! ! ! ! ! AN!INVESTIGATION!OF!THE!KINESTHETIC!ABILITY! AND!EFFECTS!OF!BIMANUAL!COORDINATION! IN!PATIENTS!WITH!MULTIPLE!SCLEROSIS!! ! By! ! Faith!Lincoln! ! ! ! ! ! ! ! ! ! ! ! ! A!THESIS! ! Submitted!to! Michigan!State!University! in!partial!fulfillment!of!the!requirements! for!the!degree!of! ! Kinesiology!–!Master!of!Science! ! 2015! ! ABSTRACT' ! AN!INVESTIGATION!OF!THE!KINESTHETIC!ABILITY! AND!EFFECTS!OF!BIMANUAL!COORDINATION! IN!PATIENTS!WITH!MULTIPLE!SCLEROSIS!! ! By! ! Faith!Lincoln! ! Previous!research!has!shown!that!balance!and!proprioception!of!the!lower!limbs!are! impaired!in!patients!with!multiple!sclerosis!(MS).!The!extent!of!kinesthetic!impairment!in! the!upper!limb!for!this!population!is!not!well!known.!This!study!identifies!the!kinesthetic! impairment!in!the!upper!limb!in!MS!patients!and!determines!if!this!performance!can!be! modulated!by!simultaneous!utilization!of!the!contralateral!limb.!Patients!with!MS,!aged!32[ 61!with!mild!to!moderate!severity!and!diagnosed!within!the!last!ten!years,!as!well!as!age[! and!gender[matched!healthy!controls,!performed!center[out!movements!by!controlling!a! cursor!on!a!horizontally!positioned!computer!screen!with!a!joystick!underneath!so!the! hand!was!not!visible.!This!task!was!performed!unimanually!and!bimanually!under!visual! and!kinesthetic!control.!Results!show!that!kinesthetically!guided!movements!of!MS!patients! in!both!unimanual!and!bimanual!conditions!are!slower,!less!linear,!and!less!accurate! compared!to!controls.!They!improved!movement!linearity!in!the!dominant!kinesthetically! guided!arm!when!utilizing!bimanual!coordination!compared!to!unimanual.!However,!the! overall!kinesthetic!performance!of!MS!patients!did!not!improve!with!visual!guidance!from! the!contralateral!limb,!nor!did!it!get!worse.!Patients!with!MS!have!impaired!visual! integration!and!kinesthetic!ability.!Damage!to!the!corpus!callosum!might!be!an!indicator!of! this.!Simultaneous!use!of!the!upper!limbs!does!not!seem!to!improve!fine!motor!functions!or! aid!kinesthesia.! ! ! ! ! ! ! ! ! ! ! Copyright!by! FAITH!LINCOLN! 2015! ! ! ACKNOWLEDGEMENTS! ! ! ! I!would!like!to!express!my!gratitude!to!my!committee!members!for!their!guidance! and!patience:!Dr.!Florian!Kagerer,!my!advisor!and!committee!chair;!Dr.!Jayne!Ward;!and!Dr.! Rajiv!Ranganathan.! The!completion!of!this!project!would!not!have!been!possible!without!the!assistance! of!Doozie!Russell!and!the!research!staff!in!the!Neurology!and!Ophthalmology!Clinic!at! Michigan!State!University.! Finally,!many!thanks!go!to!my!family!and!David!for!all!their!continued!support!and! encouragement.! ! iv! LIST!OF!TABLES! ! ! ! LIST!OF!FIGURES! ! ! ! KEY!TO!ABBREVIATIONS! ! ! CHAPTER!1! ! ! ! Introduction! ! ! ! ! ! ! ! !!!!!!!!!!!! CHAPTER!2! ! ! ! Literature!Review! ! ! ! CHAPTER!3! ! ! ! Methods! ! ! ! ! 3.1!Participants! ! ! 3.2!Materials! ! ! ! 3.3!Procedure!! ! ! 3.4!Data!Analysis! ! ! CHAPTER!4! ! ! ! Results! ! ! ! ! 4.1!Visual!condition! ! ! 4.2!Kinesthetic!condition! ! CHAPTER!5! ! ! ! Discussion! ! ! ! ! 5.1!Unimanual!condition! ! 5.2!Bimanual!condition! ! 5.3!Conclusions! ! ! REFERENCES!! ! ! TABLE!OF!CONTENTS! ! ! ! ! ! ! ! ! ! ! !!!!!!!!!!vi! ! ! ! ! ! ! ! !!!!!!!!vii! ! ! ! ! ! ! ! !!!!!!!viii! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!!!!!!!!!1! !!!!!!!!!!!1! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!!!!!!!!!9! !!!!!!!!!!!9! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!!!!!!28! !!!!!!!!28! !!!!!!!!28! !!!!!!!!28! !!!!!!!!28! !!!!!!!!31! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!!!!!!! ! ! ! ! !!!!!!!!! !!!!!!!!33! !!!!!!!!33! !!!!!!!!34! !!!!!!!!36! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!!!!!!41! !!!!!!!!41! !!!!!!!!41! !!!!!!!!44! !!!!!!!!52! ! ! ! ! ! ! ! !!!!!!!!54! v!! LIST!OF!TABLES! ! ! ! Table!1:!Means!and!Standard!Deviations!for!Unimanual!and!Bimanual!Movements!! Under!Kinesthetic!and!Visual!Feedback!for!Patients!and!Controls! ! !!!!!!!!33! ! vi! LIST!OF!FIGURES! ! ! ! Figure!1:!Average!results!of!the!nine!hole!peg!test!for!patients!(MS)!and!controls!! for!each!hand,!(NHPT_L=left!hand,!NHPT_R=right!hand).!! !!!!!!!!! ! !!!!!!!!34! ! Figure!2:!Movement!times!for!patients!(MS)!and!controls!for!each!hand,!(lh=left!hand,!! rh=right!hand),!in!both!unimanual!and!bimanual!conditions!with!! visual!feedback;!error!bars!are!in!SD.! !!!!!!!!! ! ! ! ! !!!!!!!!35! ! Figure!3:!Movement!linearity!for!patients!(MS)!and!controls!for!each!hand,!(lh=left!! hand,!rh=right!hand),!in!both!unimanual!and!bimanual!conditions!with!! visual!feedback;!error!bars!are!in!SD.! ! ! ! ! ! !!!!!!!!!!36! ! Figure!4:!Movement!times!for!patients!(MS)!and!controls!for!each!hand,!(lh=left!hand,!! rh=right!hand),!in!both!unimanual!and!bimanual!conditions!under!! kinesthetic!control;!error!bars!are!in!SD.!! ! ! ! ! ! !!!!!!!!!!37! ! Figure!5:!Movement!linearity!for!patients!(MS)!and!controls!for!each!hand,!(lh=left!! hand,!rh=right!hand),!in!both!unimanual!and!bimanual!conditions!under!! kinesthetic!control;!error!bars!are!in!SD.! ! ! ! ! ! !!!!!!!!38! ! Figure!6:!Absolute!end!point!error!for!patients!(MS)!and!controls!for!each!hand,!! (lh=left!hand,!rh=right!hand),!in!both!unimanual!and!bimanual!conditions!! under!kinesthetic!control;!error!bars!are!in!SD.! ! ! ! ! !!!!!!!!39! ! Figure!7:!Orthogonal!end!point!error!for!patients!(MS)!and!controls!for!each!hand,!! (lh=left!hand,!rh=right!hand),!in!both!unimanual!and!bimanual!conditions!! under!kinesthetic!control;!error!bars!are!in!SD.! ! ! ! ! !!!!!!!!40! ! Figure!8:!Parallel!end!point!error!for!patients!(MS)!and!controls!for!each!hand,!(lh=left!! hand,!rh=right!hand),!in!both!unimanual!and!bimanual!conditions!under!! kinesthetic!control;!error!bars!are!in!SD.! ! ! ! ! ! !!!!!!!!40! ! ! vii! KEY!TO!ABBREVIATIONS! ! ! ! ADL!–!Activities!of!Daily!Living! ! ANOVA!–!Analysis!of!Variance! ! CC!–!Corpus!Callosum! ! CNS!–!Central!Nervous!System! ! CP!–!Cerebral!Palsy! ! DTI!–!Diffusion!Tensor!Imaging! ! EPE!–!Absolute!End!Point!Error! ! EPort!–!Orthogonal!End!Point!Error! ! EPpar!–!Parallel!End!Point!Error! ! LCD!–!Liquid!Crystal!Display! ! MRI!–!Magnetic!Resonance!Imaging! ! MS!–!Multiple!Sclerosis! ! MT!–!Movement!Time! ! NHPT!–!Nine!Hole!Peg!Test! ! PD!–!Parkinson’s!disease! ! RMSE!–!Root!Mean!Squared!Error! ! ! ! ! ! ! ! ! ! ! viii! CHAPTER'1' Introduction' ! ! Multiple!sclerosis!(MS)!is!an!autoimmune!disorder!of!increasing!prevalence!in!the! United!States!and!Europe!that!includes!inflammation!and!demyelination!of!the!neurons!in! the!central!nervous!system!(CNS)!(Lassmann,!Brück,!&!Lucchinetti,!2007;!Tullman,!2013).! Typically!this!disease!becomes!clinically!apparent!when!there!are!lesions!in!the!brain!or! spinal!cord!visible!by!magnetic!resonance!imaging!(MRI),!but!it!has!recently!been!found!to! include!injury!of!the!normal!appearing!white!matter,!such!as!diffusion!of!the!tissue!that! cannot!be!seen!by!MRI!(Lassmann!et!al.,!2007).! ! Clinical!diagnosis!of!MS!may!be!challenging!as!the!symptoms!can!vary!widely,! including!muscle!weakness,!fatigue,!numbness,!impaired!balance,!and!vertigo!(Lassmann!et! al.,!2007;!Tullman,!2013).!These!symptoms!were!commonly!found!to!be!detrimental!to!a! patient’s!quality!of!life!and!activities!of!daily!living!(ADL)!(Einarsson,!Gottberg,!Fredrikson,! Koch,!&!Holmqvist,!2006).!An!increased!risk!of!falling!in!affected!individuals!has!been!a! noted!concern!and!an!important!topic!of!past!research.!Most!studies!have!focused!on!the! contributing!factors!to!falls,!which!include!proprioception,!kinesthesia,!and!muscle! weakness!(Hoang,!Cameron,!Gandevia,!&!Lord,!2014;!Nilsagård,!Denison,!Gunnarsson,!&! Boström,!2009a;!Prosperini,!Leonardi,!De!Carli,!Mannocchi,!&!Pozzilli,!2010).! Proprioception!is!influential!in!falls,!thus!it!has!mainly!been!studied!in!the!lower!limbs!or! torso!as!it!relates!to!balance,!posture,!and!gait!(Cameron,!Horak,!Herndon,!&!Bourdette,! 2008;!Cattaneo!et!al.,!2014;!Fjeldstad,!Pardo,!Bemben,!&!Bemben,!2011;!Frzovic,!Morris,!&! Vowels,!2000;!Hebert!&!Corboy,!2013;!Huisinga,!St!George,!Spain,!Overs,!&!Horak,!2014;! Rougier!et!al.,!2007;!Thoumie,!2002).! ! 1! ! Proprioception!is!defined!as!the!ability!to!determine!limb!location!in!the!absence!of! vision!based!on!peripherally!and!centrally!based!mechanisms!(Fortier!