Changes in Phonation and Their Relations with Progress of Parkinson’s Disease

applied sciences A icle Changes in Phona ion and Thei Rela ions wi h P og ess o Pa kinson’s Disease Zol an Galaz 1, Ji i Mekyska 1, Voj ech Z oncak 1, Jan Mucha 1, Tomas Kiska 1, Zdenek Smekal 1, Ilona Eliaso a 2,3, Ma ina M acko a 2,3, Milena Kos alo a 3,4, I ena Rek o o a 2,3,*, Ma cos Faundez-Zanuy 5, Jesus B. Alonso-He nandez 6 and Ped o Gomez-Vilda 7 1Depa men o Telecommunica ions, B no Uni e si y o Technology, Technicka 10, 616 00 B no, Czech Republic; [email p o ec ed].cz (Z.G.); [email p o ec ed].cz (J.M.); [email p o ec ed] (V.Z.); [email p o ec ed].cz (J.M.); [email p o ec ed].cz (T.K.); [email p o ec ed].cz (Z.S.) 2Fi s Depa men o Neu ology, S . Anne’s Uni e si y Hospi al, Peka ska 53, 656 91 B no, Czech Republic; [email p o ec ed] (I.E.); [email p o ec ed] (M.M.) 3Applied Neu oscience Resea ch G oup, Cen al Eu opean Ins i u e o Technology, Masa yk Uni e si y, Kamenice 5, 625 00 B no, Czech Republic; [email p o ec ed] 4Depa men o Neu ology, Facul y Hospi al and Masa yk Uni e si y, Jihla ska 20, 639 00 B no, Czech Republic 5Escola Supe io Poli ecnica, Tecnocampus, A da. E nes Lluch 32, 083 02 Ma a o, Ba celona, Spain; [email p o ec ed] 6Ins i u e o Technological De elopmen and Inno a ion in Communica ions (IDeTIC), Uni e si y o Las Palmas de G an Cana ia, 35001 Las Palmas de G an Cana ia, Spain; [email p o ec ed] 7Neu omo phic P ocessing Labo a o y (NeuVox Lab), Cen e o Biomedical Technology, Uni e sidad Poli ecnica de Mad id, Campus de Mon egancedo, s/n, Pozuelo de Ala con, 28223 Mad id, Spain; [email p o ec ed] *Co espondence: i ena. ek o [email p o ec ed]; Tel.: +420-543-182-639 Recei ed: 17 Oc obe 2018; Accep ed: 19 No embe 2018; Published: 22 No embe 2018   Abs ac : Hypokine ic dysa h ia, which is associa ed wi h Pa kinson’s disease (PD), a ec s se e al speech dimensions, including phona ion. Al hough he scien i ic communi y has deal wi h a quan i a i e analysis o phona ion in PD pa ien s, a complex esea ch e ealing p obable ela ions be ween phona o y ea u es and p og ess o PD is missing. The e o e, he aim o his s udy is o explo e hese ela ions and model hem ma hema ically o be able o es ima e p og ess o PD du ing a wo-yea ollow-up. We en olled 51 PD pa ien s who we e assessed by h ee commonly used clinical scales. In addi ion, we quan i ied eigh possible phona o y diso de s in i e owels. To iden i y he ela ionship be ween baseline phona o y ea u es and changes in clinical sco es, we pe o med a pa ial co ela ion analysis. Finally, we ained XGBoos models o p edic he changes in clinical sco es du ing a wo-yea ollow-up. Fo wo yea s, he pa ien s’ oices became mo e ape iodic wi h inc eased mic ope u ba ions o equency and ampli ude. Nex , he XGBoos models we e able o p edic changes in clinical sco es wi h an e o in ange 11–26%. Al hough we iden i ied some signi ican co ela ions be ween changes in phona o y ea u es and clinical sco es, hey a e less in e p e able. This s udy sugges s ha i is possible o p edic he p og ess o PD based on he acous ic analysis o phona ion. Mo eo e , i ecommends u ilizing he sus ained owel /i/ ins ead o /a/. Keywo ds: phona ion; acous ic analysis; ollow-up s udy; hypokine ic dysa h ia; Pa kinson’s disease Appl. Sci. 2018,8, 2339; doi:10.3390/app8122339 www.mdpi.com/jou nal/applsci Appl. Sci. 2018,8, 2339 2 o 18 1. In oduc ion Pa kinson’s disease (PD) is a equen neu odegene a i e diso de ha is associa ed wi h a subs an ial educ ion o dopamine gic neu ons especially in subs ancia nig a pa s compac a [ 1 ]. The p ima y mo o symp oms o PD comp ise emo a es , muscula igidi y, b adykinesia, and pos u al ins abili y [ 1 ]. Pa ien s wi h PD also de elop a a ie y o non-mo o symp oms [ 2 ] such as sleep dis u bances, dep ession, cogni i e impai men , e c. To diagnose, a e and moni o mo o and non-mo o symp oms o PD, a ious clinical a ing scales such as Uni ied Pa kinson’s