyes!and!20!seconds!with!closed!eyes. 188 Figure!57. rsfMRI!standalone!ICA!analysis!diagram.!First!analysis!consisted!on!a! Temporal!Concatenation!Group!ICA!using!all!rsfMRI!series!from!the!control! subjects!(orange).!Second!analysis!was!a!subjectYbyYsubject!singleYICA!using!the! concatenation!of!OpenedYclosed!rsfMRI!concatenation!(blue).!Input!data!matrix! to!ICA!algorithm;!spatial!maps!and!representative!timecourse!from!ICA;! correlation!of!IC!timecourses!(only!for!second!ICA!analysis);!and,!visual! exploratory!of!the!spatial!maps!are!depicted. 195 Figure!58. Complete!Preprocessing!and!analysis!pipeline!for!EEG!standalone,!fMRI! standalone!and!EEGYfMRI!analysis 196 Figure!59. The!openedYclosed!epochs!(block!design)!obtained!from!one!typical! control!subject!(ID=1)!inside!(5!cycles,!3:20!minutes)!and!outside!the!scanner!(3! cycles,!2!minutes).!The!RMS!value!per!each!segment!of!2.88!s!(corresponding!to! the!TR!of!the!fMRI!scan)!is!shown!for!theta,!alpha!and!beta!(subbeta1,!subbeta2,! subeta3) 198 Figure!60. Visually!identified!groupYlevel!components!obtained!by!temporal! concatenation!group!independent!component!analysis!(TCYGICA).!Sagittal!and! axial!views!(showed!as!x!and!z!according!to!MNI152!standard!space)!of!these! eight!functionally!relevant!groupYlevel!ICs!are!displayed!according!to! neurological!convention!(right!on!right).!The!zYstatistic!map!legend!for!all! networks!is!shown!in!the!right!side!(z>2.3). 199 Figure!61. An!example!of!correlations!between!IC!timeYseries!for!openedYeyes!and! closedYeyes!conditions!in!one!typical!subject!(ID=1).!Spatial!maps,!timecourses! and!their!power!spectrums!for!two!noisy!components!(ICs!16!and!20)!are! displayed!on!the!bottom. 201 Figure!62. GroupYlevel!(n=6!healthy!subjects)!positive!(red)!and!negative!(blue)! significant!results!(=0.05,!TFCE!corrected!and!cluster!size!10)!per!band!and! condition!are!depicted.!Sagittal!(x)!and!axial!(z)!views!(x!and!z!coordinate! according!to!MNI152!standard!space!are!shown!for!each!slice)!are!displayed! according!to!neurological!convention!(right!on!right).!The!zYstatistic!map!legend! is!shown!in!the!left!side. 202 Figure!63. !. The!openedYclosed!epochs!(block!design)!obtained!from!one!typical! xiii!.
(20) !. ! control!subject!(ID=1),!for!patient!1!and!for!patient!2!inside!(5!cycles,!3:20! minutes)!and!outside!the!scanner!(3!cycles,!2!minutes)!for!the!same!control! subject!and!patient!1.!The!RMS!value!per!each!segment!of!2.88!s!(corresponding! to!the!TR!of!the!fMRI!scan)!is!shown!for!theta,!alpha!and!beta!(subbeta1,! subbeta2,!subeta3) 206 Figure!64. EEG!topographical!maps!for!closedYeyes!epochs!(2!minutes)!of!patient!1! and!patient!2!outside!the!scanner.!Peaks!in!the!spectral!content,!in!theta,!alpha! and!low!beta!band,!EEG!topographical!maps!are!shown. 207 Figure!65. IC!identified!as!an!attentional!network!by!GICA!in!controls!(top!row)! and!through!singleYICA!in!patient!1!(middle!row)!and!patient!2!(bottom!row).! The!spatial!map!appears!in!the!left!and!the!associated!timecourse!in!the!right.! For!patient!1,!lowYfrequencies!oscillations!are!found!only!for!closed!eyes!as!it!is! shown!in!the!time!course!(first!half!=!0Y345s!Y>!openedYeyes!condition;!second! half!=!345sY691s!Y>!closed!eyes).!All!spatial!maps!are!thresholded!at!z>2.3)208 Figure!66. Statistically!significant!correlations!between!IC!timeYseries!for!closedY eyes!condition!in!patient!2.!Colored!rectangles!underscore!those!biologically! relevant!resting!state!networks!found!as!correlated.!Visual!network!=!IC15);!left! frontoYparietal!networks!=!IC8);!occipitalYcerebellum!network!=!IC25;!the!motor! network!=!IC16;!and!the!attentional!network!=!IC19.!The!maps!are!showed!in! neurological!convention!(right!on!right) 209 Figure!67. EEGYinformed!fMRI!results!for!patient!1.!Positive!(red)!and!negative! (blue)!significant!results!(=0.05,!TFCE!corrected!and!cluster!size!10)!per!band! and!condition!are!depicted.!Sagittal!(x)!and!axial!(z)!views!(x!and!z!coordinate! according!to!MNI152!standard!space!are!shown!for!each!slice)!are!displayed! according!to!neurological!convention!(right!on!right).!The!zYstatistic!map!legend! is!shown!in!the!left!side. 210 Figure!68. Patient!1,!onlyYclosed!brain!network!(redYyellow)!from!singleYICA! analysis!(Figure!57)!and!subbeta1!activation!map!in!EEGYinformed!closedYeyes! rsfMRI!serie!(greenYblue)!(z>2.3) 212 Figure!69. EEGYinformed!fMRI!results!for!patient!2.!Positive!(red)!and!negative! (blue)!significant!results!(=0.05,!TFCE!corrected!and!cluster!size!10)!per!band! and!condition!are!depicted.!Sagittal!(x)!and!axial!(z)!views!(x!and!z!coordinate! according!to!MNI152!standard!space!are!shown!for!each!slice)!are!displayed! according!to!neurological!convention!(right!on!right).!The!zYstatistic!map!legend! is!shown!in!the!left!side. 214 Figure!70. Patient!1!previous!closed!eyes!EEG!recording!outside!the!scanner!(A)! and!EEG!inside!the!scanner!after!removal!of!gradient!and!pulse!MR!related! artifacts!(B) 224 ! ! ! !. ! xiv!.
