Vol.:(0123456789)
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Jou nal o Neu ology
h ps://doi.o g/10.1007/s00415-022-11398-z
ORIGINAL COMMUNICATION
S uc u al b ain changes inpa ien s wi hpe sis en headache
a e COVID‑19 esolu ion
Ál a oPlanchuelo‑Gómez1,2 · Da idGa cía‑Azo ín3,4 · ÁngelL.Gue e o3,4 · Ma ga i aRod íguez5 ·
San iagoAja‑Fe nández1 · Rod igodeLuis‑Ga cía1
Recei ed: 10 Augus 2022 / Re ised: 21 Sep embe 2022 / Accep ed: 22 Sep embe 2022
© The Au ho (s) 2022
Abs ac
Headache is among he mos equen ly epo ed symp oms a e esolu ion o COVID-19. We assessed s uc u al b ain
changes using T1- and di usion-weigh ed MRI p ocessed da a om 167 subjec s: 40 pa ien s who eco e ed om COVID-
19 bu su e ed om pe sis en headache wi hou p io his o y o headache (COV), 41 heal hy con ols, 43 pa ien s wi h
episodic mig aine and 43 pa ien s wi h ch onic mig aine. To e alua e g ay ma e and whi e ma e changes, mo phome y
pa ame e s and di usion enso imaging-based measu es we e employed, espec i ely. COV pa ien s showed signi ican
lowe co ical g ay ma e olume and co ical hickness han heal hy subjec s (p < 0.05, alse disco e y a e co ec ed) in he
in e io on al and he usi o m co ex. Lowe ac ional aniso opy and highe adial di usi i y (p < 0.05, amily-wise e o
co ec ed) we e obse ed in COV pa ien s compa ed o con ols, mainly in he co pus callosum and le hemisphe e. COV
pa ien s showed highe co ical olume and hickness han mig aine pa ien s in he cingula e and on al gy i, pa acen al
lobule and supe io empo al sulcus, lowe olume in subco ical egions and lowe cu a u e in he p ecuneus and cuneus.
Lowe di usion me ic alues in COV pa ien s compa ed o mig aine we e iden i ied p ominen ly in he igh hemisphe e.
COV pa ien s p esen di e se changes in he whi e ma e and g ay ma e s uc u e. Whi e ma e changes seem o be associ-
a ed wi h impai men o ibe bundles. Besides, he g ay ma e changes and o he whi e ma e modi ica ions such as axonal
in eg i y loss seemed sub le and less p onounced han hose de ec ed in mig aine, showing ha pe sis en headache a e
COVID-19 esolu ion could be an in e media e s a e be ween no mali y and mig aine.
Keywo ds COVID-19· Headache· G ay ma e · Di usion enso imaging· Mig aine
* Da id Ga cía-Azo ín
[email p o ec ed]
1 Labo a o io de P ocesado de Imagen (LPI), Uni e sidad de
Valladolid, 47011Valladolid, Spain
2 Ca di Uni e si y B ain Resea ch Imaging Cen e
(CUBRIC), Ca di Uni e si y, Ca di CF244HQ, UK
3 Depa men o Neu ology, Headache Uni , Hospi al Clínico
Uni e si a io de Valladolid, A enida Ramón y Cajal, 3,
47003Valladolid, Spain
4 Depa men o Medicine, Uni e sidad de Valladolid,
47005Valladolid, Spain
5 Depa men o Radiology, Hospi al Clínico Uni e si a io de
Valladolid, 47003Valladolid, Spain
Abb e ia ions
AD Axial di usi i y
ANCOVA Analysis o co a iance
CM Ch onic mig aine
COVID-19 Co ona i us disease 2019
COV G oup o pa ien s wi h pe sis en headache
a e COVID-19 esolu ion
DTI Di usion enso imaging
DWI Di usion-weigh ed imaging
EM Episodic mig aine
FA F ac ional aniso opy
FDR False disco e y a e
FEW Family wise e o
GM G ay ma e
HC Heal hy con ols
ICHD-3 In e na ional Classi ica ion o Headache
Diso de s, 3 d edi ion
MD Mean di usi i y
MNI Mon eal Neu ological Ins i u e
RD Radial di usi i y
RT-PCR Re e se- ansc ip ase-polyme ase-chain-
eac ion
TBSS T ac -based spa ial s a is ics
TE Echo ime
Jou nal o Neu ology
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TFCE Th eshold- ee clus e enhancemen
TI In e sion ime
TR Repe i ion ime
WM Whi e ma e
Backg ound
Co ona i us disease 2019 (COVID-19) p esen s wi h a
combina ion o espi a o y and sys emic symp oms, wi h
headache being one o he mos p ominen ea u es. Head-
ache is desc ibed by app oxima ely a qua e o pa ien s [1,
2], wi h a pheno ype ha combines ea u es o ension- ype
headache and mig aine [3]. The p esence o headache has
been associa ed wi h a mo e e icien immune esponse [4,
5] and a be e sho -and-mid- e m p ognosis [6–8]. The
median du a ion o headache is a ound 2weeks [2], bu in a
i h o pa ien s, headache becomes pe sis en and adop s a
ch onic pa e n, pa icula ly i i pe sis s 2mon hs a e he
acu e phase [9].
In o de o in es iga e on he biological unde pinnings o
pe sis en headache a e COVID-19 esolu ion, magne ic
esonance imaging (MRI) e eals i sel as an ideal echnique
o assess he s uc u al changes in he b ain due o i s associ-
a ed good con as o issue and non-in asi eness. MRI da a
p ocessing allows o analyze quan i a i e p ope ies o he
g ay ma e (GM) and whi e ma e (WM). To assess GM
changes, mo phome y analysis om T1-weigh ed images
allows he p ecise quan i ica ion o ea u es such as he ol-
ume, co ical cu a u e, hickness and su ace a ea o di -
e en co ical and subco ical GM a eas [10]. In headache
diso de s, olume has been widely assessed [11], while a ea,
cu a u e and hickness ha e been ba ely employed [12,
13]. On he o he hand, di usion MRI acquisi ions allow
he quan i a i e desc ip ion o he WM p ope ies. Di u-
sion enso imaging (DTI) is commonly employed o model
he di usion MRI da a, and whi e ma e desc ip o s can be
es ima ed om i . F ac ional aniso opy (FA), mean di usi -
i y (MD), axial di usi i y (AD), and adial di usi i y (RD)
a e common choices. These me ics ha e been ex ensi ely
used o s udy he p esence o b ain changes in pa ien s wi h
ch onic headache diso de s, especially mig aine [14–18].