Disease Ra ing Scale (UPDRS) [ 3 ], F eezing O Gai Ques ionnai e (FOG-Q) [ 4 ], o Addenb ooke’s Cogni i e Examina ion-Re ised (ACE–R) [ 5 ] ha e been de eloped. Ne e heless, eliabili y o he assessmen is o en educed by in e - a e a iabili y [6]. Up o 90% [ 7 ] o pa ien s wi h PD de elop a mul i-dimensional speech diso de named hypokine ic dysa h ia (HD) [ 8 ], which is mani es ed in phona ion, a icula ion, and p osody [ 9 – 11 ]. In he a ea o phona ion, insu icien b ea h suppo , educ ion in phona ion ime, inc eased acous ic noise, ins abili y o a icula o y o gans, mic ope u ba ions o equency/ampli ude, and ha sh b ea hy oice quali y has been obse ed [ 9 , 12 ]. HD leads o se ious complica ions in daily communica ion o pa ien s wi h PD [13]. Gene ally, HD was ound o be mo e se e e in he ad anced s ages o PD [14]. As epo ed by he ecen s udies, acous ic analysis o HD can p o ide clinicians wi h non-in asi e and eliable me hodology o PD diagnosis, assessmen and moni o ing [ 9 , 15 ]. Mo eo e , his me hodology has also been used o moni o he e iciency o PD ea men [ 10 , 16 – 18 ]. In he ield o acous ic analysis o PD phona ion, he au ho s mos ly ocused on he sus ained owel /a/ [ 9 ]. Con en ional phona o y ea u es such as ji e , shimme , ha monic- o-noise a io, deg ee o un oiced segmen s, and o man -based pa ame e s ex ac ed om his owel ha e been widely used o diagnose PD [ 12 , 19 – 23 ]. Al hough Hazan e al. [ 24 ] employed analysis o sus ained phona ion o diagnosis o PD e en in i s ea ly s age, based on he ecen e iew [ 9 ], mos o he esea che s ind ele an applica ions o he phona o y analysis especially in mode a e o se e e s ages o his diso de . Fo example, he analysis o sus ained phona ion has been u ilized du ing PD se e i y assessmen . In 2010, Tsanas e al. [ 15 ] en olled 42 PD pa ien s and pa ame e ized hei sus ained phona ion o owel /a/ by a se o con en ional ea u es ha we e consequen ly mapped o UPDRS, pa III (mo o examina ion) and he o al sco e o his scale. Using classi ica ion and eg ession ees, hey es ima ed he UPDRSIII sco e wi h MAE (mean absolu e e o ) equal o 5.95. The o al UPDRS sco e was es ima ed wi h MAE = 7.52. A pa ame ic e sion o his da ase has been made a ailable o esea ch pu poses and o he esea ch eams u he dec eased he es ima ion e o [ 25 – 27 ]. Ano he wo k ha deals wi h he au oma ic clinical sco es es ima ion was published by Mekyska e al. [ 21 ]. In his s udy, hey acqui ed sus ained phona ion o owels /a/, /e/, /i/, /o/, /u/ in 84 PD pa ien s. Modeling con en ional and ad anced ea u es by andom o es s p o ided he es ima ion o UPDRSIII wi h MAE = 5.70. In addi ion, he au ho s es ima ed se e al o he clinical sco es such as UPDRS, pa IV (complica ions o he apy) wi h MAE =1.30 o Beck dep ession in en o y (BDI) wi h MAE =3.12. E en hough HD is one o he mos p oblema ic aspec s o PD, he numbe o longi udinal s udies in es iga ing he e olu ion o HD in PD o e ime (based on he acous ic analysis) is e y limi ed [ 28 – 31 ]. I we ocus speci ically on longi udinal moni o ing o sus ained phona ion, hen, in ac , we can iden i y only one s udy, which is published by Skodda e al. [ 31 ]. In his wo k, he au ho s epea edly (wi h a e age ime in e al 32.50 mon hs) acqui ed sus ained owel /a/ in 32 emale and 48 male PD pa ien s (age in session 1: 66.28 ± 8.11 yea s; PD du a ion in session 1: 6.10 ± 4.63 yea s; UPDRSIII in session 1: 20.16 ±10.96; UPDRS III in session 2: 19.58 ±8.29). The oice was quan i ied by ji e , shimme , noise- o-ha monic a io, and mean undamen al equency. Based on he pai ed - es , he au ho s iden i ied signi ican changes in shimme and noise- o-ha monic a io. In bo h cases, he alues o hese pa ame e s inc eased. Ano he in e es ing inding is ha , al hough some phona o y ea u es signi ican ly changed, UPDRS III was held widely s able o e ime. The au ho s p o ide wo possible explana ions: (1) oice impai men could be he esul o an escala ion o axial dys unc ion