Resea ch A icle
CPAP T ea men Pa ly No malizes Sleep Spindle Fea u es in
Obs uc i e Sleep Apnea
Tiia Saunamäki,1Ee o Huupponen,2Juho Loponen,3and Sa i-Leena Himanen2,3
1Depa men o Neu ology and Rehabili a ion, Tampe e Uni e si y Hospi al, Tampe e, Finland
2Depa men o Clinical Neu ophysiology, Medical Imaging Cen e and Hospi al Pha macy, Pi kanmaa Hospi al Dis ic ,
Tampe e, Finland
3Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland
Co espondence should be add essed o Sa i-Leena Himanen; sa i-leena.himanen@u a. i
Recei ed 28 Oc obe 2016; Re ised 26 Decembe 2016; Accep ed 15 Janua y 2017; Published 2 Feb ua y 2017
Academic Edi o : Ma co Zucconi
Copy igh © 2017 Tiia Saunam¨
aki e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License,
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Objec i e. Obs uc i e sleep apnea (OSA) dec eases sleep spindle densi y and equency. We e alua ed he e ec s o con inuous
posi i e ai way p essu e (CPAP) ea men on di e en ea u es o sleep spindles. Me hods. Twen y OSA pa ien s unde wen wo
nigh polysomnog aphies in a diagnos ic phase and one nigh polysomnog aphy a e 6 mon hs o CPAP ea men . The con ol
g oup comp ised 20 heal hy con ols. Sleep spindles we e analyzed by a p e iously de eloped au oma ed me hod. Unila e al and
bila e al spindles we e iden i ied in cen al and on opola b ain loca ions. Spindle densi y and equency we e de e mined o
he i s and las hal o he NREM ime. Resul s. The densi y o bila e al cen al spindles, which did no change in he un ea ed
OSA pa ien s, inc eased owa ds he mo ning hou s du ing CPAP ea men and in he con ols. Cen al spindles did no become
as e wi h sleep in OSA pa ien s and he cen al spindles emained slow in he le hemisphe e e en wi h CPAP. Conclusion.
CPAP ea men no malized spindle ea u es only pa ially. The changes may be associa ed wi h de ici s in halamoco ical spindle
gene a ing loops. Signi icance. This s udy shows ha some sleep spindle changes pe sis a e CPAP ea men in OSA pa ien s. The
associa ion o hese changes o day ime symp oms in OSA pa ien s needs o be u he e alua ed.
1. In oduc ion
By s anda d de ini ion, sleep spindles a e composed o
ansien elec oencephalog aphy (EEG) oscilla ions in he
equency ange o 11 Hz o 16 Hz las ing a leas 0.5 s [1].
In heal hy subjec s, as e spindles o spindle ac i i y occu
mo e o en in he pa ie al a ea, while slowe spindles a e
mo e p e alen in he on al egions [2–8]. The in aspindle
equency inc eases du ing he mo ning hou s [2, 9]. Pa ic-
ula ly he cen al spindles occu in pe iodic sequences which
a e ound o be mo e equen a he mo ning hou s [10].
Spindles a e abundan in ligh non-REM (NREM) sleep
and a e supposed o p e en a ousing s imuli om eaching
heco ex[11], husensu ingsolidsleep[2].Mo e ecen ly,
spindles ha e been ound o play an impo an ole in many
b ain unc ions such as in lea ning and memo y p ocesses
[12]. These unc ions seem o be dependen on he long-
e m po en ia ion (LTP) induced by he spindle bu s s [13]. In
pa icula , he as spindles (usually >13 Hz) ha e been ound
o ha e an impo an ole in connec ing he hippocampus and
heneoco exandin ans e ing empo a yhippocampal
memo ies o he neoco ex o s o age [14, 15]. In addi ion,
local spindles ha e been p esen ed o a ise in co ical a eas
ha we e ac i e in mo o o isuomo o asks du ing p eced-
ing wake ulness [16, 17].
Obs uc i e sleep apnea (OSA) is cha ac e ized by epe -
i i e episodes o uppe ai way obs uc ion du ing sleep
and esul s in oxygen desa u a ion and a ousals om sleep.
In OSA pa ien s, spindle densi y dec eases, he pe cen age
o slow spindles inc eases, and he spindles emain slow
h oughou he nigh [18–20]. Con inuous posi i e ai way
p essu e (CPAP) ea men is a i s -line he apy in mod-
e a e and se e e OSA. CPAP ea men educes obs uc i e
b ea hing e en s and no malizes oxyhemoglobin sa u a ion
and sleep agmen a ion. The esul o CPAP ea men is
imp o ed sleep quali y and educed day ime symp oms.
Hindawi
Sleep Diso de s
Volume 2017, A icle ID 2962479, 10 pages
h ps://doi.o g/10.1155/2017/2962479
2Sleep Diso de s
Howe e ,someday imesymp omssuchascogni i ede ici s
seem o emain [21, 22]. The e ec o CPAP ea men
on spindle ac i i y in OSA pa ien s is, howe e , an open
ques ion.
In he p esen s udy, i is assumed ha CPAP mos ly
no malizes he dis u bed sleep spindle p ocess in OSA bu
ha some impai men in he spindle p ocess may s ill emain.
Since many spindle ea u es change dynamically du ing
noc u nal sleep [9], spindle ea u es a e e alua ed in he i s
and las pa o he noc u nal NREM sleep.
