Clinical value of cortical bursting in preterm infants with intraventricular haemorrhage

2.1 Inf ant s This projec t was d efi n ed a s a re tro s p e cti ve s erv ice e valu a tio n by t he UCL H Re sea r ch a nd Deve lopm ent Direc tora te a nd the re fore indiv idual c ons ent fr o m par ent s wa s no t r equired . All cl inica l data rev iew was c onduct ed b y a UCL H - af fil ia ted, s tat e- r e gi ste r ed Clinic al Neuro physiol og ist (KW) . We ide nti fie d in fan t s born be twe e n 2007 and 202 2 who underwent E EG m onitoring du ring the neona t a l peri od (d e fin ed he re a s ≤ 40 we eks cor rect ed ge st a t i onal a ge ( CG A) ) whic h wa s a vail able for revie w. S el ec t i on cri teri a c ompri s e d ge st ational ag e < 35 we ek s (A ncel e t al., 2015 ; As o et al ., 1993; Conne ll et al . , 1988; Radva nyi -Bouve t et al., 1 987) and evide nce o f ≥grad e I I G M -I VH on rou tine cran ial im aging . Exc lusion c r i teri a incl ude d ev idenc e of in tra par tum hyp oxic -is c h e mic insult, o r ac ute seve re me ta bolic di st u rban ce a t th e t i me of EE G . Thi s r e s ul ted in a tot al sample o f 34 infant s with medi an ge sta tional ag e 25+5 w eek s+d ay s . 2.2 EEG monitoring for su spec ted sei zure s A mini mum of 4 Ag / Ag Cl r e cor ding elec tr ode s we r e po s i t io ne d at bil a te ral c ent r a l and fro ntal si te s (C4, C3 , F4, F3) , ac cording to the in tern at iona l 10/20 el ectrod e pla cem e nt s ys tem. Ei ght/ 3 4 infan t s had mor e th an one EEG . This r e sult ed in a tota l of 52 r e c ording s (Tab l e 1), w hich were al l revie w ed for el ec trog r a phic s ei z u re s ( Pre s sl er e t al ., 2021). . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Tabl e 1: Infant demog r a phics Total no. o f in fa nts w it h G M -I VH Grad e II Ven tricul ar dil ata tion a With int rapa renc hymal le sion ( s ) Total a s y mme tric i njury 34 7/ 3 4 5/ 3 4 22/34 26/34 (5 gra de I I, 2 v en tricul ar dil at atio n, 1 9 with in t r apar en chym al le sio n( s) Se x (femal e: male ) 12:22 Media n ( r a nge ) bi rth w eight (gr ams ) 821 (533 - 1999) Media n ( r a nge ) g e s ta tion a l age (we ek s+ d ays) 25+5 (23 +4 - 34+ 2) Media n ( r a nge ) Apg ar s c o r e at 1 mi nu t e 4 (1 - 9) Media n ( r a nge ) Apg ar s c o r e at 5 mi nu t e s 8 (2 - 10) No. o f EE Gs 52 EEGs f rom 34 in f a n t s Media n ( r a nge ) c orrec te d ges ta tional ag e (we ek s+day s ) at di sch arg e home f r om ho s pi ta l (in su rviv or s ) 42+6 (36 +5 - 56+ 3) No. o f EE Gs s uitabl e fo r an aly si s of co rtic a l burstin g b 47 EEGs f rom 33 in f a n t s Media n ( r a nge ) po stn atal a ge (da y s) 20 (2 - 10 4) Media n ( r a nge ) c orrec te d ge sta tional ag e (we ek s+day s ) c 30+1 (24 +0 - 40+ 1) Morphine e xposu re 27/47 Anti - s e iz u re d r ug expo sur e d 16/47 a D e f i n ed h e r e as d il at at io n ≥ 97 th centi le an d /or a nterior ho r n wi d t h > 6 m m (Kid o k o ro e t a l., 2 0 14; L eijs er et a l ., 20 1 8 ; Vr ies et a l . , 2 002) . b The i n fa n t w it hout a ny E EG s u ita b le fo r b u rsting analys i s di e d o n p o st nata l day 1; t hey ha d asym me tri c GM-IV H w it h intra p a renchyma l les i o n . I n ca ses of > 1 EE G be i ng analys ed from the sam e i n fa nt, t h e m ea n i n te r-r e cording inte rval wa s 1 0 days, wh ich d o e s not u nd e restima te the va ri a n c e o f EE G-l e ve l a n a l y ses (s ee th e su p ple menta l in f orma tion i n (Fa b rizi et a l. , 201 1 )). c A t w hi c h ana lyse d E EG end e d. C o rre cted gestation a l ag e = Ges tatio na l ag e + po st nata l a ge. d 15 P hen o bar bit al , 3 Ben zo d i az epine, 2 P h e n y to i n, 1 Le ve ti ra c e tam, 1 P ara l dehyde. (Tota l a d d s up to > 1 6 bec ause 6 E EGs we r e ac q u i re d du ri ng exposu r e t o 2 a nti-seizure d ru g s). 