A ew s udies ha e assessed b ain changes a e COVID-
19 esolu ion using MRI, none o hem ocused on pe sis en
headache. In a s udy ca ied ou 3mon hs a e COVID-19
eco e y, pa ien s p esen ed highe global GM olume, and,
wi h ega d o he WM, highe FA and lowe MD, RD, and
AD in compa ison wi h heal hy con ols [19]. These ends
e lec con a y pa e ns o wha usually has been associ-
a ed wi h a ophy o de e io a ion. In con as , a la ge s udy
wi h he UK Biobank composed o hund eds o longi udinal
acquisi ions o heal hy con ols and pa ien s wi h p e ious
COVID-19 in ec ion has epo ed lowe co ical hickness in
he pa ien g oups [20]. In ano he s udy wi h a 1-yea ol-
low-up, eco e ed pa ien s p esen ed a lowe olume ac ion
o in acellula wa e han heal hy con ols, and dec eased
FA was ound in pa ien s who we e admi ed o an in en-
si e ca e uni compa ed o hose who we e no admi ed
[21]. Finally, in a s udy assessing pa ien s who eco e ed
om COVID-19 accompanied by anosmia o hyposmia, he
au ho s ound lowe FA and highe RD in eco e ed pa ien s
[22].
To da e, he e a e no s udies assessing s uc u al changes
in pa ien s wi h pe sis en headache a e COVID-19 eso-
lu ion (he eina e e e ed o as COV g oup). The main
objec i e o his s udy is he e alua ion and cha ac e iza-
ion o long- e m b ain s uc u al changes in COV pa ien s.
In addi ion, a seconda y objec i e is he compa ison o hese
changes wi h hose disco e ed in mig aine, he headache dis-
o de ha has been mos ex ensi ely s udied using MRI da a.
Ma e ials andme hods
Pa icipan s
An obse a ional s udy wi h a case–con ol design, nes ed
in a p ospec i e coho [2, 9], was conduc ed o assess he
po en ial s uc u al b ain changes o COV pa ien s. One he
one hand, a g oup composed o heal hy con ols was used
as a e e ence o a case–con ol s udy design. On he o he
hand, o be e cha ac e ize he changes associa ed wi h
headache, he COV pa ien s we e compa ed wi h a g oup
composed o episodic mig aine (EM), and ano he g oup
composed o ch onic mig aine (CM) pa ien s.
Fo he COV pa ien s, he inclusion c i e ia we e adap ed
om acu e-phase s udies [2]: (1) mic obiologically con-
i med COVID-19 diagnosis based on a eal- ime e e se-
ansc ip ase-polyme ase-chain- eac ion (RT-PCR) assay
om espi a o y ac samples, o al e na i ely by he p es-
ence o an i-SARS-CoV-2 IgM + IgA an ibodies, ollowing
he Wo ld Heal h O ganiza ion p o ocols [23, 24]; (2) new-
onse headache p esen ed du ing he acu e phase o COVID-
19, ul illing c i e ia o acu e headache a ibu ed o sys-
emic i al in ec ion [25], ha was no be e accoun ed o
ano he seconda y headache diso de acco ding o he In e -
na ional Classi ica ion o Headache Diso de s, 3 d edi ion
(ICHD-3) [25]; (3) age g ea e o equal o 18yea s old; and
also he ollowing speci ic inclusion c i e ia: (4) pe sis ence
o headache o a leas 3mon hs a e he acu e phase o
COVID-19; (5) no esolu ion o he headache a he momen
o MRI acquisi ion; (6) ag eemen o pa icipa e; (7) lack
o use o d ugs wi h po en ial e ec on he cen al ne ous
sys em (be e speci ied in exclusion c i e ia).
The s udy was conduc ed in he Headache Uni o
Hospi al Clínico Uni e si a io de Valladolid (Valladolid,
Jou nal o Neu ology
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Spain), a hi d-le el uni e si y public hospi al. All con-
secu i e pa ien s ha we e in ec ed om COVID-19
in Valladolid Eas heal h a ea be ween Ma ch 8, 2020,
and Ap il 11, 2020, we e sc eened (n = 580 hospi alized
pa ien s and n = 1614 cases managed in an ou pa ien se -
ing, ou a popula ion a isk o 162,431 inhabi an s) [2]
and p ospec i ely ollowed up o a leas 9mon hs [9].
All hese pa ien s and hose ha we e e e ed o he head-
ache ou pa ien clinic we e assessed o eligibili y. Fo
he COV pa ien s included in he sample, di e se clinical
ea u es o headache and he p esence o anosmia we e
collec ed.
All he pa icipan s we e aged be ween 18 and 60yea s.
