This is an elec onic ep in o he o iginal a icle.
This ep in may di e om he o iginal in pagina ion and ypog aphic de ail.
Au ho (s):
Ti le:
Yea :
Ve sion:
Please ci e he o iginal e sion:
All ma e ial supplied ia JYX is p o ec ed by copy igh and o he in ellec ual p ope y igh s, and
duplica ion o sale o all o pa o any o he eposi o y collec ions is no pe mi ed, excep ha
ma e ial may be duplica ed by you o you esea ch use o educa ional pu poses in elec onic o
p in o m. You mus ob ain pe mission o any o he use. Elec onic o p in copies may no be
o e ed, whe he o sale o o he wise o anyone who is no an au ho ised use .
S uc u al changes induced by daily music lis ening in he eco e ing b ain a e
middle ce eb al a e y s oke: a oxel-based mo phome y s udy
Sä kämö, Teppo; Ripollés, Pablo; Vepsäläinen, Henna; Au i, Taina; Sil ennoinen, Heli
M.; Salli, Ee o; Lai inen, Sa i; Fo sblom, Ani a; Soinila, Seppo; Rod íguez-Fo nells,
An oni
Sä kämö, T., Ripollés, P., Vepsäläinen, H., Au i, T., Sil ennoinen, H. M., Salli, E.,
Lai inen, S., Fo sblom, A., Soinila, S., & Rod íguez-Fo nells, A. (2014). S uc u al
changes induced by daily music lis ening in he eco e ing b ain a e middle ce eb al
a e y s oke: a oxel-based mo phome y s udy. F on ie s in Human Neu oscience,
8, A icle 245. h ps://doi.o g/10.3389/ nhum.2014.00245
2014
HUMAN NEUROSCIENCE
ORIGINAL RESEARCH ARTICLE
published: 17 Ap il 2014
doi: 10.3389/ nhum.2014.00245
S uc u al changes induced by daily music lis ening in he
eco e ing b ain a e middle ce eb al a e y s oke: a
oxel-based mo phome y s udy
Teppo Sä kämö1,2*, Pablo Ripollés3,4, HennaVepsäläinen1,Taina Au i5, Heli M. Sil ennoinen5, Ee o Salli5,
Sa i Lai inen6,Ani a Fo sblom7, Seppo Soinila8and An oni Rod íguez-Fo nells3,4,9
1Cogni i e B ain Resea ch Uni , Cogni i e Science, Ins i u e o Beha iou al Sciences, Uni e si y o Helsinki, Helsinki, Finland
2Finnish Cen e o In e disciplina y Music Resea ch, Uni e si y o Helsinki, Helsinki, Finland
3Cogni ion and B ain Plas ici y G oup, Bell i ge Biomedical Resea ch Ins i u e (IDIBELL), L’Hospi ale de Llob ega , Ba celona, Spain
4Depa men o Basic Psychology, Uni e si y o Ba celona, Ba celona, Spain
5Depa men o Radiology, HUS Medical Imaging Cen e , Helsinki Uni e si y Cen al Hospi al, Uni e si y o Helsinki, Helsinki, Finland
6Miina Sillanpää Founda ion, Helsinki, Finland
7Depa men o Music, Uni e si y o Jy äskylä, Jy äskylä, Finland
8Depa men o Neu ology,Tu ku Uni e si y Hospi al,Tu ku, Finland
9Ins i ució Ca alana de Rece ca i Es udis A ança s (ICREA), Ba celona, Spain
Edi ed by:
Ecka Al enmülle , Uni e si y o
Music and D ama Hanno e , Ge many
Re iewed by:
Jens Die e Rollnik, BDH-Klinik
Hessisch Oldendo , Ge many
Be nha d Haslinge ,Technische
Uni e si ä München, Ge many
*Co espondence:
Teppo Sä kämö, Cogni i e B ain
Resea ch Uni , Cogni i e Science,
Ins i u e o Beha iou al Sciences,
Uni e si y o Helsinki,
Sil a uo enpenge 1B, P.O. Box 9,
Helsinki FI-00014, Finland
e-mail: eppo.sa kamo@helsinki. i
Music is a highly complex and e sa ile s imulus o he b ain ha engages many empo al,
on al, pa ie al, ce ebella , and subco ical a eas in ol ed in audi o y, cogni i e, emo ional,
and mo o p ocessing. Regula musical ac i i ies ha e been shown o e ec i ely enhance
he s uc u e and unc ion o many b ain a eas, making music a po en ial ool also in neu o-
logical ehabili a ion. In ou p e ious andomized con olled s udy, we ound ha lis ening o
music on a daily basis can imp o e cogni i e eco e y and imp o e mood a e an acu e mid-
dle ce eb al a e y s oke. Ex ending his s udy, a oxel-based mo phome y (VBM) analysis
u ilizing cos unc ion masking was pe o med on he acu e and 6-mon h pos -s oke s age
s uc u al magne ic esonance imaging da a o he pa ien s (n=49) who ei he lis ened o
hei a o i e music [music g oup (MG), n=16] o e bal ma e ial [audio book g oup (ABG),
n=18] o did no ecei e any lis ening ma e ial [con ol g oup (CG), n=15] du ing he 6-
mon h eco e y pe iod. Al hough all g oups showed signi ican g ay ma e olume (GMV)
inc eases om he acu e o he 6-mon h s age, he e was a speci ic ne wo k o on al
a eas [le and igh supe io on al gy us (SFG), igh medial SFG] and limbic a eas [le en-
al/subgenual an e io cingula e co ex (SACC) and igh en al s ia um (VS)] in pa ien s
wi h le hemisphe e damage in which he GMV inc eases we e la ge in he MG han in he
ABG and in he CG. Mo eo e , he GM eo ganiza ion in he on al a eas co ela ed wi h
enhanced eco e y o e bal memo y, ocused a en ion, and language skills, whe eas he
GM eo ganiza ion in he SACC co ela ed wi h educed nega i e mood.This s udy adds on
p e ious esul s, showing ha music lis ening a e s oke no only enhances beha io al
eco e y, bu also induces ine-g ained neu oana omical changes in he eco e ing b ain.
Keywo ds: music, speech, s oke, magne ic esonance imaging, oxel-based mo phome y, en i onmen al en ich-
men , neu oplas ici y, ehabili a ion
INTRODUCTION
Du ing he pas 10 yea s, ad anced magne ic esonance imag-
ing (MRI) analysis me hods, such as oxel-based mo phome y
(VBM) and di usion enso imaging (DTI), ha e p o ided no el
in o ma ion abou he dynamics o he s uc u al neu oplas ic
changes unde lying spon aneous eco e y and ehabili a ion a e
s oke. Based on longi udinal VBM and DTI s udies o s oke
pa ien s, he eco e y o cogni i e and mo o de ici s is associ-
a ed wi h g ay ma e olume (GMV) changes in many on al,
empo al, ce ebella , and subco ical (e.g., hippocampus) a eas
(G au-Oli a es e al., 2010;Dang e al., 2013;Fan e al., 2013)
as well as changes in he in eg i y o he whi e ma e (WM)
ac s connec ing and p ojec ing om hese a eas (Liang e al.,
2008; an Mee e al., 2012;Thiebau de Scho en e al., 2014). In
longi udinal in e en ion s udies, in ensi e mo o ehabili a ion
using cons ain -induced mo emen he apy (CIMT) has been
shown o inc ease GMV in on al and pa ie al senso y–mo o
a eas and in he hippocampus (Gau hie e al.,2008) and in ensi e
aphasia ehabili a ion using cons ain -induced language he apy
(CILT) o melodic in ona ion he apy (MIT) has been obse ed o
enhance he in eg i y o he WM acks connec ing on al and
empo al egions (a cua e asciculus) in he le (B eie e al.,
2011) and igh (Schlaug e al., 2009) hemisphe es, espec i ely.
All in all, hese indings sugges ha bo h beha io al eco e y and
ac i e ehabili a ion a e s oke a e closely linked o ine-g ained
neu oana omical changes in he eco e ing b ain. Howe e , e y
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 1
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
li le is known abou he wide po en ial e ec s o he eco e y
en i onmen on s uc u al b ain plas ici y a e s oke in humans.
Con e ging e idence om bo h animal (Johansson, 2004;
Ni hianan ha ajah and Hannan, 2006) and human s udies
(Johansson, 2012;Janssen e al., 2014) indica es ha an en i-
onmen al en ichmen (EE), which p o ides addi ional senso y,
cogni i e,mo o ,and/o social s imula ion compa ed o a s anda d
en i onmen , plays an impo an ole in enhancing beha io al
eco e y a e an acu e s oke. In addi ion, e idence om animal
s udies sugges s ha he pos -s oke EE can induce a numbe o
cellula and molecula neu oplas ic e ec s in he b ain, including
inc ease in dend i ic complexi y (Bie naskie and Co be , 2001;
Johansson and Belichenko,2002),neu al s em and p ogeni o cells
(Komi o a e al., 2005;Ma sumo i e al., 2006), and neu o ophic
and neu al g ow h ac o le els (Gobbo and O’Ma a, 2004;Söde -
s öm e al.,2009),and ha hese changes a e associa ed wi h be e
cogni i e o mo o eco e y. In e es ingly, especially a mul isen-
so y EE, which includes audi o y, isual, and ol ac o y s imuli,
has been ound o be e ec i e in imp o ing cogni i e and mo o
eco e y and educing lesion olume (Maegele e al., 2005a,b).