2.3 EEG anal ysi s o f cor tical bur s t ing 2.3. 1 Incl u s i o n criteria f or E EG an aly s i s o f c or tic al bu r s tin g For the a naly s i s o f c ortic al bu rst ing, w e e x clude d 5 reco r di ng s with >20 % s eizure burden ( Pay ne et al. , 2014) a nd / o r du r in g tre a tment with 3 anti- se iz ur e d r ug s , w hich preclud e d ap prai sal o f bac kground EEG fe atu re s ( A rk ilo e t al ., 2 013; O s redka r et a l ., 200 5; Ran a sing he e t al. , 2015). I n th e remain ing 47 r e cor dings , w e se lect ed se g ments w it h no or f ew er s e i z ure s, inc ludi ng up to 2 da ys o f data pe r r e co rding: 41/47 segmen t s incl u ded no s eizur e s , and the rema ining 6 se gment s had ≤ 0 .5% seiz ur e bu rden . 2.3. 2 Bur s t oc currenc e rate Cor tica l bur s t s whic h c ompri s e f a s t o scil l ation s (8 -30Hz) ne s t ed i nt o s low er rhyth ms are the domina nt bac kground pa ttern o f th e neo natal EEG ( Whit ehe ad e t a l., 2 016) . To i d enti fy the se bu r sts, we fir s t r emove d ar te factu al se ctio ns by v is ua l in spec t io n u s i ng ‘pop _ eegplo t’ in E EGLAB v.14 (D elorme a n d Makei g, 200 4) . We then c a lcu lated r oot -mea n- squ are (RMS ) a mplit ude v alue s . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint betwe e n 8-30Hz, u sing sliding 400-m s int erval s (An tony et a l., 2018; Ha rtl ey et al. , 20 12; Rana s in ghe et al . , 2015). We iden tifi ed s eg men t s for ea ch c hanne l that we re c on secu tiv ely a b ove a se t t h re shold (1.5 tim e s the s t anda r d d evia t io n o f it s R M S signal ove r the w hol e rec ordi ng (An t ony e t al., 20 18; Vanha t a lo et al ., 2005) ) fo r ≥0 .5 secon ds (Con de e t al., 2005; Omidva r n ia e t al . , 2014), u s ing ‘det ec teven t’ i n EEGLAB (f or ill u s t rati on, se e (Ko ske la et al ., 2021b )). Pl ea se s ee S upplemen tary Info rmatio n fo r fur the r det ail s ab ou t dat a pre -proce s sing . 2.3. 3 Bur s t tem po r al dynam ics The r e la tive t i ming of c or t i cal burs t s over lyin g differ ent b rain reg ion s of fe rs insigh t i nto function a l co nnection s (L eiko s et al ., 2020; Tokari e v et al ., 2012 ). To ex amine whe ther GM -I VH i nfluenc e d the tempor al r el a tion s h ip b etwe e n bur s t o ns et s at r ecording cha nn el s overly ing di ffe r ent reg io ns, we repr ese nt ed th eir la tenc ie s wi t h a gau ssi an w indow of 3 s t a nda rd dev iati on s arou nd ea ch v alue, using ‘g au s s ’ i n EEGLAB . W e t h en ca lcula t e d cro s s-c or r ela ti on s fo r 6 po s i t iv e an d 6 neg ative l ag va lues b etwe e n -1500 a nd +150 0 ms, no rmalis ed to the a u tocor rela tion b e t w ee n id entica l bur st laten ci es (i. e. cor rela tion o f 1 .00 at l ag 0 m s ) (Har tley e t a l., 20 12; Ko skela et al ., 2 021a; Leroy- Terque m e t al., 2017 ). 2.3. 