(21) !. !. LIST%OF%TABLES* Table!I.! Summary!of!main!interictal!EEG!abnormalities!and!the!kind!of!seizures!in! FoS!subjects.!FoS!=!fixationYoff!sensitivity.!IGE!=!idiopathic!generalized! epilepsy.!CGE!=!cryptogenic!generalized!epilepsy.!GSW!=!Generalized!SpikeY Wave! 86! Table!II.! Summary!of!SpRETI!performance!tests!including!the!values!of!the!most! relevant!combination!of!parameters! 140! Table!III.! Scan!time,!volume!execution!TR,!slice!execution!TR,!opuser7,!opuser9!and! opuser10!(needed!to!proper!execution!TRs),!spiral!number!of!points!and!Pfile! size!for!the!SpRETI!validation!tests.! 141! Table!IV.! Number!of!activated!voxels!in!gray!matter!(p<0.05,!FWE!corrected)!for! both!volunteers.! 146! Table!V.! Number!of!activated!voxels!in!gray!matter!(p<0.05,!FWE!corrected)!for! both!volunteers! 148! Table!VI.! Temporal!features!of!MR!scanner!trigger!signal!for!GE!Y!EPIv14,!GE!Y! EPIv15,!GE!–!SPRLIO,!GE!Y!SPEP!(BOLD),!GE!Y!SPEP!(ASLYDualEcho)!and!EG!Y! SPRETI.!The!execution!and!nominal!TRs!differ!for!GE!Y!EPIv14,!GE!Y!SPEP! (BOLD)!and!GE!Y!SPEP!(ASLYDualEcho).! 150! Table!VII.!Temporal!features!of!MR!scanner!trigger!signal!for!GE!Y!EPIv14m,!GE!Y! SPEP!(BOLD),!GE!Y!SPEP!(ASLYDualEcho).!The!execution!and!nominal!TRs!for!GE! Y!EPIv14m!and!GE!Y!SPEP!(BOLD)!and!GE!Y!SPEP!(ASLYDualEcho)!are!equal.151! Table!VIII.! PHANTOM!DATA:!Euclidean!distance!from!EPI!and!Spiral!VSD!with! respect!to!the!background!VSD! 162! Table!IX.! PHANTOM!DATA:!Euclidean!distance!from!EPI!and!Spiral!VSDs!with! respect!to!the!background!VSD!for!the!frequency!range!2Y125!Hz!and!10Y125Hz! for!the!worstYcase!electrode!(F3)! 164! Table!X.! HUMAN!DATA:!Euclidean!distance!from!EPI!and!Spiral!VSDs!with!respect! to!the!background!VSD!for!the!frequency!range!2Y125!Hz!and!11Y125Hz! 167! Table!XI. FoSYrelated!abnormal!EEG!activity!and!seizure!types!for!the!two!patients. ! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!185 Table!XII. Broad!brain!regions,!peak!MNI!coordinates!and!number!of!significant! voxels!per!band!and!condition!(rsfMRI!series)!are!displayed.!Red!and!blue!texts! inside!the!table!are!highlighting!positive!and!negative!associations!respectively. ! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!204 Table!XIII. Broad!brain!regions,!peak!MNI!coordinates!and!number!of!significant! voxels!per!band!and!condition!(EEGYinformed!fMRI!analyses)!for!patient!1!are! displayed.!Red!and!blue!texts!inside!the!table!are!highlighting!positive!and! negative!associations!respectively.! 212 !. xv!.
(22) !. ! Table!XIV. Broad!brain!regions,!peak!MNI!coordinates!and!number!of!significant! voxels!per!band!and!condition!(EEGYinformed!fMRI!analyses)!for!patient!2!are! displayed.!Red!and!blue!texts!inside!the!table!are!highlighting!positive!and! negative!associations!respectively.! 216 !. ! ! !. !. xvi!.
(23) !. !. * * * SECTION!A! ! ! !. BASIC&CONCEPTS&&AND&THESIS&PLAN! *. !. *.
(24) !. !. * *. !.
(25) !. I. INTRODUCTION* ! Neuroimaging! techniques! include! electrophysiological,! structural! and! functional! imaging! systems.! The! diagnosis! of! almost! any! neurological! disease,! such! as! epilepsy,! tumors,! psychiatric! or! neurodegenerative! diseases,! comprises! typically! the! use! of! more! than! one! of! those! techniques.! Multimodal! neuroimaging! can! be! referred!to!the!independent!use!of!a!variety!of!those!techniques!and!its!posterior! information!combination!after!some!kind!of!postprocessing.!On!the!other!hand,!the! simultaneous! combination! of! different! techniques! can! provide! more! accurate! information!because!it!obtains!the!data!in!the!same!patient!state!and!condition.!It! has!also!the!advantage!of!reducing!time!costs!for!physicians!and/or!technicians.! One! of! those! multimodal! techniques! is! simultaneous! EEGdfMRI.! Combination! of! ElectroEncephaloGraphy! (EEG)[1]and! functional! Magnetic! Resonance! Imaging! (fMRI)![2]!data!provides!an!ideal!combination!of!the!excellent!spatial!resolution!of! fMRI! with! the! millisecond! temporal! resolution! of! EEG! [3].! The! concurrent! utilization!of!both!methods!has!only!been!established!more!broadly!in!the!last!few! years.!The!use!of!this!technique!is!perfect!for!the!study!in!epilepsy!as!it!is!the!only! way! to! correlate! the! identified! electrical! epileptic! activity! in! the! EEG! (goldd standard! in! epilepsy)! with! its! hemodynamic! response,! having! whole! brain! coverage,!giving!the!opportunity!to!nondinvasively!identify!the!epileptogenic!focus! in! both! cortical! surfaces! and! deep! brain! structures.! Furthermore,! recent! developments! in! Neuroimaging! has! been! focused! in! the! study! of! the! brain! as! a! whole! system! subdivided! in! functional! networks.! This! kind! of! brain! analyses! can! also! potentially! become! a! new! epilepsy! diagnosis! tool.! The! impairment! or! disruption!in!brain!networks!can!be!related!to!the!cause!or!the!consequence!of!a! specific! neurological! disorder.! A! simultaneous! capture! of! electrophysiological! signatures,! which! provides! information! about! state,! alertness,! changes! in!!. !. 1!.
(26) SECTION!A!. I.!INTRODUCTION!. ! electrical! topography! etc.! of! a! subject,! with! functional! MRI! provides! unique! information!in!the!interpretation!of!brain!networks.!! From! the! technical! point! of! view,! simultaneous! EEGdfMRI! is! challenging! because! both! acquired! signals,! EEG! and! fMRI,! are! disrupted! by! the! other! acquisition! system.! Above! all,! the! EEG! signal! is! completely! altered! by! electromagnetic! induction!caused!by!the!timedvarying!electromagnetic!fields!of!both!RF!pulses!and! gradient! switching.! Although! the! potential! of! the! technique! is! very! high! as! we! discussed!before,!the!characterization,!evaluation!and!validation!of!its!capabilities! and!limitations!is!mandatory!to!make!this!multimodal!technique!present!in!clinical! routine.! The!first!application!of!simultaneous!EEGdfMRI!was!the!study!of!spontaneous!brain! activity! both! in! health! and! disease.! One! of! the! most! relevant! ones! is! the! study! of! patients!with!epilepsy.!The!combination!of!both!kind!of!information!can!potentially! improve!the!diagnosis!and/or!the!localization!of!the!epileptic!focus![4].!! Epilepsy! is! the! chronic! brain! affection! that! is! more! widely! widespread.! About! 50! million!people!around!the!world!suffer!some!kind!of!epileptic!syndrome.!Around!a! 90%! has! been! found! in! the! developed! countries! (probably! because! it! is! infradiagnosed! in! underddeveloped! countries).! In! Europe,! there! are! around! 6! million! people! affected! by! a! combination! of! epileptic! syndromes,! and! around! 400,000!new!patients!are!diagnosed!every!year![5].!Epilepsy!is!the!most!frequent! visit!reason!to!the!neurological!ambulatory!services.!It!can!appear!in!any!person,! without! distinction! of! sex,! race! or! sociodeconomic! level.! As! epilepsy! is! a! combination!of!symptoms!that!are!grouped!in!a!combination!of!syndromes!based! on! theirs! characteristics,! onset! age,! familiar! history,! etc.! we! can! talk! about! “epilepsies”!more!than!about!“epilepsy”![6].! Antiepileptic! drugs! (AEDs)! can! approximately! control! about! 70%! of! the! patients.! These!patients!present,!in!general,!a!good!prognosis!with!complete!control!of!the! epileptic! crisis! and! even,! in! some! cases,! the! interruption! of! the! drug! treatments.! Pharmacological! treatment! selection! and! its! posology! depend! on! the! epilepsy! diagnosis,!which!is!linked!to!the!clinical!manifestations!of!the!epileptic!crises.!This!. !. 2!.