Also e idence om de elopmen al animal s udies shows ha a
pu ely audi o y EE, which con ains complex sounds o music,
can enhance he s uc u e and unc ion o he audi o y co ex
(Enginee e al., 2004;Bose e al., 2010) as well as imp o e lea n-
ing and memo y and up egula e a ious neu o ansmi e s (e.g.,
dopamine, glu ama e) and neu o ophins associa ed wi h hem
(Su oo and Akiyama, 2004;Angelucci e al., 2007;Nichols e al.,
2007). O e all, hese indings indica e ha audi o y en ichmen
can be bene icial o he b ain and sugges ha i could po en-
ially con ibu e o be e cogni i e and neu al eco e y also a e
s oke.
In he human b ain, music and speech cons i u e he wo mos
complex and e sa ile audi o y s imuli in e ms o hei acous ic
ichness and he b ead h o he neu al ne wo ks in ol ed in hei
pe cep ion and lea ning (Za o e, 2013). Neu oimaging s udies o
heal hy subjec s ha e demons a ed ha music p ocessing engages
a as bila e al ne wo k o empo al, on al, pa ie al, ce ebel-
la , and limbic/pa alimbic a eas associa ed wi h he pe cep ion
o complex acous ic ea u es (e.g., melody, hy hm), syn ac ic and
seman ic p ocessing, a en ion and wo king memo y, episodic and
seman ic memo y, mo o and hy hm p ocessing, and expe ienc-
ing emo ions and ewa d (Blood and Za o e, 2001;Jana a e al.,
2002a,b;Pla el e al., 2003;Koelsch e al., 2004, 2005, 2006;Menon
and Le i in, 2005;Beng sson e al., 2009;Salimpoo e al., 2011,
2013;Allu i e al., 2012;He dene e al., 2014; o ecen e iews
see, Koelsch, 2010, 2011;Za o e, 2013). E idence om VBM and
DTI s udies also indica es ha equen musical ac i i ies, such as
playing an ins umen o singing, can lead o long- e m s uc u al
changes in he b ain, especially in on al, empo al, and pa ie al
a eas and in he WM pa hways (e.g., co pus callosum, a cua e as-
ciculus) connec ing hem (Gase and Schlaug, 2003;Hyde e al.,
2009;Halwani e al., 2011;James e al., 2014). Imp o emen s in
a en ion and execu i e unc ioning ha e also been epo ed in
heal hy olde adul s a e egula music playing ac i i ies, such as
piano playing (Bugos e al., 2007), and one longi udinal s udy also
highligh ed he ole o playing musical ins umen s and dancing
as leisu e ac i i ies associa ed wi h a educed isk o de eloping
demen ia (Ve ghese e al., 2003). Rega ding he po en ial ehabili-
a i e use o music a e s oke, esul s om ecen clinical s udies
sugges ha ac i e music-based in e en ions ha u ilize singing
(MIT) o ins umen playing (music-suppo ed he apy, MST),
can be e ec i e in imp o ing speech and mo o eco e y h ough
enhancing he unc ioning and connec i i y o empo al audi o y
and on al mo o a eas (Schlaug e al., 2008, 2009;Al enmülle
e al., 2009;Rojo e al., 2011;Rod íguez-Fo nells e al., 2012;
G au-Sánchez e al., 2013). Ve y li le, howe e , is known abou
he po en ial neu oplas ic changes induced by e e yday musical
ac i i ies, such as music lis ening, a e s oke.
P e iously, we pe o med a andomized con olled ial (RCT)
conce ning he po en ial ehabili a i e e ec s o an en iched
sound en i onmen on s oke eco e y. Six y pa ien s wi h an
acu e le (n=29) o igh (n=31) hemisphe e middle ce e-
b al a e y (MCA) b ain in a c ion we e andomized o a music
g oup (MG) (daily lis ening o sel -selec ed music), an audio
book g oup (ABG) (daily lis ening o sel -selec ed audio books),
and a con ol g oup (CG) (s anda d ca e only) and hei eco -
e y was ollowed o 6 mon hs using beha io al measu es (neu-
opsychological es s and ques ionnai es on mood), an audi o y
magne oencephalog aphy (MEG) measu emen , and s uc u al
MRI. Fi y- ou pa ien s comple ed he whole 6-mon h ollow-
up. Beha io al esul s showed ha e bal memo y and ocused
a en ion imp o ed mo e in he MG han in he ABG o CG
a e he in e en ion pe iod a he 3-mon h ollow-up and also
emained be e a he longi udinal 6-mon h ollow-up (Sä kämö
e al., 2008), sugges ing ha egula music lis ening enhanced cog-
ni i e eco e y. Compa ed o he CG, he MG also expe ienced less
dep essed and con used mood a he 3-mon h ollow-up (Sä kämö
e al., 2008). MEG esul s showed ha he misma ch nega i i y
(MMN) esponse o equency changes s eng hened mo e in he
MG and ABG compa ed o he CG a he 6-mon h ollow-up,indi-
ca ing ha egula exposu e o bo h music and speech enhanced
ea ly audi o y encoding in he eco e ing b ain (Sä kämö e al.,
2010a).
In he p esen s udy, ou aim was o de e mine wi h a VBM
analysis o he longi udinal s uc u al MRI da a (baseline acu e
s age and 6-mon h s age) om he same pa ien sample whe he
daily music lis ening could also lead o s uc u al GM and WM
eo ganiza ion in he b ain and i his change would also be ela ed
o he p e iously ound posi i e e ec s o music on cogni i e and
emo ional eco e y a e s oke.
MATERIALS AND METHODS
SUBJECTS AND STUDY DESIGN
Six y s oke pa ien s we e ec ui ed du ing 2004–2006 om he
Depa men o Neu ology o he Helsinki Uni e si y Cen al Hos-
pi al (HUCH). All pa ien s had an acu e ischemic MCA s oke
in he le (n=29) o igh (n=31) empo al, on al, pa ie al,
o subco ical b ain egions. Addi ional inclusion c i e ia we e:
no p io neu ological/psychia ic disease, d ug/alcohol abuse, o
hea ing de ici ; igh -handed; ≤75 yea s old; Finnish-speaking;
and able o co-ope a e. Rec ui ed pa ien s we e andomly assigned
o one o h ee g oups (n=20 in each): an MG, an ABG, o a CG.
Randomiza ion was pe o med wi h a andom numbe gene a-
o by a esea che no in ol ed in he pa ien en ollmen . The
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 2
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
s udy was app o ed by he HUCH E hics Commi ee, and all
pa ien s signed an in o med consen .All pa ien s ecei ed s anda d
ea men o s oke in e ms o medical ca e and ehabili a ion.
Du ing he ollow-up, he pa ien s unde wen a neu opsycho-
logical assessmen (including cogni i e es s and ques ionnai es)
and an audi o y MEG measu emen 1 week (baseline), 3 mon hs,
and 6 mon hs pos -s oke, and a s uc u al MRI wi hin 2 weeks o
he s oke onse and 6 mon hs pos -s oke. De ails ega ding he
me hodology and esul s o he neu opsychological assessmen s
and he MEG expe imen a e a ailable in he p e ious published
a icles (Sä kämö e al., 2008, 2010a).
O he 60 pa ien s o iginally ec ui ed in o he s udy, 55 com-
ple ed he s udy up o he 3-mon h s age and 54 up o he 6-mon h
s age. Fo he pu pose o he longi udinal VBM analyses, app o-
p ia e MRI da a we e una ailable in h ee pa ien s and he image
quali y was insu icien in wo u he pa ien s. Thus, da a om 49
pa ien s we e used in he p esen s udy. Demog aphic and clini-
cal cha ac e is ics as well as he musical and linguis ic ac i i ies o
he pa ien s a e shown in Tables 1 and 2, p esen ed sepa a ely o
he pa ien s wi h le hemisphe e damage (LHD, n=23) and igh
hemisphe e damage (RHD, n=26). The e we e no signi ican di -
e ences be ween he MG, ACG, and CG on any demog aphic o
clinical a iables, p io musical o linguis ic ac i i ies, o in o he
ehabili a ion ecei ed du ing he 6-mon h ollow-up whe eas he
equency o lis ening o music and audio books di e ed highly
signi ican ly be ween he g oups bo h a he 3-mon h and he
6-mon h s age. Howe e , he e we e no s a is ically signi ican di -
e ences be ween he MG andABG on how many hou s pe day he
pa ien s lis ened o he p o ided ma e ial (music in he MG, audio
books in he ABG) on a e age, al hough wi hin he RHD pa ien s
he daily lis ening amoun s we e sligh ly highe in he MG han
in he ABG. O e all, hese esul s indica e ha he g oups we e
compa able and ha he in e en ion p o ocol wo ked well.