4 Bur s t mag n it ude The magnitude o f bur s t s ca n b e ind exed b y their pow er (µ V 2 ) . To cha r a ct eri se po we r c hang e s o f detec t e d bur st s rel ative t o ba selin e, we c onvol ut e d the EEG signa l with a Mo rle t wav elet be t w een 0.1– 45Hz u sing an inc re asi ng range o f cy cle s (3 – 270) , empl oying ‘newtime f ’ in EE GL AB. Fo r bur s t s detec t e d a t ea ch c hann el, we e xtr acted t he 8-30Hz po we r at t hat c han nel over th e c ourse o f t he burst, and then no rma li s e d thi s value by di viding by i t s dura tion i n s e cond s (Ko ske la et al ., 2021a) . 2.3. 5 Cortical b ur s tin g a n d mo tor o utco m e Po sitive n eurod evel opmen tal o u t c ome w as s pe ci fied a s s u rviv al w ithout s e ver e impa irment (de fine d here a s B a yley Sc ale s of I nfa nt D ev elopm ent 3 rd edi tion moto r c ompo s i te s c o r e ≤7 0/100, or unabl e to be a sse s s e d us i ng Bay ley S cal e s be cau se o f sev ere globa l del a y and cereb ral vis ual im pairmen t; medi an 2 y ear s fo llow-up, r a nge 1 -2 year s corr ecte d) . 2.4 Stati stic al a naly si s To a sse s s di f f e r e n ce s betw ee n match e d i ntra - s ubj ect v ari able s or unpai r e d variab l es we u se d p a ire d and unpair ed t t e st s re sp ec t iv ely. To t e st for a ssoci a tion s be tween t w o con t i nuou s variabl e s w e us ed Pea r s on c or r ela ti on s . To i nvestiga te mu lti ple f ac to r s p ote ntial l y unde r l ying varianc e in cortical bu r s ting, we c onduc t e d a hierarc hica l lin ea r r eg r e ssio n in whic h CG A was en ter ed a s th e fi r s t explana tory v a riable give n it s kno wn la r g e ef fec t (Whi teh ea d e t al . , 2016). Aft er th at, w e ex amine d whethe r ad di ng furth er EEG - lev el v ariable s o f morphin e or an ti- se iz ur e dr ug ( s ) ex posu r e, o r elec t rogr aph ic s eiz ure( s) during th e ana lys ed s egment (a ll ye s/n o) impr oved model fi t (Be ll et al ., 1993; Ran a singhe e t al., 2015; Tata r a n no et al. , 2020) . F inall y, w e t e s te d whether a dd ing the i n fan t-l evel variabl e of intraparenc hyma l le sio n( s) op t i mi s e d mo del f i t. To e xami ne whe t he r cortical bu r s ting pre dicted surviv al w ithou t impairmen t, we c onducted a rece iver opera ting cha r a c teri stic (R O C ) a naly s i s and i ) ca lcula te d the area u nder t he cu r v e (AUC ) whi ch is a combin ed mea su re o f s en sitivi ty and speci f i city: a n AUC of 0 .5 i ndica tes p redic tion n o bett er t han c hanc e an d s erve s a s th e nul l hypothe si s, wh ile 1.0 would re f l ect a pe r f e ct p redic tor, a nd . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint then i i) exa mined RO C c ur v e co or di nat e s to identi fy c ut -o f f thre sho ld s whi ch w ere optimall y predic tive . S ta ti s tic al an alysi s wa s pe rfo r med using IB M SPSS v. 2 6 and sign ific anc e w as s e t a t p < .05. 3. Re su l t s 3.1 Seizur e s At th e EEG-l ev el, 17 / 52 (33%) EE Gs inc lu ded e lec trogra phi c s eizure s. At the i n fan t -level , 15 /34 (44% ) infan t s had elec t rogr aphi c s eizure s rec o rd ed during at l ea st on e E EG . The s e s eizures w ere reco rded betwe e n po stna tal da y s 0-104 a n d 25-40 w eeks C GA , in l ine w ith pr evious r epor t s that seizu re s can oc cur many wee ks a ft er t h e initial injury (Pi s ani et al ., 2018, 2 008; S cher et al ., 19 93). Pl ea se se e Supp lemen tary Fig. 1 fo r a s eizure exam ple. 3.2 Char acte ri sati on of c o rt i cal burs t s In 33 / 34 inf ant s, a t lea s t one EEG wa s sui table for bu rs ting a naly si s ( s e e Table 1 f o r demog r a phic and medi cation in for ma t i on ). The 47 ana lyse d EEGs we re of medi an dura tion 8 hou rs (minimum 0.5 hour s in 45/47 rec o rding s) . Cor t i cal bur st s had mea n dura tion 1. 