(27) SECTION!A!. I.!INTRODUCTION!. ! means!that!this!disease!is!infradiagnosed,!there!are!no!biomarkers!to!identify!the! subjects!at!risk!or!therapies!to!prevent!epilepsy![5,!7].! On! the! other! hand,! there! is! a! group! of! epileptic! patients! whose! situation! is! more! dramatic!as!crises!are!not!controlled!by!medication.!They!represent!the!30%!of!the! patients! and! it! is! known! as! pharmacorresistent! or! refractory! epilepsy.! It! is! associated! with! high! rate! of! depression,! dependency,! social! isolation,! morbidity! and! mortality.! Death! rate! in! people! with! epilepsy! is! 2d3! times! higher! than! in! general!population,!and!life!expectancy!is!reduced!by!2d10!years![8].!The!total!cost! of!epilepsy!in!Europe!is!about!€20!billion!per!year![5].! The! European! Forum! on! Epilepsy! Research! (ERF2013)! defined! the! shortdterm,! mediumdterm!and!longdterm!research!priorities!in!epilepsy!in!2013.!In!the!shortd term!and!mediumdterm,!a!better!understanding!and!diagnosis!of!different!epileptic! childhood! syndromes! was! identified! including! the! study! of! glial! activity! implications! in! the! epileptogenesis! and! genetic! studies.! Nowadays,! an! early! diagnosis! of! epilepsy! is! still! a! utopia.! The! development! of! early! biomarkers! and! prevention!therapies!is!an!important!topic!in!the!community.!The!creation!of!new! forms!of!treatments!based!on!gene!or!cell!therapies!as!well!as!other!AEDs!is!a!longd term!research!priority.!! In!this!way,!a!better!understanding!and!diagnosis!are!crucial!to!arrive!to!the!longd term!objectives.!The!inclusion!of!multimodal!neuroimaging!techniques!in!a!routine! diagnostic! setup! is! proposed! to! improve! the! delineation! of! epileptogenesis,! to! define!biomarkers!and!to!identify!brain!network!dysfunctions!in!the!patient’s!brain! and!human!brain!in!general![9].!Specifically,!simultaneous!EEGdfMRI!is!one!of!these! promising!multimodal!techniques!that!have!the!potential!to!provide!new!insights! and!early!diagnosis!information.! THESIS*ORGANIZATION* This! PhD! thesis! is! organized! in! four! main! sections! and! fourteen! chapters.! It! also! contains!nine!annex!chapters.! The! first! section! will! include! the! entire! introduction! to! this! work! describing! the! fundamental!concepts!and!the!recent!state!of!the!art.!This!section!will!contain!four! !. 3!.
(28) SECTION!A!. I.!INTRODUCTION!. ! chapters:! •. This! current! chapter! is! an! introduction! to! the! motivation! of! the! work! that! will!be!developed!in!this!PhD!thesis.! !. •. In!chapter!II,!a!basic!summary!of!key!fundamental!concepts!about!epilepsy! and!the!technical!characteristics!of!the!imaging!modalities!that!are!used!in! this!work:!Electroencephalography,!functional!Magnetic!Resonance!Imaging! (including! an! introduction! to! MRI! pulse! sequence! development)! and! its! simultaneous!combination.! !. •. Chapter! III! constitutes! the! revision! of! the! state! of! the! art! of! simultaneous! EEGdfMRI!taken!from!its!technical!challenges!to!the!main!applications!and! available!literature.!There!are!three!main!focuses!in!the!chapter:!EEG!signal! quality,! fMRI! image! quality! and! the! techniques! and! applications! of! the! combination!of!EEG!and!fMRI.! !. •. In! chapter! IV,! the! hypothesis! and! objectives! of! this! work! are! presented! in! the!way!that!they!solve!or!alleviate!the!challenges!highlighted!in!the!state!of! the!art!in!chapter!III.!. The!second!section!contains!the!technological!methods,!studies!and!improvements! made!during!this!thesis!work.!It!is!subdivided!in!three!chapters:! •. Chapter!V!contains!an!introduction!to!the!chapter.! !. •. Chapter! VI! describes! the! materials,! both! hardware! and! software,! and! the! methods! that! were! used! to! achieve! the! technological! objectives! defined! in! chapter!IV.! !. •. Chapter! VII! presents! the! obtained! results! about! the! methodological! setup! analyses!and!the!proposed!improvements!in!simultaneous!EEGdfMRI.! !. !. 4!.
(29) SECTION!A!. I.!INTRODUCTION!. ! •. Chapter!VIII!contains!the!discussion!of!the!obtained!results!with!respect!to! the! best! practices! in! the! literature! and! the! planned! objectives! for! the! improvements!proposed!in!this!thesis!work.!. The!third!section!describes!the!clinical!study!of!two!epileptic!patients!including!a! group! of! healthy! volunteers! for! comparison! using! simultaneous! EEGdfMRI.! The! optimized!setup!during!the!first!part!of!the!second!section!of!the!thesis!was!used!to! run!the!study.!This!section!contains!an!introduction!(chapter!IX),!methods!(chapter! X),!results!(chapter!XI)!and!discussion!(chapter!XII).!It!is!written!in!the!form!of!an! original!contribution!work!and!it!can!be!read!isolated!from!the!rest!of!this!thesis! work.! The!forth!section!of!this!thesis!contains!the!final!conclusions!about!the!developed! work.!It!is!subdivided!in!two!chapters.! •. Chapter!XIII!includes!the!joint!conclusions!from!section!B!and!section!C.! !. •. Finally,!Chapter!XIV!presents!some!ideas!and!future!research!lines!related! to!this!thesis!work.!. * ! !. !. 5!.
(30) !. !.