INTERVENTION
As soon as possible a e hei en ollmen o he s udy (mean
8.8 days pos -s oke, ange 3–21 days), he MG and ABG pa ien s
we e indi idually con ac ed by a music he apis . In he MG, he
he apis p o ided he pa ien s wi h po able CD playe s and CDs
o hei own a o i e music in any musical gen e (mos ly popula
music wi h ly ics bu also jazz, olk, o classical music). Simi-
la ly, he he apis p o ided he ABG wi h po able playe s and
sel -selec ed na a ed audio books. The pa ien s we e ained in
using he playe s and we e ins uc ed o lis en o he ma e ial by
hemsel es daily ( o a minimum o 1 h pe day) o he ollow-
ing 2 mon hs in addi ion o s anda d ca e and ehabili a ion. A e
his in e en ion pe iod (3-mon h s age), hey we e encou aged o
con inue lis ening o he ma e ial on hei own. In o de o ensu e
ha he pa ien s we e able o engage in he lis ening p o ocol, he
he apis kep close weekly con ac wi h he pa ien s and he nu ses
and/o ela i es o he pa ien s we e asked o help. F equency o
lis ening was e i ied om he lis ening dia ies, which he pa ien s
kep du ing he in e en ion pe iod and om ques ionnai es a
he 3- and 6-mon h s ages. The CG was no gi en any lis ening
ma e ial and ecei ed only he s anda d ca e and ehabili a ion
du ing he ollow-up.
MRI DATA ACQUISITION
S uc u al MRI was pe o med wi hin 2 weeks o s oke onse and
6 mon hs pos -s oke using he 1.5 T Siemens Vision scanne o
Table 1 | Demog aphic and clinical cha ac e is ics o he pa ien s (n=49).
Le hemisphe e damage (n=23) Righ hemisphe e damage (n=26)
MG
(n=7)
ABG
(n=8)
CG
(n=8)
p- alue MG
(n=9)
ABG
(n=10)
CG
(n=7)
p- alue
DEMOGRAPHICAL CHARACTERISTICS
Age (yea s) 55.3 (11.0) 57.9 (7.4) 60.0 (8.9) 0.615 (F) 59.6 (7.9) 59.4 (9.0) 63.4 (4.7) 0.519 (F)
Gende (male/ emale) 3/4 6/2 5/3 0.439 (χ2) 6/3 2/8 3/4 0.111 (χ2)
Educa ion (yea s) 10.9 (4.4) 12.9 (3.1) 9.9 (3.4) 0.262 (F) 11.1 (4.5) 11.3 (2.9) 9.3 (3.9) 0.518 (F)
CLINICAL CHARACTERISTICS
Time om s oke onse o acu e MRI (days) 7.0 (3.2) 7.6 (3.7) 7.6 (2.8) 0.922 (F) 6.9 (1.6) 9.1 (3.4) 8.2 (4.3) 0.366 (F)
Time om s oke onse o 6-mon h MRI (days) 184.4 (6.2) 184.6 (15.9) 192.4 (16.2) 0.449 (F) 189.0 (5.9) 182.7 (8.8) 193.9 (22.0) 0.228 (F)
Hemipa esis (yes/no) 5/2 4/4 3/5 0.409 (χ2) 9/0 10/0 7/0 –
Aphasia (yes/no) 4/3 6/2 6/2 0.701 (χ2)
Lesion size (max. diame e in cm) 47.0 (17.8) 39.7 (18.8) 52.5 (17.6) 0.384 (F) 57.3 (28.9) 58.5 (20.5) 62.1 (25.3) 0.924 (F)
OTHER REHABILITATION DURINGTHE 6-MONTH FOLLOW-UPa
Physical he apy 19.7 (30.5) 11.3 (30.0) 4.0 (9.4) 0.732 (K) 26.9 (41.6) 30.2 (37.7) 20.1 (26.5) 0.991 (K)
Occupa ional he apy 14.3 (22.7) 0.4 (0.8) 8.0 (20.3) 0.627 (K) 9.8 (12.9) 10.0 (14.7) 5.9 (6.4) 0.886 (K)
Speech he apy 15.3 (20.5) 3.7 (9.4) 10.9 (11.5) 0.340 (K) 15.3 (20.5) 3.7 (9.4) 10.9 (11.5) 0.340 (K)
Neu opsychological ehabili a ion 4.0 (10.9) 2.3 (4.3) 1.0 (1.9) 0.851 (K) 2.9 (5.1) 2.5 (4.9) 0.7 (1.0) 0.976 (K)
Da a a e mean (SD) unless o he wise s a ed. MG, music g oup; ABG, audio book g oup; CG, con ol g oup; F, one-way ANOVA; χ2, chi-squa e es (likelihood a io);
K, K uskal–Wallis es .
aNumbe o he apy sessions.
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 3
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
Table 2 | Musical and linguis ic ac i i ies o he pa ien s (n=49).
Le hemisphe e damage (n=23) Righ hemisphe e damage (n=26)
MG (n=7) ABG (n=8) CG (n=8) p- alue MG (n=9) ABG (n=10) CG (n=7) p- alue
BEFORE STROKE
Lis ening o music 0.592 (K) 0.617 (K)
Ne e 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (14.3)
Ra ely 1 (14.3) 1 (12.5) 2 (25) 2 (22.2) 2 (20) 0 (0)
Once a mon h 0 (0) 0 (0) 1 (12.5) 0 (0) 1 (10) 0 (0)
Once a week 1 (14.3) 3 (37.5) 1 (12.5) 0 (0) 1 (10) 2 (28.6)
2–3 Times a week 3 (42.9) 4 (50) 2 (25) 2 (22.2) 3 (30) 0 (0)
Daily 2 (28.6) 0 (0) 2 (25) 5 (55.6) 3 (30) 4 (57.1)
Lis ening o adio 0.991 (K) 0.163 (K)
Ne e 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Ra ely 1 (14.3) 0 (0) 1 (12.5) 0 (0) 1 (10) 0 (0)
Once a mon h 0 (0) 0 (0) 1 (12.5) 0 (0) 1 (10) 0 (0)
Once a week 1 (14.3) 2 (25) 0 (0) 0 (0) 1 (10) 1 (14.3)
2–3 Times a week 0 (0) 1 (12.5) 0 (0) 1 (11.1) 1 (10) 3 (42.9)
Daily 5 (71.4) 5 (62.5) 6 (75) 8 (88.9) 6 (60) 3 (42.9)
Reading 0.686 (K) 0.220 (K)
Ne e 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Ra ely 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Once a mon h 0 (0) 0 (0) 1 (12.5) 1 (11.1) 0 (0) 0 (0)
Once a week 0 (0) 1 (12.5) 1 (12.5) 4 (44.4) 4 (40) 0 (0)
2–3 Times a week 3 (42.9) 1 (12.5) 1 (12.5) 2 (22.2) 2 (20) 3 (42.9)
Daily 4 (57.1) 4 (50) 5 (62.5) 2 (22.2) 4 (40) 4 (57.1)
DURINGTHE FIRST 3 MONTHS POST-STROKE
Lis ening o music 0.003 (K) 0.001 (K)
Da a missing 1 (14.3) 0 (0) 0 (0) 1 (11.1) 0 (0) 0 (0)
Ne e 0 (0) 6 (75) 5 (62.5) 0 (0) 2 (20) 3 (42.9)
Ra ely 0 (0) 1 (12.5) 1 (12.5) 0 (0) 3 (30) 1 (14.3)
Once a mon h 0 (0) 0 (0) 0 (0) 0 (0) 1 (10) 0 (0)
Once a week 0 (0) 0 (0) 0 (0) 0 (0) 1 (10) 0 (0)
2–3 Times a week 0 (0) 0 (0) 1 (12.5) 0 (0) 2 (20) 2 (28.6)
Daily 6 (85.7) 1 (12.5) 1 (12.5) 8 (88.9) 1 (10) 1 (14.3)
Lis ening o audio books <0.001 (K) <0.001 (K)
Da a missing 1 (14.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Ne e 5 (71.4) 0 (0) 6 (75) 9 (100) 1 (10) 6 (85.7)
Ra ely 1 (14.3) 0 (0) 2 (25) 0 (0) 0 (0) 0 (0)
Once a mon h 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Once a week 0 (0) 1 (12.5) 0 (0) 0 (0) 0 (0) 0 (0)
2–3 Times a week 0 (0) 2 (25) 0 (0) 0 (0) 0 (0) 0 (0)
Daily 0 (0) 5 (62.5) 0 (0) 0 (0) 9 (90) 1 (14.3)
Hou s pe day lis ening o g oup ma e iala1.6 (0.7) 1.3 (0.5) – 0.484 (T) 2.1 (0.6) 1.4 (0.7) – 0.076 (T)
DURING 3–6 MONTHS POST-STROKE
Lis ening o music 0.010 (K) 0.018 (K)
Da a missing 0 (0) 0 (0) 1 (12.5) 1 (11.1) 0 (0) 0 (0)
Ne e 0 (0) 0 (0) 2 (25) 0 (0) 2 (20) 2 (28.6)
Ra ely 0 (0) 1 (12.5) 2 (25) 0 (0) 1 (10) 1 (14.3)
Once a mon h 0 (0) 2 (25) 0 (0) 0 (0) 3 (30) 1 (14.3)
Once a week 0 (0) 1 (12.5) 2 (25) 1 (11.1) 2 (20) 0 (0)
2–3 Times a week 3 (42.9) 0 (0) 1 (12.5) 3 (33.3) 1 (10) 2 (28.6)
Daily 4 (57.1) 4 (50) 0 (0) 4 (44.4) 1 (10) 1 (14.3)
(Con inued)