2. Ma e ials and Me hods
Thes udycoho included20maleOSApa ien sand20age-
ma chedheal hycon ols.Thepa ien shadbeen e e ed o
he sleep labo a o y because o suspec ed OSA. All pa ien s
me he diagnos ic c i e ia o OSA, and hei i s ea men
choice was CPAP. The con ol subjec s we e heal hy olun-
ee s ec ui ed h ough ad e isemen s. They we e no paid
o hei pa icipa ion in he s udy.
Bo h pa ien s and con ols we e i s in e iewed o
ensu e hey me he ini ial eligibili y c i e ia: wo king-aged,
igh -handed, no (o he ) sleep diso de s, no clinically sig-
ni ican medical diso de (e.g., neu ological o psychia ic
disease, hypo/hype hy oidism, o lung disease o he han
asymp oma ic as hma), and no subs ance o alcohol abuse.
Bo h s udy g oups unde wen a clinical in e iew and
diagnos ic polysomnog aphy (PSG) in a sleep labo a o y. The
OSA diagnosis was based on a clinical pic u e, subjec i e
complain s and an apnea/hypopnea index (AHI) alue o >10
pe hou o sleep.Thecon olshad obeasymp oma icand
ha e an AHI alue o <5 pe hou o sleep. The pa ien s and
con ol subjec s who, acco ding o he esul s o he i s all-
nigh diagnos ic PSG, me he eligibili y c i e ia unde wen a
second all-nigh PSG, and he da a om his nigh we e used
in he analysis.
A e 6 mon hs o CPAP ea men , he pa ien s unde -
wen a hi dPSG.Objec i eCPAPcompliancemeasu eswe e
downloaded om he de ices and he minimum equi ed
CPAP adhe ence was se a 4 hou s pe nigh and a leas 5
nigh s pe week. All pa ien s me he CPAP adhe ence c i e ia
and we e included in o he analyses. The s udy was app o ed
by he E hical Commi ee o he Pi kanmaa Hospi al Dis ic
and all subjec s ga e hei w i en in o med consen .
2.1. Reco dings and Visual Analysis. Subjec s wen o sleep
be ween 10 pm and 12 pm, acco ding o hei own habi ual
bed imes. Six EEG de i a ions (Fp1-A2, Fp2-A1, C3-A2, C4-
A1, O1-A2, and O2-A1), wo elec ooculog aphy channels,
submen al muscle onus, elec oca diog am, ai low p essu e
by nasal ansduce , he mis o , ho acoabdominal espi a-
o y mo emen s, and blood oxygen sa u a ion we e eco ded.
In addi ion, anscu aneous ca bon dioxide ension, leg
mo emen s, body posi ion and body mo emen s we e also
eco ded. Polysomnog aphies we e eco ded wi h an Embla
N7000 de ice (Embla, Na us Medical Inc., USA). The EEG
signalswe esampleda 200Hz(16bi s)wi habandwid ho
0.3 Hz o 90 Hz.
As he s udy began be o e he e ision o he sleep
s aging ules, he on opola EEG channels Fp1 and Fp2
we e used ins ead o he on al channels F3 and F4 ha
a e ecommended nowadays. The sleep s aging was, howe e ,
pe o med in acco dance wi h he ules es ablished by he
AASM in 2007 [23] wi h he excep ion o he EEG channels.
Somnologicaso wa e (Medca e/Flaga, Iceland) was used
o he isual analyses. The second diagnos ic nigh and he
ea men nigh we e classi ied by wo independen sco e s
in o s ages. The le el o ag eemen be ween he 2 sco e s was
86.4% (𝐾= 0.76). Based on he independen sco ings, he
consensus sleep s aging was o med and used in he s a is ical
analyses.TheAHI aluewascalcula edas henumbe o
obs uc i e apneas and hypopneas (las ing ≥10 s) pe hou
o sleep. Obs uc i e apneas we e de ined as a leas a 90%
educ ion in he he mal signal ampli ude, whe eas hypop-
neas we e de ined as diminu ion o a leas 30% o he nasal
p essu e signal ha was associa ed wi h an a ousal o desa u-
a ion o 3% [24]. Mic oa ousals we e sco ed acco ding o he
c i e ia o he Ame ican Sleep Diso de s Associa ion [25].
In he diagnos ic nigh , 20 pa ien s had an AHI alue
o ≥10/h (p e-CPAP g oup). Thei sleep pa ame e s and
spindle ea u es we e compa ed wi h he pa ame e s o he
age-ma ched heal hy olun ee s (con ol g oup). A e 6
mon hs o CPAP ea men , he pa ien s unde wen ano he
polysomnog aphy and he alues o ha nigh (CPAP g oup)
we e compa ed wi h he p e-CPAP alues and wi h he alues
o he con ol g oup.
2.2. Spindle Analysis. Spindles we e analyzed by applying
p e iously de eloped au oma ed spindle analysis me hods
[3, 26]. The main componen o hese me hods is a sigma
index ha is based on he as Fou ie ans o m (FFT). The
equency band o 10.5 Hz o 16 Hz was used in compu ing
he sigma index. A high sigma index alue indica es a high
p obabili yo aspindleand ice e sa,and u he indica es
how dominan he spindle peak is when compa ed wi h o he
EEG ac i i ies. Sigma index alues o e 4.5 gene ally indica e
spindles [26]. The sigma index has buil -in a i ac ejec ion
unc ionali ies[3],andi canalsobecomplemen edwi h
spindle ampli ude in o ma ion [26].
In he p esen wo k, he wo cen al (C3-A2, C4-A1) and
he wo on opola (Fp1-A2, Fp2-A1) EEG channels we e
analyzed sepa a ely. Thus, he p e ious me hod, desc ibed
p e iously [3] needed some mino adjus men s. As a esul ,
wo EEG channels we e p ocessed a a ime ins ead o ou .