&!Basset,!2012).! Adequate!balance!requires!proprioception,!and!it!has!been!found!that!functional!reach!is! impaired!before!there!were!any!differences!observed!in!balance!control!of!stance!or!stride! (Frzovic!et!al.,!2000).!This!means!that!there!could!be!more!apparent!proprioceptive! problems!in!the!upper!limb!before!there!are!any!issues!evident!in!balance.!Additionally,! there!were!many!ADLs!that!were!found!to!be!difficult!for!patients!including!the!use!of!the! upper!limbs,!but!there!was!little!research!on!how!the!upper!limbs!are!functionally!affected! by!MS!(Einarsson!et!al.,!2006).!The!nine[hole!peg!test!(NHPT)!is!a!clinical!tool!for!assessing! upper!limb!function!and!has!a!high!level!of!predictability!for!activity!limitations! (Kierkegaard,!Einarsson,!Gottberg,!Koch,!&!Holmqvist,!2012).!It!has!yet!to!be!exhibited! across!various!modalities!how!proprioception!and!kinesthesia!are!utilized!in!the!upper! limb!in!individuals!with!MS.!Differences!in!proprioceptive!abilities!could!be!detected!earlier! in!the!upper!limb!as!there!was!evidence!toward!proprioception!being!more!distinguished! and!accurate!in!the!arm!compared!to!the!leg!(Paschalis!et!al.,!2010)!in!addition!to!its!affect! on!daily!functioning.!It!was!important!to!define!the!level!of!upper!limb!function!and!how!it! was!altered!in!those!with!MS!compared!to!their!healthy!peers.!This!information!could!lead! to!a!greater!understanding!of!the!mechanisms!underlying!proprioception!and!kinesthesia! in!individuals!with!MS,!outside!of!the!coping!mechanisms!and!neural!activity.!This! additional!knowledge!could!inform!us!of!the!possible!rehabilitation!techniques!to! positively!influence!their!quality!of!life!and!ADLs.!! ! Multiple!different!tools!have!been!used!to!assess!upper!limb!impairment!in!MS.!The! NHPT!has!been!one!test!that!has!greatly!benefited!both!rehabilitation!techniques!and! ! 2! research.!It!allows!for!the!assessment!of!movement!efficiency!and!manipulation!techniques.! It!has!shown!that!movements!were!slower,!less!smooth,!less!straight,!and!with!a!decreased! manipulation!ability!in!those!with!MS!compared!to!healthy!controls!(Carpinella,!Cattaneo,! &!Ferrarin,!2014;!Lambercy!et!al.,!2013;!Nociti!et!al.,!2008).!In!addition!to!the!NHPT,!hand! grip!strength!has!also!been!a!common!measure!used!in!many!studies!focusing!on!the!upper! limb!function!in!those!with!MS!(Lamers,!Kelchtermans,!Baert,!&!Feys,!2014).!Grip!strength! was!irregular!in!patients!with!MS!because!they!tended!to!utilize!an!increased!grip!strength! compared!to!their!healthy!peers!and!have!issues!with!coordinating!that!strength!to!the!load! required!(Gorniak,!Plow,!McDaniel,!&!Alberts,!2014;!Krishnan!&!Jaric,!2008;!Krishnan,!de! Freitas,!&!Jaric,!2008;!Marwaha,!Hall,!Knight,!&!Jaric,!2006).!This!unusual!response!was! expected!when!movements!of!the!upper!limb!were!known!to!be!variable!due!to!a!lack!of! sensation!and!decreased!strength,!and!the!individuals!had!a!difficult!time!adapting!to!new! tasks!or!outside!forces,!had!a!decreased!processing!speed,!or!had!less!control!over!their! movements!(Basteris!et!al.,!2011;!Benedict!et!al.,!2011;!Casadio,!Sanguineti,!Morasso,!&! Solaro,!2008;!Guclu[Gunduz,!Citaker,!Nazliel,!&!Irkec,!2012;!Leocani!et!al.,!2007;!Llufriu!et! al.,!2012;!Longstaff!&!Heath,!2006).!! ! Functional!adaptations,!learning!strategies,!and!processing!speed!were!difficulties! faced!while!completing!tasks!that!contribute!to!an!increased!cognitive!effort!during!upper! limb!movements,!especially!in!the!use!of!the!nondominant!arm!(Tacchino!et!al.,!2013).! These!impaired!movements!of!the!upper!limb!were!not!exclusive!to!gross!motor! movements!as!some!fine!motor!movements!and!manipulations!had!the!same!results.!Those! with!MS!showed!impaired!manual!dexterity!with!characteristics!such!as!slower!movement! times,!which!affected!their!ability!to!manipulate!small!objects!or!write!(Schenk,!Walther,!&! ! 3! Mai,!2000;!Scherer,!Bauer,!&!Baum,!1997).!This!impaired!movement!performance!in!the! upper!limb!was!found!to!be!related!to!the!amount!of!axonal!loss!found!in!the!CNS!(Solaro!et! al.,!2007).! ! As!previously!mentioned,!the!number!of!lesions!in!the!CNS!is!not!the!only!factor!that! is!related!to!motor!impairment!in!patients!with!MS,!as!other!neural!tissue!injuries!can!be!a! factor.!The!research!on!upper!limb!function!has!led!to!the!study!of!brain!and!neural! structures!to!determine!how!they!were!associated!with!upper!limb!movement.!There!were! severe!cases!where!the!two!arms!were!disconnected!from!one!another.!Characteristics! included!one!non[responsive!limb,!spontaneous!activity!of!one!arm!when!the!opposite!arm! moved,!or!loss!of!kinesthesia!(Hamada,!Okamoto,!&!Okuda,!2005;!Hashimoto,!Kanho,! Fujimoto,!&!Tanaka,!1997;!Kurne,!Cakmakli,!&!Karabudak,!2008).!These!symptoms!have! been!linked!to!lesions!on!the!posterior!cervical!spinal!cord,!but!were!more!commonly! associated!with!lesions!or!disconnection!of!the!corpus!callosum!(CC)!(Hamada!et!al.,!2005;! Lunardelli,!Sartori,!Mengotti,!Rumiati,!&!Pesavento,!2014;!Moroni,!Belin,!Haguenau,!&! Salama,!2004).!Other!structures!of!the!CNS!have!been!thought!to!play!an!important!role!in! the!control!of!upper!limb!movements!and!are!related!to!the!duration!and!complexity!of!the! task!being!completed,!such!as!the!cerebellum,!motor!insula,!mirror!neurons,!motor!cortex,! and!spinal!cord!(Anderson!et!al.,!2011;!Meyenburg!et!al.,!2013;!Pantano!et!al.,!2011;! Prosperini!et!al.,!2014;!Rocca!et!al.,!2009;!2008;!White,!Lee,!Light,!&!Light,!2009).!The!CC! has!been!a!subject!of!many!studies!in!those!looking!at!function!in!MS!and!was!shown!to! have!a!strong!relationship!to!the!upper!limb!function.!There!was!atrophy!and!a!decreased! volume!of!white!matter!in!the!CC!which!correlated!to!the!level!of!disability!observed!in! those!with!MS!(Audoin!et!al.,!2007;!L.!N.!Brown,!Zhang,!Mitchell,!Zabad,!&!Metz,!2010;! ! 4! Evangelou!et!al.,!2000b;!Sbardella!et!al.,!2013).!More!specifically!than!just!atrophy!and! injury!to!white!matter!in!the!CC,!there!was!an!increased!diffusivity!in!the!CC!that!preceded! atrophy!and!visible!damage!to!the!white!matter!and!was!a!better!marker!for!fine!motor! skills!as!assessed!by!clinical!tests!such!as!the!NHPT!(Kern,!Sarcona,!Montag,!Giesser,!&! Sicotte,!2011;!Lenzi!et!al.,!2007;!Ozturk!et!al.,!2010;!Ranjeva!et!al.,!2003).!When!it!came!to! simultaneous!movement!of!the!two!arms!and!hands,!the!lack!of!coordination!stemmed! from!the!lack!of!interhemispheric!transfer!and!lack!of!transcallosal!inhibition;!there!was! further!evidence!that!the!anterior!part!of!the!CC!was!responsible!for!influencing!the! bimanual!fine!motor!movements!in!the!fingers!(Bonzano!et!al.,!2008;!L.!N.!Brown!et!al.,! 2010;!Lenzi!et!al.,!2007;!Manson!et!al.,!2008;!Pelletier!et!al.,!1993).!! Bimanual!coordination!of!fine!motor!movements!is!important!to!daily!living!and! was!found!to!be!impaired!in!those!with!MS!compared!to!their!healthy!peers!measured!by! the!time!it!took!to!complete!the!task!or!the!length!of!their!reaction!time!(Bonzano!et!al.,! 2013;!Larson,!Burnison,!&!Brown,!2002).!Other!studies!that!focused!on!the!bimanual! coordination!in!patients!with!MS!were!not!entirely!measuring!coordination!of!the! movements.!Rather,!they!were!frequently!measuring!the!coordination!of!grip!and!force! utilized!to!manipulate!an!object!(Gorniak!et!al.,!2014;!Krishnan!et!al.,!2008;!Krishnan!&! Jaric,!2008).!Bimanual!coordination!impairments!were!not!solely!based!on!the!coupling!of! grip!and!load!force,!it!also!included!sensorimotor!control!and!deficits!in!the!case!of!patients! with!MS!(Marwaha!et!al.,!2006).!! These!sensorimotor!deficits!point!back!to!the!lack!of!interhemispheric!transfer!in! the!CC,!and!possibly!proprioception!and!kinesthesia.!Difficulties!in!moving!the!arm!in! patients!with!MS!was!influenced!by!proprioception!and!the!group!I!spindle!afferents! ! 5! because!when!proprioception!was!inhibited,!the!tremors!in!movement!were!decreased! (Quintern!et!al.,!1999).!There!were!few!studies!that!investigated!the!proprioceptive! influences!in!the!fine!motor!skills!of!the!upper!limb!in!those!with!MS.!Those!that!have!done! so!focused!on!the!static!position!sense!in!the!fingers!(Beckmann,!Çiftçi,!&!Ertekin,!2013;! Fukutake,!Kuwabara,!Kaneko,!Kojima,!&!Hattori,!1998).!This!limited!the!scope!of!the! proprioceptive!influence,!as!one!digit!of!the!hand!did!not!provide!adequate!information!on! how!fine!motor!movements!involved!proprioception.!Furthermore,!there!was!evidence!that! kinesthesia!was!more!important!to!movements!of!the!upper!limb.!There!was!a!decreased! accuracy!and!speed!in!those!with!MS!compared!to!healthy!controls!when!they!attempted!to! visualize!the!movements!of!their!hands!