Rega ding he speci ic inclusion and exclusion c i e ia o
he o he h ee g oups in his s udy (heal hy con ols, EM
and CM), hey a e a ailable elsewhe e [18]. B ie ly, he
diagnosis o pa ien s wi h EM and CM was based on he
ICHD-3 c i e ia [25], and hese pa ien s p esen ed a s a-
ble clinical si ua ion wi h a leas 1yea su e ing om
mig aine. The exclusion c i e ia we e common in all ou
g oups and we e: (1) dea h du ing ollow-up; (2) una ail-
abili y o pa icipa e due o uns able medical condi ion;
(3) p io his o y o cogni i e impai men o demen ia; (4)
speech o language diso de s ha made headache e alu-
a ion impossible; (5) consen wi hd awal o pa icipa e
in he s udy; (6) use o he apeu ic o illici d ugs wi h
po en ial e ec s on he ne ous sys em, including an i-
dep essan s, ba bi u a es, neu olep ics, an iepilep ics, and
opia es; (7) p io his o y o o he p ima y o seconda y
headache diso de s, excluding in equen ension- ype
headache (less han one a ack pe mon h); (8) p e ious
his o y o mode a e- o-se e e c anio-ce ical auma; (9)
p io his o y o neu ological o neu osu gical diso de s
o he han COVID-19 (in he COV g oup); (10) su e ing
om o he pain ul synd omes, o neu ological o psy-
chia ic diso de s; (11) p egnancy o childbea ing; (12)
condi ions ha con aindica ed an MRI acquisi ion; (13)
claus ophobia; (14) p esence o unexpec ed ascula
mal o ma ion in MRI ha could a ec he mo phologi-
cal e alua ion; (15) any clinical condi ion ha a oided
an accu a e desc ip ion o he headache pheno ype. Bo h
mig aine pa ien s and COV pa ien s we e excluded i
hey had used any p io p e en i e ea men be o e MRI
acquisi ion. The pa ien s wi h mig aine we e ec ui ed
a e hei i s isi o he a o emen ioned Headache
Uni and, in case o p esc ibed p e en i e ea men , i
began jus a e he MRI acquisi ion in a pe iod sho e
han 1mon h. Da a and imaging om pa ien s wi h
mig aine and con ols we e ob ained be o e he begin-
ning o he COVID-19 pandemic. The E hics Re iew
Boa d o Valladolid Eas heal h a ea app o ed his s udy
(PI-GR-20-2017).
MRI acquisi ion
T1- and di usion-weigh ed images (DWI) we e collec ed
o he ou g oups o subjec s. Fo he iden i ica ion o pos-
sible abno mali ies, T2-weigh ed and FLAIR images we e
addi ionally acqui ed om he COV g oup. All pa ien s we e
scanned in he same MRI scanne , a Philips Achie a 3T
MRI uni (Philips Heal hca e, Bes , The Ne he lands) wi h
a 32-channel head coil.
T1-weigh ed images we e acqui ed using a Tu bo Field
Echo sequence wi h he ollowing pa ame e s: epe i ion
ime (TR) = 8.1ms, echo ime (TE) = 3.7ms, lip angle = 8º,
256 × 256 ma ix size, spa ial esolu ion o 1 × 1 × 1 mm3 and
160 sagi al slices co e ing he whole b ain.
Fo he di usion-weigh ed da a, TR = 9000 ms,
TE = 86ms, lip angle = 90º, 61 di usion g adien o ien a-
ions, one baseline olume, b- alue = 1000s/mm2, 128 × 128
ma ix size, spa ial esolu ion o 2 × 2 × 2 mm3 and 66
axial slices co e ing he whole b ain we e he employed
pa ame e s.
The pa ame e s o he acquisi ion o he T2-weigh ed
images we e: Tu bo Spin Echo sequence, TR = 3000ms,
TE = 80ms, lip angle = 90º, 560 × 560 ma ix size, spa ial
esolu ion o 0.43 × 0.43 × 5 mm3, and 28 axial slices.
Finally, 3D high- esolu ion FLAIR images we e
ob ained using TR = 4800ms, TE = 308ms, in e sion ime
(TI) = 1650ms, lip angle = 90º, 240 × 240 ma ix size, spa-
ial esolu ion o 0.56 × 1.04 × 1.04 mm3, and 321 sagi al
slices o co e he whole b ain.
Image p ocessing
The analysis was ocused on he assessmen o he GM and
WM s uc u e. In he ollowing sec ions, he co esponding
p ocessing s eps ollowed o he sepa a e analysis o each
ype o issue a e desc ibed.
G ay ma e mo phome y
The au oma ic co ical pa cella ion pipeline om he F ee-
Su e so wa e ( 6.0.0) was applied o he T1-weigh ed
images. The s eps om his p ocedu e included he seg-
men a ion o co ical and subco ical GM s uc u es and he
calcula ion o geome ical desc ip o s o u he analysis.
Speci ically, he p e ious p ocessing s eps o he pipeline
we e skull s ipping, Talai ach ans o ma ion, segmen a ion
o subco ical g ay and whi e ma e , including he bound-
a y essella ion o bo h issue ypes, in ensi y no maliza ion,
and su ace de o ma ion [26–29]. The pipeline was used
o ex ac he mean co ical cu a u e, hickness, su ace
a ea and GM olume o 68 (34 bila e al) co ical egions.
Jou nal o Neu ology
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In addi ion, GM olume was compu ed o se en bila e al
egions and he bila e al ce ebellum (16 egions). This yields
a o al o 288 mo phome ic ea u es o he GM.
Di usion MRI p ocessing
Fi s , DWIs we e p ep ocessed. The p ep ocessing s eps
we e denoising ollowing he Ma chenko-Pas u P incipal
Componen Analysis p ocedu e, Gibbs inging emo al, co -
ec ion o eddy cu en s, mo ion and B1 ield inhomogenei-
ies. These s eps we e ca ied ou wi h he “dwidenoise”,
“m degibbs”, “dwi slp ep oc” and “dwibiasco ec ” ools
om MR ix ( e sion 3.0.2) [30–36]. Once he p ep ocess-
ing was inished, a whole b ain mask excluding he skull
was ex ac ed using he “dwi2mask” ool om MR ix [37].
A e p ep ocessing, di usion enso i ing was pe -
o med on he DWIs using leas squa es, and ac ional ani-
so opy (FA), mean di usi i y (MD), and axial di usi i y
(AD), we e ob ained as WM desc ip o s using he “d i i ”
ool om FSL so wa e sui e ( e sion 5.0.9) [38]. An addi-
ional desc ip o , he adial di usi i y (RD) was also calcu-
la ed as he a e age o he second and hi d eigen alues om
he di usion enso , also ob ained wi h “d i i ”.