The NREM sleep ime was included in he p esen analysis.
Asa i s s ep, hep ocedu ede ailedin he o me wo k[26]
was used o ob ain a eco ding-speci ic ampli ude h eshold
o he b ain egion ( wo EEG channels) by es ima ing he
lowe limi o he spindle ampli udes. Then, in o de o de ec
a spindle ( om one EEG channel a a ime), he sigma
index had o exceed 4.5 and also he ampli ude h eshold
had o be exceeded a he same ime ins an (as in Sec ion
2.2.4 in [3]). The ini ial spindle de ec ion, ob ained a 0.33-s
ime esolu ion, was hen p ocessed u he , and in his way
indi idual unila e al (as in Sec ion 2.2.5 in [3] using m om
one EEG channel a a ime) and bila e al (as in Sec ion 2.2.6
in [3] wi h 𝐷=1) spindles we e iden i ied.
Sleep Diso de s 3
Table 1: Median and ange o he sleep pa ame e s in he s udy g oups and he 𝑝 alues o he compa isons.
Con ols P e-CPAP CPAP Con ols e sus
p e-CPAP1Con ols e sus
CPAP1P e-CPAP e sus
CPAP2
Median Range Median Range Median Range 𝑝 alue 𝑝 alue 𝑝 alue
Age 48.5 34–60 50.0 37–65 0.170
BMI 24.9 20.1–30.2 29.6 24.7–41.4 <0.001
TST min 431.5 348–527 435.8 375–532 395 264–503 0.344 0.256 0.006
SEI% 90.6 76.7–97.1 93.2 80.0–97.5 92.0 58.2–97.0 0.417 0.946 0.322
N1% 5.4 2.2–16.3 5.0 1.2–11.2 4.8 1.5–16.1 0.285 0.617 0.490
N2% 60.0 45.4–71.6 73.0 59.5–85.3 68.0 46.8–79.0 <0.001 0.016 0.005
N3% 12.5 2.1–25.4 2.6 0.0–14.1 6.6 0.6–29.3 <0.001 0.029 0.002
REM% 20.0 13.1–27.8 16.8 8.6–27.3 17.6 11.4–26.4 0.117 0.285 0.563
SL min 8.3 3.5–32.5 6.3 1.0–33.0 4.5 2.0–22.0 0.163 0.014 0.162
AHI 𝑛/h 1.8 0.0–4.9 42.0 14.0–103.0 0.7 0.0–14.0 <0.001 0.080 <0.001
ARI 𝑛/h 12.8 4.3–22.8 30.0 8.0–99.6 16.0 4.6–27.0 <0.001 0.152 <0.001
ODI4 𝑛/h 0.5 0.0–6.0 34.0 0.0–88.0 0.8 0.0–3.0 <0.001 0.496 <0.001
Sa02min% 91.0 83.0–95.0 79.0 62.0–92.0 90.5 84.0–94.0 <0.001 0.713 <0.001
Sa02mean% 95.9 93.0–97.0 93.6 83.1–97.5 96.1 93.3–97.3 <0.001 0.551 <0.001
1Mann-Whi ney 𝑈 es ; 2Wilcoxon es . The Bon e oni co ec ed 𝑝 alues a e epo ed: Bon e oni co ec ion ac o = 3.
BMI = body mass index; min = minu es; n/h = numbe /hou ; TST = o al sleep ime; SEI%= sleep e iciency index; N1%–N3%= ime pe cen age o sleep
s ages N1–N3 e e ed o as TST; REM%= ime pe cen age o REM sleep e e ed o as TST; SL = sleep la ency; AHI = apnea/hypopnea index; ARI = a ousal
index; ODI4 = oxygen desa u a ion index; Sa02min%= minimum oxygen sa u a ion pe cen age; Sa02mean%= mean oxygen sa u a ion pe cen age. Bold on
= s a is ically signi ican 𝑝 alue.
Spindle ea u es we e hen de i ed. These ea u es
included spindle densi y (numbe o spindles pe hou o
NREM sleep) and median o he in aspindle equency
alues (10.5 Hz o 16 Hz, numbe o cycles pe second, in
Hz; in bila e al spindles he equency alues we e calcula ed
o bo h hemisphe es sepa a ely) du ing NREM sleep. In
addi ion, he bila e ali y index (C bil index 1 = he numbe o
bila e al cen al spindles di ided by he numbe o unila e al
C4 spindles (bil C/C4), C bil index 2 = bil C/C3, Fp bil index
1 = bil Fp/Fp2, Fp bil index 2 = bil Fp/Fp1) o he spindles
was calcula ed. I he bila e ali y index is <1, he spindles a e
mo e o en unila e al han bila e al. Finally, he ime occupied
by spindle sequences (as a pe cen age o NREM ime, a leas
h ee consecu i e spindles, wi h in e spindle in e al ≤5s)
was calcula ed.
As spindle ea u es a e ound o change dynamically
du ing henigh ,wecalcula edallspindle ea u essepa a ely
o he i s and las pa o noc u nal NREM sleep. Fo his,
he NREM ime was di ided in o wo. The di ision was made
a he hal -way poin be ween he i s and las second o he
NREM sleep.
The ob ained ampli ude h eshold o he on opola
spindles was 9.6 𝜇V in he con ol g oup (median, ange 6.5 o
13.3), 10.6 𝜇V(7.4 o15.2)in hep e-CPAPg oup,and10.0𝜇V
(6.9 o 14.6) in he CPAP g oup. The espec i e h esholds o
he cen al spindles we e 11.7 𝜇V (median, ange 8.5 o 16.6),
11.7 𝜇V (8.2 o 15.4), and 11.1 𝜇V (8.3 o 16.0). The indi idually
de e mined ampli ude h esholds did no di e s a is ically
be ween he g oups.