(Tabrizi!et!al.,!2013).!It!was!even!more!important! that!the!motions!in!rehabilitation!were!active!rather!than!passive!in!order!to!maintain!their! bimanual!coordination,!which!pointed!to!the!involvement!of!kinesthesia!(Bonzano!et!al.,! 2014).!! Past!research!on!the!upper!limb,!especially!involving!kinesthesia,!in!the!healthy! adult!population!was!not!entirely!comprehensive.!The!available!information!was!predictive! of!what!to!expect!in!those!lacking!complete!coordination!of!their!upper!limbs.!Other!studies! showed!that!bimanual!tasks!were!performed!more!accurately!than!unimanual!(Blinch!et!al.,! 2014;!Gorman!&!Crites,!2013),!and!movement!variability!within!a!given!limb!improved! when!completing!a!bimanual!task!compared!to!being!used!unimanually!(Helmuth!&!Ivry,! 1996).!There!was!even!some!variability!in!the!type!of!bimanual!movements.!Mirror! movements!were!typically!found!to!be!more!accurate!and!synchronous!than!isodirectional! movements!(Cohen,!1971;!Li,!Levin,!Forner[Cordero,!&!Swinnen,!2005),!which!was! explained!by!the!use!of!homologous!rather!than!non[homologous!muscles!in!the!limb.! ! 6! Additionally,!isodirectional!movements!showed!decreased!accuracy!and!multi[joint,! intralimb!coordination!(Li!et!al.,!2005).!Isodirectional!as!well!as!unimanual!movements! also!showed!an!increased!interhemispheric!connectivity!due!to!their!need!for! communication!between!the!two!limbs!or!lack!there!of,!respectively!(Grefkes,!Eickhoff,! Nowak,!Dafotakis,!&!Fink,!2008;!Serrien,!2008).!In!addition,!the!nondominant!limb!was! found!to!be!more!accurate!in!a!unimanual!task!(Han,!Waddington,!Adams,!&!Anson,!2013),! especially!when!utilizing!proprioception!(Goble!&!Brown,!2010).!These!findings!supported! the!notion!that!movements!in!either!arm!had!separate,!specialized,!and!complementary! control!mechanisms!(Mutha,!Haaland,!&!Sainburg,!2013).!When!having!to!rely!on! proprioception!or!kinesthesia,!both!bimanual!and!unimanual!coordination!was!negatively! impacted!–!reaction!and!movement!time!increased!and!accuracy!decreased!(Cardoso!de! Oliveira!&!Barthelemy,!2005;!Gooijers!&!Swinnen,!2014).!However,!it!was!found!that!losing! visual!feedback!from!one!limb!during!a!bimanual!task!is!preferable!when!losing!visual! feedback!on!the!limb!during!a!unimanual!task!because!the!limb!relying!on!kinesthesia!was! more!accurate!when!coupled!with!the!visible,!contralateral!limb!(Kagerer,!2014).!These! findings!shaped!the!present!study.! There!was!little!research!conducted!on!the!dynamic!movement!perceptions!in!the! upper!limb!including!bimanual!coordination!in!patients!with!MS,!it!was!a!goal!of!this!study! to!investigate!the!relationship!between!kinesthesia!and!bimanual!coordination!and!define! how!this!relationship!was!affected!in!those!with!MS!compared!to!the!healthy!population.! The!main!measures!for!kinesthesia!in!this!study!was!end!point!error!(EPE),!its!directional! characteristics,!and!linearity!of!the!movement!trajectory!by!root!mean!squared!error! (RMSE).!The!characterization!of!kinesthesia!in!this!way!with!the!assistance!of!a!visible! ! 7! contralateral!limb!has!not!been!done!in!this!patient!population,!but!would!provide!valuable! insight!into!possible!rehabilitation!techniques,!interhemispheric!communication,!or! integration!of!multisensory!feedback.!The!present!study!maintained!the!hypothesis!that!the! movements!in!those!with!MS!would!be!more!variable!in!their!trajectories,!or!less!linear,! and!less!accurate!compared!to!the!healthy!controls.!When!visual!feedback!for!the!trajectory! of!movement!was!taken!away,!the!movements!of!MS!patients!would!be!less!linear!and!less! accurate!than!when!visual!feedback!was!available!in!both!the!unimanual!and!mixed! bimanual!conditions.!This!would!also!be!true!when!compared!to!healthy!controls.!It!was! also!hypothesized!that!when!visual!feedback!was!taken!away!for!the!trajectory!of! movement!for!one!hand,!that!it!would!still!be!functionally!accurate!with!the!assistance!of! the!simultaneous!movement!of!the!opposite!hand!when!compared!to!unimanual!use,!but! that!it!would!be!less!accurate!in!MS!patients!than!when!compared!to!their!healthy!controls.! This!expected!result!was!important!because!it!could!be!useful!for!rehabilitation!or!ADLs.! However,!if!the!kinesthetic!movement!aided!by!a!contralateral!visual!movement!was!not! improved!in!MS!patients,!then!it!could!be!concluded!that!MS!patients!had!a!more!severe! inhibition!of!kinesthesia!compared!to!the!healthy!population.!It!was!expected!that!the! nondominant!arm!would!be!more!accurate!than!the!dominant!one!in!the!kinesthetic! condition!across!all!participants.! ! 8! CHAPTER'2' Literature'Review' ! ! In!order!to!understand!how!movements!of!the!upper!limb!and!kinesthesia!are! affected!in!patients!with!MS,!normal!movements!in!the!healthy!population!had!to!be! assessed.!Understanding!the!unimanual!and!bimanual!performances!of!the!healthy! population!would!help!to!see!any!abnormalities!in!the!MS!population.!Studying!the! characteristics!of!the!disease,!the!influence!on!the!patient’s!activities!of!daily!living,!and! identifying!the!areas!of!the!brain!most!affected!would!assist!in!understanding!MS!and!how! their!movements!and!kinesthetic!ability!would!be!affected.!Proprioceptive!ability!in! patients!with!MS!has!been!looked!at!and!provided!insight!as!to!how!kinesthetic!ability! would!be!similarly!affected.!The!clinical!tests!assessing!upper!limb!movement!and!other! research!on!other!areas!of!upper!limb!ability!showed!that!there!were!deficits!in!MS! patients,!and!these!findings!helped!to!characterize!dysfunction!in!MS!but!also!identified!the! gaps!in!research.! ! Upper!limb!performance!in!the!healthy!population,!specifically!on!unimanual!tasks,! showed!that!connections!to!the!contralateral!primary!motor!cortex!caused!activation!while! the!ipsilateral!motor!areas!were!simultaneously!inhibited!(Grefkes!et!al.,!2008).!With! reference!to!proprioception,!there!have!been!similar!results!from!various!methods.!After! task!performance!from!passive!movements,!angle!matching!tasks!and!pointing!to!visual! targets!revealed!that!the!nondominant!arm!had!fewer!errors!in!the!angle!matching!task,! but!the!dominant!arm!had!fewer!errors!in!the!visual!pointing!task!(Goble!&!Brown,!2008).! The!nondominant!arm!showed!an!advantage!in!static!proprioceptive!position!matching! conditions!from!another!study,!but!it!also!showed!a!larger!movement!amplitude!(Goble,! ! 9! Lewis,!&!Brown,!2006).!This!same!finding!was!also!seen!in!a!dynamic!position!sense!task! when!the!previously!passively!set!angle!had!to!be!determined!during!continuous!passive! movement!(Goble!&!Brown,!2010).! Bimanual!movements!in!healthy!people!also!showed!activation!in!the!primary!and! sensory!motor!areas,!but!it!also!revealed!an!increased!interhemispheric!connectivity! (Grefkes!et!al.,!2008).!Bimanual!movements!were!found!to!be!more!accurate!when! compared!to!unimanual!movements!with!reference!to!movement!velocity!and!movement! variability,!which!was!explained!to!be!from!transitioning!from!a!simple!to!a!more!complex! task!(Gorman!&!Crites,!2013).!This!result!was!also!found!when!measuring!proprioception! with!active!bimanual!movements,!and!the!non!dominant!hand!was!only!found!to!be! advantageous!in!the!unimanual!condition!(Han!et!al.,!2013).!The!decrease!in!movement! variability!within!a!specific!hand!from!unimanual!to!bimanual!movements!was!due!to! coupling!because!there!were!timing!mechanisms!integrated!prior!to!the!execution!of!the! movement!(Helmuth!&!Ivry,!1996).!This!temporal!and!spatial!coupling!was!unchanged!with! tasks!that!required!moving!a!cursor!on!a!screen!with!or!without!visual!feedback,!and!the! reaction!times!and!movement!amplitudes!were!increased!in!the!conditions!without!visual! feedback!(Cardoso!de!Oliveira!&!Barthelemy,!2005).!However,!there!were!contrasting! results.!Another!study!found!that!bimanual!coordination!was!worse!without!visual! feedback!but!that!movements!were!more!accurate!in!the!dominant!hand!only!when!both! hands!moved!at!the!same!temporal!frequency,!which!directly!correlated!to!the!amount!of! the!white!matter!in!the!CC!(Gooijers!et!al.,!2013).!This!was!further!characterized!by!the! findings!that!only!the!spatial!aspects!of!the!grasp!and!not!the!reaching!movement!was! affected!by!the!amount!of!visual!feedback!(Bruyn!&!Mason,!2009).!In!addition,!movements! ! 