Fo he pos e io s a is ical analysis, he a o emen ioned
di usion pa ame e s we e compa ed in di e se WM ac s.
Speci ically, ac -based spa ial s a is ics (TBSS) was used
as a p ocedu e o de ine a WM skele on whe e he alues
om he di usion pa ame e s a e assessed [39]. B ie ly, he
TBSS me hod consis s o a non-linea egis a ion o he FA
images o a empla e in he Mon eal Neu ological Ins i u e
(MNI) space wi h he FNIRT and FLIRT ools om FSL.
The egis e ed images we e a e aged, and a mean FA skel-
e on o he WM ac s was gene a ed using a FA alue o 0.2
as h eshold o dis inguish WM om GM. The TBSS p o-
cess was epea ed o he non-FA pa ame e s using he FA
egis a ion as e e ence. To iden i y speci ic WM egions,
he JHU ICBM-DTI-81 Whi e-Ma e A las was used [40,
41]. Mo eo e , he minimum olume pe egion o conside
s a is ically signi ican esul s was 30 mm3.
S a is ical analysis
The main objec i e o he analysis was he compa ison o he
pa ame e s o he COV pa ien s wi h heal hy con ols (HC).
To be e cha ac e ize he p ope ies o he COV g oup, hese
pa ien s we e compa ed agains EM, and CM. The de ailed
compa isons o GM and WM di usion desc ip o s be ween
he wo mig aine g oups and HC is a ailable elsewhe e [12,
18, 42].
Two-by- wo g oup compa isons o age and sex we e ca -
ied ou using he Mann–Whi ney U es and Fishe ’s exac
es , espec i ely.
Wi h ega d o he compa ison o he GM mo phome y
pa ame e s be ween he COV and HC g oups, da a we e
es ed o no mal dis ibu ion wi h he Shapi o–Wilk es . I
his assump ion was no me , a Mann–Whi ney U es was
applied. Fu he mo e, he homogenei y o a iance assump-
ion was es ed by he Le ene es . I no mali y assump ion
was me , a - es was used o compa e he alues be ween wo
g oups, conside ing equal o di e en a iance depending
on he esul s o he Le ene es . An analysis o co a iance
(ANCOVA) was always used o compa e GM olume alues
conside ing in ac anial olume as co a ia e o no in e es .
Fo any seconda y compa ison wi h he EM o CM g oups,
an ANCOVA was employed including age as co a ia e o
no in e es . As seconda y assessmen , sex was also added as
co a ia e o no in e es o he ANCOVA. In addi ion, o he
main compa isons be ween COV and HC, esul s we e also
co ec ed o age and sex ollowing he same ANCOVA p o-
cedu e conduc ed in he compa ison be ween COV and he
mig aine g oups. The Benjamini–Hochbe g False Disco e y
Ra e (FDR) p ocedu e was applied o co ec he esul s o
mul iple compa isons [43]. The h eshold o s a is ical sig-
ni icance was se a p < 0.05.
Rega ding he TBSS analysis o he di usion desc ip-
o s, he “ andomise” ool om FSL wi h he h eshold- ee
clus e enhancemen (TFCE) op ion was employed o de e -
mine he di e ences be ween he g oups o in e es [44, 45].
B ie ly, his ool is used o pe o m a pe mu a ion es . We
employed 5000 pe mu a ions and es ablished he s a is ical
h eshold o s a is ical signi icance a p < 0.05 a e applying
a amily-wise e o (FWE) co ec ion o mul iple compa i-
sons. Fo he compa isons be ween he COV g oup and he
EM and CM g oups, conside ing ha pa ien s om he i s
g oup a e, on a e age, olde han pa ien s wi h mig aine,
esul s we e age-co ec ed. As a seconda y analysis, in he
compa ison be ween COV and he o he h ee g oups, esul s
we e addi ionally co ec ed o sex.
In addi ion, o assess he magni ude o he iden i ied di -
e ences o he mo phome y and di usion pa ame e s, he
Cohen’s d was compu ed o he compa isons wi h s a is i-
cally signi ican di e ences. The alues employed o assess
each pa ame e and speci ic egion we e hose included in
he Desikan–Killiany a las o mo phome y, and he skel-
e on and a ea o each egion acco ding o he JHU ICBM-
DTI-81 a las o di usion pa ame e s. The pooled s anda d
de ia ion was compu ed as he squa ed oo o he addi ion
o he a iance o each assessed g oup mul iplied by he
pe inen sample size minus one di ided by he o al sample
size o he wo g oups minus wo. The inal Cohen’s d alue
was he di e ence be ween he mean alue o he wo g oups
di ided by he pooled s anda d de ia ion.
To assess he ela ionship be ween clinical pa ame e s
o COV pa ien s and g ay and whi e ma e desc ip o s,
Spea man’s ank co ela ion coe icien was employed. The
Jou nal o Neu ology
1 3
clinical a iables we e he disease du a ion and he head-
ache equency. The alues o he g ay ma e mo phome y
pa ame e s we e he same as hose used o he s a is ical
compa isons be ween g oups. Fo he whi e ma e desc ip-
o s, a ROI-based app oach was ca ied ou . Indi idual label
maps o each subjec we e ex ac ed applying he in e se
wa p ields o he egis a ion o he FA images desc ibed o
he TBSS p ocedu e o he JHU ICBM-DTI-81 a las. Fo he
g ay ma e and whi e ma e esul s, only he egions and
pa ame e s wi h s a is ically signi ican di e ences be ween
COV pa ien s and any o he g oup we e conside ed.
Resul s
In o al, 66 COV pa ien s we e ini ially ec ui ed. The inal
sample was composed o 42 COV pa ien s and 43 HC bal-
anced o age and sex. Median ime be ween onse o head-
ache a ibu ed o COVID-19 and MRI acquisi ion in COV
pa ien s was 10mon hs ( ange 3–20mon hs). In addi ion, 43
pa ien s wi h EM, and 43 pa ien s wi h CM we e conside ed.