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 4

Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
Table 2 | Con inued
Le hemisphe e damage (n=23) Righ hemisphe e damage (n=26)
MG (n=7) ABG (n=8) CG (n=8) p- alue MG (n=9) ABG (n=10) CG (n=7) p- alue
Lis ening o audio books <0.001 (K) 0.004 (K)
Da a missing 0 (0) 0 (0) 1 (12.5) 0 (0) 0 (0) 0 (0)
Ne e 6 (85.7) 0 (0) 5 (62.5) 8 (88.9) 2 (20) 6 (85.7)
Ra ely 1 (14.3) 0 (0) 2 (25) 0 (0) 1 (10) 0 (0)
Once a mon h 0 (0) 2 (25) 0 (0) 0 (0) 0 (0) 0 (0)
Once a week 0 (0) 0 (0) 0 (0) 0 (0) 2 (20) 0 (0)
2–3 Times a week 0 (0) 3 (37.5) 0 (0) 1 (11.1) 1 (10) 1 (14.3)
Daily 0 (0) 3 (37.5) 0 (0) 0 (0) 4 (40) 0 (0)
Da a shown as equency (pe cen age) unless o he wise s a ed. MG, music g oup; ABG, audio book g oup; CG, con ol g oup; K, K uskal–Wallis es ;T, - es .
aMusic lis ening in he MG and audio book lis ening in he ABG [da a a e mean (SD)].
he HUCH Depa men o Radiology. Clinically, he MRI was
used by wo expe ienced neu o adiologis s (au ho s Taina Au i
and Heli M. Sil ennoinen) o e i y he s oke diagnosis and o
e alua e he size and loca ion o he lesion. The MRI sequence
included a 3D se o high- esolu ion T1 images (TE=3.68 ms,
TR=1900 ms, TI=1100 ms, lip angle 15°, iso opic oxel size o
1 mm3), which we e used in he p esen VBM analysis. In addi-
ion, also a smalle se o luid-a enua ed in e sion eco e y (2D
FLAIR) images, which a e sensi i e o acu e in a c s, we e acqui ed
and used in accu a ely loca ing he lesion a ea, especially in he
acu e s age.
VOXEL-BASED MORPHOMETRY ANALYSIS
Mo phome ic analysis was ca ied ou using VBM (Ashbu ne
and F is on, 2000) and S a is ical Pa ame ic Mapping so wa e
(SPM8; The Welcome Depa men o Imaging Neu oscience,Lon-
don) unde MATLAB 7.8.0 (The Ma hWo ks Inc., Na ick, MA,
USA). The no maliza ion o b ain images is a p e equisi e in any
mul i-subjec oxel-wise MRI da a analysis and especially impo -
an when dealing wi h abno mal b ains. In o de o achie e an
accu a e segmen a ion and no maliza ion o lesioned GM and
WM issue, Uni ied Segmen a ion (Ashbu ne and F is on, 2005)
wi h medium egula iza ion and cos unc ion masking (CFM)
was applied o he s uc u al T1-weigh ed images o each sub-
jec (B e e al., 2001). The cos unc ion masks we e de ined by
manually depic ing o each pa ien a each ime (acu e and 6-
mon h s age) bina y lesion masks o he lesioned issue using he
MRIc on so wa e package1(Ro den and B e , 2000). This ech-
nique has been widely used wi h pa ien s su e ing om s oke
(C inion e al., 2007;Ande sen e al., 2010;Ripollés e al., 2012),
achie ing op imal no maliza ion wi h no pos - egis a ion lesion
sh inkage o ou -o -b ain dis o ion (Ripollés e al., 2012). Du -
ing no maliza ion, he GM and WM images we e modula ed in
o de o p ese e he o al amoun o he signal. The esul ing
no malized GM and WM issue p obabili y maps we e smoo hed
by using an iso opic spa ial il e (FWHM =6 mm) o educe
esidual in e -indi idual a iabili y.
1h p://www.mccauslandcen e .sc.edu/m ic o/m ic on/index.h ml
All no malized and smoo hed GM and WM images we e u -
he analyzed in o de o compa e he di e ences in he GMV o
whi e ma e olume (WMV). Because he p ocessing o music
and speech a e gene ally known o in ol e he le and igh
hemisphe es o a di e en deg ee (e.g., Za o e e al., 2002;Te -
aniemi and Hugdahl, 2003) and hey a e he e o e di e en ially
a ec ed by lesion la e ali y, we pe o med sepa a e analyses o he
LHD pa ien s (MG: n=7, ABG: n=8, CG: n=8) and he RHD
pa ien s (MG: n=9, ABG: n=10, CG: n=7). Thus, ou sepa a e
mixed-design analysis o a iance (ANOVA) models (GMV–LHD,
GMV–RHD, WMV–LHD, WMV–RHD) we e buil wi h G oup
(MG/ABG/CG) as a be ween-subjec s a iable and Time (acu e
s age/6-mon h s age) as a wi hin-subjec s a iable ( he eby ensu -
ing ha each subjec ac ed as i s own con ol). To al in ac a-
nial olume (TIV) was included as a nuisance a iable in o de
o co ec o global di e ences o head size. Th ee di e en
G oup ×Time in e ac ions we e calcula ed: MG >CG and ABG,
ABG >CG and MG,CG >MG andABG. In o he wo ds,we es ed
i he inc emen s in pos –p e GMV in one g oup (e.g., MG) we e
g ea e han in he o he wo g oups (e.g., CG and ABG). In addi-
ion, pos hoc pai ed - es s we e planned o check he di ec ion o
he e ec o Time wi hin each G oup (6 mon hs >acu e). I has
been sugges ed ha combined in ensi y and clus e size h esholds
such as p<0.005 wi h a 10 oxel ex en p oduce a desi able balance
be ween Type I and Type II e o s (Liebe man and Cunningham,
2009). Taking a sligh ly mo e s ingen app oach, he esul s a e
epo ed in ables a p<0.001 (unco ec ed h eshold) wi h a clus-
e size o ≥50 oxels o spa ial ex en . Fo he sake o isual cla i y,
esul s a e shown in igu es a p<0.01 (unco ec ed h eshold),
al hough only clus e s epo ed in he ables a e labeled and com-
men ed h oughou he ex . Ana omical and cy oa chi ec onical
a eas we e iden i ied using he Au oma ed Ana omical Labeling
(Tzou io-Mazoye e al.,2002) and he Talai ach Daemon da abase
a lases (Lancas e e al., 2000) included in he xjView oolbox2.
Finally, o any clus e o oxels whe e a signi ican
G oup ×Time in e ac ion was ound, mean GMV o WMV
inc ease (6 mon hs −acu e s age) was calcula ed o each pa ien
and co ela ed wi h beha io al changes (also 6 mon hs −acu e
2h p://www.ali elea n.ne /xj iew8/
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 5
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
s age) in cogni i e es s and mood scales. Fo he cogni i e mea-
su es, changes in he summa y sco es o he es s measu ing
he ollowing cogni i e domains we e included: e bal memo y,
sho - e m and wo king memo y,language skills, isuospa ial cog-
ni ion, execu i e unc ions, ocused a en ion (co ec esponses
and eac ions imes), and sus ained a en ion (co ec esponses
and eac ions imes; o de ails,see Sä kämö e al.,2008). Simila ly,
o he mood measu es,changes in he eigh P o ile o Mood S a es
(POMS) scales ( ension,dep ession,i i abili y, igo , a igue,ine -
ia, con usion, and o ge ulness) we e included ( o de ails, see
Sä kämö e al., 2008).