10! of!only!one!hand!without!visual!feedback!under!bimanual!conditions!were!more!accurate! when!paired!with!the!contralateral!hand!movements!that!were!under!visual!conditions! compared!to!the!unimanual!movements!(Kagerer,!2014).!There!were!differences!in!how! the!hands!responded!to!bimanual!movements.!The!dominant!hand!was!found!to!be!able!to! move!more!accurately!for!a!longer!period!of!time!that!the!nondominant!hand!without! visual!feedback.!Although!the!dominant!hand!had!a!smoother!trajectory,!it!needed!vision! for!end!point!accuracy!whereas!the!nondominant!hand!did!not!(Srinivasan!&!Martin,!2010).! In!a!directed!reaching!task!where!the!starting!positions!were!shifted!with!reference!to!the! targets!after!some!time,!the!dominant!arm!adapted!and!maintained!an!accurate!trajectory! but!the!nondominant!arm!deviated!back!to!the!previously!learned!trajectory,!which! revealed!that!the!dominant!arm!relied!on!predictive!mechanisms!while!the!nondominant! arm!relied!on!positional!stability!(Mutha!et!al.,!2013).! ! The!direction!of!movement!also!seemed!to!play!a!role!in!how!bimanual!coordination! is!modulated.!There!was!a!significant!difference!between!bimanual!performance!in! isodirectional!and!anisodirectional!movements.!There!was!a!tendency!to!conform!to! anisodirectional!movements!rather!than!isodirectional.!The!switching!from!isodirectional! movements!to!anisodirectional!was!not!due!to!the!preferred!use!of!homologous!muscles! but!was!because!of!spatial!and!perceptual!symmetry!and!coupling!(Mechsner,!Kerzel,! Knoblich,!&!Prinz,!2001).'There!was!found!to!be!a!cost!of!isodirectional!movements! compared!to!anisodirectional!because!it!required!more!complex!preparation!and!was!due! to!the!result!of!interference!of!interhemispheric!connectivity!(Blinch!et!al.,!2014).!There! was!increased!hemispheric!connectivity!found!for!isodirectional!and!unimanual! movements,!which!suggested!that!brain!regions!were!flexible!in!coupling!and!decoupling!to! ! 11! implement!processing!requirements!for!coordination!(Serrien,!2008).!The!costs!of! isodirectional!movements!caused!them!to!be!more!variable!and!less!synchronous! compared!to!anisodirectional!movements,!which!supported!the!existence!of!a!coupling! mechanism!for!anisodirectional!movements!(Cohen,!1971).!Contrastingly,!anisodirectional! movements!were!more!coordinated!and!stable,!and!isodirectional!coordination!had!a! negative!influence!on!the!accuracy!and!stability!of!intralimb!coordination!as!well!as! interlimb!coordination!(Li!et!al.,!2005).!! These!patterns!were!also!seen!in!continuous!movements!rather!than!just!discrete! reaching!movements.!When!isodirectional!and!anisodirectional!circle!drawing!was! performed!with!differing!temporal!patterns,!the!dominant!arm!was!more!accurate!in!its! trajectory,!but!it!reversed!movement!from!isodirectional!to!anisodirectional!(Byblow,! Summers,!Semjen,!Wuyts,!&!Carson,!1999).!This!bimanual!continuous!circle!drawing!was! also!performed!while!blindfolded.!When!vibration!was!applied!to!the!tendons!to!inhibit!any! proprioceptive!feedback,!the!circles!lost!their!shape,!became!smaller,!and!caused!drifting!of! the!hands!(Verschueren,!Swinnen,!Cordo,!&!Dounskaia,!1999a).!In!addition,!the!dominant! hand!increased!its!temporal!lead!over!the!nondominant!hand!(Verschueren,!Swinnen,!&! Cordo,!1999b).!This!showed!that!proprioceptive!feedback!was!necessary!to!movements! that!were!performed!without!visual!feedback.! Patients!with!multiple!sclerosis!suffer!from!many!motor!deficits,!but!those!of!the! upper!limb!had!not!been!characterized!in!their!entirety.!MS!is!a!disease!that!affects!much! more!than!the!motor!system.!It!is!primarily!an!autoimmune,!inflammatory,!and! demyelinating!disease!that!includes!lesions!and!injury!to!the!normal!appearing!white! matter,!and!it!can!have!different!manifestations!of!the!disease!such!as!relapsing[remitting! ! 12! and!progressive!(Lassmann!et!al.,!2007).!It!is!increasing!in!prevalence,!due!to! environmental!and!genetic!factors,!and!has!highly!variable!symptoms,!which!could!lead!to! disability!due!to!incomplete!recovery!from!attacks!(Tullman,!2013).!Disability!includes!a! variety!of!daily!activities!and!safety!precautions!that!must!be!taken!to!prevent!further! injury.!It!was!found!that!the!patients’!social!activities!were!maintained!but!independence! was!decreased!by!difficulty!with!daily!activities!such!as!dressing,!household!maintenance! and!cleaning,!gardening,!and!transportation!(Einarsson!et!al.,!2006).!Falling!in!MS!patients,! leading!to!physical!injury,!is!common!due!to!their!disabilities.!Potential!factors!that!lead!to! falls!were!found!to!be!decreased!attention,!fatigue,!impaired!proprioception,!and!limited! vision,!and!some!risk!activities!included!bathing,!housekeeping,!and!cooking!(Nilsagård!et! al.,!2009a).!Frequent!occurrences!of!falling!were!identified!by!increased!postural!sway! without!visual!feedback,!decreased!coordination,!and!poor!performance!on!the!NHPT! (Hoang!et!al.,!2014).!Discerning!factors!between!those!with!frequent!and!occasional!falls! were!disability!status!and!proprioception,!but!the!proprioceptive!measurement!was!only! performed!in!the!lower!limb!(Nilsagård,!Lundholm,!Denison,!&!Gunnarsson,!2009b).!It!was! found!that!the!risk!for!falling!could!be!decreased.!Visio[proprioceptive!training!increased! balance!and!decreased!the!risk!of!falls,!which!implied!that!patients!with!MS!relied!on!vision! for!balance!and!had!decreased!proprioception!(Prosperini!et!al.,!2010).!! MS!stems!from!the!demyelination!of!white!matter!in!the!CNS!and!is!thought!to!be! the!reason!for!some!of!its!symptoms.!Some!of!these!injured!areas!have!been!identified!with! reference!to!affecting!the!upper!limbs.!Diffusion!tensor!imaging!(DTI)!was!used!to!find! asymmetrical!structural!abnormalities!that!affected!the!conduction!time!from!the!motor! areas!to!the!muscle,!which!were!correlated!with!anatomical!changes!in!the!spinal!cord!and! ! 13! normal!appearing!white!matter!(Meyenburg!et!al.,!2013).!More!specifically!the! transcallosal!hand!motor!fibers!in!the!corticospinal!tracts!of!MS!patients!showed!an! association!with!upper!limb!functionality!assessed!by!the!NHPT!where!radial!diffusivity!of! these!fibers!was!especially!predictive!(Kern!et!al.,!2011).!Movement!deficits!have!been! correlated!most!often!to!the!damaged!brain!structures.!Some!major!differences!were!found! between!the!MS!patients!and!healthy!controls!with!regard!to!white!and!gray!matter! damage.!Gray!matter!atrophy!and!white!matter!damage!were!correlated!with!clinical! assessments!of!disability!status!and!functional!impairment!as!measured!by!the!NHPT! (Sbardella!et!al.,!2013).!Postural!instability!was!also!associated!with!atrophy!of!both!white! and!gray!matter.!This!postural!instability!was!thought!to!be!due!to!a!disconnection! between!the!spinal!cord,!cerebellum,!and!cerebral!cortex!(Prosperini!et!al.,!2013).! Furthermore,!the!atrophy!of!the!cerebellum!and!spinal!cord!was!found!to!be!most!related! to!balance!deficits!measured!by!the!center!of!pressure!while!standing!with!or!without! visual!feedback!(Prosperini!et!al.,!2014).!The!cerebellum!is!associated!with!balance,!but! also!plays!a!role!in!upper!limb!function.!DTI!measurements!have!identified!decreased!white! matter!in!the!cerebellum!of!MS!patients!compared!to!healthy!controls!and!found!it!was! significantly!related!to!a!decreased!upper!limb!function!(Anderson!et!al.,!2011).!Functional! MRI!(fMRI)!was!utilized!during!hand!movements!and!revealed!that!there!was!a!reduced! deactivation!or!inhibition!in!the!ipsilateral!pre!and!post[central!gyri!in!MS!patients,! specifically!those!with!relapsing[remitting,!compared!to!healthy!controls!(Manson!et!al.,! 2008;!Pantano!et!al.,!2011).!In!addition,!fMRI!during!fine!upper!limb!movements!showed! more!activation!of!the!contralateral!primary!and!supplementary!sensorimotor!areas,! specifically!that!of!the!inferior!frontal!gyrus!(Rocca!et!al.,!2008).!However,!these! ! 14! correlations!were!moderated!by!other!factors!such!as!fatigue.!Before!being!fatigued,!MS! patients!showed!a!greater!activation!of!the!contralateral!primary!motor!area,!insula,!and! cingulate!gyrus!compared!to!healthy!controls,!which!showed!an!adaptive!change!to!the! demyelination!(White!et!al.,!2009).!Contrastingly,!fMRI!found!that!movement!complexity! and!rate!affect!what!areas!of!the!brain!were!utilized!independent!of!the!level!of!fatigue! (Rocca!et!al.,!2009).! In!addition!to!these!areas,!the!CC!stood!out!as!a!key!component!to!upper!limb! function!and!bimanual!coordination.!It!was!known!to!have!both!inhibitory!and!excitatory! influences!on!the!motor!areas!of!the!brain!