2.3. S a is ics. Since some o he pa ame e s we e no no -
mally dis ibu ed, median and ange we e used as desc ip i e
s a is icsandnonpa ame ic es swe echosenino de o
compa e he s udy g oups. The Mann-Whi ney 𝑈 es was
used o compa e he con ols wi h he pa ien g oups. The
Wilcoxon es was used o compa e p e-CPAP pa ien s wi h
heCPAPg oup.Tohandle hemul iplecompa isons,app o-
p ia e Bon e oni co ec ion ac o s we e used ( he o iginal 𝑝
alues we e mul iplied wi h he numbe o compa isons). In
his way, he signi icance le el was se a 0.05 o all analyses
and he epo ed 𝑝 alues a e based on wo- ailed es s.
3. Resul s
The demog aphic da a and sleep pa ame e s o he s udy
g oups a e p esen ed in Table 1. The g oups did no di e
acco ding o age. The OSA pa ien s we e mo e obese han he
con ols. The con ols had mo e N3 and less N2 han he p e-
CPAP g oup, and hey had ewe a ousals, desa u a ions and
b ea hing e en s han he p e-CPAP g oup. CPAP ea men
dec eased he o al sleep ime o he pa ien s and no malized
henumbe o apneas,a ousals,obs uc i eb ea hinge en s
and hypoxemic e en s. Howe e , pa ien s wi h CPAP con in-
ued o show mo e N2 sleep and less N3 sleep han heal hy
con ols, and hei sleep la ency was sho e .
3.1.SpindleFea u esin heFi s Pa o heNREMTime. In
he i s pa o he nigh , nei he on opola (bil Fp, Fp1,
andFp2)no cen al(bilC,C3,andC4)spindledensi ies
di e ed be ween he g oups (Table 2). In all g oups, he Fp-
and C- spindles we e mo e o en unila e al han bila e al, as
e ealed by he alues o he bila e ali y indices (Table 2).
The e we e no s a is ical di e ences in he bila e ali y indices
be ween he g oups. Spindle sequences we e ew in he i s
4Sleep Diso de s
Table 2: Median and ange o he spindle ea u es in he s udy g oups in he i s pa o he NREM ime.
Con ols P e-CPAP CPAP Con ols e sus
p e-CPAP1Con ols e sus
CPAP1P e-CPAP e sus
CPAP2
Median Range Median Range Median Range 𝑝 alue 𝑝 alue 𝑝 alue
Densi y 𝑛/h
Bil Fp dens 33.7 3.4–94.8 22.5 0.3–117.7 23.7 0.0–0.0 0.671 1.0 1.0
Fp2 dens 77.5 14.6–138.6 48.2 8.8–183.9 50.8 0.0–0.0 1.0 1.0 1.0
Fp1 dens 68.0 15.0–129.0 49.0 6.9–143.0 50.9 0.0–0.0 0.912 1.0 1.0
Bil C dens 55.9 11.8–161.2 29.1 1.0–215.7 27.8 1.4–202.8 0.250 0.361 1.0
C4 dens 104.7 36.4–194.2 58.3 13.7–194.3 79.6 16.5–181.5 0.369 1.0 0.741
C3 dens 116.7 50.2–219.6 56.3 17.3–216.3 85.3 29.0–221.5 0.085 0.224 0.574
F equency Hz
Bil Fp2 eq 11.8 10.9–12.5 11.5 10.9–13.1 11.4 10.6–12.9 0.702 0.250 0.068
Bil Fp1 eq 11.8 10.9–12.9 11.5 10.7–13.1 11.5 10.8–12.8 0.874 0.516 1.0
Fp2 eq 11.8 10.9–12.3 11.5 10.8–13.1 11.5 10.8–12.8 1.0 1.0 0.013
Fp 1 eq 11.8 11.0–12.5 11.5 10.9–13.0 11.4 10.9–12.8 0.893 0.272 0.042
Bil C4 eq 12.9 11.2–14.4 13.1 11.0–14.6 12.6 10.7–14.0 1.0 0.703 0.006
Bil C3 eq 12.9 11.1–14.3 13.1 11.3–14.9 12.8 10.9–14.4 0.670 1.0 0.007
C4 eq 12.5 11.2–13.7 12.5 11.0–14.2 11.9 11.0–13.8 1.0 0.283 0.043
C3 eq 12.5 11.1–13.8 12.8 11.3–15.1 11.7 11.0–13.9 1.0 0.207 0.001
Sequences %
Fp sequences 0.0 0.0–0.4 0.0 0.0–1.1 0.0 0.0–0.3 1.0 1.0 0.999
C sequences 0.3 0.0–2.4 0.1 0.0 4.4 0.0–3.1 0.720 0.176 0.224
Bila e ali y indices
Fp bil index 1 0.48 0.21–0.98 0.36 0.02–0.81 0.44 0.07–0.68 0.185 0.388 1.0
Fp bil index 2 0.54 0.21–0.89 0.36 0.04–1.18 0.44 0.06–0.95 0.388 0.275 1.0
C bil index 1 0.64 0.20–1.31 0.40 0.03–1.16 0.38 0.08–1.12 0.297 0.085 1.0
C bil index 2 0.50 0.14–1.13 0.35 0.06–1.0 0.33 0.05–0.98 0.611 0.145 1.0
1Mann-Whi ney 𝑈 es ; 2Wilcoxon es . The Bon e oni co ec ed 𝑝 alues a e epo ed: Bon e oni co ec ion ac o = 3.