RESULTS
GRAY AND WHITE MATTER VOLUME CHANGES DURING RECOVERY
Signi ican GMV inc eases we e ound pos -in e en ion
(6 mon hs −acu e) o all h ee g oups o LHD pa ien s (see
Table 3;Figu e 1) and RHD pa ien s (see Table 4;Figu e 2). A eas
iden i ied we e mos ly loca ed in he empo al, on al,mo o , lim-
bic, and ce ebella b ain egions, especially in he con alesional
hemisphe e, wi h he la ges and mos ex ensi e olume inc eases
occu ing in he MG.
In LHD pa ien s, signi ican G oup ×Time in e ac ions in
GMV we e ound o he MG >ABG and CG con as (see Table 5;
Figu e 3) in i e di e en clus e s: h ee in on al a eas [le and
igh supe io on al gy us (SFG) and igh medial SFG] and wo
in limbic a eas [le en al/subgenual an e io cingula e co ex
(SACC) and igh en al s ia um (VS) / globus pallidum). The
e e sed con as s (ABG >CG and MG, CG >MG and ABG) did
no yield any signi ican egions.
In RHD pa ien s, he e we e no signi ican G oup ×Time in e -
ac ions in GMV in any a ea a he selec ed h eshold (p<0.001
unco ec ed). Howe e , when using a sligh ly mo e lenien h esh-
old (p<0.005 unco ec ed), a single clus e eme ged in he le
insula (MNI −33 −6−8; 73 oxels o ex en ; (22) =3.36) o
he MG >ABG and CG con as (see Figu e 4). Again, no o he
clus e s we e ound using he e e sed con as s (ABG >CG and
MG, CG >MG and ABG) a his same h eshold.
The e we e no signi ican Time e ec s o G oup ×Time
in e ac ions in he WMV in LHD o RHD pa ien s.
CORRELATION BETWEEN GRAY MATTER CHANGES AND BEHAVIORAL
RECOVERY
In o de o de e mine he unc ional ele ance o he obse ed
GMV inc eases induced by he music lis ening in e en ion, we
pe o med co ela ion analyses wi h he longi udinal beha io al
da a (also 6 mon hs −acu e). In LHD pa ien s, he inc ease in
GMV in he iden i ied on al a eas co ela ed signi ican ly wi h
imp o emen in e bal memo y, language skills, and ocused
a en ion (see Table 6 o indi idual clus e co ela ions; in
Figu e 5 he on al clus e s a e pooled oge he o illus a i e
Table 3 | GMV inc eases (6-mon h−acu e) in LHD pa ien s (n=23).
Ana omical a ea MNI coo dina es Clus e size - alue
CG Le ce ebellum −14 −59 −40 189 4.75
Righ empo al pole (BA 38) 34 5 −20 111 4.46
Righ ce ebellum 14 −59 −42 59 4.27
Le pons −7−29 −35 203 4.08
Righ pos e io cingula e gy us 12 −40 24 83 3.96
ABG Righ calca ine/cuneus (BA 17, 18) 17 −77 12 1084 5.14
Le ce ebellum −7−53 −17 166 4.75
Righ pons −18 −35 −42 85 4.71
Righ calca ine (BA 17) 9 −82 4 239 4.66
Righ p ecen al gy us (BA 6) 47 0 31 110 4.18
MG Le en al/subgenual an e io cingula e co ex (BA 10) −10 34 −3 185 5.75
Righ supe io on al gy us (BA 32, 6) 19 4 51 588 5.54
Righ middle on al gy us (BA 32, 9) 21 24 39 1367 5.39
Righ in e io on al gy us 31 13 21 153 5.35
Righ en al s ia um 12 15 −11 484 4.85
Righ usi o m gy us (BA 19) 32 −45 −9 130 4.82
Righ o bi o on al co ex (BA 11) 28 44 −6 264 4.80
Righ supe io on al gy us (BA 10) 22 51 2 490 4.74
Righ supe io medial on al gy us (BA 8) 8 32 51 76 4.67
Righ p ecuneus (BA 7) 19 −53 46 166 4.60
Righ pos e io cingula e gy us 14 −40 25 471 4.46
Righ en al s ia um/globus pallidum 14 6 −2 252 4.43
Le supplemen a y mo o a ea −11 10 50 54 4.07
Resul s a e epo ed a a p<0.001 (unco ec ed h eshold) wi h 50 oxels o spa ial ex en . CG, con ol g oup; ABG, audio book g oup; MG, music g oup; BA,
B odmann a ea.
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 6
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
FIGURE 1 | GMV inc eases (6-mon h −acu e) in LHD pa ien s (n=23).
Lesion o e lap indica ing he numbe o pa ien s wi h damage a a pa icula
oxel and GMV inc eases wi hin he h ee g oups a e shown in
blue–g een– ed and ed–yellow, espec i ely. Neu ological con en ion is used.
Resul s a e shown a p<0.01 (unco ec ed) wi h ≥50 oxels o spa ial ex en
and o e laid o e a canonical empla e wi h MNI coo dina es a he bo om
igh o each slice. Only clus e s su i ing a p<0.001 h eshold a e labeled
(see alsoTable 3). TP, empo al pole; PCG, pos e io cingula e gy us; C ,
ce ebellum; P CG, p ecen al gy us; Calc, calca ine; P ec, p ecuneus; SFG,
supe io on al gy us; VS, en al s ia um; IFG, in e io on al gy us; SACC,
en al/subgenual an e io cingula e co ex; OFC, o bi o on al co ex; F G,
usi o m gy us; L, le hemisphe e; R, igh hemisphe e.
pu poses). Simila ly, inc ease in GMV in he limbic egions
(le SACC) was signi ican ly co ela ed wi h a dec ease in sel -
epo ed dep ession, ension, a igue, o ge ulness, and i i abili y
and ma ginally co ela ed also wi h a dec ease in sel - epo ed
con usion. In RHD pa ien s, he GMV inc eases in he le insula
clus e we e also ound o co ela e wi h he imp o emen o lan-
guage skills ( =0.63, p<0.002; Figu e 4). The e we e no o he
signi ican co ela ions.
DISCUSSION
The no el key inding o he p esen VBM s udy was ha eg-
ula music lis ening du ing he 6-mon h pos -s oke s age can
lead o s uc u al eo ganiza ion in he eco e ing b ain. Speci -
ically, compa ed wi h pa ien s who lis ened daily o audio books
(ABG) o who did no ecei e any addi ional lis ening ma e -
ial (CG), he pa ien s who lis ened daily o hei own a o i e
music (MG) showed mo e inc ease in GMV om he acu e o
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 7
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
Table 4 | GMV inc eases (6-mon h−acu e) in RHD pa ien s (n=26).
Ana omical a ea MNI coo dina es Clus e size - alue
CG Le sup ama ginal gy us (BA 40) −44 −28 28 1597 6.13
Le halamus −15 −6 6 946 5.97
Le b ains em −4−20 −10 695 5.27
Le in e io empo al lobe (BA 20, 21) −44 −5−35 208 4.42
Righ ce ebellum 14 −42 −25 93 4.19
Le sup./mid. occipi al gy us −21 −86 12 405 4.18
Le cuneus (BA 18) −5−85 22 340 4.18
Le o bi o on al co ex (BA 47) −16 25 −21 85 3.97
ABG Le ce ebellum −9−52 −40 874 6.42
Le pos e io cingulum −12 −43 21 322 5.85
Righ pos e io cingulum 20 −43 26 79 4.83
Le middle cingulum −12 −11 35 546 4.78
Righ o bi o on al co ex (BA 10) 15 53 1 185 4.66
Righ ce ebellum 16 −71 −51 268 4.64
Le halamus −15 −6 11 105 4.40
Le insula −33 −14 10 61 4.21
Le p ecuneus −20 −50 14 59 4.19
Le p ecen al gy us (BA 6) −29 −11 45 102 4.18
Le pos cen al gy us (BA 4) −43 −17 51 169 4.13
MG Righ p ecuneus (BA 31) 16 −45 21 1544 6.35
Le pos /middle/an cingula e gy us; le sup./mid. on al gy us; le supp.