(31) !. II. PRELIMINARY*CONCEPTS* ! This! thesis! work! consists! of! the! combination! of! two! neuroimaging! techniques,! ElectroEncephaloGraphy! (EEG)! and! functional! Magnetic! Resonance! Imaging! (fMRI)!and!its!application!in!epileptic!patients.!This!chapter!describes!briefly!both! neuroimaging!techniques!separately,!focusing!on! how!the!brain!at!rest!is!studied! with!both!techniques.!Additionally,!as!the!first!part!of!this!thesis!work!consists!of! the! development! of! a! new! MRI! pulse! sequence,! an! introduction! about! the! functional! modules! of! MRI! pulse! sequences! is! included.! Last,! basic! concepts! of! epilepsy!are!included!in!order!to!introduce!the!most!common!terms!related!to!this! pathology.!!. 1.. ELECTROENCEPHALOGRAPHY**. EEG! was! discovered! by! Caton! and! recorded! for! the! first! time! in! human! scalp! by! Berger!a!century!ago![10].!EEG!consists!of!the!sum!of!the!volumetric!ionic!currents! generated!by!populations!of,!mainly,!cortical!pyramidal!neurons.!The!neurons!are! excitable!cells!which!have!electrical!properties,!and!their!activity!generates!electric! and! magnetic! fields! that! can! be! captured! by! electrodes,! both! internally! and! externally.! EEG! is! referred! as! the! mechanism! of! brain! electrical! activity! recorded! nondinvasively! using! scalp! electrodes.! A! schema! of! the! generation! of! the! brain! volumetric!electrical!currents!that!can!be!captured!by!EEG!is!depicted!in!Figure!1.! Neurons! generate! electrical! signals! when! activated.! The! neural! function! is! normally! maintained! by! ionic! gradients! established! by! neuronal! membranes.! These!membranes!have!a!resting!membrane!potential!of!d75!mV!maintained!by!an! electrochemical! equilibrium! of! K+! efflux.! The! ionic! currents! are! generated! at! the! cellular! membranes.! We! can! distinguish! two! main! forms! of! neuronal! activation! !. 7!.
(32) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! [11]:! the! fast! depolarization! of! the! neuronal! membrane! mediated! by! NA2+!and! K+! that!generates!an!action!potential!and!the!slower!changes!in!neuronal!membrane! due! to! the! synaptic! activation! that! it! is! mediated! by! different! kinds! of! neurotransmitters.!The!action!potential!is!characterized!by!a!rapid!change!on!the! state! of! the! membrane! potential! from! negative! to! positive! followed! by! a! quick! return! to! the! resting! potential! in! about! 1d2! ms.! The! action! potential! allows! the! conduction! between! adjacent! segments! of! the! membrane.! However,! the! synaptic! potentials! are! the! main! important! source! of! the! extracellular! current! flow! that! produces!potentials!in!the!EEG.!They!are!longer!in!time!and!their!contribution!to! the! volumetric! current! (Jv)! is! summed! in! a! population! of! neurons,! working! synchronously,! generating! a! net! current! that! can! be! captured! by! the! EEG! electrodes.!Volume!conduction!characterizes!the!process!of!current!flow!from!the! brain! generator! to! the! recording! electrode.! Pyramidal! cells! are! the! major! contributor! of! the! synaptic! potentials! that! make! up! EEG.! These! neurons! are! perpendicular! to! the! cortical! surface.! A! population! of! neurons! covering! an! area! greater! than! 6! cm2! is! necessary! to! create! enough! volumetric! current! to! be! acquired!by!an!EEG!system.!This!neuronal!activation!is!normally!referred!as!dipole! as!it!generates!an!electric!and!a!magnetic!field.!The!EEG!is!measured!as!a!voltage! difference! between! two! electrodes! giving! as! a! result! a! display! of! continuous! and! changing!voltage!fields!varying!with!different!locations!on!the!scalp.! !. 8! !.
(33) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. ! Figure!1.. EEG!signal!generation!schema!from!the!electric!currents!generated!inside!. one!pyramidal!neuron!to!the!typical!oscillations!seen!in!an!ambulatory!EEG.!. The!main!limitation!of!EEG!is!the!identification!of!the!neuronal!population!sources! that!generate!the!captured!EEG!signal,!the!spatial!map!in!the!scalp.!This!is!known! as!the!inverse!problem.!In!general!terms,!an!infinite!number!of!possible!electrical! sources! combinations! can! generate! a! given! scalp! topographical! spatial! map! in! a! specific!time!point.!There!are!numerous!algorithms!that!aim!to!solve!this!sodcalled! inverse!problem!by!introducing!reasonable!a!priori!constraints![12].!For!example,! one!of!the!characteristics!that!has!to!be!taken!into!account!by!these!algorithms!is! the! completely! different! EEG! spatial! map! generated! by! pyramidal! neuron! populations! close! in! space! but! located! tangential! to! the! scalp! (brain! sulcus)! or! perpendicular! to! it! (brain! convolution)! (Figure! 2).! For! tangential! dipoles! (in! the! sulcus),!electrodes!over!the!occipital!cortex!will!measure!the!negative!part!of!the! field!while!electrodes!over!the!frontal!cortex!will!measure!the!positive!part.!In!the! case!of!radial!dipoles!(in!the!convolution),!the!electrodes!over!the!active!area!will! record!maximal!positive!potential,!while!the!lowest!temporal!electrodes!will!pick! up!some!part!of!the!negative!potential!of!the!field![13].! 9! !.
(34) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. ! Figure!2.. Topographical!spatial!maps!generated!by!the!activation!of!a!group!of!. neurons!in!the!vertex!of!the!brain!located!tangential!to!the!scalp!(left)!and! perpendicular!to!the!scalp!(right).!. EEG! is! typically! recorded! by! multiple! electrodes,! depending! on! the! clinical! or! research!application!from!a!minimum!of!3!electrodes!(ground,!reference,!electrode! of! interest)! to! highddense! configurations! with! 256d1024! electrodes.! Electrode! placement!has!been!standardized!by!international!systems!like!the!10–20!system.! They!use!anatomical!landmarks!on!the!skull!(nasion!and!inion).!From!these!sites,! the!electrodes!are!placed!in!intervals!of!10%!or!20%!of!the!distance!between!those! landmarks.! The! electrodes! are! identified! by! a! letter! and! a! number,! the! letter! indicates!the!brain!anatomical!area!and!the!number!indicate!the!hemisphere.!The! letters! in! 10d20! are:! Fp! (frontopolar),! F! (frontal),! T! (temporal),! O! (occipital),! C! (central),! and! P! (parietal)! Subsequently,! numbers! reflect! either! the! left! (odd! numbers)! or! right! (even! numbers)! hemisphere! of! that! electrode.! The! “z”! designation! reflects! midline! placement! (i.e.,! Pz! =! parietal! midline)! (Figure! 3).! Additionally,! ElectroOculoGram! (EOG)! and/or! ElectroCardiaGram! (ECG)! electrodes! are! typically! added! in! the! same! recording! systems.! The! recordings! in! these! polygraphic! channels! can! be! used! for! patient! monitoring! and! for! artifact! rejection![14].! 10! !.