Bil Fp/bil C = bila e al on opola /cen al spindle; bil C4, bil C3 = bila e al igh -side and le -side spindles, espec i ely; Fp2, Fp1, C4, and C3 =unila e al
spindles; sequences = pe cen age o ime e e ed o as TST occupied by pe iodic on opola o cen al spindles; Fp bil index 1 = numbe o bil Fp spindles
di ided by he numbe o unila Fp2 spindles (bil Fp/Fp2); Fp bil index 2 = numbe o bil Fp spindles di ided by he numbe o unila Fp1 spindles (bil Fp/Fp1);
C bil index 1 = numbe o bil C spindles di ided by he numbe o unila C4 spindles (bil C/C4); C bil index 2 = numbe o bil C spindles di ided by he numbe
o unila C3 spindles (bil C/C3).
pa o he nigh in all g oups and no g oup-wise di e ences
we e ound. Hemisphe ic compa isons e ealed ha heal hy
con ols had mo e unila e al cen al spindles in he le han
in he igh hemisphe e. The p e-CPAP g oup p esen ed
mo e on opola spindles in he le han in he igh
hemisphe e. O he hemisphe ic spindle densi y di e ences
we e no p esen (Table 3).
Rega ding he in aspindle equency, all cen al spindle
ypes (bil C4, bil C3, C4, and C3) we e as e han he
co esponding on opola spindles (bil Fp2, bil Fp1, Fp2, and
Fp1, esp.) in all g oups (𝑝 alues in Table 4). The equency
o he on opola o cen al spindles o he con ol g oup did
no di e om he alues o he p e-CPAP o CPAP g oups
(Table 2). The p e-CPAP g oup had as e Fp2, Fp1, bil C4,
bil C3, C4, and C3 spindle equencies han he CPAP g oup.
Heal hy con ols did no ha e hemisphe ic spindle equency
di e ences (Table 3). Ins ead, bo h he p e-CPAP and CPAP
g oups p esen ed a mino bu signi ican di e ence; unila e al
on opola spindles we e as e in he igh hemisphe e han
in he le .
3.2. Spindle Fea u es in he Las Pa o he NREM Time. In
he las pa o he nigh , he con ol g oup’s bil C and C3
spindle densi ies we e highe han he densi ies in he p e-
CPAP g oup (Table 5). The con ol g oup had mo e bil C
spindles han heCPAPg oup.Thep e-CPAPg ouphad
mo e Fp1 and C4 spindles han he CPAP g oup. The cen al
spindles o he con ol g oup we e mo e o en bila e al han in
he wo pa ien g oups, as assessed by he bila e ali y indices.
No s a is ical di e ences be ween he g oups we e ound in
he spindle sequence imes. Heal hy con ols did no p esen
in e hemisphe ic spindle densi y di e ences, bu bo h pa ien
g oupshadmo e on opola spindlesin he igh hemisphe e
han in he le (Table 3).
As in he i s pa o he NREM ime, all cen al spindle
ypes we e as e han he espec i e on opola spindles
Sleep Diso de s 5
Table 3: 𝑝 alues o he hemisphe ic igh -le compa isons o he
bila e al and unila e al spindle equencies and unila e al densi ies
in he di e en s udy g oups.
Con ols P e-CPAP CPAP
Fi s pa o heNREM ime
Densi y
Fp2 e sus Fp1 0.575 0.044 0.550
C4 e sus C3 0.030 0.737 0.156
F equency
Bil Fp2 e sus bil Fp1 0.717 0.809 0.070
Fp2 e sus Fp1 0.126 0.035 0.014
Bil C4 e sus bil C3 0.588 0.235 0.064
C4 e sus C3 0.173 0.145 0.794
Las pa o he NREM ime
Densi y
Fp2 e sus Fp1 0.601 0.006 0.048
C4 e sus C3 0.469 0.478 0.502
F equency
Bil Fp2 e sus bil Fp1 0.717 0.658 0.225
Fp2 e sus Fp1 0.444 0.225 0.313
Bil C4 e sus bil C3 0.444 0.097 0.896
C4 e sus C3 0.365 0.082 0.911
Numbe s e e o 𝑝 alues based on he Wilcoxon es .
Table 4: 𝑝 alues o he compa isons be ween he cen al and
on opola spindle equencies in he di e en s udy g oups.
Con ols P e-CPAP CPAP
Fi s pa o he NREM ime
Bil C4 e sus bil Fp2 <0.001 <0.001 0.003
Bil C3 e sus bil Fp1 <0.001 <0.001 0.003
C4 e sus Fp2 <0.001 0.001 0.022
C3 e sus Fp1 <0.001 <0.001 0.002
Las pa o he NREM ime
Bil C4 e sus bil Fp2 <0.001 0.002 <0.001
Bil C3 e sus bil Fp1 <0.001 <0.001 <0.001
C4 e sus Fp2 <0.001 0.001 0.001
C3 e sus Fp1 <0.001 <0.001 <0.001
Numbe s e e o 𝑝 alues based on he Wilcoxon es .
(Table 4). The spindle equencies o he con ol g oup did no
di e om he equencies o he p e-CPAP o CPAP g oups
(Table 5). The CPAP g oup had slowe spindles han he p e-
CPAP g oup wi h he excep ion o he equency o he bil Fp1
spindles. Hemisphe ic spindle equency di e ences we e no
oundinanyo heg oups(Table3).