oo sub le o be mi o ed by UPDRSIII; (2) al e a ions o speech pa ame e s could be Appl. Sci. 2018,8, 2339 3 o 18 comple ely independen o mo o pe o mance ha may be based upon non-dopamine gic mechanisms. Inconsis encies in e ms o he L-dopa e ec on HD a e u he discussed in B abenec e al. [9]. To sum i up, al hough he scien i ic communi y equen ly add esses phona ion in associa ion wi h HD (especially when diagnosing o assessing PD), o he bes o ou knowledge, he e is only one s udy ha ocuses on HD phona o y diso de s om a longi udinal pe spec i e. Mo eo e , he wo k deals wi h he analysis o phona ion jus pa ially, i conside s only he sus ained owel /a/, and i does no explo e a possibili y o PD p og ess p edic ion based on a combina ion o acous ic analysis and machine lea ning. The e o e, in he ame o ou wo-yea ollow-up s udy, we a e going much u he wi h he ollowing aims: 1. o iden i y phona o y acous ic ea u es a baseline ha a e signi ican ly co ela ed wi h changes in a ious clinical a ing scales, 2. o in es iga e ela ionship be ween changes in he phona o y acous ic ea u es and he clinical a ing scales a e he wo-yea ollow-up, 3. o es ablish ma hema ical models ha will es ima e he change in clinical a ing scales based on he change in acous ic measu es, 4. o compa e esul s based on i e owels: /a/, /e/, /i/, /o/, /u/. The es o his a icle is o ganized as ollows: Sec ion 2desc ibes a da ase o PD pa ien s as well as me hodology in e ms o acous ic analysis, s a is ical analysis and machine lea ning. Resul s a e epo ed in Sec ion 3and consequen ly discussed in Sec ion 5. Finally, conclusions a e gi en in Sec ion 4. 2. Ma e ials and Me hods 2.1. Da ase In his wo k, we en olled 51 pa ien s wi h idiopa hic PD. All o hem a e Czech na i e speake s (17 emales and 34 males; age: 65.47 ± 7.46 yea s; PD du a ion: 7.61 ± 4.01 yea s; mean LED (L-dopa equi alen daily dose) [ 32 ]: 1033.67 ± 567.96 mg/day) a he Fi s Depa men o Neu ology, S . Anne’s Uni e si y Hospi al in B no, Czech Republic. A e wo yea s, he pa ien s we e e-examined (age: 67.61 ± 7.38 yea s; PD du a ion: 9.57 ± 4.50 yea s; mean LED: 1115.11 ± 484.38 mg/day). All pa ien s signed an in o med consen o m ha has been app o ed (including he s udy) in 14 Ma ch 2016 by he Resea ch E hics Commi ee o Masa yk Uni e si y ( e . no.: EKV-2016-004, p ojec i le: E ec s o non-in asi e b ain s imula ion on hypokine ic dysa h ia, mic og aphia, and b ain plas ici y in pa ien s wi h Pa kinson’s disease, in es iga o : P o . MD. I ena Rek o o a, PhD.). None o he pa ien s had a disease a ec ing he cen al ne ous sys em o he han PD. All pa ien s we e examined on hei egula dopamine gic medica ion app oxima ely 1 h a e he L-dopa [ 32 ] dose. The ollowing a ing scales we e used o e alua e he clinical symp oms o PD: UPDRSIII and UPDRSIV [ 3 ], FOG-Q [ 4 ], REM sleep beha io diso de sc eening ques ionnai e (RBDSQ) [ 33 ], and ACE-R [ 5 ]. The ull clinical cha ac e is ics o he da ase , ie., mean ± sd alues o he clinical a ing scales in session 1, session 2, and session ∆ ( session 2 −session 1 ) can be seen in Table 1. Mo eo e , o iden i y s a is ically signi ican di e ences, he able epo s p- alues o he Wilcoxon signed- ank es be ween he da a acqui ed in session 1 (baseline examina ion) and session 2 ( wo-yea ollow-up examina ion) oo. The clinical da a om he ∆ session we e also used o gene a e desc ip i e isualiza ions (i.e., his og ams, eg ession and esidual plo s) o he change in selec ed clinical a ing scales, mo e speci ically: LED, UPDRS III, UPDRSIV, FOG-Q, RBDSQ, ACE-R, see Figu e 1. Wi h his app oach, i is possible o assess he imp o emen and/o decline in mo o and non-mo o de ici s associa ed wi h PD in he ho izon o wo yea s as well as a ela ionship be ween he change in each o he scales ela i e o o he scales in he selec ed se . Appl. Sci. 2018,8, 2339 4 o 18 Table 1. Clinical cha ac e is ics o he pa ien s. Scale Mean ±sd (s1) Mean ±sd (s2) Mean ±sd (∆)p(Wilcoxon) LED 917.61 ±544.78 1129.92 ±477.50 212.31 ± −67.28 0.188 UPDRSIII 22.49 ±13.47 27.45 ±12.68 4.96 ± −0.79 0.000 UPDRSIV 2.82 ±2.58 3.44 ±2.94 0.62 ±0.36 0.632 FOG-Q 6.57 ±5.40 8.33 ±5.97 1.76 ±0.57 0.000 RBDSQ 3.98 ±3.25 3.78 ±2.28 −0.2 ± −0.98 0.522 ACE-R 87.92 ±7.62 85.89 ±9.48 −2.03 ±1.86 0.000 s1— i s session; s2—second session; ∆ —del a session ( session 2 −session 1 ); p(Wilcoxon) — p- alue o Wilcoxon signed- ank es (pai ed samples); LED—L-dopa equi alen daily dose (mg/day) [ 32 ]; UPDRSIII—Uni ied Pa kinson’s Disease Ra ing Scale, pa III: e alua ion o mo o unc ion [ 3 ], UPDRSIV—Uni ied Pa kinson’s Disease Ra ing Scale, pa IV: e alua ion o complica ions o he apy [ 3 ]; FOG-Q—F eezing o gai ques ionnai e [ 4 ]; RBDSQ—The REM sleep beha io diso de sc eening ques ionnai e [33]; ACE-R—Addenb ooke’s Cogni i e Examina ion-Re ised [5].                                                Figu e 1. Desc ip i e s a is ical g aphs o clinical cha ac e is ics o he PD pa ien da ase : on he main diagonal, his og ams a e isualized. Nex , he uppe iangula pa o he g aph-g id shows sca e plo s wi h he i ed lines o linea eg ession models. Finally, he lowe iangula pa o he g aph-g id is used o display esiduals o he models shown in he uppe g id. Colo no a ion: he blue colo ep esen s da a o session 1, and he g een colo ep esen s da a o session 2. Appl. Sci. 2018,8, 2339 5 o 18 2.2. Vocal Tasks To quan i y he de e io a ion o phona ion in pa ien s wi h PD, we used a sus ained phona ion o owels: /a/, /e/, /i/, /o/, /u/ as a basis o ou expe imen s. The eason behind using all o he i e owels is o employ he analysis wi h he emphasis on quan i ying all posi ions o a ongue du ing phona ion. Fo mo e in o ma ion, see he Hellwag ( owel) iangle [ 34 ]. In ou iew, using only a sus ained phona ion o he owel /a/ is no ully jus i ied as he e is e y li le o no eason o assume ha his pa icula posi ion o he ongue can p o ide mo e in o ma ion abou phona o y diso de s. In ac , as shown by p e ious s udies, he analysis o o he owels is impo an o a mo e obus desc ip ion o HD [19–21,23,24,35–37]. Sus ained phona ion o a owel is a s anda d measu e used o assess quali y o phona ion [ 9 ]. Du ing his pa icula ocal ask, a speake is asked o sus ain phona ion o a owel, a emp ing o main ain s eady equency and ampli ude a a com o able le el [ 38 ]. The ad an age o his ask in compa ison wi h o he commonly used ocal asks is i s independence o a icula o y and o he linguis ic con ounds [ 38 ]. Mo eo e , i is also p esen in mos o he da abases and he e o e he expe imen s p oposed in ou wo k a e compa able wi h o he commonly used da abases [39,40]. The sus ained phona ion ask used in his s udy is a pa o a speech acquisi ion p o ocol de i ed om he s anda dized 3F Dysa h ia P o ile [ 41 ]. Du ing he da a acquisi ion, a la ge capsule ca dioid mic ophone M-AUDIO No a (Cumbe land, RI, Uni ed S a es) moun ed o a boom a m RODE PSA1 (Sil e wa e , Aus alia) and posi ioned a a dis ance o app oxima ely 20cm om he pa ien ’s mou h was used o he eco ding. Consequen ly, he signals we e digi ized by audio in e ace M-AUDIO Fas T ack P o (Cumbe land, RI, Uni ed S a es) wi h he sampling equency o 48kHz (16-bi esolu ion) and checked by a ained acous ic enginee wi hou ha ing seen he pa ien ’s clinical da a. Finally, he signals we e pa ame e ized using P aa [ 42 ] so wa e as well as a se o MATLAB (MATLAB 9.4, Ma hWo ks, Na ick, MA, Uni ed S a es) pa ame iza ion unc ions [ 43 ] de eloped a he B no Uni e si y o Technology. 