mo o a ea; le in e io on al gy us; pa s iangula is (BA 32, 31, 24, 9)
−10 −12 34 11173 6.16
Le sup ama ginal gy us; le pos cen al gy us (BA 40) −48 −23 27 1472 6.09
Le in e io on al gy us; le p ecen al gy us (BA 6) −42 9 17 799 5.92
Righ middle cingula e gy us (BA 24) 18 30 26 970 4.90
Le o bi o on al co ex (BA 47, 11) −25 23 −16 1661 4.85
Le in ./mid. empo al gy us (BA 20) −46 −5−31 717 4.56
Le usi o m gy us −34 −17 −27 266 4.42
Le insula −34 −12 −7 387 4.39
Le pa ahippocampal gy us 26 −65 −38 191 4.21
Righ ce ebellum 11 31 −11 280 4.18
Righ an e io cingula e (BA 32) 19 43 4 72 4.14
Le p ecen al gy us −34 5 35 188 4.12
Le middle empo al gy us −56 −46 −8 372 4.06
Righ usi o m gy us 36 −42 −16 246 4.05
Resul s a e epo ed a a p<0.001 (unco ec ed h eshold) wi h 50 oxels o spa ial ex en . CG, con ol g oup; ABG, audio book g oup; MG, music g oup; BA,
B odmann a ea.
he 6-mon h s age in a ne wo k o on olimbic a eas, p ima ily
in he heal hy con alesional side bu also pe ilesionally. Impo -
an ly, he obse ed GMV inc eases in his ne wo k we e di ec ly
associa ed wi h he beha io al imp o emen in cogni i e unc ion-
ing and educ ion in nega i e mood shown p e iously o music
lis ening (Sä kämö e al., 2008;Fo sblom e al., 2012). The a ea-
speci ic co ela ions ob ained (a en ion, memo y, and language
o on al a eas; mood o limbic egions), he lack o di e -
ences in he e e sed con as s (ABG >CG and MG, CG >MG
and ABG), and he ac ha e ec s eme ge in a eas ha ha e
p e iously been ound o be closely associa ed wi h music p ocess-
ing and cogni i e/emo ional p ocessing (see below), a gue agains
ou esul s being alse posi i es. Mo eo e , gi en ha he pa ien
g oups we e compa able a baseline and he po en ial e ec s o
o he ypes o ehabili a ion (s anda d s oke ehabili a ion) and
ac i i ies (audio book lis ening) we e con olled o , hese indings
sugges ha a musically en iched en i onmen can be bene icial
o acu e s oke eco e y and ha neu oplas ic changes in he
on olimbic ne wo k may unde lie i s e icacy.
In he p esen s udy, he on al GMV inc eases associa ed wi h
music lis ening in LHD pa ien s we e loca ed in he le and igh
SFG and he igh medial SFG and co ela ed wi h he imp o e-
men o e bal memo y,language skills,and ocused a en ion o e
he 6-mon h ollow-up. These co ela ions a e well in line wi h
he p e ious indings o he s udy showing ha music lis ening
enhanced he eco e y o e bal memo y and ocused a en ion
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 8
Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
ascula mild cogni i e impai men . Ce eb o asc. Dis. 30, 157–166. doi:10.1159/
000316059
G au-Sánchez, J., Amengual, J. L., Rojo, N., Veciana de Las He as, M., Mon e o, J.,
Rubio, F., e al. (2013). Plas ici y in he senso imo o co ex induced by music-
suppo ed he apy in s oke pa ien s: a TMS s udy. F on . Hum. Neu osci. 7:494.
doi:10.3389/ nhum.2013.00494
G een, A. C., Bae en sen, K. B., S ødkilde-Jø gensen, H., Wallen in, M., Roep-
s o , A., and Vuus , P. (2008). Music in mino ac i a es limbic s uc u es:
a ela ionship wi h dissonance? Neu o epo 19, 711–775. doi:10.1097/WNR.
0b013e3282 d0dd8
G eicius, M. D., Flo es, B. H., Menon, V., Glo e , G. H., Sol ason, H. B., Kenna, H.,
e al. (2007). Res ing-s a e unc ional connec i i y in majo dep ession: abno -
mally inc eased con ibu ions om subgenual cingula e co ex and halamus.
Biol. Psychia y 62, 429–437. doi:10.1016/j.biopsych.2006.09.020
G ie e, S. M., Ko gaonka , M. S., Koslow, S. H., Go don, E., and Williams, L. M.
(2013). Widesp ead educ ions in g ay ma e olume in dep ession. Neu oimage
Clin. 3, 332–339. doi:10.1016/j.nicl.2013.08.016
Halwani, G. F., Loui, P., Rübe , T., and Schlaug, G. (2011). E ec s o p ac ice and
expe ience on he a cua e asciculus: compa ing singe s, ins umen alis s, and
non-musicians. F on . Psychol. 2:156. doi:10.3389/ psyg.2011.00156
He dene , M., Humbel, T., Esposi o, F., Habe meye , B., Ca apan-Ludewig, K., and
Sei i z, E. (2014). Jazz d umme s ec ui language-speci ic a eas o he p ocess-
ing o hy hmic s uc u e. Ce eb. Co ex 24, 836–843. doi:10.1093/ce co /bhs367
Hoekzema, E., Ca mona, S., T emols, V., Gispe , J. D., Gui a , M., Fauque , J., e al.
(2010). Enhanced neu al ac i i y in on al and ce ebella ci cui s a e cogni i e
aining in child en wi h a en ion-de ici /hype ac i i y diso de . Hum. B ain
Mapp. 31, 1942–1950. doi:10.1002/hbm.20988
Huang, S., Seidman, L. J., Rossi, S., and Ah eninen, J. (2013). Dis inc co ical ne -
wo ks ac i a ed by audi o y a en ion and wo king memo y load. Neu oimage
83, 1098–1108. doi:10.1016/j.neu oimage.2013.07.074
Hyde, K. L., Le ch, J., No on, A., Fo gea d, M., Winne , E., E ans, A. C., e al.
(2009). Musical aining shapes s uc u al b ain de elopmen . J. Neu osci. 29,
3019–3025. doi:10.1523/jneu osci.5118-08.2009
James, C. E., Oechslin, M. S., Van De Ville, D., Haue , C. A., Descloux, C., and
Lazy as, F. (2014). Musical aining yields opposi e e ec s on g ey ma e densi y
in cogni i e e sus senso imo o ne wo ks. B ain S uc . Func . 219, 353–366.
doi:10.1007/s00429-013-0504-z
Jana a, P. (2009). The neu al a chi ec u e o music-e oked au obiog aphical mem-
o ies. Ce eb. Co ex 19, 2579–2594. doi:10.1093/ce co /bhp008
Jana a, P., Bi k, J. L., Van Ho n, J. D., Leman, M., Tillmann, B., and Bha ucha, J. J.
(2002a). The co ical opog aphy o onal s uc u es unde lying Wes e n music.
Science 298, 2167–2170. doi:10.1126/science.1076262
Jana a, P., Tillmann, B., and Bha ucha, J. J. (2002b). Lis ening o polyphonic music
ec ui s domain-gene al a en ion and wo king memo y ci cui s. Cogn. A .
Beha . Neu osci. 2, 121–140. doi:10.3758/CABN.2.2.121
Janssen,H.,Ada,L.,Be nha d , J., McEldu ,P.,Pollack,M.,Nilsson,M., e al. (2014).
An en iched en i onmen inc eases ac i i y in s oke pa ien s unde going eha-
bili a ion in a mixed ehabili a ion uni : a pilo non- andomized con olled ial.
Disabil. Rehabil. 36, 255–262. doi:10.3109/09638288.2013.788218
Je de, T. A., Childs, S. K., Handy, S. T., Nagode, J. C., and Pa do, J. V. (2011). Dis-
sociable sys ems o wo king memo y o hy hm and melody. Neu oimage 57,
1572–1579. doi:10.1016/j.neu oimage.2011.05.061
Johansson,B. B. (2004). Func ional and cellula e ec s o en i onmen al en ichmen
a e expe imen al b ain in a c s. Res o . Neu ol. Neu osci. 22, 163–174.
Johansson, B. B. (2012). Mul isenso y s imula ion in s oke ehabili a ion. F on .
Hum. Neu osci. 6:60. doi:10.3389/ nhum.2012.00060
Johansson, B. B., and Belichenko, P. V. (2002). Neu onal plas ici y and dend i ic
spines: e ec o en i onmen al en ichmen on in ac and pos ischemic a b ain.
J. Ce eb. Blood Flow. Me ab. 22, 89–96. doi:10.1097/00004647-200201000-00011
Kang, D. H.,Jo,H. J.,Jung,W. H.,Kim,S. H., Jung,Y. H., Choi,C. H.,e al. (2013). The
e ec o medi a ion on b ain s uc u e: co ical hickness mapping and di usion
enso imaging. Soc. Cogn. A ec . Neu osci. 8, 27–33. doi:10.1093/scan/nss056
Ki ayama, S., Chua, H. F., Tompson, S., and Han, S. (2013). Neu al mechanisms
o dissonance: an MRI in es iga ion o choice jus i ica ion. Neu oimage 69,
206–212. doi:10.1016/j.neu oimage.2012.11.034
Klebe , B., Bi baume , N., Vei , R., T e o ow, T., and Lo ze, M. (2007). O e and
imagined singing o an I alian a ia. Neu oimage 36, 889–900. doi:10.1016/j.
neu oimage.2007.02.053
Koelsch, S. (2010). Towa ds a neu al basis o music-e oked emo ions. T ends Cogn.