3.3. Compa ison o he Spindle Fea u es be ween he Fi s and
he Las Pa o he NREM Time. None o he on opola
spindle pa ame e s (densi y, bila e ali y index, sequences,
and equency) showed any s a is ical di e ences be ween he
i s and he las pa o he nigh in any o he s udy g oups.
In he con ol g oup and he CPAP g oup, he densi y o
he bila e al cen al spindles inc eased owa ds he end o he
Bil C C4 C3 Bil C C4 C3 Bil C C4 C3
Fi s pa
Las pa
Con ols P e-CPAP CPAP
p = 0.002
p = 0.028
0
20
40
60
80
100
120
Numbe /hou
∗
∗
Figu e 1: Cen al spindle densi ies in he i s and he las pa o
he NREM sleep in he s udy g oups. The s a is ically signi ican
di e ences a e ma ked wi h an as e isk and deno ed wi h he 𝑝
alues.
Con ols P e-
CPAP
CPAP Con ols P e-
CPAP
CPAP
Fi s pa
Las pa
Bila e ali y index 1 Bila e ali y index 2
p = 0.001
p < 0.001
p = 0.007
0
0.2
0.4
0.6
0.8
1
∗
∗
∗
Figu e 2: Bila e ali y indices o he cen al spindles in he i s and
las pa o he NREM sleep. The s a is ically signi ican di e ences
a e ma ked wi h an as e isk and deno ed wi h he 𝑝 alues.
nigh (Figu e 1). Ins ead, unila e al cen al spindle densi ies
did no show any ma ked changes du ing he nigh in any o
he g oups.
In he con ol g oup, he p opo ion o bila e al cen al
spindles washighe in he las pa o he nigh han in he i s
(Figu e 2). In he CPAP g oup, bila e ali y index 2 showed an
inc ease in la e sleep. The p e-CPAP g oup did no p esen
signi ican changes.
In hecon ols, he imeoccupiedwi hcen alspindle
sequences inc eased owa ds he end o he nigh , whe eas he
sequence ime o he pa ien g oups did no change du ing he
nigh (Figu e 3).
In he con ols, all cen al spindle ypes we e as e in he
las pa o he nigh han in he i s pa (Figu e 4). The
spindle equencies o he p e-CPAP pa ien s did no change
ma kedly du ing he nigh , while bo h bila e al and unila e al
C4 spindles became as e in he CPAP g oup.

6Sleep Diso de s
Table 5: Median and ange o he spindle ea u es in he s udy g oups a he las pa o he NREM ime.
Con ols P e-CPAP CPAP Con ols e sus
p e-CPAP1Con ols
e sus CPAP1P e-CPAP e sus
CPAP2
Median Range Median Range Median Range 𝑝 alue 𝑝 alue 𝑝 alue
Densi y 𝑛/h
Bil Fp dens 43.7 7.3–110.3 23.2 0.5–105.7 23.6 1.1–102.6 0.350 0.533 1.0
Fp2 dens 85.1 26.6–136.9 52.5 10.6–157-7 54.4 10.1–159.3 0.768 1.0 0.741
Fp1 dens 65.6 15.9–150.5 43.8 7.1–141.3 46.4 12.7–129.0 0.223 0.518 0.033
Bil C dens 76.5 18.3–215.7 32.6 0.5–282.5 35.4 4.4–282.0 0.010 0.018 0.436
C4 dens 111.5 63.8–183.5 78.2 21.6–196.8 90.1 18.6–191.8 0.223 0.626 0.027
C3 dens 117.1 46.4–229.7 64.3 20.2–231.6 85.4 26.9–217.7 0.033 0.093 0.238
F equency Hz
Bil Fp2 eq 11.7 11.1–12.4 11.6 11.0–13.6 11.3 10.8–13.0 1.0 0.074 0.001
Bil Fp1 eq 11.8 11.1–12.4 11.6 10.8–13.3 11.4 10.7–13.0 1.0 0.243 0.131
Fp2 eq 11.7 11.2–12.4 11.7 10.9–13.0 11.5 11.0–12.8 1.0 0.395 0.022
Fp 1 eq 11.9 11.2–12.4 11.6 11.1–13.0 11.4 11.0–12.9 0.640 0.159 0.037
Bil C4 eq 13.1 11.4–14.3 13.3 10.8–14.9 13.0 10.9–14.6 1.0 1.0 0.007
Bil C3 eq 13.1 11.2–14.3 13.3 10.8–14.8 12.8 10.9–14.8 0.912 1.0 0.004
C4 eq 12.9 11.2–14.1 12.6 11.0–14.5 12.5 10.9–13.9 1.0 1.0 0.041
C3 eq 12.8 11.1–14.3 13.0 10.9–15.0 12.4 10.9–13.9 1.0 1.0 0.005
Sequences %
Fp sequences 0.0 0.0–0.5 0.0 0.0–0.5 0.0 0.0–0.5 1.355 1.0 0.999
C sequences 0.6 0.0–4.0 0.1 0.0–7.3 0.0 0.0–7.1 0.086 0.097 1.0
Bila e ali y indices
Fp bil index 1 0.47 0.15–1.22 0.36 0.04–0.73 0.43 0.11–0.75 0.168 0.388 1.0
Fp bil index 2 0.61 0.15–1.07 0.48 0.04–1.15 0.46 0.09–1.05 0.506 0.191 1.0
C bil index 1 0.79 0.17–1.55 0.36 0.03–1.44 0.42 0.14–1.47 0.006 0.008 1.0
C bil index 2 0.72 0.20–1.38 0.45 0.03–1.22 0.36 0.15–1.30 0.015 0.009 1.0
1Mann-Whi ney 𝑈 es ; 2Wilcoxon es . The Bon e oni co ec ed 𝑝 alues a e epo ed: Bon e oni co ec ion ac o = 3.