2.3. Acous ic Fea u es To desc ibe a a ie y o phona o y diso de s associa ed wi h HD, we quan i ied he ollowing: (a) mic ope u ba ions in equency o oice using pe iod pe u ba ion quo ien (PPQ); (b) mic ope u ba ions in in ensi y o oice using ampli ude pe u ba ion quo ien (APQ); (c) i egula pi ch luc ua ions using coe icien o a ia ion o undamen al equency (F0 (CV)); (d) i egula ampli ude luc ua ions using coe icien o a ia ion o Teage –Kaise ope a o (TKEO (CV)); (e) emo o a icula o y o gans (such as jaw, ongue and lips), coe icien o a ia ion o 1s o man (F1 (CV)), coe icien o a ia ion o 2nd o man (F2 (CV)), coe icien o a ia ion o 3 d o man (F3 (CV)); ( ) inc eased acous ic noise using median o ha monic- o-noise a io (HNR (Q2)), median o ene gy a io (ER (Q2), ene gy a io o bands 2000–4000Hz and 70–900Hz)), median o glo al- o-noise exci a ion a io (GNE (Q2)), median o no malized noise ene gy (NNE (Q2)); (g) i egula acous ic noise luc ua ions using s anda d de ia ion o ha monic- o-noise a io (HNR (SD)), coe icien o a ia ion o ene gy a io (ER (CV)), s anda d de ia ion o glo al- o-noise exci a ion a io (GNE (SD)), s anda d de ia ion o no malized noise ene gy (NNE (SD)); and (h) ape iodici y o oice using ac ion o locally un oiced ames (FLUF). All o hese ea u es a e s anda d and clinically in e p e able dysphonic measu es and we e selec ed based on a ecommenda ion gi en in ou ecen e iew on acous ic analysis o oice/speech signals in pa ien s su e ing om HD [ 9 ]. Fo mo e in o ma ion abou he oice/speech pa ame iza ion, see [43]. 2.4. S a is ical Analysis Be o e desc ibing he analy ical se up applied in his wo k, i is impo an o men ion ha he da ase did no con ain any missing alues, and he e o e all da a samples we e used. Fu he mo e, e en hough we used six clinical a ing scales when desc ibing he da ase (see Sec ion 2.1), only ou Appl. Sci. 2018,8, 2339 6 o 18 o hese scales we e used o he analysis, speci ically: UPDRSIII, UPDRS IV, RBDSQ, and FOG-Q. The eason is ha p e ious s udies ha e al eady shown ha non-mo o mani es a ions o PD a e no linked wi h he phona o y aspec s o HD, bu a he wi h he impai men s o p osody and a icula ion [ 44 ] ha a e commonly being quan i ied using a sen ence eading ask, ee speech (monologue), e c. Since his s udy is ocused on he phona o y aspec s o HD, clinical a ing scales desc ibing only mo o symp oms o PD we e used. To e eal and assess he s eng h o a ela ionship be ween he compu ed acous ic ea u es and pa ien s’ clinical da a (UPDRSIII, UPDRSIV, RBDSQ, and FOG-Q), Spea man’s co ela ion coe icien was compu ed ( he s a is ical assump ions o Spea man’s co ela ion coe icien we e sa is ied as: (a) he acous ic ea u es as well as he he clinical da a a e bo h a iables ha a e measu ed on a leas an o dinal scale, and (b) he e is a mono onic ela ionship be ween he wo a iables). Since age, gende , and p obably L-dopa, a e mani es ed in a oice o PD pa ien s [ 9 ], o he pu pose o his wo k, we employed pa ial Spea man’s co ela ion con olling o he e ec o he ollowing con ounding ac o s (also known as co a ia es): pa ien s’ age, gende [ 29 , 45 ], and dopamine gic medica ion [ 32 , 46 ]. The signi icance le el o co ela ion was se o 0.05. Mo e speci ically, wo co ela ion scena ios we e conside ed: (a) co ela ion be ween he acous ic ea u es a he baseline and he change in alues o he selec ed clinical a ing scales, and (b) co ela ion be ween he change in he acous ic ea u es and he change in he alues o he selec ed clinical a ing scales. Wi h his app oach, we aimed a iden i ying hose acous ic ea u es ha a e signi ican ly co ela ed wi h he speci ic mo o and non-mo o symp oms assessed by he selec ed clinical a ing scales in bo h scena ios. Nex , o e alua e he powe o he acous ic ea u es a he baseline o p edic he change o he pa ien s’ clinical da a in he ho izon o wo yea s, we used he acous ic ea u es compu ed o he eco dings acqui ed in session 1 (baseline examina ion) and buil ma hema ical models p edic ing he change in he selec ed clinical a ing scales ( ∆ ). Fo his pu pose, we employed G adien Boos ed T ees (mo e speci ically, he amous XGBoos algo i hm [ 47 ]) in a supe ised lea ning se up: 10- old c oss- alida ion wi h 20 epe i ions [ 48 ]. The XGBoos algo i hm belongs o he s a e-o - he-a in machine lea ning, which is suppo ed by he ac ha i has been ecen ly used o win compe i ions on Kaggle. I wo ks well e en on