(Gooijers!&!Swinnen,!2014).!The!CC!was!found!to! be!an!important!area!of!the!brain!to!assist!in!the!characterization!of!disability.!MS!patients! showed!increased!diffusivity!of!the!CC!at!the!earliest!stage!of!the!disease,!before!any! atrophy!of!the!CC!was!observed!by!MRI!(Ranjeva!et!al.,!2003).!In!addition,!MRI!measured! atrophy!of!the!CC!after!an!attack!and!found!that!it!occurred!within!a!year!of!the! inflammatory!episode!and!was!correlated!to!the!change!in!disability!status!(Audoin!et!al.,! 2007).!A!significant!loss!in!the!number!of!axons!crossing!the!CC!in!MS!patients!was! correlated!with!axon!density!and!lesion!load!(Evangelou!et!al.,!2000b).!A!postmortem! investigation!of!the!CC!of!MS!patients!showed!that!the!number!of!axons,!in!both!density!and! area,!in!the!white!matter!of!the!CC!were!decreased!compared!to!healthy!controls! (Evangelou,!Esiri,!Smith,!Palace,!&!Matthews,!2000a).!The!CC!also!showed!some! connections!to!other!brain!areas.!MRI!and!DTI!showed!a!correlation!between!the!amount!of! diffusivity!and!the!ipsilateral!motor!cortex,!and!the!latency!and!duration!of!the! transcallosal!inhibition!were!altered!in!MS!patients!(Lenzi!et!al.,!2007).!Abnormalities!in! the!CC!were!associated!with!upper!limb!dysfunction.!As!measured!by!the!NHPT,!upper!limb! ! 15! function!correlated!with!diffusivity!but!not!with!lesion!load!or!white!matter!volume!of!the! CC!(Ozturk!et!al.,!2010).!On!the!other!hand,!the!white!matter!in!the!CC!was!preserved!after! active!rehabilitation!of!the!upper!limb!compared!to!passive!(Bonzano!et!al.,!2014).!Other! fine!motor!movements!such!as!an!alternate!finger[tapping!test!showed!a!relationship!to!the! CC!as!measured!by!MRI.!The!interhemispheric!transfer!and!integration!were!impaired!in! MS!patients!in!proportion!to!their!callosal!atrophy!and!white!matter!lesions!(Pelletier!et!al.,! 1993).!These!upper!limb!movements!were!not!limited!to!correlations!with!CC!activation,! but!also!with!structural!damage.!This!damage!was!also!related!to!the!bimanual! coordination!of!these!movements.!A!significant!difference!in!performance!and!the!accuracy! of!timing!of!bimanual!coordination!was!found!in!MS!patients!compared!to!healthy!controls! and!was!contributed!to!micro!tissue!damage!of!the!CC!as!measured!by!DTI!(Bonzano!et!al.,! 2008).!Overall!CC!volume!also!related!to!the!threshold!at!which!the!MS!patients!believed! their!bimanual!movements!were!simultaneous.!It!was!found!to!be!negatively!correlated!to! the!threshold!in!MS!patients!and!significantly!different!from!healthy!controls!(L.!N.!Brown! et!al.,!2010).!The!literature!provided!a!large!amount!of!evidence!showing!that!the!CC!is! important!to!upper!limb!function.! Proprioception!has!also!been!found!as!an!important!characteristic!in!MS.!It!has!been! studied!in!various!areas!of!the!body.!Proprioception!is!defined!as!the!sense!of!knowing! where!the!limbs!are!in!space!at!any!given!point!by!peripheral!and!central!signals.! Proprioception!is!position!sense!and!kinesthesia!is!the!position!sense!during!a!movement! (Fortier!&!Basset,!2012).!Proprioception!has!predominantly!been!studied!in!the!lower! limbs!and!torso,!as!it!was!important!to!balance!and!gait.!Proprioceptive!sensory!loss,!as! measured!by!leg!position,!was!found!to!relate!to!impaired!balance,!gait,!and!muscle! ! 16! strength!in!MS!patients!compared!to!healthy!controls!(Thoumie,!2002).!Proprioception!was! also!measured!in!fine!motor!movements!of!the!lower!limb.!Static!position!sense!of!the!big! toe!after!passive!movement!was!found!to!be!more!influential!to!sensory!evoked!potentials! compared!to!a!tactile!stimulus!(Fukutake!et!al.,!1998).!As!proprioception!was!so!important! to!sensory!information!of!the!lower!limb,!even!in!fine!motor!movements,!it!was!important! to!sensory!integration!of!gait.!Sensory!integration!is!affected!by!fatigue!and!balance! measures.!Fatigue!and!balance!were!associated,!and!there!were!differences!seen!in!those! measures!between!those!that!have!cerebellar!and!brainstem!involvement,!and!those!who! do!not!(Hebert!&!Corboy,!2013).'Patients!with!MS!that!had!slower!walking!speeds!also!had! delayed!postural!responses!compared!to!healthy!controls,!which!was!also!associated!with! increased!motion!of!the!trunk!during!walking!(Huisinga!et!al.,!2014).!The!torso!is!important! to!balance,!which!was!another!area!of!dysfunction!identified!for!MS!patients.!Greater! postural!instability!was!found!in!MS!patients!compared!to!healthy'controls,!no!matter!what! severity!level!their!disability.!Balance!was!impaired!in!all!MS!patients!(Fjeldstad!et!al.,! 2011).'Patients!with!MS!showed!larger!scaled!postural!responses!with!longer!delays! compared!to!healthy!individuals.!Slowed!spinal!somatosensory!conduction,!specifically! afferent!proprioceptive!conduction!was!found!to!be!the!cause!rather!than!cerebellar! dysfunction!(Cameron!et!al.,!2008).'However,!no!differences!were!found!during!quiet! standing!in!various!positions!between!MS!patients!and!healthy!controls!(Frzovic!et!al.,! 2000).'Proprioception!functioned!as!the!perceptions!of!position!and!movement!after! certain!tasks.!After!tasks!of!the!trunk!or!lower!limb,!MS!patients!were!found!to!have!worse! balance!in!quiet!standing!and!following!activity!compared!to!healthy!controls!(Cattaneo!et! al.,!2014).'Typically,!proprioceptive!impairment!was!measured!by!center!of!pressure!while! ! 17! standing!with!eyes!open!or!closed.!It!was!found!that!MS!patients!use!other!strategies!to! make!up!for!the!impairment!(Rougier!et!al.,!2007).!Research!has!shown!that!there!were! proprioceptive!deficits!in!MS!patients!regarding!balance,!gait,!and!the!torso!or!lower!limbs.!! Less!research!has!been!done!on!proprioceptive!ability!of!the!upper!limb,!because!it! has!not!been!linked!to!risks!such!as!falls.!However,!it!was!found!that!functional!reach!was! impaired!in!MS!patients!compared!to!controls,!which!meant!that!proprioceptive!issues!may! be!evident!in!the!upper!limb!before!the!lower!limbs!or!balance!(Frzovic!et!al.,!2000).!This! was!characterized!by!separating!movements!of!the!joints!in!the!upper!limb.!When!the!digits! of!the!hand!were!used,!movements!combining!two!joints!were!utilized!as!well!as! movements!around!a!single!joint.!There!was!no!difference!when!using!the!position!sense!of! digits!using!single!joints,!but!differences!were!found!in!dual!joint!position!sense!of!the!right! hand!digits!but!not!the!left!(Beckmann!et!al.,!2013),!implying!that!multiple!joints!are!useful! to!proprioception.!When!proprioception!was!inhibited!and!visual!feedback!was!taken!away! during!pointing!tasks,!the!MS!patients!had!more!variation!in!movement!path!and!larger! movement!angles!in!the!wrist!compared!to!healthy!controls!(Quintern!et!al.,!1999).!MS! patients!had!difficulty!with!sensing!proprioceptive!movements!as!well!as!discerning!hand! positions.!Their!accuracy!and!response!times!were!worse!when!determining!how!to! position!their!hands!in!various!orientations!(Tabrizi!et!al.,!2013).!However,!research!shows! that!proprioceptive!rehabilitation!could!be!effective!in!MS!patients.!Bimanual!function!was! maintained!after!active!rehabilitation!and!was!worse!after!passive!rehabilitation,!but!there! were!no!differences!seen!in!unimanual!performance!(Gooijers!&!Swinnen,!2014).!! As!rehabilitative!efforts!were!found!to!be!successful!and!deficits!were!found!in!the! upper!limb,!it!would!appear!to!be!an!effective!area!for!characterizing!fine!motor! ! 18! movements!in!MS.!Arms!are!more!accustomed!to!finer!movements.!Specifically,!the!elbow! was!found!to!be!more!accurate!in!determining!position!than!the!knee!due!to!the!higher! number!of!muscle!spindles!and!lower!innervation!ratios!(Paschalis!et!al.,!2010).!The!NHPT! is!the!most!utilized!clinical!tool!for!assessing!upper!limb!function!in!MS.!It!was!predictive!of! physical!and!social!participation!limitations!(Kierkegaard!et!al.,!2012).'The!time!to! complete!the!NHPT!alone!did!not!characterize!impairment.!When!accelerometers!were! used!during!the!NHPT,!it!was!found!that!MS!patients!had!trouble!with!the!manipulation,! transportation,!and!release!of!objects!and!reaching.!There!was!also!a!decreased!velocity! and!smoothness!that!differed!between!the!levels!of!impairment!