Abb e ia ionsasinTable2.
4. Discussion
The indings o ou s udy ha e alua ed sleep spindles a e
six mon hs o CPAP ea men e ealed ha many spindle
ea u es we e no malized by CPAP ea men , bu some
de ici s emained.
P e ious s udies ha e shown an inc ease in spindle
densi y ac oss consecu i e NREM sleep episodes in heal hy
subjec s [20, 27–29]. The p esen esul s sugges ha he
densi y inc ease is mos ly induced by he cen al, as e
spindlesbu no by on opola spindles.Thisisinlinewi h
he indings o Sch¨
onwald and cowo ke s [18]. In con as o
heal hy con ols, ou un ea ed OSA pa ien s did no p esen
any signi ican inc ease in cen al spindle densi y du ing
sleep, bu wi h CPAP ea men he inc ease was eco e ed.
The inc ease o cen al spindles in heal hy con ols and
CPAP- ea ed pa ien s was es ic ed o bila e al cen al
spindles only. The densi y o local cen al spindles did no
show any ma ked changes du ing sleep in any o he g oups.
Acco ding o he ea lie s udies, local spindles a e equen
and e en mo e equen han global spindles [30, 31]. Ou
esul s a e in line wi h hese indings; bila e ali y indices show
ha he numbe o unila e al on opola and cen al spindles
is highe han bila e al spindles in all g oups. Howe e ,
spindles a e ound o become mo e global in la e sleep in a
small g oup o neu osu gical pa ien s [30, 31]. Ou inding
ha he p opo ion o bila e al cen al spindles inc eased
in la e sleep in he heal hy con ols co esponds wi h his
inding. In OSA pa ien s be o e CPAP ea men , howe e ,
no inc ease was ob ained. CPAP ea men pa ly no malized
his phenomenon as he sha e o cen al bila e al spindles
inc eased when compa ed wi h le -sided unila e al spindles,
bu no changes we e ound in he igh hemisphe e.
Spindles a e abundan in a mode a e le el o co ico ha-
lamic hype pola iza ion, in ligh sleep [32, 33]. Wi h u he
hype pola iza ion, in deep sleep, he e a e only a ew spindles
[32, 34–36]. Co ically gene a ed slow oscilla ion seems o
be he p incipal p ocess behind NREM sleep [32, 37–39]
by sp eading o he halamus in synch onous olleys and
d i ing spindles o he co ex h ough he halamoco ical
ne wo k [40, 41]. The e o e, we wonde whe he he de ec
in he inc easing bila e ali y o spindles in OSA would be
a consequence o dis up ed co ico halamic spindle d i ing
loops. As pe iodic spindles e lec he pe iodically ecu ing
Sleep Diso de s 7
Con ols P e-CPAP CPAP
Fi s pa
Las pa
p = 0.004
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
(%)
∗
Figu e 3: Pe cen age o ime occupied wi h cen al spindle
sequences in he i s and las pa o he NREM sleep. The
s a is ically signi ican di e ences a e ma ked wi h as e isk and
deno ed wi h he 𝑝 alues.
Bil C4
Bil C3
C4
C3
Bil C4
Bil C3
C4
C3
Bil C4
Bil C3
C4
C3
p = 0.001
p = 0.012
p = 0.022
p = 0.024
p = 0.033
p = 0.007
Fi s pa
Las pa
0
2
4
6
8
10
12
14
(Hz)
Con ols P e-CPAP CPAP
∗
∗∗
∗
∗∗
Figu e 4: F equency o he cen al spindles in he i s and las pa
o he NREM sleep in he s udy g oups. The s a is ically signi ican
di e ences a e ma ked wi h an as e isk and deno ed wi h he 𝑝
alues.
spindle d i ing slow oscilla ion du ing ligh sleep [39], ou
inding ha spindle sequences we e no ound in OSA
pa ien s suppo s his hough . CPAP ea men did no ha e
an e ec on he occu ence o spindle sequences. This migh
implica e a mo e pe manen de ec in he co ico halamic
ne wo k ha dis u bs he spindle p ocess.
On he o he hand, spindle densi y has been ound o
inc easelocallyin hosea easo heb ain ha ha ebeen
ained du ing wake ulness in a use-dependen manne [16,
17]. In he p esen s udy, he i s pa o he NREM ime
did no e eal any spindle densi y di e ences be ween he
g oups, bu local spindles in he le cen al a ea (unila e al
C3) we e mo e abundan han local spindles in he igh
cen al a ea (unila e al C4) in he con ols. Pa ien s wi h o
wi hou CPAP did no p esen hemisphe ic di e ences in
he unila e al cen al spindle densi ies. In he las pa o
he NREM ime, he densi y o unila e al le -side cen al
spindles was highe in he con ol g oup han in he OSA
pa ien s be o e ea men . I is possible ha he le -side
abundance in cen al spindles in heal hy con ols s ems om
he inding ha he le hemisphe e needs mo e sleep han
he igh hemisphe e, possibly due o di e ences in day ime
ac i i y [42]. I unila e al spindle densi y is conside ed use-
dependen , hen i can be specula ed ha ou con ol subjec s
had used hei le cen al co ical a eas mo e han hei igh
ones and ha he OSA pa ien s had used hei le cen al
b ain a eas less ac i ely han he con ols.