(35) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! !. ! Figure!3.. 1.1. International!10d20!system!electrode!placement!for!35!EEG!channels.!. Spontaneous!activity!and!evoked!potentials!. Normal! EEG! at! rest! can! be! characterized! by! the! combination! of! rhythmical! oscillations!at!multiple!frequencies.!Distinct!dominant!electrical!brain!oscillations! (EEG!rhythms!or!EEG!bands)!characterize!different!brain!states!ranging!from!alert! wakefulness! to! deep! sleep.! Here,! we! present! a! conventional! separation! of! the! rhythms! by! frequency! bands! or! dominant! frequencies,! indicating! a! brief! description! of! the! main! brain! states! that! they! represent! [15].! However! these! rhythms! at! different! frequencies! can! coexist! and! interact! with! each! other! to! produce!a!much!wider!range!of!brain!states.!! •. Delta!rhythm!(1d4!Hz).!W.!G.!Walter!in!1937!gave!this!name!to!these!waves! of!low!frequency!and!high!intensity!(hundreds!of!µV).!This!rhythm!appears! in!very!young!children,!in!deep!sleep!and!unconsciousness!in!adults.!It!also! appears! when! intracranial! pressure! increases,! due! to! brain! tumors! for! example.!. 11! !.
(36) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! ! •. Theta!rhythm!(4d8!Hz).!W.!G.!Walter!in!1953!gave!the!name!to!these!waves! with! amplitudes! less! than! 20! µV.! This! rhythm! appears! in! the! maturation! process!of!the!cortex,!mainly!in!occipital,!temporal!and!it!is!faster!in!frontal! areas.!It!is!the!dominant!rhythm!in!5d7!years!old!children.!In!youngsters!and! adults,!it!is!related!to!emotions!and!creative!thoughts,!stress!or!psychiatric! disorders.! !. •. Alpha! rhythm! (8d12! Hz).! The! name! was! first! used! by! Berger! to! define! the! bursts!of!20d100!µV!and!high!periodicity!in!those!frequencies.!This!rhythm! appears!predominantly!in!occipital!regions.!It!has!been!associated!to!relax! and!inactivity!states!and!it!is!present!in!the!absence!of!visual!stimuli!(when! closing! eyes! without! falling! asleep).! There! is! a! huge! interpersonal! variability,!people!with!permanent!alpha!rhythm!and!people!without!it.! !. •. Beta!rhythm!(12d30!Hz).!Berger!also!defined!this!term!to!characterize!these! signals!of!low!amplitude,!bellow!20µV.!This!rhythm!is!predominant!in!adult! life.!It!is!typically!subdivided:! o Low!beta:!mainly!in!frontal!and!occipital!regions.! o Medium!and!high!beta:!not!so!well!localized.! It!is!more!irregular!than!alpha.!It!is!associated!with!psychophysics!activity,! alertness!and!problem!solving!situations.! !. •. Gamma!rhythm!(>30!Hz).!It!was!defined!in!1938!by!Jasper!and!Andrews!in! 1938.!Berger!considered!30d50!Hz!range!part!of!beta!rhythm.!This!band!has! a!resonance!peak!around!40Hz!(epsilon).!It!is!associated!to!abstract!mental! activity!(face!recognition,!person!voice!or!specific!odor!identification).!The! amplitude! of! gamma! waves! is! very! small! and! the! waveforms! are! typically! more! triangular! in! shape! than! the! rest! of! the! rhythms.! Its! existence! has! been!controversial!during!years!but!its!neuronal!origin!is!nowadays!widely! accepted.!. 12! !.
(37) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! Besides!the!rhythms,!the!Event!Related!Potentials!(ERP)!are!also!analyzed!in!EEG! data.!ERPs!are!voltage!fluctuations!in!the!EEG!formed!by!the!sum!of!a!large!number! of! neuronal! action! potentials! time! locked! to! a! stimulus! or! event! (sensorial,! cognitive,!etc.).!They!are!a!useful!diagnostic!tool.!It!is!usually!necessary!to!average! several!repetitions!of!the!same!stimulus!in!order!to!see!them!clearly.!ERPs!can!be! quantitatively! characterized! by! their! latency,! peak! amplitude! and! scalp! distribution.!Those!characteristics!can!differentiate!health!and!disease.!An!example! of! a! Visual! Evoked! Potential! (VEP)! can! be! seen! in! Figure! 4.! ‘P’! indicates! positive! peaks!and!‘N’!negative!peaks!in!the!VEP.!A!very!interesting!peak!in!Neuroscience!is!. !. the! P300 which! is! a! well! known! cognitive! evoked! potential! and! it! is! related! to! decision!making.!It!is!typically!more!prominent!in!parietal!regions.!. ! Figure!4.. Example!of!an!Event!Related!Potential!(ERP),!more!especifically,!a!Visual! Evoked!Potential!(VEP)!. 2.. FUNCTIONAL*MAGNETIC*RESONANCE*IMAGING*. In! general,! fMRI! is! related! to! the! study! of! the! BOLD! (Blood! Oxygen! Level! Dependent)!signal!in!the!brain![16].!Its!first!application!in!humans!were!shown!by! Belleveau! et! al.! in! 1991! demonstrating! an! increase! in! the! local! blood! flow! in! the! primary!visual!cortex!in!response!to!a!visual!paradigm![17,!18].! BOLD! measures! the! hemodynamic! and! metabolic! changes! that! are! coupled! with! the! neuronal! activity.! The! basic! assumption! of! this! method! is! the! lack! of! inner! energy! storage,! in! the! form! of! Glucose! or! Oxygen,! inside! the! neurons.! Under! this! hypothesis,!that!energy!has!to!be!obtained!during!the!process!known!as!the!brain! 13! !.