Two pa ien s o each o he i s wo g oups we e disca ded
o he di usion MRI analysis due o egis a ion e o s. The
s udy lowcha de ailing he sample a each s age is shown
in Fig.1. The wo-by- wo compa isons o he demog aphic
cha ac e is ics be ween he COV g oup and he o he h ee
g oups a e a ailable in Table1. Fu he in o ma ion abou
speci ic clinical cha ac e is ics ela ed o headache in COV
pa ien s, i.e., pheno ype, loca ion, mean in ensi y, quali y,
and symp oms du ing headache, oge he wi h he p esence
o anosmia, is a ailable in Table2.
G ay ma e mo phome y pa ame e s
Compa ison be weenCOV andHC
Compa ed o HC, COV pa ien s showed s a is ically sig-
ni ican lowe GM olume in he bila e al pa s o bi alis
(co ec ed p = 0.029 le ; co ec ed p = 0.033 igh ), and
he igh usi o m gy us (co ec ed p = 0.033) and on al
pole (co ec ed p = 0.033). Mo eo e , pa ien s also p e-
sen ed lowe co ical hickness han HC in he igh pa s
o bi alis (co ec ed p = 0.008). No s a is ically signi ican
di e ences we e ound in co ical cu a u e o su ace
Fig. 1 Flowcha o he s udy. The numbe o pa ien s wi h pe sis en headache a e COVID-19 esolu ion and heal hy con ols is di e en in he
g ay ma e and whi e ma e assessmen s due o egis a ion e o s wi h he di usion images o una ailable di usion MRI acquisi ions

Jou nal o Neu ology
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a ea. The loca ion o hese indings is g aphically shown
in Fig.2. A e he co ec ion o age and sex, hese esul s
we e s a is ically signi ican , and, addi ionally, lowe co -
ical hickness alues we e ound in COV compa ed o
HC in he le os al an e io cingula e gy us (co ec ed
p = 0.024).
Compa ison be weenCOV andmig aine
Rega ding he di e ences be ween COV and EM pa ien s
a e co ec ing o age, signi ican ly highe co ical hick-
ness (co ec ed p = 0.012) in he le pa acen al co ex,
and lowe subco ical olume alues in he le accumbens
(co ec ed p = 0.022) and he igh halamus (co ec ed
Table 1 Clinical and demog aphic cha ac e is ics o pa ien s wi h pe sis en headache a e COVID-19 esolu ion, heal hy con ols (HC), epi-
sodic mig aine (EM) and ch onic mig aine (CM) pa ien s
† Fishe ’s exac es . ‡Mann–Whi ney U es . §Two- ailed, unpai ed S uden ’s - es (Welch es ). 1. COVID-19 headache s. HC. 2. COVID-19
headache s. EM. 3. COVID-19 headache s. CM. Da a a e exp essed as means ± SD. The pheno ype o he does no adhe e o mig aine o TTH
ollowing ICHD-3 guidelines. TTH = ension- ype-headache
COVID-19 headache (n = 42) HC (n = 43) EM (n = 43) CM (n = 43) S a is ical es
Gende , male/ emale 11/31 (26/74%) 11/32 (26/74%) 9/34 (21/79%) 6/37 (14/86%) 1. p = 1†
2. p = 0.62†
3. p = 0.18†
Age (yea s) 43.8 ± 10.2 41.8 ± 10.2 40.1 ± 6.4 41.3 ± 7.1 1. U = 1015, p = 0.33‡
2. = 2.00, p = 0.049§
3. U = 1110, p = 0.070‡
Disease du a ion 10.1 ± 3.4mon hs 16.0 ± 11.4yea 21.9 ± 10.2yea
Headache equency (days/mon h) 30 ± 0 3.5 ± 1.9 22.8 ± 6.7
Di usion MRI sample n = 40 n = 41 n = 43 n = 43
Gende , male/ emale 11/29 (28/72%) 11/30 (27/73%) 9/34 (21/79%) 6/37 (14/86%) 1. p = 1†
2. p = 0.61†
3. p = 0.17†
Age (yea s) 43.7 ± 10.3 41.0 ± 9.6 40.1 ± 6.4 41.3 ± 7.1 1. U = 959, p = 0.19‡
2. = 1.90, p = 0.062§
3. U = 1050, p = 0.084‡
Disease du a ion 10.2 ± 3.5mon hs 16.0 ± 11.4yea 21.9 ± 10.2yea
Headache equency (days/mon h) 30 ± 0 3.5 ± 1.9 22.8 ± 6.7
Table 2 Speci ic clinical
cha ac e is ics ela ed o
headache o pa ien s wi h
pe sis en headache a e
COVID-19 esolu ion
Mean in ensi y was exp essed as mean ± SD. The pheno ype o he does no adhe e o mig aine o TTH ol-
lowing ICHD-3 guidelines. TTH = ension- ype-headache. Anosmia was no a cha ac e is ic di ec ly ela ed
o headache, bu i was included due o i s ela ionship wi h COVID-19
Headache cha ac e is ic Full sample (n = 42) Di usion MRI sample (n = 40)
Pheno ype, mig aine/TTH/o he 20/13/9 (47.6/31.0/21.4%) 20/12/8 (50/30/20%)
Mean in ensi y (1–10) 7.3 ± 1.6 7.4 ± 1.6
Anosmia 22 (52.4%) 21 (52.5%)
Loca ion
Hemic anial 10 (23.8%) 9 (22.5%)
Holoc anial 31 (73.8%) 30 (75%)
Quali y
P essing 30 (71.4%) 28 (70%)
Th obbing 20 (47.6%) 20 (50%)
Bu ning 1 (2.4%) 1 (2.5%)
Symp oms du ing headache
Pho o- and phonophobia 21 (50%) 20 (50%)
Nausea o omi ing 16 (38.1%) 16 (40%)
Agg a a ed by mo emen 22 (52.4%) 21 (52.5%)
Jou nal o Neu ology
1 3
p = 0.025) we e obse ed in he COV g oup. No s a is ically
signi ican di e ences we e iden i ied in co ical cu a u e o
su ace a ea. The egions wi h s a is ically signi ican di e -
ences we e he same a e addi ionally co ec ing he esul s
o sex.