Sci. 14, 131–137. doi:10.1016/j. ics.2010.01.002
Koelsch, S. (2011). Towa d a neu al basis o music pe cep ion – a e iew and upda ed
model. F on . Psychol. 2:110. doi:10.3389/ psyg.2011.00110
Koelsch, S., F i z, T., Schulze, K., Alsop, D., and Schlaug, G. (2005). Adul s
and child en p ocessing music: an MRI s udy. Neu oimage 25, 1068–1076.
doi:10.1016/j.neu oimage.2004.12.050
Koelsch, S., F i z, T., V C amon, D. Y., Mülle , K., and F iede ici, A. D. (2006). In es-
iga ing emo ion wi h music: an MRI s udy. Hum. B ain Mapp. 27, 239–250.
doi:10.1002/hbm.20180
Koelsch, S., Kaspe , E., Sammle , D., Schulze, K., Gun e , T., and F iede ici, A. D.
(2004). Music, language and meaning: b ain signa u es o seman ic p ocessing.
Na . Neu osci. 7, 302–307. doi:10.1038/nn1197
Komi o a, M., Ma sson, B., Johansson, B. B., and E iksson, P. S. (2005). En iched
en i onmen inc eases neu al s em/p ogeni o cell p oli e a ion and neu ogene-
sis in he sub en icula zone o s oke-lesioned adul a s. S oke 36, 1278–1282.
doi:10.1161/01.s .0000166197.94147.59
Lai, C. H. (2013). G ay ma e olume in majo dep essi e diso de : a me a-
analysis o oxel-based mo phome y s udies. Psychia y Res. 211, 37–46.
doi:10.1016/j.pscych esns.2012.06.006
Lancas e , J. L., Woldo , M. G., Pa sons, L. M., Lio i, M., F ei as, C. S., Rainey,
L., e al. (2000). Au oma ed Talai ach a las labels o unc ional b ain mapping.
Hum. B ain Mapp. 10, 120–131. doi:10.1002/1097-0193(200007)
Lappe, C., S eins ä e , O., and Pan e , C. (2013). Rhy hmic and melodic de ia ions
in musical sequences ec ui di e en co ical a eas o misma ch de ec ion.
F on . Hum. Neu osci. 7:260. doi:10.3389/ nhum.2013.00260
Lee, Y. S., Jana a, P., F os , C., Hanke, M., and G ange , R. (2011). In es iga ion o
melodic con ou p ocessing in he b ain using mul i a ia e pa e n-based MRI.
Neu oimage 57, 293–300. doi:10.1016/j.neu oimage.2011.02.006
Liang, Z., Zeng, J., Zhang, C., Liu, S., Ling, X., Xu, A., e al. (2008). Longi udinal
in es iga ions on he an e og ade and e og ade degene a ion in he py amidal
ac ollowing pon ine in a c ion wi h di usion enso imaging. Ce eb o asc.
Dis. 25, 209–216. doi:10.1159/000113858
Liebe man, M. D., and Cunningham,W. A. (2009). Type I and Type II e o conce ns
in MRI esea ch: e-balancing he scale. Soc. Cogn. A ec . Neu osci. 4, 423–428.
doi:10.1093/scan/nsp052
Maegele, M., Lippe -G uene , M., Es e -Bode, T., Ga be, J., Bouillon, B., Neuge-
baue , E., e al. (2005a). Mul imodal ea ly onse s imula ion combined wi h
en iched en i onmen is associa ed wi h educed CNS lesion olume and
enhanced e e sal o neu omo o dys unc ion a e auma ic b ain inju y in
a s. Eu . J. Neu osci. 21, 2406–2418. doi:10.1111/j.1460-9568.2005.04070.x
Maegele, M., Lippe -G uene , M., Es e -Bode, T., Saue land, S., Schä e , U., Mol-
canyi, M., e al. (2005b). Re e sal o neu omo o and cogni i e dys unc ion
in an en iched en i onmen combined wi h mul imodal ea ly onse s im-
ula ion a e auma ic b ain inju y in a s. J. Neu o auma 22, 772–782.
doi:10.1089/neu.2005.22.772
Ma sumo i, Y., Hong, S. M., Fan, Y., Kayama, T., Hsu, C. Y., Weins ein, P. R., e al.
(2006). En iched en i onmen and spa ial lea ning enhance hippocampal neu o-
genesis and sal ages ischemic penumb a a e ocal ce eb al ischemia. Neu obiol.
Dis. 22, 187–198. doi:10.1016/j.nbd.2005.10.015
Menon, V., and Le i in, D. J. (2005). The ewa ds o music lis ening: esponse and
physiological connec i i y o he mesolimbic sys em. Neu oimage 28, 175–184.
doi:10.1016/j.neu oimage.2005.05.053
Mi e schi hale , M. T., Fu, C. H., Dal on, J. A., And ew, C. M., and Williams, S.
C. (2007). A unc ional MRI s udy o happy and sad a ec i e s a es induced by
classical music. Hum. B ain Mapp. 28, 1150–1162. doi:10.1002/hbm.20337
Mon ag, C., Reu e , M., and Axmache , N. (2011). How one’s a o i e song ac i a es
he ewa d ci cui y o he b ain: pe sonali y ma e s! Beha . B ain Res. 225,
511–514. doi:10.1016/j.bb .2011.08.012
Nichols, J. A., Jakkamse i, V. P., Salgado, H., Dinh, L., Kilga d, M. P., and A zo i, M.
(2007). En i onmen al en ichmen selec i ely inc eases glu ama e gic esponses
in laye II/III o he audi o y co ex o he a . Neu oscience 145, 832–840.
doi:10.1016/j.neu oscience.2006.12.061
Ni hianan ha ajah,J.,and Hannan,A. J. (2006). En iched en i onmen s,expe ience-
dependen plas ici y and diso de s o he ne ous sys em. Na . Re . Neu osci. 7,
697–709. doi:10.1038/n n1970
No ho , G., and Be mpohl, F. (2004). Co ical midline s uc u es and he sel .
T ends Cogn. Sci. 8, 102–107. doi:10.1016/j. ics.2004.01.004
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 15

Sä kämö e al. Music lis ening enhances neu oplas ici y a e s oke
Oma , R., Henley, S. M., Ba le , J. W., Hails one, J. C., Go don, E., Sau e , D.
A., e al. (2011). The s uc u al neu oana omy o music emo ion ecogni ion:
e idence om on o empo al loba degene a ion. Neu oimage 56, 1814–1821.
doi:10.1016/j.neu oimage.2011.03.002
Osuch, E. A., Bluhm, R. L., Williamson, P. C., Thébe ge, J., Densmo e, M., and
Neu eld, R. W. (2009). B ain ac i a ion o a o i e music in heal hy con-
ols and dep essed pa ien s. Neu o epo 20, 1204–1208. doi:10.1097/wn .
0b013e32832 4da3
Pla el, H., Ba on, J. C., Desg anges, B., Be na d, F., and Eus ache, F. (2003). Seman-
ic and episodic memo y o music a e subse ed by dis inc neu al ne wo ks.
Neu oimage 20, 244–256. doi:10.1016/S1053-8119(03)00287-8
P ice,C. J. (2010). The ana omy o language: a e iew o 100 MRI s udies published
in 2009. Ann. N.Y. Acad. Sci. 1191,62–88. doi:10.1111/j.1749-6632.2010.05444.x
Ripollés, P., Ma co-Palla és, J., de Diego-Balague , R., Mi ó, J., Falip, M., Juncadella,
M., e al. (2012). Analysis o au oma ed me hods o spa ial no maliza ion
o lesioned b ains. Neu oimage 60, 1296–1306. doi:10.1016/j.neu oimage.2012.
01.094
Rod íguez-Fo nells, A., Rojo, N., Amengual, J. L., Ripollés, P., Al enmülle , E., and
Mün e, T. F. (2012). The in ol emen o audio-mo o coupling in he music-
suppo ed he apy applied o s oke pa ien s. Ann. N. Y. Acad. Sci. 1252, 282–293.
doi:10.1111/j.1749-6632.2011.06425.x
Rojo, N., Amengual, J. L., Juncadella, M., Rubio, F., Cama a, E., Ma co-Palla és, J.,
e al. (2011). Music-suppo ed he apy induces plas ici y in he senso imo o
co ex in ch onic s oke: a single-case s udy using mul imodal imaging ( MRI-
TMS). B ain Inj. 25, 787–793. doi:10.3109/02699052.2011.576305
Ro den, C., and B e , M. (2000). S e eo axic display o b ain lesions. Beha . Neu ol.
12, 191–200. doi:10.1155/2000/421719
Salimpoo , V. N., Beno oy, M., La che , K., Daghe , A., and Za o e, R. J. (2011).