(Carpinella!et!al.,!2014).! Another!study!found!similar!results.!Movements!were!found!to!be!slower,!less!straight,!and! more!variable!along!the!trajectory!due!to!a!tremor!compared!to!healthy!controls! (Lambercy!et!al.,!2013).!The!amount!of!time!it!took!to!complete!the!NHPT!was!correlated! with!nervous!system!activation.!MS!patients!with!abnormal!somatosensory!evoked! potentials!took!longer!to!complete!the!NHPT.!In!particular,!the!median!nerve! somatosensory!evoked!potentials!correlated!with!the!upper!limb!performance!measures! (Nociti!et!al.,!2008).! Most!research!investigating!the!fine!motor!movements!of!the!upper!limb!focused!on! grip!and!load!performance!as!well!as!the!coordination!of!these!two!things.!Hand!grip! strength!was!used!frequently!with!the!NHPT!because!the!NHPT!alone!was!not!sufficient!to! describe!upper!limb!performance!(Lamers!et!al.,!2014).!MS!patients!had!a!tendency!to! overgrip!compared!to!healthy!controls.!This!was!found!during!both!static!and!dynamic! tasks!performed!under!unimanual!and!bimanual!conditions!with!or!without!feedback! (Krishnan!et!al.,!2008;!Krishnan!&!Jaric,!2008).!These!findings!were!important!because!they! ! 19! affect!daily!activities!such!as!opening!or!closing!a!jar.!With!a!task!like!this,!MS!patients! showed!an!increased!grip!force!and!a!decrease!in!kinetic!timing!compared!to!healthy! controls!(Gorniak!et!al.,!2014).!In!contrast,!MS!patients!had!trouble!producing!the! necessary!load!forces!required!by!a!task.!This!impaired!ability!to!produce!the!load!forces! necessary!to!complete!a!task!was!not!affected!by!the!conditions!of!the!task!whether!it!was! unimanual!or!bimanual,!with!or!without!visual!feedback!(Krishnan!et!al.,!2008;!Krishnan!&! Jaric,!2008).!This!result!was!not!consistent!across!studies.!When!static!tasks!were! performed!with!visual!feedback!or!feedforward!mechanisms,!MS!patients!had!worse!load! force!production!compared!to!healthy!controls!under!visual!feedback!but!not!when!they! relied!on!feedforward!mechanisms!(Marwaha!et!al.,!2006).!MS!patients!showed!deficits!in! producing!both!grip!and!load!forces.! Most!daily!activities!combine!these!two!forces.!Further!research!studied!the! coordination!effects!of!grip!and!load!forces.!Abnormal!grip[load!force!coupling!was!seen!in! unimanual!conditions,!but!coordination!was!worse!in!the!bimanual!condition!and!finer! manipulations!were!more!difficult!(Gorniak!et!al.,!2014).!The!MS!patients!showed!an! inability!to!couple!the!grip!and!load!forces!characterized!by!an!unusual!grip/load!ratio,! which!meant!that!the!MS!patients!were!lacking!the!coordination!(Krishnan!&!Jaric,!2008).! The!combination!of!overgripping!and!a!lack!of!load!force!caused!a!higher!grip!to!load!ratio.! The!sensorimotor!impairments!and!overgripping!were!found!to!precede!the!decoupling!of! grip!and!load!force!coordination!(Krishnan!et!al.,!2008;!Marwaha!et!al.,!2006).!MS!patients! lacked!the!ability!of!coordination,!both!of!forces!within!a!limb!as!well!as!coordinating!those! movements!bimanually.! ! 20! A!variety!of!unimanual!tasks!have!been!used!to!determine!the!characteristics!and! deficits!of!upper!limb!function!in!patients!with!MS.!When!TMS!was!used!to!produce! movement,!the'silent!period!of!movement!in!the!ipsilateral!upper!limb!was!correlated!with! disability!status!in!MS!patients,!which!was!due!to!the!abnormalities!of!the!CC!found!by!MRI! and!DTI!(Llufriu!et!al.,!2012).!Other!tasks!drew!out!deficits!that!were!related!to!the!CC.!An! alternate!finger!tapping!test!showed!that!MS!patients!were!significantly!slower!than! healthy!controls,!and!was!thought!to!be!related!to!the!CC!(Scherer!et!al.,!1997).!More!gross! movements!of!the!upper!limb!also!showed!a!relationship!to!tissue!damage.!A!reaching! movement!from!the!center!of!the!body!outwards!with!and!without!visual!feedback!was! recorded!on!a!digitizing!tablet!and!compared!to!MRI,!which!revealed!that!the!motor! performance!was!related!to!lesion!load!(Solaro!et!al.,!2007).!This!type!of!movement!also! revealed!other!cognitive!limitations.!A!motor!tracking!task!performed!with!the!dominant! arm!showed!that!MS!patients!were!slower!than!healthy!controls!and!also!performed!worse! on!those!tasks!that!required!more!depth!perception,!which!implies!that!there!is!impaired! motor!learning,!and!that!sensory!and!cognitive!limitations!need!to!be!taken!into!account!for! upper!limb!movements!(Leocani!et!al.,!2007).'A!few!studies!looked!at!unimanual! performance!with!reference!to!daily!activities.!Hand!writing!and!drawing!were!found!to!be! impaired.!MS!patients!used!the!open[loop!method!of!writing,!which!did!not!require! proprioceptive!feedback.!They!were!incapable!of!using!closed[loop!handwriting!like!the! healthy!controls!(Schenk!et!al.,!2000).!With!the!use!of!spiral!drawing,!the!MS!patients!drew! slower!and!with!less!pressure,!more!variability,!and!at!a!smaller!scale!than!controls.!They! used!adaptive!strategies!to!reduce!movement!variability!(Longstaff!&!Heath,!2006).! Unimanual!performance!in!MS!patients!had!been!studied!more!extensively!than!under! ! 21! bimanual!conditions.!Fine!motor!tasks!such!as!moving!finger!to!thumb!was!impaired!in!MS! patients!compared!to!controls,!especially!with!bimanual!coordination!(Bonzano!et!al.,! 2013).!During!completion!of!a!gross!movement!task,!the!MS!patients!were!slower!on!the! bimanual!coordination!test,!as!well!as!in!the!unimanual!condition,!compared!to!healthy! controls.!The!difference!in!response!time!between!the!unimanual!and!bimanual!conditions! was!larger!for!patients!than!controls.!Specifically,!it!was!found!to!be!contributed!to!those! with!abnormal!evoked!potentials!of!the!CC!transmission!(Larson!et!al.,!2002).!There!were! significant!impairments!in!both!unimanual!and!bimanual!task!performance!in!MS!patients! compared!to!healthy!controls,!but!they!seemed!to!improve!from!unimanual!to!bimanual.! Adaptive!mechanisms!were!utilized!to!account!for!these!impairments.!MS!patients! were!able!to!improve!performance!on!a!resistance!force!task!between!and!within!sessions! (Basteris!et!al.,!2011).!The!same!was!true!for!reaching!movements!with!and!without! applied!forces.!When!making!reaching!movements!with!either!no!force!or!a!changing!force! field,!MS!patients!initially!showed!more!variability!in!their!movements.!Adjustments!were! later!made!based!on!sensory!feedback,!but!the!rate!of!adaptation!to!the!changing!force!field! was!the!same!between!patients!and!controls!(Casadio!et!al.,!2008).!Adaptations!and! improvement!were!possible!for!MS!patients!just!as!with!the!healthy!population.! These!adaptations!to!performance!seemed!to!be!moderated!by!other!factors.!Upper! limb!function!as!measured!by!the!NHPT!in!MS!patients!was!predicted!by!cognitive!function,! specifically!their!processing!speed!(Benedict!et!al.,!2011).!A!similar!task!of!pointing!arm! movements!as!measured!by!an!optoelectronic!device!showed!another!aspect!of!cognitive! input.!This!task!showed!that!MS!patients!had!longer!actual!movement!duration!than!when! utilizing!mental!imagery!compared!to!healthy!controls,!and!that!mental!prediction!was!not! ! 22! preserved!in!MS!patients!because!they!needed!an!increased!cognitive!effort!for! nondominant!movements!(Tacchino!et!al.,!2013).!In!a!more!general!sense,!upper!limb! strength,!function!and!sensation!were!worse!in!MS!patients!than!controls.!In!this!case,! sensation,!proprioception,!and!strength!were!factors!in!upper!limb!functional!ability! (Guclu[Gunduz!et!al.,!2012).! ! In!addition!to!these!measurements!previously!taken!from!the!MS!population,!there! were!findings!from!research!on!similar!neurological!conditions!that!lent!insight!into!what! expectations!were!for!this!study.!Patients!with!Parkinson’s!disease!(PD)!showed!similar! movement!characteristics!to!those!of!the!MS!patients.!PD!patients!had!slower!movements! with!alternating!acceleration!and!deceleration,!slower!reaction!times,!and!were!less! accurate!than!healthy!controls!when!they!reached!for!a!target!without!utilizing!visual! feedback!(Flash,!Inzelberg,!Schechtman,!&!Korczyn,!1992).'Specifically,!these!patients!were! slower!when!making!isotonic!movements!and!had!lower!peak!velocities.!When!performing! bimanual!movements,!the!movement!time!increased!and!the!peak!velocities!decreased.! This!showed!that!PD!patients!dissociated!the!two!limbs!(Lazarus!&!Stelmach,!1992).!This! bimanual!dysfunction!and!disassociation!was!similar!to!that!found!in!MS!patients!due!to! the!damage!in!the!CC.!Similar!dysfunction!was!observed!in!those!with!cerebral!palsy!(CP),! and!they!also!utilized!similar!adaptive!techniques!compared!to!the!MS!population.!Upper! limb!movements!in!hemiplegic!CP!were!longer!due!to!slower!movement!speed!and!were! less!straight!compared!to!healthy!controls.!Movement!of!the!torso!was!used!to!compensate! for!the!upper!limb!