Wi h espec o he compa ison be ween COV and CM
pa ien s a e co ec ing o age, s a is ically signi ican
di e ences we e ound o e e y pa ame e excep he
su ace a ea. Fi s , lowe co ical cu a u e alues in he
le cuneus (co ec ed p = 0.007) and he igh p ecuneus
(co ec ed p = 0.028) we e obse ed in COV pa ien s.
Also, highe co ical GM olume in he le caudal mid-
dle on al gy us (co ec ed p = 0.012), pa acen al co ex
(co ec ed p = 0.032) and pos e io cingula e gy us (co -
ec ed p = 0.038) we e ound in COV pa ien s. Mo eo e ,
highe co ical hickness in he le banks o he supe-
io empo al sulcus (co ec ed p = 0.007) and pa acen-
al co ex (co ec ed p = 0.007) we e iden i ied in COV
pa ien s. The egions wi h s a is ically signi ican di e -
ences emained he same a e addi ionally co ec ing he
esul s o sex.
A summa y o hese esul s can be ound in Fig.3,
and de ailed esul s conside ing all g oups a e a ailable
in he Supplemen a y ma e ial (Tables S1–3). Rega ding
he e ec size o he compa isons wi h signi ican di e -
ences, all he alues we e in he ange o medium e ec
size (0.5 ≤ d < 0.8), as shown in Fig.4.
Fig. 2 G ay ma e egions ha p esen s a is ically signi ican
changes be ween pa ien s wi h pe sis en headache a e COVID-
19 esolu ion (COV) and heal hy con ols (HC). A e alse disco -
e y a e co ec ion, COV pa ien s showed lowe g ay ma e olume
(GMV) and co ical hickness (CT) han HC. L le , R igh . These
esul s we e also s a is ically signi ican a e co ec ing o age and
sex. Addi ional esul s a e his co ec ion a e no shown
Jou nal o Neu ology
1 3
Compa ison be weenpa ien s wi hmig aine andHC
The esul s o he compa isons be ween CM, EM and HC,
which a e no he ocus o his s udy, ha e been published
elsewhe e, employing a highe sample size and balancing
age and sex acco ding o he mig aine pa ien s’ cha ac e -
is ics [12]. To be e unde s and he esul s o his esea ch,
we he e summa ize hese esul s. B ie ly, co ical cu a u e
was highe and co ical hickness, su ace a ea and co ical
GM olume we e lowe in bo h mig aine g oups compa ed
o HC. Cu a u e alues we e highe in mig aine pa ien s in
egions such as he cingula e gy us, la e al occipi al co ex,
he p ecuneus and he pa acen al co ex. Co ical hickness
was lowe in pa ien s, wi h highe le el o signi icance, in
he in e io empo al and usi o m gy i. GM olume and
su ace a ea we e commonly lowe in pa ien s in he insula,
he supe io empo al gy us, pa s iangula is and pa s o bi -
alis, and addi ionally lowe a ea alues we e ound in he
p ecuneus, cingula e gy us, sup ama ginal gy us and di e se
on al, empo al and pa ie al gy i. Mo eo e , GM olume
and widesp ead su ace a ea egions p esen ed lowe alues
in CM compa ed o EM, in con as o co ical hickness, o
Fig. 3 G ay ma e egions ha p esen s a is ically signi ican
changes be ween pa ien s wi h pe sis en headache a e COVID-19
esolu ion (COV) and pa ien s wi h episodic mig aine (EM) and/o
ch onic mig aine (CM). A e alse disco e y a e co ec ion, COV
pa ien s showed highe co ical g ay ma e olume (GMV) and co -
ical hickness (CT) han EM and CM, lowe subco ical GMV han
EM, and lowe co ical cu a u e (CC) han CM. L le , R igh
Jou nal o Neu ology
1 3
which highe alues we e iden i ied in CM in he in e io
empo al gy us.
Di usion pa ame e s inwhi e ma e
Compa ison be weenCOV andHC
S a is ically signi ican lowe FA was ound in COV com-
pa ed o HC in 15 egions, and in 7 addi ional egions a e
co ec ing o sex. These egions we e he in e nal and
ex e nal capsule, he ce eb al peduncle, he co icospinal
ac , he bila e al co ona adia a, he co pus callosum, he
halamic adia ion, he supe io longi udinal asciculus, and
he supe io on o-occipi al asciculus. In addi ion, highe
RD alues we e ound in COV pa ien s in h ee egions om
he le hemisphe e, and in eigh addi ional le egions a e
co ec ing o sex: supe io longi udinal asciculus, co ona
adia a, he ex e nal and in e nal capsule, he ce eb al pedun-
cle, and he sagi al s a um. These FA and RD di e ences
a e shown in de ail in Fig.5, showing he di e ences o
each egion in Tables S4–7.
Figu e6 shows a g aphical depic ion o hese WM
changes. The dis ibu ion o he alues o he ou DTI
pa ame e s o COV and HC g oups is shown o he h ee
egions wi h RD signi ican di e ences and he le e o-
len icula pa o in e nal capsule. These ou egions a e
ep esen ed o obse e he dis ibu ion o he alues o all
he RD di e ences and he egion wi h he highes e ec size
in he FA compa ison, o be e app ecia e he FA di e ences
be ween g oups. In o de o gain insigh abou he di ec ion
and magni ude o hese di e ences, Fig.7 p esen s he p es-
ence o absence o s a is ically signi ican changes o each
WM egion, oge he wi h hei di ec ion and Cohen’s d. The
e ec size o he iden i ied di e ences was e y low (d < 0.2)
excep o compa isons in ol ing he in e nal capsule.