(38) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! Hemodynamic!Response!(HR).!The!hemodynamic!system!reacts!to!the!activation!of! a! neuronal! population! increasing! the! oxygenated! blood! flow! locally! to! that! brain! area.! From! the! Magnetic! Resonance! physical! point! of! view,! the! sensitivity! to! the! local! blood! flow! is! related! to! the! magnetic! properties! of! the! hemoglobin.! The! hemoglobin! is! diamagnetic! when! it! is! oxygenated! and! paramagnetic! when! it! contains! Oxygen.! A! relative! change! between! the! oxyhemoglobin! and! deoxyhemoglobin!levels!in!the!blood!flow!causes!small!differences!in!the!Magnetic! Resonance!signal.!A!relative!increase!of!oxyhemoglobin!produces!a!local!distortion! of! the! magnetic! field! which! decreases! the! received! MR! signal.! In! this! way,! assuming! that! the! oxygenation! level! of! the! blood! flow! varies! according! to! the! neuronal!activity,!these!variations!can!be!captured!and!located!using!fMRI![19].!! In!Figure!5!a!schema!of!the!event!chain!that!generates!the!BOLD!response!is!shown! as! explained! by! the! balloon! model! [16,! 20].! A! stimulus! or! a! task! induces! the! beginning!of!neuronal!activity!in!localized!brain!region,!which!triggers!an!increase! in! the! blood! flow,! in! the! local! blood! volume! and! in! the! Oxygen! and! Glucose! consumption.! The! neuronal! activity! causes! an! initial! increase! in! the! Oxygen! consumption! of! the! cells! of! the! region.! This! phenomenon,! in! turn,! causes! an! increase! in! the! concentration! of! deoxyghemoglobin! versus! oxyhemoglobin! with! respect!to!the!concentrations!of!these!substances!in!resting!state.!In!this!situation,! BOLD! signal! has! a! small! and! short! decay,! or! dip.! Then,! the! hemodynamic! system! responds! increasing! the! local! blood! flow,! lasting! about! 4! or! 5! seconds,! to! compensate! the! lack! of! Oxygen.! This! fact! produces! the! oxyhemoglobin! concentration! increment! with! respect! to! deoxyhemoglobin,! different! from! the! basal!state,!causing!a!positive!peak!in!the!BOLD!signal.!From!there,!the!blood!flow! drops!towards!a!new!basal!state!(only!if!the!stimulus!that!triggered!the!neuronal! activity! has! finished).! Before! reaching! the! new! basal! state,! the! BOLD! MR! signal! presents! an! undershoot.! In! the! balloon! model,! local! cerebral! blood! volume! increase! is! identified! as! the! cause! for! this! undershoot.! However,! recent! studies! have! demonstrated! that! the! appearance! of! the! HR! undershoot! has! a! neuronal! origin,!neuronal!activity!and!local!cerebral!blood!flow!decrease[21].!!!. 14! !.
(39) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. ! Figure!5.. Balloon!model:!Schema!of!the!key!factors!that!generate!the!hemodynamic!. response!cascade!to!a!stimulus!that!generates!the!BOLD!signal!!(Source:!Faro!et!al.! [22])!. The!main!limitations!of!typical!BOLD!fMRI!are:!its!poor!temporal!resolution!on!the! order! of! seconds;! the! inherent! problem! of! reconstructing! the! subjacent! multidimensional!neuronal!activity!from!a!unidimensional!vascular!signal;!and!the! need! of! a! model! to! describe! the! functional! map! that! describes! the! interpretation! between!the!“function”!or!the!task,!the!neuronal!activity!and!the!MR!signal![23].!. 2.1. Restingdstate!fMRI!. While! the! study! of! spontaneous! activity! in! the! EEG! started! with! the! beginning! of! the!technique,!the!greater!part!of!the!knowledge!from!fMRI!research!comes!from! the! analysis! of! the! brain! response! associated! to! a! specific! stimulus! or! task.! However,!the!brain!remains!active!even!in!the!absence!of!any!specific!internal!or! 15! !.
(40) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! external!stimuli.!BOLD!fluctuations!due!to!stimuli!correspond!to!approximately!the! 5%!of!the!increment!or!decrement!of!the!neuronal!metabolism;!whileas!the!brain! energy! consumption! constitutes! a! 20%! of! the! total! energy! consumption! of! the! human! body.! In! taskdfMRI! experiments! the! basal! fluctuations! of! the! BOLD! signal! are! typically! treated! as! random! noise! and! only! the! relative! change! between! task! and!nondtask!BOLD!signal!are!further!analyzed.!! Biswal!et!al.!in!1995!compared!the!brain!areas!activated!during!a!motor!task!with! the!temporal!correlation!of!BOLD!fluctuations!at!rest!in!the!same!brain!areas[24].! The!same!topographical!maps,!which!included!primary!and!supplementary!motor! areas,!were!obtained!for!both!approaches.!For!the!resting!state!tests,!fluctuations! in! some! other! brain! areas! related! to! the! motor! function! were! also! temporally! correlated!with!the!primary!and!supplementary!motor!cortex.!This!study!proposed! for!the!first!time!that!low!frequency!BOLD!fluctuations! in!the!resting!brain!could! have!a!neural!origin!and!a!function!in!the!brain!organization.!! Subsequent!studies!of!these!low!frequency!spontaneous!fluctuations!of!the!BOLD! signal! at! rest! have! revealed! synchronized! cortical! activity! patterns[25d28].! This! means! that! the! neuronal! activity! in! separated! brain! areas! covariates! in! time! following! the! same! variation! pattern! presumably! reflecting! the! existence! of! a! functional!network.!Most!of!those!functional!networks!have!shown!high!interd!and! intrad! subject! stability! and! consistent! across! methods,! subjects,! conditions,! rest! states! and! consciousness[28d33].! Moreover,! topographically,! it! is! possible! to! identify!that!some!of!this!resting!networks!are!anatomically!located!in!brain!areas! associated! with! sensorimotor! functions,! visual! or! auditory! processing! or! some! cognitive! processes! like! language,! working! memory! or! attention[24,! 29,! 31,! 32,! 34].!This!means!that!those!resting!networks!are!spatially!located!in!the!same!brain! regions! that! are! activated! in! response! to! a! motor,! perception! or! cognitive! task,! respectively.!Figure!6!shows!the!most!common!and!stable!resting!state!networks! identifying!which!functional!process!they!support.!. 16! !.
(41) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! FRONTAL. DMN. MESOLIMBIC. MOTOR. EXECUTIVE FRONTOPARIETAL FRONTOPARIETAL FUNCTIONS RIGHT LEFT ATTENTIONAL. VISUAL. ! Figure!6.. !!Restingdstate!networks!identifying!the!brain!function!they!support![33]!. Apart! from! this! kind! of! functional! networks,! which! appears! in! resting! state! and! increases!their!activity!in!the!execution!of!a!task!that!demands!its!activity,!there!is! another!type!of!network!that!presents!low!frequency!synchronous!fluctuations!at! rest!but!it!decreases!its!activity!when!the!person!focuses!on!any!kind!of!task.!This! is! the! sodcalled! defaultdmode! network,! DMN[25].! This! network! mainly! includes! frontal,! temporal! and! parietal! brain! areas! (Figure! 6,! DMN)! and! it! has! been! associated! with! the! internal! processing! of! autodreferential! data,! autobiographical! memories!or!future!evaluation.!On!the!other!hand,!it!has!been!also!suggested!that! this!network!has!a!preparation!to!the!action!function.!This!means!the!exploratory! monitoring! of! the! external! environment! while! the! person! is! not! focused! to! any! specific!external!stimuli.!Those!two!theories!are!both!based!on!the!‘anticorrelation! phenomenon’,!the!DMN!increases!its!activity!when!a!task!network!is!deactivated!or! attenuated! and! vice! versa.! This! suggests! that! there! are! two! types! of! functional! systems! competing! between! them,! one! focused! on! the! external! information! processing!and!the!other!manages!the!inner!mental!explorations![26,!31,!35].!! 17! !.