(Jaspers,!Desloovere,!Bruyninckx,!&!Molenaers,!2009).!These!findings! were!consistent!across!all!ages.!Children!with!hemiplegic!CP!had!slower!movements!than! healthy!controls!and!used!trunk!movement!to!compensate!for!the!upper!limb.!3D! ! 23! kinematics!showed!deficits!in!timing,!range!of!motion,!and!adaptive!movement!strategies.! Bilateral!movement!did!not!change!the!outcome!measures!(Mackey,!Walt,!&!Stott,!2006).! Those!with!hemiplegic!CP!showed!unimanual!movement!deficits,!but!the!bimanual!did!not! seem!to!be!beneficial.!Bilateral!movements!were!found!to!be!temporally!and!spatially! coupled!due!to!the!unaffected!limb!making!alterations.!Sequential!bilateral!movements! improved!movement!times!in!both!limbs!(Langan,!Doyle,!Hurvitz,!&!Brown,!2010).! Movement!of!the!upper!limbs!in!this!patient!population!revealed!other!correlations!that! were!important!to!be!aware!of.!Assessment!of!handwriting,!cognitive!function,!visual! perception,!and!kinesthesia!of!children!with!hemiplegic!CP!and!their!healthy!peers! revealed!correlations!between!handwriting!skills!with!upper!limb!movement!speed,! proprioception,!bimanual!coordination,!and!visual!perception!of!the!unaffected!limb! (Bumin!&!Kavak,!2010).! ! In!order!to!address!the!issue!of!whether!MS!patients!suffered!from!disinhibition!and! lack!of!interhemisherpic!communication!through!the!CC,!it!was!informative!to!look!at!how! movements!of!callosotomy!patients!compared.!Bimanual!coordination!was!specifically! important!here!because!the!posterior!part!of!the!CC!was!found!to!be!involved.!Split[brain! patients!did!not!show!a!decrease!in!temporal!coupling!of!bilateral!movements.!Instead,!the! spinal!cord!was!found!to!be!important!to!temporal!coupling!(Tuller!&!Kelso,!1989).! However,!the!temporal!coupling!was!not!maintained!over!the!whole!movement!time.! Callosotomy!patients!maintained!temporal!and!spatial!coupling,!but!the!normal!subjects! only!maintained!temporal!coupling!at!the!movement!onset.!This!showed!that!spatial! interference!relied!on!the!CC!while!temporal!coupling!did!not!(Franz,!Eliassen,!Ivry,!&! Gazzaniga,!1996).!Whether!or!not!this!temporal!coupling!was!maintained!also!depended!on! ! 24! the!nature!of!the!movement.!Temporal!coupling!was!maintained!for!discrete!movements,! but!was!lacking!in!callosotomy!patients!during!continuous!movements.!This!showed!that! synchronization!of!continuous!movements!depends!on!the!CC!(Kennerley,!Diedrichsen,! Hazeltine,!Semjen,!&!Ivry,!2002).!Continuous!movements!are!seen!in!most!of!our!daily! activities!such!as!handwriting.!Drawing!with!mirror!movements!became!less!symmetrical! and!drawing!with!isodirectional!movements!improved!(Eliassen,!Baynes,!&!Gazzaniga,! 1999).!Most!of!the!research!with!this!population!dealt!with!temporal!coupling!of!bimanual! movements,!which!could!be!evident!in!MS!patients,!but!it!failed!to!provide!any!information! of!how!CC!damage!might!affect!the!quality!and!accuracy!of!movements!especially!those! under!kinesthetic!control.! ! Finally,!specific!case!studies!that!observed!MS!patients!also!showed!alien!or!useless! hand!syndrome!and!identified!issues!with!kinesthesia.!Others!with!sensory!neuropathy!and! deafferentiation!showed!similar!issues!with!controlled!movements.!The!term!useless!hand! syndrome!was!associated!with!damage!to!the!dorsal!column!of!the!high!cervical!spinal! cord,!while!alien!hand!syndrome!was!mostly!associated!with!lesions!or!disconnection!of! the!CC.!Those!with!useless!hand!syndrome!were!found!to!have!decreased!movement!ability! without!vision,!increased!muscle!weakness,!and!loss!of!muscle!endurance!and!kinesthesia! (Hamada!et!al.,!2005;!Hashimoto!et!al.,!1997).!Where!useless!hand!syndrome!manifested!in! a!loss!of!control!over!movements,!alien!hand!syndrome!resulted!in!involuntary!movement! of!one!hand!activated!by!voluntary!action!of!the!other.!In!this!case,!there!was!no!sense!of! what!the!involuntary!hand!was!doing!and!was!influenced!by!the!damaged!CC!(Kurne!et!al.,! 2008;!Lunardelli!et!al.,!2014).!Specifically,!this!occurred!when!the!CC!was!thinner!than! compared!to!normal!healthy!controls!and!there!were!lesions!present!(Moroni!et!al.,!2004).! ! 25! Unlike!these!syndromes,!neuropathy!resulted!in!spatial!and!temporal!dysfunction!of! movements.!MS!patients!with!sensory!neuropathy!showed!curved!trajectories!and! temporally!decoupled!movements!without!vision,!which!was!improved!with!vision!but!they! still!lacked!the!ability!to!synchronize!multi[joint!movements!(Sainburg!&!Poizner,!1993).! This!showed!that!kinesthesia!was!important!to!inter[joint!coordination!during!movements.! More!specifically,!the!temporal!decoupling!caused!the!curved!trajectories,!and!that! feedforward!mechanisms!were!impaired!which!caused!the!lack!of!kinesthesia!(Sainburg,! Ghilardi,!&!Poizner,!1995).!Similar!findings!were!seen!in!deafferented!MS!patients.!Bilateral! and!unilateral!deafferentiation!showed!a!deformation!from!the!given!trajectory!and!a! decrease!in!temporal!stability!during!continuous!bimanual!isodirectional!drawing.!Spatial! coupling!and!movement!variability!were!worse!in!both!anisodirectional!and!isodirectional! movements!with!or!without!vision!compared!to!unimanual!movements.!(Spencer,!Ivry,! Cattaert,!&!Semjen,!2005).!For!this!study,!in!order!to!determine!the!movement! characteristics!of!MS!patients,!movement!onset!and!offset!were!determined!based!on! temporal!location.!This!typically!involved!the!transition!from!centrally!and!peripherally! controlled!mechanisms!of!movement.!An!algorithm!was!defined!for!use!in!the! measurements!of!our!study!(Teasdale,!Bard,!Fleury,!Young,!&!Proteau,!1993).! ! The!past!research!provided!insight!into!how!movements!should!be!executed.!When! this!was!not!the!case!in!MS!patients,!specific!areas!of!the!CNS!were!identified!as!causing!the! dysfunction.!Abnormal!movement!characteristics!of!MS!patients!were!observed,!and! proprioception!was!studied!in!this!patient!population!with!respect!to!the!lower!body!and! balance.!Research!was!lacking!on!a!clear!view!of!how!kinesthesia,!especially!in!the!fine! motor!function!of!the!upper!limb,!was!affected.!It!was!shown!that!MS!patients!utilize! ! 26! adaptation!mechanisms,!but!it!had!yet!to!be!seen!whether!this!is!true!for!kinesthesia.! Bimanual!coordination!for!fine!motor!movements!was!identified!with!respect!to!grip!and! load!forces!and!was!also!looked!at!for!more!gross!motor!function!in!the!upper!limb,!but!it! was!not!studied!including!kinesthesia!and!fine!motor!movements.! ! ! ! ! 27! 3.1'Participants' CHAPTER'3' Methods' ! ! Participants!included!eleven!multiple!sclerosis!patients!with!mild!to!moderate!clinical! diagnosed!severity!and!eleven!age[!and!gender[matched!healthy!controls.!The!patients! were!recruited!through!Michigan!State!University’s!Neurology!and!Ophthalmology!Clinic.! The!control!participants!were!recruited!from!the!East!Lansing!and!Sault!Ste.!Marie! communities!in!the!state!of!Michigan.! ! 3.2'Materials' Two!joysticks!were!placed!next!to!each!other!and!positioned!underneath!a!horizontal!19”! LCD!widescreen!computer!monitor.!This!placement!insured!that!the!hand!movements!were! not!visible!to!the!participant!during!the!procedure.!Each!joystick!corresponded!to!a!cursor! on!the!screen,!which!was!shown!directly!above!the!actual!joystick’s!position.!The!computer! software!utilized!for!the!procedure!presentation!and!data!collection!was!Presentation®!by! Neurobehavioral!Systems.!The!position!time!series!in!the!(x,y)!position!time!series!was! collected!at!a!60!Hz!sampling!rate.! ! 3.3'Procedure' Informed!consent!was!obtained!from!all!participants.!They!were!evaluated!by!a!nine[hole! peg!test!to!determine!the!level!of!clinical!functionality,!and!completed!a!handedness!survey! to!determine!the!dominant!upper!limb.!The!main!movement!task!using!the!joystick! apparatus!involved!moving!the!joysticks!and!respective!cursors!from!the!home!position!to! ! 