small da ase s (whe e i ou pe o ms deep lea ning app oaches), i is obus o ou lie s and i is able o model complex in e dependencies. Fo hese easons, i has been used by many esea che s in a ious biomedical ields, e.g., [49–51], e c. The pe o mance o he models (p ecision o he p edic ions) was e alua ed by MAE and es ima ion e o a e (EER). These measu es a e de ined as: MAE =1 n n ∑ i=1 |yi−ˆ yi|, EER =1 n· n ∑ i=1 |yi−ˆ yi| · 100 [%], whe e yi s ands o he ue label o i - h obse a ion, ˆ yi ep esen s he p edic ed label o he i - h obse a ion, n deno es he numbe o obse a ions, and inally s ands o he ange o alues in he p edic ed clinical a ing scale (no he ange ha can be heo e ically eached, bu he ac ual ange o he alues in he da ase ). As can be seen, EER he e o e desc ibes a pe cen age o e o p edic ions wi h espec o s a is ical p ope ies o he da ase , which is pa icula ly use ul o easy in e p e a ion o he esul s. 3. Resul s The alues o 16 acous ic ea u es ex ac ed om bo h sessions, as well as alues o hei di e ences (session 2 − session 1), a e epo ed in Table 2. Based on he Wilcoxon signed- ank es , we can obse e ha none o he ea u es ex ac ed om owel /a/ signi ican ly changed a e wo yea s. Rega ding owel /e/, we iden i ied signi ican ly inc eased mic ope u ba ions in in ensi y o oice and also Appl. Sci. 2018,8, 2339 7 o 18 inc eased ape iodici y. The same signi ican changes we e iden i ied in owel /i/ and /u/. In he case o owel /u/, in addi ion, we moni o ed he inc ease o mic ope u ba ions in equency o oice. The epea ed acquisi ion o owel /o/ was associa ed wi h inc eased ape iodici y and mo e dominan mic ope u ba ions in equency o oice. Table 2. S a is ical desc ip ion o acous ic ea u es o all ocal asks. Fea u e Mean ±sd (s1) Mean ±sd (s2) Mean ±sd (∆)p(Wilcoxon) owel /a/ PPQ 1.31 ±1.28 1.89 ±2.52 0.58 ±1.24 0.069 APQ 10.69 ±4.23 12.81 ±6.66 2.12 ±2.42 0.063 FLUF 3.87 ±5.28 4.77 ±5.61 0.90 ±0.32 0.386 HNR (Q2) 13.35 ±2.90 12.81 ±3.73 −0.54 ±0.83 0.390 HNR (SD) 4.17 ±0.86 4.18 ±0.89 0.02 ±0.03 0.928 F1 (CV) 0.15 ±0.06 0.18 ±0.10 0.02 ±0.04 0.180 F2 (CV) 0.22 ±0.15 0.23 ±0.15 0.00 ±0.00 0.913 F3 (CV) 8.25 ±40.44 4.50 ±21.67 −3.75 ± −18.77 0.575 ER (Q2) 6.98 ±33.97 7.40 ±36.43 0.42 ±2.46 0.954 ER (CV) 0.57 ±0.26 0.57 ±0.30 0.01 ±0.05 0.880 F0 (CV) 0.30 ±0.74 0.36 ±1.15 0.06 ±0.41 0.763 GNE (Q2) −0.46 ±1.85 −0.46 ±1.85 0.00 ± −0.00 0.997 GNE (SD) 0.23 ±0.74 0.30 ±0.97 0.07 ±0.23 0.679 TEO (CV) −0.34 ±1.71 −0.31 ±1.75 0.03 ±0.04 0.931 NNE (Q2) −1.45 ±7.41 −1.33 ±7.08 0.13 ± −0.34 0.932 NNE (SD) 1.80 ±0.76 1.79 ±0.78 −0.01 ±0.02 0.955 owel /e/ PPQ 1.31 ±1.17 1.80 ±3.06 0.50 ±1.89 0.269 APQ 11.21 ±6.82 15.05 ±9.95 3.84 ±3.13 0.036 FLUF 2.62 ±3.58 5.31 ±6.02 2.69 ±2.44 0.007 HNR (Q2) 14.36 ±3.92 13.75 ±4.40 −0.61 ±0.48 0.394 HNR (SD) 4.19 ±0.96 4.32 ±1.18 0.13 ±0.21 0.533 F1 (CV) 0.62 ±0.23 0.56 ±0.24 −0.05 ±0.01 0.173 F2 (CV) 0.19 ±0.07 0.19 ±0.09 −0.00 ±0.02 0.965 F3 (CV) 12.41 ±86.28 7.06 ±48.94 −5.36 ± −37.34 0.709 ER (Q2) 3.46 ±23.30 3.39 ±22.83 −0.07 ± −0.47 0.989 ER (CV) 0.59 ±0.28 0.61 ±0.37 0.02 ±0.10 0.702 F0 (CV) 0.42 ±1.47 0.19 ±0.50 −0.24 ± −0.97 0.293 GNE (Q2) −0.36 ±1.77 −0.17 ±1.18 0.19 ± −0.59 0.536 GNE (SD) 0.08 ±0.36 0.06 ±0.30 −0.02 ± −0.07 0.726 TEO (CV) −0.07 ±0.50 −0.19 ±1.31 −0.11 ±0.80 0.571 NNE (Q2) −0.19 ±1.35 −0.21 ±1.44 −0.01 ±0.10 0.961 NNE (SD) 1.67 ±0.56 1.83 ±0.61 0.17 ±0.05 0.055 owel /i/ PPQ 1.26 ±1.68 1.92 ±3.08 0.66 ±1.40 0.196 APQ 10.49 ±5.31 14.83 ±9.65 4.35 ±4.34 0.005 FLUF 2.13 ±3.73 4.60 ±6.89 2.46 ±3.15 0.013 HNR (Q2) 17.16 ±3.38 16.17 ±5.32 −0.98 ±1.95 0.212 HNR (SD) 4.51 ±1.12 4.53 ±1.40 0.02 ±0.28 0.921 F1 (CV) 0.67 ±0.48 0.58 ±0.40 −0.09 ± −0.08 0.170 F2 (CV) 0.14 ±0.07 0.16 ±0.08 0.02 ±0.00 0.088 F3 (CV) 0.09 ±0.21 38.22 ±207.82 38.14 ±207.61 0.205 ER (Q2) 0.09 ±0.08 8.35 ±33.15 8.27 ±33.07 0.087 ER (CV) 0.61 ±0.37 0.56 ±0.44 −0.05 ±0.07 0.490 F0 (CV) 0.36 ±1.39 0.35 ±1.17 −0.01 ± −0.22 0.961 GNE (Q2) −0.30 ±1.49 −0.30 ±1.48 0.01 ± −0.01 