Compa ison be weenCOV andmig aine
Widesp ead s a is ically signi ican di e ences we e ound
be ween he COV g oup and pa ien s wi h EM and CM
conside ing he ou WM desc ip o s ha we e employed
(Fig.7).
Rega ding FA, COV pa ien s showed lowe alues han
EM and CM in 15 (also in i e addi ional egions a e co -
ec ion o sex) and 17 egions (also in one addi ional egion
a e co ec ion o sex), espec i ely. Fo all FA compa i-
sons, he main egions wi h di e ences we e he co pus cal-
losum, bila e al co ona adia a, and le ex e nal and in e nal
capsule, le ce eb al peduncle, and le halamic adia ion,
inding addi ional di e ences in he le supe io longi udi-
nal asciculus in he compa ison wi h EM.
Wi h espec o he AD, COV pa ien s p esen ed s a is i-
cally signi ican lowe alues in compa ison wi h EM in 39
egions (same numbe a e co ec ing o sex), in 14 egions
compa ed o CM, mos ly in he igh hemisphe e, and in 8
ou o hese 14 egions a e co ec ing o sex. The main
bila e al egions whe e di e ences agains CM and EM we e
obse ed we e he ce ebella and ce eb al peduncles, he
in e nal capsule, and he halamic adia ion. Mo eo e , di -
e ences agains EM we e also ound in he co pus callosum,
co ona adia a, co icospinal ac , supe io longi udinal as-
ciculus, ex e nal capsule, and halamic adia ion.
S a is ically signi ican lowe MD alues we e ound
in COV pa ien s wi h espec o EM, in 25 egions (in
h ee egions less a e co ec ion o sex), and CM, in 14
egions (in i e egions less a e co ec ion o sex). Mos
Fig. 4 Cohen’s d alues o he compa isons wi h s a is ically sig-
ni ican di e ences o g ay ma e mo phome y pa ame e s. Cells in
ed e lec compa isons wi h lowe alues in pa ien s wi h pe sis en
headache a e COVID-19, while cells in g een e lec he opposi e
end. *Resul s ob ained exclusi ely when adding sex as a co a ia e
Jou nal o Neu ology
1 3
COV pa ien s would p esen some p ope ies ela ed o a
si ua ion simila bu milde han EM. A hypo hesis ha may
explain his si ua ion is ha changes in he a o emen ioned
di ec ion could be ela ed o he e ec o ime, conside ing
ha pa ien s wi h mig aine ha e su e ed om headaches a
longe ime compa ed o he COV pa ien s. Mo eo e , i is
in e es ing o no e ha FA and RD di e ences be ween COV
pa ien s and con ols we e ound in he le hemisphe e. On
he o he hand, lowe MD and RD alues in COV pa ien s
compa ed o mig aine pa ien s we e iden i ied in he igh
hemisphe e, al hough highe RD alues we e also ound
mos ly in ew le hemisphe e egions in COV pa ien s com-
pa ed o CM only a e co ec ing he esul s o sex.
Wi h ega d o he addi ional di e ences ound in he
compa ison be ween pa ien g oups, and in line wi h p e i-
ous s udies wi h he same coho o mig aine pa ien s, COV
pa ien s showed simila AD di e ences compa ed o hose
ound in CM wi h espec o EM, wi h widesp ead lowe
AD alues [18, 42, 46]. Thus, COV pa ien s p esen ed a
si ua ion simila o CM, wi h a possible in ensi ied com-
ponen o he axial di usion. This e ec sugges s ha he
axial pa ame e s could be highly ela ed o he headache e-
quency. CM and COV pa ien s p esen a high headache e-
quency, wi h 15 o mo e a acks pe mon h and almos e e y
day, espec i ely [9]. In ac , in he sample employed in his
s udy, all COV pa ien s su e ed om daily headache. On
he con a y, pa ien s wi h EM, especially excluding pa ien s
wi h high- equency EM (mo e han eigh headache days
pe mon h), p esen ed opposi e alues in compa ison wi h
he o he wo headache g oups. This e ec is in line wi h
he la es mig aine s udies assessing AD in pa ien s wi h
EM [16, 18, 59, 60]. Thus, in ela ion o he almos daily
headache a acks o COV pa ien s, he pe manen ac i a-
ion o he b ain can cause speci ic changes possibly associ-
a ed wi h axonal damage o loss, o sho - e m demyelina-
ion [48, 61–63]. Conside ing he di e ences be ween he
headache g oups, we expec ed di e ences in AD be ween
COV pa ien s and HC, bu we ob ained no s a is ically sig-
ni ican esul s. The eason o his lack o di e ences may
be associa ed wi h he highe age o con ols in his s udy,
which may be a key ac o in he changes o di usion in
he main o axonal di ec ion. Ne e heless, o conside he
po en ial di e ences caused by he age di e ence, esul s
we e co ec ed by age. In heal hy adul s, i has been epo ed
ha AD signi ican ly changes wi h age. In egions such as
he co ona adia a, which p esen ed s a is ically signi ican
di e ences in COV pa ien s acco ding o ou esul s, AD
has been epo ed o dec ease wi h age in adul s [64]. This
esul seems o be in line wi h ou co ela ion esul s in COV
pa ien s, as we ound a nega i e co ela ion be ween disease
du a ion and mean AD alues in he pos e io co ona adia a.
Howe e , he opposi e esul s ha e also been epo ed in GM
and o he WM egions such as he o nix [64, 65].
GM esul s showed a simila se o di e ences in com-
pa ison wi h he desc ibed RD and MD di e ences in WM,
i.e., a si ua ion analogous bu milde han EM. In con as
o a p e ious s udy ha iden i ied di e ences mo phome y
pa ame e s be ween pa ien s wi h mig aine (EM and CM)
and con ols in di e se egions, s a is ically signi ican di -
e ences we e de ec ed in a small g oup o egions [12].