As expec ed, all on opola spindle ypes we e slowe
han he co esponding cen al spindles. The equency o
he on opola spindles did no change du ing he nigh
in any o he g oups. Ins ead, all cen al spindle ypes
became as e owa ds he mo ning hou s in he con ols,
whe eas no equency changes we e obse ed in he newly
diagnosed OSA pa ien s. CPAP ea men pa ly no malized
he spindle equencies as bila e al and unila e al igh -side
cen al spindles became as e . Howe e , he equencies o
he le -sided cen al spindles did no change.
The occu ence o spindles has been p o en o be depen-
den on he le el o he hype pola iza ion in he halamo-
co ical ne wo k, whe eas he equency o spindles has been
ound o depend on he du a ion o he hype pola iza ion-
ebound sequences o he halamoco ical cells [43]. I
ebound sequences a e long, he spindle is slow. In heal hy
subjec s, hese wo p ocesses in ol ed in de e mining spindle
ea u es seem o co ela e because, in gene al, spindles a e
abundan and as inligh sleepand ewandslowindeep
sleep [9, 33]. Howe e , hese p ocesses a e p esen ed o be
dissocia edinOSApa ien ssinceslowspindlesa e ound
in ligh sleep [19]. Co esponding esul s we e ound in he
p esen s udy as spindles o he p e-CPAP g oup did no
become as e in la e sleep. In addi ion, he p esen indings
sugges ha his dissocia ion is pa ly dissol ed wi h CPAP
ea men because only le -sided cen al spindles did no
become as e in la e sleep wi h CPAP ea men .
A somewha su p ising inding was ha mos spindle
equencies we e slowe wi h CPAP han wi hou ea men
in OSA pa ien s in bo h he i s and he las pa o he
nigh . Ano he in e es ing inding was ha spindle sequences
we e no eco e ed wi h CPAP ea men . Howe e , OSA
pa ien s do no usually ha e deep sleep, which means ha
halamoco ical hype pola iza ion s ays a mode a e le els.
Wi h CPAP, he pa ien s each slow wa e sleep wi h mo e neg-
a i e memb ane po en ials o he halamoco ical ne wo k.
This migh explain he eme gence o slow spindles [9] and
a dec ease in he numbe o pe iodic spindles [10]. In his
way, he inc ease in hype pola iza ion would explain bo h
hese indings. In addi ion, i migh be ha 6 mon hs o CPAP
ea men does no abolish he inc eased sleep p essu e o
OSA pa ien s p ope ly and inc eased sleep p essu e inc eases
he hype pola iza ion le el esul ing in slowe spindles wi h
no pe iodici y.
The inc ease in spindle densi y has been ound o be
associa ed wi h memo y unc ion imp o emen , and i is
only he as spindles ha ha e been associa ed wi h memo y
and lea ning p ocessing [14, 44–48]. The e o e, we wonde
whe he he changes in spindle dynamics migh be ela ed
o he di e en symp oms o OSA pa ien s such as di e en
cogni i e p oblems [49, 50]. CPAP ea men is known o,
8Sleep Diso de s
a leas pa ially, educe di e en symp oms in OSA pa ien s
[21, 51], and he ac ha many spindle ea u es no malized
wi h CPAP is in line wi h ou hypo hesis.
The numbe and equency o spindles a e dependen on
many ac o s ( o e iew see [33]). Spindles and SWA ha e a
ecip ocal ela ionship [52], and sleep dep i a ion dec eases
spindling [53]. In addi ion, age, gende and ci cadian hy hm
all a ec spindle ac i i y [27, 54–56]. In he p esen s udy,
we s udied g oup-wise di e ences be ween heal hy con ols
and OSA pa ien s wi h and wi hou CPAP ea men , bu
mo e impo an ly we used a wi hin-subjec design o OSA
pa ien s wi hou and wi h CPAP ea men o e alua e spindle
ea u es.This,inpa , educed hee ec so heabo e
men ioned ac o s ha a ec he spindle p ocess. A clea
limi a ion o ou s udy is ha he assessmen o di e en
cogni i e domains was no included and u u e s udy is
needed o e alua e he e ec o CPAP ea men on bo h
spindle ea u es and di e en cogni i e skills.
To conclude, CPAP ea men only pa ially no malizes
sleep spindle ea u es. Fu he s udies a e he e o e needed
o e alua e whe he hese spindle p ocess changes a e ela ed
o he emaining cogni i e p oblems o OSA pa ien s.
Addi ional Poin s
Highligh s.(i)Obs uc i esleepapneadis o ssleepspindle
p ocess. (ii) CPAP ea men no malizes many spindle ea-
u es bu some de ici s emain. (iii) The emaining spindle
changes migh be ela ed o cogni i e diso de s o CPAP-
ea ed pa ien s.
Compe ing In e es s
None o he au ho s ha e con lic o in e es s o be disclosed.
Au ho s’ Con ibu ions
Saunam¨
aki Tiia execu ed he p ojec , analyzed da a, in e -
p e edda a,d a ed hemanusc ip ,andapp o ed he e sion
o be published. Huupponen Ee o de eloped he sleep spindle
de ec o , analyzed spindles in he p esen wo k, w o e spindle
analysis me hods, and app o ed he e sion o be published.
Loponen Juho pe o med p elimina y s a is ical analyses,
analyzed da a, in e p e ed da a, d a ed he manusc ip ,
and app o ed he e sion o be published. Himanen Sa i-
Leena analyzed polysomnog aphies, calcula ed s a is ics,
in e p e ed da a, d a ed he manusc ip , and app o ed he
e sion obepublished.
Acknowledgmen s
This s udy was inancially suppo ed by Compe i i e S a e
Resea ch Financing o he Expe Responsibili y A ea o
Tampe e Uni e si y Hospi al (G an s 9P013, 9R007, and
9S007).
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