0.980 GNE (SD) 0.07 ±0.32 0.12 ±0.40 0.06 ±0.08 0.449 TEO (CV) 0.78 ±0.55 0.36 ±2.47 −0.42 ±2.47 0.238 NNE (Q2) −0.01 ±0.18 −0.20 ±11.53 −0.19 ±1.15 0.228 NNE (SD) 1.44 ±0.55 1.40 ±0.70 −0.05 ±0.15 0.727 Appl. Sci. 2018,8, 2339 8 o 18 Table 2. Con . Fea u e Mean ±sd (s1) Mean ±sd (s2) Mean ±sd (∆)p(Wilcoxon) owel /o/ PPQ 1.14 ±1.06 1.68 ±2.06 0.54 ±0.99 0.047 APQ 11.09 ±4.41 14.16 ±9.94 3.06 ±5.53 0.051 FLUF 2.64 ±4.32 5.63 ±7.24 2.99 ±2.91 0.008 HNR (Q2) 15.49 ±3.30 15.28 ±4.79 −0.22 ±1.49 0.773 HNR (SD) 4.93 ±1.14 4.57 ±1.36 −0.36 ±0.21 0.149 F1 (CV) 0.24 ±0.19 0.31 ±0.22 0.06 ±0.03 0.091 F2 (CV) 0.14 ±0.10 0.14 ±0.10 0.00 ±0.01 0.867 F3 (CV) 8.75 ±35.36 23.86 ±96.34 15.11 ±60.97 0.317 ER (Q2) 8.17 ±32.52 8.07 ±32.42 −0.10 ± −0.10 0.989 ER (CV) 0.64 ±0.39 0.61 ±0.36 −0.03 ± −0.02 0.705 F0 (CV) 0.40 ±0.91 0.63 ±1.81 0.24 ±0.89 0.434 GNE (Q2) −0.91 ±2.72 −1.25 ±3.11 −0.35 ±0.39 0.582 GNE (SD) 0.30 ±0.75 0.39 ±0.90 0.09 ±0.15 0.580 TEO (CV) −0.74 ±3.27 −0.28 ±1.30 0.46 ± −1.97 0.376 NNE (Q2) −0.19 ±0.79 −0.11 ±0.47 0.09 ± −0.31 0.530 NNE (SD) 1.62 ±0.83 1.58 ±0.91 −0.04 ±0.08 0.843 owel /u/ PPQ 1.35 ±1.17 2.60 ±3.07 1.26 ±1.90 0.009 APQ 12.66 ±5.60 17.03 ±9.50 4.37 ±3.91 0.007 FLUF 2.77 ±5.13 8.52 ±9.83 5.75 ±4.69 0.001 HNR (Q2) 15.28 ±4.23 14.32 ±5.22 −0.96 ±0.99 0.270 HNR (SD) 5.40 ±1.56 5.08 ±1.46 −0.32 ± −0.10 0.252 F1 (CV) 0.69 ±0.44 0.71 ±0.34 0.03 ± −0.10 0.667 F2 (CV) 0.17 ±0.09 0.18 ±0.09 0.01 ± −0.00 0.468 F3 (CV) 10.28 ±52.21 15.04 ±104.80 4.76 ±52.58 0.779 ER (Q2) 8.27 ±33.82 3.63 ±25.29 −4.64 ± −8.53 0.453 ER (CV) 0.67 ±0.39 0.74 ±0.43 0.06 ±0.04 0.431 F0 (CV) 0.23 ±0.67 0.18 ±0.10 −0.05 ± −0.57 0.586 GNE (Q2) −0.19 ±1.31 0.00 ±0.00 0.19 ± −1.31 0.323 GNE (SD) 0.09 ±0.40 0.10 ±0.70 0.01 ±0.30 0.966 TEO (CV) −0.51 ±2.69 −0.07 ±0.51 0.43 ± −2.18 0.275 NNE (Q2) −1.27 ±7.09 −0.31 ±2.190 0.96 ± −4.91 0.373 NNE (SD) 1.57 ±0.73 1.68 ±0.49 0.11 ± −0.24 0.379 The esul s o Spea man’s pa ial co ela ion be ween he baseline acous ic ea u es (session 1) and change in clinical da a ( ∆ ) can be seen in Table 3. None o he ea u es signi ican ly co ela ed wi h UPDRS, pa III. On he o he hand, in he case o pa IV, we can obse e nega i e co ela ion wi h ape iodici y (FLUF, owels /e/, /i/, /o/, /u/), i.e., low ape iodici y a he baseline esul ed in inc eased complica ions wi h he apy. Simila ly, we iden i ied nega i e co ela ion wi h emo o jaw (F2 (CV), owel /a/), bu posi i e co ela ion wi h he emo o lips (F3 (CV), owel /o/). Ano he posi i e co ela ions we e obse ed wi h median o ene gy a io ( owels /o/, /u/), i egula pi ch luc ua ions (F0 (CV), owel /a/), and a iabili y o oice quali y (GNE (SD), owel /a/). Change in UPDRSIV nega i ely co ela ed wi h i egula ampli ude luc ua ions (TEO (CV), owel /u/), acous ic noise (NNE (Q2), owel /u/) and i s a ia ion (NNE (SD), owel /a/). Resul s linked wi h he acous ic noise quan i ied by he median GNE a e no consis en . RBDSQ signi ican ly and posi i ely co ela ed wi h mic ope u ba ions in equency o oice (PPQ, owel /u/) and mic ope u ba ions o i s in ensi y (APQ, owel /a/), i.e., inc eased mic ope u ba ions in equency/ampli ude a he baseline esul ed in de e io a ion o sleep. In addi ion, RBDSQ nega i ely co ela ed wi h he a ia ion o oice quali y (HNR (SD), owel /o/). Rega ding gai di icul ies, as assessed by FOG-Q, we can obse e wo posi i e co ela ions wi h emo o jaw (F1 (CV), owel /i/) and i egula pi ch luc ua ions (F0 (CV), owel /a/). The o al sco e o his ques ionnai e nega i ely co ela es wi h a ia ion o acous ic noise (NNE (SD), owel /o/). Appl. Sci. 2018,8, 2339 9 o 18 Table 3. Spea man’s co ela ion coe icien s be ween baseline acous ic ea u es and ∆o clinical da a. Fea u e /a/ /e/ /i/ /o/ /u/ /a/ /e/ /i/ /o/ /u/ UPDRSIII UPDRSIV PPQ −0.07 −0.08 0.26 −0.09 −0.10 −0.11 −0.26 −0.08 −0.17 −0.08 APQ −0.06 −0.05 0.17 −0.10 −0.09 0.08 0.12 −0.01 0.06 −0.09 FLUF 0.10 0.08 0.11 0.10 0.16 −0.23 −0.47 ** −0.33 * −0.34 * −0.32 * HNR (Q2) 0.16 0.07 −0.05 