(42) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. 3.. PULSE*SEQUENCE*DEVELOPMENT*. A! MRI! pulse! sequence! (psd)! is! a! preselected! set! of! gradient! and! RF! pulses! that! controls! the! excitation! and! reception! of! the! NMR! signal! which! affects! the! MR! images!characteristics.!The!pulse!sequences!are!defined!as!software!that!controls! different!hardware!aspects!during!the!execution!of!it!in!the!MR!scanner.! A!pulse!sequence!is!graphically!represented!like!in!Figure!7.!The!rows!indicate!the! shape,!length!and!amplitude!of!the!different!hardware!devices:!RF!pulse,!Gradient! X! or! readout! (RO),! Gradient! Y! or! phasedencoding! (PE)! and! Gradient! Z! or! slice! selection!(SS)!along!the!time![36].!. Preparation Data acquisition module module: Excitation + echo generaTagging tion + encoding. Correctionmodule: spoiler. Correctionmodule: Crusher. Figure!7.. ! Example!of!a!pulse!sequence!including!a!tagging!preparation!module,!. excitation,!echo!generation!and!encoding,!and!correction!gradients.!The!schema!also! shows!how!the!excitation!can!be!repeated!in!time!for!encoding!purposes.!. A! pulse! sequence! can! be! divided! by! its! different! functional! modules.! Here,! we! distinguish:!the!preparation;!the!data!acquisition!which!is!subdivided!in!excitation,! echo! generation! and! readout! modules;! and! the! correction! modules1.! Two! typical!. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 1!http://www.indiana.edu/~mri/CE/slides! 18! !.
(43) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! module! configuration! for! fMRI! acquisition! and! one! for! diffusion! weighting! MRI! (dwMRI)!acquisition!are!depicted!in!Figure!8!as!examples!of!these!combinations.! PSD*functional*modules*for*fMRI*(type*1)! Preparation:!!. Excitation:!!. Fat! suppression!. Sinc!pulse! θ≤90°!. Echo! generation:!. Encoding:!. Correction:!. EPI!. Crusher!. GradientdEcho!. PSD*functional*modules*for*fMRI*(type*2)* Excitation!+!Prep:!!. Echo! generation:!. Spatialdspectral!pulse! θ≤90°!. GradientdEcho!. Encoding:!. Correction:!. EPI!. Crusher!. PSD*functional*modules*for*dwMRI* Prep:!. Excitation:!!. Prep:!!. Fat!Sup.!. Sinc!pulse! θ=90°!. Diffusion! gradients!. Figure!8.. Echo! generation:! SpindEcho!. Encoding:!. Correction:!. EPI!. Crusher!. Pulse!sequence!functional!modules!for:!(Top)!one!type!of!fMRI!psd;!. (Center)!second!type!of!fMRI!psd!where!the!excitation!and!the!preparation!are! combined;!and,!(Bottom)!an!example!of!a!typical!dwMRI!psd.!!. 3.1. Preparation!module!. This! section! aims! to! modify! the! magnetization! characteristics! prior! to! the! acquisition!of!the!signal.!It!is!defined!as!the!gradient!and!RF!pulses!that!are!played! before! or! after! the! excitation! pulse! with! a! specific! purpose.! This! magnetization! preparation!can!be!based!on:!! RF phase / a.u.RF Magntude / a.u.. C. 0.08. 1. −1. Gcm. Magnitude RF pulse: GE − SPRLIO out. selective! pulse! that! aims! to! null! the! signal! of! specific!. 0 −1. frequency! range.! It! is! broadly! used! to! suppress! the! fat! 0. 0.01. 0.02. −1. 2 0. 0.04. 0.05. 0.06. 0.07. 0.08. 0.06. 0.07. 0.08. Phase RF pulse: GE − SPRLIO out. x 10. 0. 0.03. signal!to!avoid!artifacts!and!improve!contrast!(Figure!9)!! Time/s. 7. 1. Figure!9. 0. 0.08. • Chemical! shift:! This! consists! of! a! spectrally!. 7. x 10. Saturation!pulse!previous!to!excitation!pulse! 0.01. 0.02. 0.03 19! !. 0.04 0.05 Time/s Gradient X: GE − SPRLIO out.
(44) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! •. Spatial!location:!The!previous!chemical!shift!saturation!is!not!spatially!but! only! spectrally! selective.! However,! to! reduce! flow! and! motion! artifacts,! avoid!phasedwrapping!or!to!suppress!the!signal!in!specific!volumes,!the!use! of! spatial! specific! saturation! pulses! is! used.! An! example! of! a! spatially! selective!fat!saturation!can!be!seen!in!Figure!7.! !. •. Magnetization! transfer:! The! use! of! offdresonance! RF! pulse! at! specific! frequencies! saturates! the! protons! associated! to! some! macromolecules.! These! protons! have! a! too! short! T2! that! impedes! to! be! measured! by! a! normal! MRI! scheme.! However,! coupling! between! the! macromolecular! protons! and! the! mobile! or! ‘liquid’! protons! allows! the! spin! state! of! the! macromolecular! protons! to! influence! the! spin! state! of! the! liquid! protons! through! exchange! processes.! This! generates! a! unique! contrast! in! the! MR! images![37]! !. •. Relaxation! time:! T2! and! T1! preparation! can! be! achieved! by! using! RF! and! gradient! pulses! prior! to! the! acquisition! in! order! to! generate! T1! or! T2! contrasts! in! the! image! independently! of! pulse! sequence’s! TR! and! TE.! The! inversion!recovery!is!widely!used!to!suppress!the!signal!of!a!specific!tissue! or! liquid! to! increase! the! contrast! of! the! rest! of! tissues! in! the! images.! For! example,! FLAIR! images! in! brain! suppress! the! signal! from! cerebrospinal! fluid!(CSF)!to!enhance!the!identification!of!lesions!in!gray!and!white!matter.! !. •. Motion! and! flow:! Sets! of! bipolar! gradients! can! be! used! to! cancel! the! influence! of! motion! spins!(flow).!Additionally,!this! set!of!bipolar! gradients! are!also!used!to!measure!diffusion!and!flow.!Depending!on!the!position!and! setting!of!these!pulses!we!will!obtain!a!different!behavior.!!. 3.2. Excitation!module!. One!of!the!most!important!functions!of!the!radiofrequency!pulses!is!the!excitation! of!the!spin!protons.!From!the!basics!concepts!from!MRI,!in!the!presence!of!a!static! 20! !.