The numbe o egions wi h signi ican di e ences was pa -
icula ly small be ween EM and COV pa ien s. Since COV
pa ien s p esen a smalle deg ee o changes wi h espec
o HC, he e ec o ime may be impo an in GM changes.
No able limi a ions a e p esen in his s udy. Fi s ,
he e we e no baseline MRI acquisi ions o he COV
pa ien s. This implies ha we we e unable o obse e he
e ec s o he pe sis en headache be o e, du ing and a e
he in ec ion o de e mine he changes associa ed wi h
each pa hophysiological mechanism. To compensa e he
lack o longi udinal da a, we compa ed he main g oup
o in e es no only wi h heal hy con ols, bu also wi h
he wo cu en ly dis inguished mig aine ypes, EM and
CM. Howe e , pa ien s wi h mig aine, especially EM, a e
younge han COV pa ien s. Despi e all compa isons wi h
mig aine g oups we e co ec ed o age, his ac o could
ha e in luenced he esul s. Mo eo e , due o he age di -
e ence be ween he pa ien g oups, he con ols included
in his s udy we e olde wi h espec o p e ious s udies
whe e he a ge was he compa ison wi h pa ien s wi h
mig aine [12, 18, 42]. The ema kable di e ence o age
o he con ol g oups migh ha e al e ed he es ablished
hypo hesis ega ding he di e ences o he di e se pa ame-
e s be ween con ols and each pa ien g oup. We p e e ed
o ollow he esul s om p e ious s udies wi h he same
pa ien s o a oid any po en ial bias in he esul s caused
o employing con ols no balanced o age and sex in
compa ison wi h pa ien s wi h mig aine. Conside ing he
di e se pheno ypes o headache in he pa ien s who eco -
e ed om COVID-19, an assessmen o he di e ences
be ween he mig aine and con ol g oups and each long-
e m headache ype was no conduc ed. The eason was
ha we p e e ed o p ese e a g oup wi h a ela i ely high
sample size, as changes in headache diso de s ha e been
epo ed o be sub le and he e o e a small sample size can
be insu icien o iden i y s a is ically signi ican di e -
ences. Due o he lack o in lamma ion bioma ke s a he
di e se imepoin s o he ollow-up pe iod, we could no
clea ly es ablish whe he changes a e s ongly associa ed
wi h he COVID-19 in ec ion o mo e ela ed o headache.
In addi ion, no T2-weigh ed o FLAIR images we e a ail-
able in ei he he con ols o he pa ien s wi h mig aine.
Conside ing he po en ial ela ionship be ween WM hype -
in ensi ies and WM in eg i y, and also he iden i ica ion o
hese indings in pa ien s wi h mig aine [66–68], we we e
unable o assess a possible ac o ha migh in luence he

Jou nal o Neu ology
1 3
esul s. Finally, since ec ui men o he COV g oup was
pe o med ea ly in he COVID-19 pandemic e olu ion,
no gene aliza ion can be made wi h ega d o he possible
e ec s o o he COVID-19 a ian s such as del a o omi-
c on, o he e ec o accina ion o ein ec ion.
Conclusions
Pa ien s wi h pe sis en headache a e COVID-19 esolu-
ion showed di e se changes in GM and WM s uc u e.
Changes in GM we e sub le and a ec ed an e io a eas,
including he pa s o bi alis, he usi o m gy us and he
on al pole. On he one hand, he obse ed WM changes
we e di use, in ol ed mos o he WM ac s and seemed
ela ed o he impai men o WM ibe bundles. On he
o he hand, he WM changes p esen ed a si ua ion analo-
gous bu milde han mig aine. Fu u e s udies a e needed
o disc imina e long- e m and e ol ing changes associ-
a ed wi h COVID-19 in ec ion and headache o assess he
di e ences be ween long- e m headache pheno ypes a e
COVID-19 eco e y.
Supplemen a y In o ma ion The online e sion con ains supplemen-
a y ma e ial a ailable a h ps:// doi. o g/ 10. 1007/ s00415- 022- 11398-z.
Acknowledgemen s ÁP-G was unded by he Eu opean Union
(Nex Gene a ionEU).
Au ho con ibu ions ÁP-G: Analyzed and in e p e ed he da a; s a is-
ical analysis; MRI p ocessing; c ea ion o igu es; d a ed he manu-
sc ip ; e ised he manusc ip o in ellec ual con en . DG-A: S udy
concep and design; analyzed and in e p e ed he da a; ec ui men o
pa icipan s; d a ed he manusc ip ; e ised he manusc ip o in el-
lec ual con en ; s udy supe ision. ÁLG: S udy concep and design;
analyzed and in e p e ed he da a; ec ui men o pa icipan s; e ised
he manusc ip o in ellec ual con en . MR: Analyzed and in e p e ed
he da a; e ised he manusc ip o in ellec ual con en . SA-F: Ana-
lyzed and in e p e ed he da a; c ea ion o igu es; e ised he manu-
sc ip o in ellec ual con en . RL-G: Analyzed and in e p e ed he
da a; ec ui men o pa icipan s; d a ed he manusc ip ; e ised he
manusc ip o in ellec ual con en .
Funding Open Access unding p o ided hanks o he CRUE-CSIC
ag eemen wi h Sp inge Na u e. The s udy was unded by he Regional
Heal h Adminis a ion—Ge encia Regional de Salud, Cas illa y Leon
(GRS 2284/A/2020).
A ailabili y o da a and ma e ials The da a ha suppo s he indings
o his s udy a e a ailable om he co esponding au ho , upon eason-
able eques .
Decla a ions
Con lic s o in e es The au ho s epo no compe ing in e es s.
E hical app o al and consen o pa icipa e The E hics Re iew Boa d
o Valladolid Eas heal h a ea app o ed his s udy (PI-GR-20-2017).
All pa icipan s signed an in o med consen be o e hei pa icipa ion
in he s udy.
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