0.17 0.09 −0.02 −0.08 0.07 0.11 0.16 HNR (SD) 0.10 0.11 −0.04 −0.05 −0.15 0.07 −0.02 0.20 −0.22 −0.09 F1 (CV) 0.04 0.10 −0.17 −0.02 0.19 −0.27 −0.07 0.08 −0.32 * 0.08 F2 (CV) −0.15 0.20 −0.10 −0.11 0.11 −0.37 * −0.11 −0.12 −0.23 0.04 F3 (CV) −0.24 0.25 −0.23 −0.17 0.11 0.22 0.28 0.10 0.32 * 0.10 ER (Q2) −0.25 0.25 −0.14 −0.17 0.17 0.16 0.28 0.12 0.34 * 0.32 * ER (CV) 0.12 −0.09 0.22 −0.03 0.11 −0.17 −0.14 −0.22 −0.18 −0.06 F0 (CV) 0.28 −0.12 0.04 −0.08 0.17 0.33 * −0.04 −0.24 −0.16 −0.21 GNE (Q2) −0.14 0.11 −0.15 0.06 −0.17 −0.35 * 0.25 0.15 0.27 0.33 * GNE (SD) −0.16 −0.08 −0.12 −0.22 0.24 0.30 * −0.01 −0.04 0.22 0.11 TEO (CV) 0.28 −0.25 0.11 0.15 −0.25 −0.23 −0.28 −0.28 −0.23 −0.30 * NNE (Q2) 0.28 −0.25 −0.09 0.14 −0.23 −0.15 −0.28 −0.22 −0.26 −0.31 * NNE (SD) 0.09 −0.25 0.12 0.11 −0.26 −0.43 ** −0.17 −0.28 −0.12 −0.12 RBDSQ FOG-Q PPQ 0.15 0.11 0.21 −0.13 0.33 * −0.20 −0.09 0.15 −0.09 0.08 APQ 0.29 * 0.27 0.21 0.27 0.20 −0.18 −0.14 −0.16 −0.16 −0.12 FLUF −0.06 0.06 −0.22 −0.17 −0.24 0.20 0.15 0.13 0.17 0.23 HNR (Q2) −0.20 −0.17 −0.19 −0.27 −0.20 0.09 0.03 −0.03 0.09 −0.05 HNR (SD) −0.17 −0.16 0.21 −0.36 * −0.27 0.07 0.24 0.21 0.18 0.12 F1 (CV) 0.08 −0.02 0.24 0.09 0.11 0.16 −0.22 0.33 * −0.20 −0.20 F2 (CV) −0.08 −0.09 −0.26 −0.17 −0.27 0.18 −0.09 −0.03 −0.13 0.26 F3 (CV) −0.10 −0.04 −0.11 0.07 −0.08 0.03 0.22 0.14 0.08 −0.11 ER (Q2) −0.19 −0.21 −0.26 −0.12 −0.16 −0.13 0.04 0.25 0.10 −0.05 ER (CV) 0.08 0.28 0.20 −0.28 −0.11 0.04 −0.13 −0.11 0.10 0.06 F0 (CV) 0.21 0.13 0.19 0.25 0.10 0.37 * 0.20 −0.03 −0.10 0.19 GNE (Q2) −0.16 −0.17 −0.28 −0.18 −0.16 −0.29 −0.25 0.05 −0.19 −0.19 GNE (SD) −0.05 −0.09 −0.25 0.09 −0.20 0.08 0.14 −0.05 0.12 0.15 TEO (CV) 0.05 0.04 0.27 −0.17 0.15 −0.05 −0.22 −0.07 −0.25 −0.01 NNE (Q2) 0.24 0.28 0.18 0.20 0.21 −0.04 0.21 0.17 0.16 0.20 NNE (SD) −0.27 −0.05 −0.19 −0.16 0.11 −0.23 −0.12 0.16 −0.22 ** 0.05 *— p - alue o Spea man’s co ela ion coe icien <0.05; **— p - alue o Spea man’s co ela ion coe icien <0.01. The esul s o Spea man’s pa ial co ela ion be ween he change o baseline acous ic ea u es ( ∆ ) and he change in clinical da a ( ∆ ) can be seen in Table 4. Rega ding he change o UPDRSIII, i nega i ely co ela ed wi h he change o mic ope u ba ions in equency o oice (PPQ, owel /i/), ape iodici y (FLUF, owels /e/, /o/), emo o ongue (F1 (CV), owels /a/, /u/), emo o jaw (F2 (CV), owel /e/), i egula pi ch luc ua ions (F0 (CV), owels /a/, /u/), and a ia ion o acous ic noise (NNE (SD), owel /i/). Signi ican posi i e co ela ions we e iden i ied wi h he change o lips emo (F3 (CV), owel /a/), acous ic noise (ER (Q2), owel /a/), and a ia ion o oice quali y (GNE (SD), owel /e/). In he case o UPDRSIV, we iden i ied se en signi ican posi i e co ela ions wi h he change o mic ope u ba ions in equency o oice (PPQ, owel /e/), emo o jaw (F2 (CV), owel /a/), i egula ampli ude luc ua ions (TEO (CV), owels /a/, /u/), and acous ic noise (NNE (Q2), owels /o/, /u/). The change in UPDRS IV signi ican ly nega i ely co ela ed wi h he change o acous ic noise (ER (Q2), owel /u/), and i s a ia ion (ER (CV), owel /e/). Changes in RBDSQ signi ican ly nega i ely co ela ed wi h he change o mic ope u ba ions in equency o oice (PPQ, owel /u/), mic ope u ba ions o i s in ensi y (APQ, owels /e/, /i/, /u/), emo o lips (F3 (CV), owel /o/), acous ic noise (NNE (Q2), owel /e/), and i s a ia ion (ER (CV), owel /e/). Posi i e co ela ions we e iden i ied wi h he change in oice quali y (HNR (Q2), all owels) and i s a iabili y (HNR (SD), owels /e/, /o/, /u/). The simila esul s can be obse ed when assessing he quali y by GNE ( owel /e/). Appl. Sci. 2018,8, 2339 16 o 18 11. El ma ko a, N.; Gajdos, M.; M acko a, M.; Mekyska, J.; Mikl, M.; Rek o o a, I. Impac o Pa kinson’s disease and le odopa on es ing s a e unc ional connec i i y ela ed o speech p osody con ol. Pa kinsonism Rela . Diso d. 2016,22 (Suppl. 1), S52–S55. [C ossRe ] [PubMed] 12. 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