(45) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! magnetic! filed! B0,! the! spins! are! aligned! to! the! main! orientation! of! this! B0! field! rotating!at!the!Larmor!frequency!(eq.!1).!The!spins!parallel!to!the!Bo!subject!to!a! short! period! of! high! intensity! radiowaves! at! a! frequency! close! to! the! Larmor! frequency! are! excited.! This! is! called! the! B1! field,! orientated! in! a! direction! perpendicular! to,! and! rotating! about,! the! B0! field.! The! magnitude! of! B1! is! approximately!105!smaller!than!B0.!The!flip!or!tip!angle!indicates!the!angle!of!the! longitudinal!magnetization!tips!with!respect!to!the!transverse!plane![38].! ! = !!! ∙ !! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!(eq.!1)! where!w!is!the!Larmor!frequency,!γ!is!the!gyromagnetic!constant!of!the!spin! and!B0!is!the!magnitude!of!the!static!field.! There! are! multiple! RF! pulses! purposed! in! the! literature! with! its! own! advantages! and! disadvantages.! We! will! briefly! mention! three! main! types! of! excitation! RF! pulses:! •. SINC! pulses:! SINC! pulses! have! been! widely! used! for! selective! excitation.! A! SINC! pulse! consists! of! several! adjacent! lobes! of! alternating! polarity.! The! central! lobe! has! the! highest! amplitude! and! is! also! twice! as! wide! as! every! other!lobe.!The!frequency!profile!of!an!infinite!SINC!RF!pulse!is!a!rectangle! which! has! been! the! reason! for! its! use! when! a! uniform! slice! selection! is! desired.! For! 2D! excitation,! a! gradient! selection! pulse! is! simultaneously! applied! with! the! excitation! RF! pulse.! In! practice,! MR! scanners! played! truncated!SINC!pulses.!One!of!these!pulses!can!be!observed!in!Figure!7.! !. •. SLR! pulses:! Alternatively! to! the! truncated! SINC! RF! excitation! pulses,! the! tailored! RF! pulses! designed! using! ShinnardLe! Roux! (SLR)! algorithm[38]! allows!to!define!a!RF!pulse!by!its!desired!bandwidth,!duration,!flip!angle,!…! through!a!straightforward!computational!process.!. ! •. Spectraldspatial!RF!pulses:!The!two!pulses!defined!above!are!typically!used! for!slice!selective!excitations.!However,!for!some!applications!it!is!desirable! to! use! a! spectral! spatial! pulse! that! allows! to! selectively! excite! within! a!. 21! !.
(46) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. ! section!of!the!imaging!volume!for!a!specific!spectral!content.!In!this!case,!it! is!also!necessary!that!the!RF!pulse!is!played!simultaneously!with!a!gradient! pulse.! Additionally,! the! adiabatic! RF! pulses! can! be! used! for! excitation! but! are! typically! used!in!combination!with!surface!coils!or!in!3D!acquisition!sequences.!. 3.3. Echo!generation!module!. This! module! is! related! to! the! data! acquisition! of! the! pulse! sequence.! After! excitation,! the! transverse! magnetization! rotates! about! the! Z! axis! generating! a! current!in!a!coil!placed!in!the!XY!plane.!The!timecourse!of!this!wave!decays!with! the!time!constant!T2*.!This!signal!is!called!Free!Induction!Decay!(FID).!While!some! pulse!sequences!frequency!encodes!the!FID!for!generating!the!MRI!images!(some! projectiondbased!schemes!with!a!very!short!TE!to!get!images!from!very!short!T2! tissues),!the!majority!of!the!sequences!uses!echoes[39].! The! spindecho! sequence! uses! a! 90º! pulse! which! generates! that! the! transverse! magnetization!begins!to!rotate!in!the!XY!plane.!After!some!time!a!180°!refocusing! pulse! is! applied! which,! at! least! partially,! rephases! the! magnetization! and! it! generates!a!signal!called!echo.!The!use!of!the!180°!pulse!makes!the!spin!echo!decay! with!T2!(eq.!2).!!. 22! !.
(47) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. ! Figure!10. Gradientdecho!generation!scheme!. The!gradientdecho!sequence!uses!a!prephasing!gradient!to!generate!the!echo!signal! instead! of! a! refocusing! pulse! (Figure! 10).! This! makes! the! echo! generation! faster,! being! able! to! use! TE! (echo! time)! shorter! than! spin! echo.! As! the! magnetization! is! not! rephased! with! a! 180º! pulse,! the! echo! signal! depends! on! T2*! and! it! is! more! sensitive!to!offdresonance!effects!(eq.!3)! !!". !!". !!"#$_!"!! = !!!! 1 − ! !! !! !! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!(eq.!2)! ! !!". !!!! !!! !!. !!"#$%&'(_!"!! =. !!". ∗ !"# ! ! !! !!". !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!(eq.!3)!. !!!"#$!! !!. ! where!k!is!a!constant!that!depends!on!the!sensitivity!of!the!coil!and!the!ς!is! the! proton! density,! T1! is! the! longitudinal! relaxation! time,! T2! is! the! transversal!relaxation!time,!TR!is!the!repetition!time!of!the!pulse!sequence,! TE!is!the!echo!time!of!the!sequence!and! θ!is!the!flip!angle!of!the!excitation! RF!pulse.!! 23! !.
(48) SECTION!A!. II.!PRELIMINARY!CONCEPTS!. !. 3.4. Readout!module!. The!last!important!part!in!the!data!acquisition!module!of!a!pulse!sequence!is!the! spatial!encoding!of!the!generated!signal,!to!be!able!to!reconstruct!a!2D!or!3D!MR! image.! The! encoding! is! typically! made! using! frequency! and/or! phase! encoding! gradients.! Frequency!encoding!is!accomplished!by!applying!a!frequencydencoding!gradient!to! the! imaged! object! in! any! physical! direction.! This! gradient! is! called! readout! gradient! and! it! is! normally! indicated! as! Gx.! This! gradient! spatially! encodes! NMR! signals! by! assigning! a! unique! precession! frequency! to! each! cluster! of! spins! at! a! distinct! spatial! location! along! the! gradient! direction.! Under! the! influence! of! this! gradient,! timeddomain! NMR! signals! will! consist! of! a! range! of! frequencies,! each! corresponding!to!a!different!spatial!location.!An!inverse!Fourier!transform!of!the! time!domain!NMR!signal!reveals!the!frequency!content.!Each!frequency!is!linearly! related!to!the!corresponding!spatial!location!along!the!gradient!direction.! Phase! encoding! aims! to! generate! a! linear! relationship! with! the! phase! of! the! magnetization.! The! phase! encoding! gradient! is! normally! identified! as! Gy.! It! is! implemented! by! applying! a! gradient! lobe! while! the! magnetization! is! in! the! transverse! plane,! but! before! the! readout.! By! varying! the! area! under! the! phase! encoding! gradient! lobe,! different! amounts! of! the! linear! phase! variation! are! introduced.!The!resultant!signals!can!be!reconstructed!with!Fourier!transforms!to! recover!spatial!information!about!the!object![38].! A! pulse! sequence! consists! of! a! sequential! replication! of! RF! and! gradient! pulses! where! the! frequencydencoding! and/or! phasedencoding! gradients! are! modified! in! order! to! sample! all! the! kdspace.! In! Figure! 7,! the! data! acquisition! module! is! repeated!every!TR!time!in!order!to!acquire!different!kdspace!portions.!! The! kdspace! is! a! mathematical! concept! that! corresponds! to! a! domain! that! is! Fourier! conjugated! to! the! standard! spatial! domain! that! contains! the! imaged! volume.! In! a! 2D! acquisition,! an! image! represented! by! a! matrix! of! dimensions! Nx,! Ny!will!be!equivalent!to!the!inverse!Fourier!transform!of!the!kdspace!matrix!of!the!. 24! !.
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