Ana omically dis inc dopamine elease du ing an icipa ion and expe ience o
peak emo ion o music. Na . Neu osci. 14, 257–262. doi:10.1038/nn.2726
Salimpoo , V. N., an den Bosch, I., Ko ace ic, N., McIn osh, A. R., Daghe , A., and
Za o e, R. J. (2013). In e ac ions be ween he nucleus accumbens and audi o y
co ices p edic music ewa d alue. Science 340, 216–219. doi:10.1126/science.
1231059
Sä kämö, T., Pihko, E., Lai inen, S., Fo sblom, A., Soinila, S., Mikkonen, M., e al.
(2010a). Music and speech lis ening enhance he eco e y o ea ly senso y p o-
cessing a e s oke. J. Cogn. Neu osci. 22, 2716–2727. doi:10.1162/jocn.2009.
21376
Sä kämö, T., Te aniemi, M., Soinila, S., Au i, T., Sil ennoinen, H. M., Laine, M.,
e al. (2010b). Audi o y and cogni i e de ici s associa ed wi h acqui ed amu-
sia a e s oke: a magne oencephalog aphy and neu opsychological ollow-up
s udy. PLoS ONE 5:e15157. doi:10.1371/jou nal.pone.0015157
Sä kämö, T., Te aniemi, M., Lai inen, S., Fo sblom, A., Soinila, S., Mikkonen, M.,
e al. (2008). Music lis ening enhances cogni i e eco e y and mood a e middle
ce eb al a e y s oke. B ain 131, 866–876. doi:10.1093/b ain/awn013
Sä kämö, T., Te aniemi, M., Soinila, S., Au i, T., Sil ennoinen, H. M., Laine,
M., e al. (2009). Cogni i e de ici s associa ed wi h acqui ed amusia a e
s oke: a neu opsychological ollow-up s udy. Neu opsychologia 47, 2642–2651.
doi:10.1016/j.neu opsychologia.2009.05.015
Schlaug, G., Ma china, S., and No on, A. (2008). F om singing o speaking: why
singing may lead o eco e y o exp essi e language unc ion in pa ien s wi h
B oca’s aphasia. Music Pe cep . 25, 315–323. doi:10.1525/mp.2008.25.4.315
Schlaug, G., Ma china, S., and No on, A. (2009). E idence o plas ici y in whi e-
ma e ac s o pa ien s wi h ch onic B oca’s aphasia unde going in ense
in ona ion-based speech he apy. Ann. N. Y. Acad. Sci. 2009, 385–394. doi:10.
1111/j.1749-6632.2009.04587.x
Söde s öm, I., S and, M., Ing idsson, A. C., Nasic, S., and Olsson, T. (2009).
17be a-es adiol and en iched en i onmen accele a e cogni i e eco e y a e
ocal b ain ischemia. Eu . J. Neu osci. 29, 1215–1224. doi:10.1111/j.1460-9568.
2009.06662.x
Su oo, D., and Akiyama, K. (2004). Music imp o es dopamine gic neu o ansmis-
sion: demons a ion based on he e ec o music on blood p essu e egula ion.
B ain Res. 1016, 255–262. doi:10.1016/j.b ain es.2004.05.018
Te aniemi, M., and Hugdahl, K. (2003). La e aliza ion o audi o y-co ex unc-
ions. B ain Res. Re . 43, 231–246. doi:10.1016/j.b ain es e .2003.08.004
Thiebau de Scho en, M., Tomaiuolo, F., Aiello, M., Me ola, S., Sil e i, M., Lecce, F.,
e al. (2014). Damage o whi e ma e pa hways in subacu e and ch onic spa ial
neglec : a g oup s udy and 2 single-case s udies wi h comple e i ual “in i o”
ac og aphy dissec ion. Ce eb. Co ex 24, 691–706. doi:10.1093/ce co /bhs351
T os , W., E ho e , T., Zen ne , M., and Vuilleumie , P. (2012). Mapping aes he ic
musical emo ions in he b ain. Ce eb. Co ex 22, 2769–2783. doi:10.1093/ce co /
bh 353
Tzou io-Mazoye , N., Landeau, B., Papa hanassiou, D., C i ello, F., E a d, O., Del-
c oix, N., e al. (2002). Au oma ed ana omical labeling o ac i a ions in SPM
using a mac oscopic ana omical pa cella ion o he MNI MRI single-subjec
b ain. Neu oimage 15, 273–289. doi:10.1006/nimg.2001.0978
Vago, D. R., and Silbe sweig, D. A. (2012). Sel -awa eness, sel - egula ion, and sel -
anscendence (S-ART): a amewo k o unde s anding he neu obiological
mechanisms o mind ulness. F on . Hum. Neu osci. 6:296. doi:10.3389/ nhum.
2012.00296
an Mee , M. P., O e,W. M., an de Ma el, K., Nijboe , C. H., Ka elaa s,A., an de -
Sp enkel, J. W., e al. (2012). Ex en o bila e al neu onal ne wo k eo ganiza ion
and unc ional eco e y in ela ion o s oke se e i y. J. Neu osci. 32, 4495–4507.
doi:10.1523/jneu osci.3662-11.2012
Ve ghese, J., Lip on, R. B., Ka z, M. J., Hall, C. B., De by, C. A., Kuslansky, G., e al.
(2003). Leisu e ac i i ies and he isk o demen ia in he elde ly. N. Engl. J. Med.
348, 2508–2516. doi:10.1056/NEJMoa022252
Villa eal, M. F., Ce que i, D., Ca uso, S., Schwa czLópezA angu en, V., Ge -
schco ich, E. R., F ega, A. L., e al. (2013). Neu al co ela es o musical c e-
a i i y: di e ences be ween high and low c ea i e subjec s. PLoS ONE 8:e75427.
doi:10.1371/jou nal.pone.0075427
Weh um, S., Degé, F., O , U., Wal e , B., S ippekohl, B., Kage e , S., e al. (2011).
Can you hea a di e ence? Neu onal co ela es o melodic de iance p ocessing
in child en. B ain Res. 1402, 80–92. doi:10.1016/j.b ain es.2011.05.057
Yoshimu a, S., Okamo o,Y., Onoda, K., Ma sunaga, M., Okada, G., Kunisa o,Y., e al.
(in p ess). Cogni i e beha io al he apy o dep ession changes medial p e on al
and en al an e io cingula e co ex ac i i y associa ed wi h sel - e e en ial p o-
cessing. Soc. Cogn. A ec . Neu osci. doi:10.1093/scan/ns 009
Za a e, J. M., and Za o e, R. J. (2008). Expe ience-dependen neu al subs a es
in ol ed in ocal pi ch egula ion du ing singing. Neu oimage 40, 1871–1887.
doi:10.1016/j.neu oimage.2008.01.026
Za o e, R. J. (2013). P edisposi ions and plas ici y in music and speech lea ning:
neu al co ela es and implica ions. Science 342, 585–589. doi:10.1126/science.
1238414
Za o e, R. J., Belin, P., and Penhune, V. B. (2002). S uc u e and unc ion o audi-
o y co ex: music and speech. T ends Cogn. Sci. 6, 37–46. doi:10.1016/S1364-
6613(00)01816-7
Za o e, R. J., Fields, R. D., and Johansen-Be g, H. (2012). Plas ici y in g ay and
whi e: neu oimaging changes in b ain s uc u e du ing lea ning. Na . Neu osci.
15, 528–536. doi:10.1038/nn.3045
Con lic o In e es S a emen : The au ho s decla e ha he esea ch was conduc ed
in he absence o any comme cial o inancial ela ionships ha could be cons ued
as a po en ial con lic o in e es .
Recei ed: 30 Janua y 2014; accep ed: 03 Ap il 2014; published online: 17 Ap il 2014.
Ci a ion: Sä kämö T, Ripollés P, Vepsäläinen H, Au i T, Sil ennoinen HM, Salli
E, Lai inen S, Fo sblom A, Soinila S and Rod íguez-Fo nells A (2014) S uc u al
changes induced by daily music lis ening in he eco e ing b ain a e middle ce e-
b al a e y s oke: a oxel-based mo phome y s udy. F on . Hum. Neu osci. 8:245.
doi: 10.3389/ nhum.2014.00245
This a icle was submi ed o he jou nal F on ie s in Human Neu oscience.
Copy igh © 2014 Sä kämö, Ripollés,Vepsäläinen, Au i, Sil ennoinen, Salli, Lai inen,
Fo sblom, Soinila and Rod íguez-Fo nells. This is an open-access a icle dis ibu ed
unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis-
ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s)
o licenso a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in
acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is
pe mi ed which does no comply wi h hese e ms.
F on ie s in Human Neu oscience www. on ie sin.o g Ap il 2014 | Volume 8 | A icle 245 | 16