28! a!given!target!as!straight!and!as!quickly!as!possible.!Once!the!cursor!was!in!the!target,!the! participant!had!to!cease!movement!for!at!least!1500ms.!At!this!point,!the!trial!was!over,!the! target!disappeared,!and!the!participant!returned!the!joysticks!to!the!home!position!for!the! next!trial.!On!completion!of!the!trial,!visual!feedback!of!a!red!X!or!green!checkmark!were! shown!in!the!center!of!the!screen.!This!was!done!to!restrict!movement!time.!In!order!to! identify!kinesthesia!as!the!only!variable,!time!had!to!be!held!constant!between!MS!patients! and!controls.!A!time!limit!of!600[1500ms!for!movement!was!given.!If!above!or!below!this! time!range,!a!red!X!was!given!to!indicate!that!the!movement!needed!to!be!performed!faster! or!slower.!A!green!checkmark!indicated!that!the!movement!was!performed!well.!This! ensured!that!the!accuracy!could!be!directly!compared.!The!home!positions!were!1cm!in! diameter!and!centered!on!the!screen!17cm!apart.!The!targets!were!also!1cm!in!diameter! and!7.5cm!away!from!the!home!positions.!The!procedure!included!both!unimanual!and! bimanual!conditions!with!the!unimanual!being!conducted!with!each!limb.!The!bimanual! conditions!required!isodirectional!movements,!or!movements!in!the!same!direction!to!the! same!respective!target,!between!the!two!limbs.! All!unimanual!trials!had!a!kinesthetic!and!a!visual!condition.!In!the!visual!condition,! the!cursor!was!visible!to!the!participant!for!the!duration!of!the!movement.!In!the! kinesthetic!condition,!the!cursor!was!not!visible,!nor!was!the!target!responsive!to!the! joystick!position.!In!the!kinesthetic!condition,!the!participant!was!instructed!to!cease! movement!when!they!estimated!that!they!had!reached!the!given!target.!The!kinesthetic! conditions!had!targets!at!40!and!140!degrees!with!respect!to!each!home!position,!while!the! visual!condition!utilized!targets!at!55!and!125!degrees.!The!use!of!targets!at!different! angles!minimized!practice!effects.!The!unimanual!visual!condition!was!followed!by!the! ! 29! unimanual!kinesthetic!condition!with!the!dominant!and!nondominant!hand!conditions! counterbalanced.!In!each!of!these!conditions,!there!were!twenty!trials!administered!with! ten!trials/target.! Following!the!unimanual!conditions,!there!was!a!mixed!bimanual!condition!that! combined!both!visual!and!kinesthetic!characteristics.!One!hand!had!a!visible!cursor!while! the!other!did!not!and!had!to!rely!on!kinesthesia.!The!targets!for!this!condition!were!set!at! 40!and!140!degrees!away!from!the!respective!home!position.!Both!dominant!and! nondominant!hands!were!exposed!to!the!visual!and!kinesthetic!conditions,!and!the!order! was!counterbalanced.!In!each!mixed!bimanual!condition,!there!were!thirty!trials!with! fifteen!trials/target.! ! Finally,!there!was!a!visual!bimanual!condition!where!both!hands!had!a!cursor! tracing!their!movement!between!the!home!position!and!the!target.!The!targets!and!number! of!trials!were!the!same!as!those!in!the!mixed!bimanual!condition.! ! There!was!a!short!practice!period!of!only!8!trials!for!each!of!the!unimanual! conditions!and!the!bimanual!conditions.!This!ensured!that!the!participant!understood!the! procedure!and!was!able!to!perform!consistent!movements.!The!unimanual!visual!condition! was!meant!to!serve!as!a!calibration!phase,!during!which!participants!became!more! comfortable!with!the!task!requirements.!During!the!practice!condition!only!did!the! kinesthetic!trials!show!a!dot!where!the!cursor!was!at!the!end!of!the!movement!so!the! participant!had!some!visual!feedback!as!to!where!they!were!in!relation!to!the!target.!The! primary!comparison!was!between!the!kinesthetically!controlled!hand!during!the!mixed! bimanual!condition!and!the!unimanual!kinesthetic!condition.!The!secondary!comparison!of! interest!was!that!of!the!visually!controlled!hand!during!the!bimanual!condition!and!that!of! ! 30! the!visually!controlled!hand!during!the!unimanual!condition.!The!total!duration!of!the! experiment!was!approximately!forty[five!minutes.! ! 3.4'Data'Analysis' The!limb!utilizing!kinesthesia!and!its!response!to!coordination!with!the!contralateral! visually!guided!limb!was!of!interest,!thus!only!the!kinesthetic!trials!for!the!mixed!bimanual! condition!were!averaged!for!each!target!in!order!to!determine!the!kinesthetic!performance! of!each!arm!during!unimanual!and!bimanual!tasks.!Trials!in!every!other!condition!were! averaged!for!each!target!and!across!targets!after!finding!no!effect.!Each!trial!was!dual!pass! filtered!through!an!eighth!order!Butterworth!filter!with!a!cutoff!frequency!of!10Hz.!The! beginning!and!end!of!a!movement!were!determined!by!an!algorithm!from!Teasdale!et!al.! (Teasdale,!Bard,!Fleury,!Young,!&!Proteau,!1993).!Movement!time!(MT)!was!determined!by! the!time!between!this!starting!and!stopping!of!movement.! For!the!limb!lacking!visual!feedback,!the!root!mean!squared!error!(RMSE)!in! centimeters!–!defined!as!the!average!perpendicular!distance!between!the!actual!movement! and!a!straight!line!between!the!start!and!end!points!–!was!calculated!at!each!60Hz!sample! taken.!This!represented!the!linearity!of!the!movement,!which!was!solely!the!feed[forward! control!of!the!movement!trajectory.!The!absolute!end!point!error!(EPE)!in!centimeters!–! defined!as!the!distance!between!the!movement!end!point!and!the!center!of!the!target!–!was! measured!as!well!as!the!constant!end!point!error!in!centimeters!of!the!x,y!dimensions,! which!determined!over!or!under[shoot!of!the!movement.!These!error!coordinates!were! changed!into!movement!trajectory!space!by!making!the!end!point!error!in!the!x&dimension! ! 31! parallel!(EPpar)!and!those!in!the!y[dimension!perpendicular!(EPort)!to!the!direction!of! movement.! MT,!RMSE,!EPE,!EPpar,!and!EPort!were!used!in!repeated!measures!ANOVAs!where! hand,!task!condition!(unimanual!or!bimanual),!and!group!were!treated!as!within!subjects! factors.!The!Huyn[Feldt!adjusted!p[values!and!Bonferroni!adjusted!p[values!for!post[hoc! comparisons!were!reported!from!the!ANOVAs.! ! 32! CHAPTER'4' Results' ' ' In!order!to!assess!the!basic!performance!characteristics!of!the!two!groups,!the! unimanual!and!bimanual!conditions!were!performed!with!visual!feedback!in!addition!to! the!kinesthetically!controlled!unimanual!and!mixed!bimanual!conditions.!The!unimanual! conditions!showed!significant!differences!between!the!two!groups!(see!Table!1).!Both! unimanual!and!bimanual!results!were!analyzed!together!within!either!the!kinesthetic!or! the!visual!condition!using!a!2(groups)!x!2(hands)!x!2(conditions!–!unimanual/bimanual)! repeated!measures!ANOVA.! Table!1! Means-and-Standard-Deviations-for-Unimanual-and-Bimanual-Movements-Under-Kinesthetic-and-VisualFeedback-for-Patients-and-Controls! MS'patients' ! Visual' MT! Left!Hand! Right!Hand! ! RMSE! Left!Hand! Right!Hand! ! Kinesthetic' MT! Left!Hand! Right!Hand! ! RMSE! Left!Hand! Right!Hand! ! EPE! Left!Hand! Right!Hand! ! EPort! Left!Hand! Right!Hand! ! EPpar! Left!Hand! Right!Hand! ! NHPT! Left!Hand! Right!Hand! ! ! Unimanual' ! ! Control'group' Bimanual' ! ! Unimanual' ! ! Bimanual' ! ! 1.075!(0.19)! 1.067!(0.15)! 1.491!(0.304)! 1.376!(0.194)! 0.906!(0.181)! 0.909!(0.143)! 1.424!(0.209)! 1.317!(0.182)! ! 0.388!(0.155)! 0.427!(0.218)! ! 0.45!(0.125)! 0.459!(0.188)! ! 0.248!(0.107)! 0.28!(0.052)! ! 0.324!(0.184)! 0.365!(0.082)! ! ! 1.091!(0.211)! 1.073!(0.189)! ! ! 1.114!(0.224)! 1.196!(0.193)! ! ! 0.74!(0.197)! 0.771!(0.229)! ! ! 0.878!(0.25)! 0.817!(0.208)! ! 0.276!(0.097)! 0.423!(0.192)! ! 0.257!(0.077)! 0.275!(0.088)! ! 0.207!(0.078)! 0.182!(0.032)! ! 0.224!(0.114)! 0.188!(0.046)! ! 2.129!(0.84)! 2.268!(0.948)! ! 2.641!(0.591)! 2.678!(0.668)! ! 1.214!(0.51)! 1.272!(0.556)! ! 1.603!(0.547)! 1.504!(0.37)! ! 0.352!(0.815)! 0.402!(0.597)! ! 0.033!(1.074)! [0.319!(1.197)! ! 0.587!(0.422)! 0.376!(0.491)! ! 0.144!(0.897)! [0.362!(0.587)! ! 1.092!(1.662)! 1.099!(1.784)! ! 0.925!(1.699)! 1.059!(1.837)! ! [0.048!(0.89)! [0.149!(0.963)! ! 0.695!(0.701)! 0.327!(0.855)! ! 19.882!(1.874)! 19.876!(3.844)! ! ! ! ! 18.973!(1.959)! 18.03!(2.771)! ! ! ! 33! 4.1'Visual'condition' Unlike!in!previous!studies,!the!nine[hole!peg!test!(NHPT)!did!not!show!any! significant!differences!between!the!MS!patients!and!controls,!or!hands!used,!nor!was!there! a!Hand!x!Group!interaction!(see!Table!1!and!Figure!1).!Handedness!scores!were!similar,! with!the!MS!patients!showing!slightly!lower!scores!on!the!Edinburgh!handedness!survey! compared!to!the!controls!(MS!=!67,!Controls=73).! ! Figure!1:!Average!results!of!the!nine!hole!peg!test!for!patients!(MS)!and!controls!for!each!hand,! (NHPT_L=left!hand,!NHPT_R=right!hand).! ! ! In!contrast,!differences!were!seen!in!the!experimental!task.!There!was!a!trend!that! MT!was!different!between!the!two!groups,!F(1,9)=4.727,!p=0.058,!with!the!patients!taking! longer!to!complete!the!task!than!the!controls.!However,!there!was!a!significant!difference! between!the!two!conditions,!F(1,9)=139.523,!p