6 s e con ds . The se bu r s t s c ompri s e d an increa se in pow er w hich peake d b etw ee n 8-30H z a s expec te d, c oupled to a le s s p r on ou nced b u t long er-du r a t io n incr ea s e in s l ower fr equ enc ie s (Fig . 1 ). For bu r sts ide n ti fied a t ea ch c hanne l, th e large s t c hange s in 8 -30Hz po wer we re a t that cha n nel a s an tic ipat ed, al though burst s involv ed o ther ch annel s al so, e s pec iall y fo r s l ower f requ enc ie s (Fig. 1 ). 3.3 Cortic al bu rs t rat e was d epre ss ed by G M- I VH To e xami ne whe t he r injury al t e red cor tica l bur s t ra te, we fir st took adv an tage o f a subgro up of 33 EEGs from 25 in fa nts w ith a symmetr ic i njury, for wh om we could u s e the lea s t- af f ected h e mis ph ere as an in tern al c ontrol. The re w ere f ewer c entr a l (but n ot f ron tal) bu r sts pe r minu te over th e w orst - af fec te d hemi sphe re (c ent r a l: me an 7.9 v s . 9 .3, [95% CI o f di ff erenc e -2 .10 -0.62 ], p = .001, F ig. 2 ; fron tal: p = .648) . T his in ter-h e mis p h eric diff er enc e in cent ral bu rs t r a t e did no t si gni f i cantly nar row wi t h postna tal age ( p = .415 ) or C G A ( p = .169, Fig. 2). In c ompari son an d a s e xpec te d, th ere wa s n o inter -h emisph eric di ff erenc e in ce ntral b urst ra te in s y mmetr i c inj ur y (p = .2 04, Fi g. 2), w hen int er - hemi s ph eric bur sting rati o wa s mo re equ al tha n in a symme t ric injury (me an ra tio 1. 04 vs. 0.8 5, [95% CI o f ra tio dif fe r e nce 0 .09 0.2 8] , p < . 001 ) . Cen tral b urs t s ov er th e wor st - a ffe ct ed h e mis ph e r e we re l e ss lik ely to fol low bu rs ts ov e r the l ea s t - af fec te d hemi sphe re t han vic e ver sa (n e g ative l ags ha d l ower c r o s s-c orrel at ion s th an thei r pai r e d posi tive lag be t w e en 2 50-1000 m s ( e.g . - 500 v s . +500 ms ) (p ≤ . 014, F ig. 3) . I n com pa r i s on a nd a s ex pected, in symmet ric i njury inter -hemi sph eric cen tral burs t on set s w e re bal a nced (no s i gnific ant diff er enc e s be tween the cro s s-co r r ela t i o ns o f pair ed la gs: p ≥ .374 , Fig . 3 ). In a s y mme tr i c inju r y , grea ter d epre s si on of c ent r a l bur st ra te pr edi cte d hig her me an centr al bu rst pow er at the wor st - a f f e ct ed he mi s ph e r e (int er-he mi s ph e r i c rati o of cen tra l bur st ra t e vs . powe r: r = -.608, p < .0 01), bu t not the l e a s t -a ff ec te d hemisph ere (p = .350 ). P ooling EEG s f r om a ll infan ts togeth er, w ith eith er a symme t ric o r s y m metric i njury, al so showe d an a ssoci a t i on betwee n low e r burst ra te and hig h er mean b u rst powe r a t t h a t s am e r egion ( r = -.390 to - .569 , p ≤ . 007) . 3.4 Lowe r cortical bu rst ra te w a s a ssoci a ted wi t h adve rs e outco m e . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Cen tral b urs t ra te ove r the wor st- o r equ a lly-a ff ec ted h emi spher e i ncre as ed w ith CGA, and w a s slightly re duced by morphine expo s u re ( but not by ant i- s eiz u r e d r ug exp osure , or prox imal ele ctr ographic s e iz u re s ) (Table 2 ). W e re ason ed th at l owe r bur st rate t ha n ex pec t ed a fter a cc ou nt i ng for t he s e fact or s could r e flec t w orse f unc tional i njury, and pre dict a dve r s e ou tco me. To te st t hi s , w e ca lcul ated s t a nda rdi sed r esi dual s (z- scor es ) a fte r fi tt i ng th e C GA + mo rphi ne mod el: a z -s c o r e ab ove 0 in dica t e s th at bur s t r a t e wa s hig her th a n predic te d by the model , a z - sco re b el o w 0 indic ates t ha t burst ra te wa s lowe r tha n pr edic t e d by the model. Of 33 inf a nts wi t h bu rsting analy s ed , 27 infa n t s - w ho had 4 1 EEG s in to tal - h a d o utcome informa tion avai la ble (six inf ant s died a ft er redi rec ti on of c a re, an d o ut c ome w a s ava ilable f or 21/ 2 7 sur v ivin g infan t s) . Low er cen tral burs t ra t e wa s mo de stly as soc iat ed w ith adv ers e outc ome ( AU C .648 , s pe cific i ty and sen s itiv ity 93% and 3 7% respectiv ely us ing an o p tima l c ut-o f f thre shold o f -0.77 ; Fi g. 4a). Aft er addi ng p re s en c e (y e s / no) o f int raparenc hyma l le sion ( s) (I PL) to the C GA + mor phine mode l ex plaini ng burst ra te, mod el fi t w as impr oved beca u s e I PL a ttenua t e d bu r s t r ate ( Ta ble 2; visuali s ed in F ig. 4 b), and t he r e sid ua l s n o longe r pr edi cted ou tc ome (AU C .540) . T his s ug ge sts that the as s o cia tion b etwee n burst r at e and outc ome i s pa r tia lly m edi ated by whe t he r G M-I VH i s a ssoc ia ted wi t h IPL. H ow eve r, F ig. 4a s h ow s tha t bu rst ra te c an al s o pr ov ide uniq ue in form at ion: i n thre e inst ance s o f I PL bu t rela t i vely high burst rate , the c u t-of f th re shold c o r rec tly predi c ted tha t th e i n f a nt d id n o t s uf f er an a d ver s e out co m e. Tabl e 2: Hierarchic al line ar models of va riables influenc ing c e ntral burs t rate ove r t he wors t - o r equal ly-affected he mis phere B [95% CI ] s . e. p R 2 Model 1: C GA CGA .637 [.412 .8 61 ] .111 <.00 1 .421 Model 2: C GA + m orp hi ne a CGA .596 [.382 .8 10 ] .106 <.00 1 .495 Morphine -2.046 [- .427 - .3.6 64 ] .803 .014 Model 3: C GA + m orp hi ne + I PL CGA .639 [.433 .8 45 ] .102 <.00 1 .557 Morphine -2.114 [- .578 -3 .65 0] .762 .008 IPL -2.007 [- .351 -3 .66 4] .822 .019 a Anti-seizure drug e xpo sure a nd E lectrogra p h ic se iz ures wer e b o t h e xclu d e d from t h e m odel: p = .168 a n d .3 01 re s p e ctiv e l y . IP L = I ntra pare n c h y mal l e sion(s) 4. Dis c us sion GM-I V H de pre sse s burs t rat e ove r t h e s e n s it iv e period e quival en t to the thi rd tri mester o f g e s t atio n whe n cortic al bur s t i ng re fine s n eural circ ui t s in a nimal model s (Le be deva et al ., 2 017; Molná r e t al. , 2020 ; Rana singh e e t al. , 2015; T olner e t al ., 2012) . This i s al so whe n ac tiv ity-d epe nd ent em ergenc e of bil a tera l c or tic al n e t w or k s occu rs, w hi ch c ould be disrupt ed by skew ed in ter -h emisph eric cor tica l burst d ynamic s when o ne hemi sph ere i s in jur e d rela tive to the o the r (Alli ev i et al . , 2016; Marcano - Reik et al . , 2010; Tokariev e t al. , 2012; Whiteh e ad e t a l., 202 2, 2019) . The se ab nor mal itie s o f bur s t initia t i on (ra te ) and p ropa ga tion (in te r-h emisph eric dyna mics ) ar e lik ely t o r e f l ect the g r e y mat ter . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint and white ma tter d a mage a ssoci a ted wi th G M- IV H grade I I or highe r (Omidv a rnia et a l. , 2015 ; Tortor a et al ., 2018; Va s i leia di s et a l ., 20 04 ). Bur s t ra te w a s mode s tly as soci a t e d with outc ome, w hich t o ou r knowl edge i s th e only rec ent r epor t that the ba ckg r ou nd EE G is pr ogno stic i n infan t s with GM -I VH , s in ce two much e ar lier pape rs wh en neona t a l int en sive care wa s very dif fe r e n t (C onnell e t al. , 19 88; Hell st r öm -We s ta s et al. , 2 001). There for e, EEG coul d be u se d to t rack pr ognos tic i nfo r ma t i o n over time . This h as the po ten tia l to provide re al time moni toring o f the ef fec t of c linic al in terv en tion s deliv e r e d on th e ne ona tal uni t aft er th e inj ur y , e.g . to s upp o r t sle ep cyc ling as it em erge s f rom appr ox imately 28- 31 w eeks C GA (Supp lem enta ry F ig. 2 ) (Geo rgou la s e t al. , 2021; v an den H oog en e t a l. , 2017 ) . Our r e sul t s indic at e tha t th e ba ckg r ou nd EEG c ould c ontr ibu t e to neur ologic al a ss es s me nt a nd progno stica t io n a ft er brai n inju r y in pret erm infa n ts, a s i s cu stoma ry i n full- te rm infan ts . Ind ee d, in both c ohor ts inju r y is a ssoc ia ted w it h s pa r s er, hig h er p ower c o rt ic al bu r s t s , sugg estin g so me similari ty in how t h e in sult impac t s brai n functio n ( K o s ke la e t a l. , 202 1b; La mblin e t a l., 201 3; Whiteh ea d e t al. , 2020). This w or k ha s s ome limi t a t i on s . The sam ple was va r i e d, but thi s is a tru e re flec t io n of our cl inica l popul ati on and much of the int er -subje ct heter ogene i ty wa s c on tr o ll ed fo r by us e of int ra -subj ect ana lys e s . We s uc ce ss fully us ed thi s in tra - subjec t a ppro ach t o s how tha t bur s t rat e w as depr e ssed ove r t he wor st- v s . l e a st-a ff ec ted h emi sphere, bu t a c lean er c on tr ol would have b een a match e d group w ith no GM -I VH. Furth ermore , th e sample und erwen t EE G rec o rding s bec a use se iz ure s we r e su s pe c ted ; proxi mal s eizur e s c ould c ontri bute t o the d ep r e s si on of in ter -ic ta l corti ca l burstin g and ther ef ore the samp le may n ot b e repre se nt a t i ve of the tota l pop ula tio n o f infa nt s with G M- IVH. In the f utur e, a multi -cen tr e s tudy c ould be conduc ted t o mode l pr edicto r s of ou tco me acro ss thi s wi der popula tion , e .g. 52 inf ant s from f o ur centr e s allo wed t o c r e a te a four -va r i a ble mod el o f outco me a ft er G M - IVH in (Luyt et a l . 202 0 ). In summary , cli nical EEG r ecordin g s can i ndex the fu nctiona l injury a fte r G M- IVH , with hi gher c or tic al burst ra te rea ssuring f or a po s i tiv e motor outcome over t he fi r st 2 ye ars . Th is an al ysis h a s the poten tial to provide comple m enta ry pro gnostic in for m a tion , but al s o to be u s e d as a c o tside non - inv as i ve mon ito r o f cortical h ealt h a nd d eve lopmen t, pa rtic ularly during t her ape utic inte rven t i on s. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Fig . 1: Gra n d a verag e time-fr e quenc y changes as socia te d w i th cort i c al bursts. Bursts id e n t ified a t the c entral c h a nnel overlying th e l e ast-a ffect e d brai n hem i sp here (or r i g h t hemisp h e r e in t he ca se o f sy mme tric i nj u ry) (upper pa nel) a nd worst-affected b ra in h e misp h e re (o r left h e misp he r e in the cas e o f sym me t ri c i njury) (lo we r pa n e l ). P ower cha nge s betwe en 0. 1 -4 5 Hz (loga rith m i c sc ale) are sh ow n i n dec i bels, relative to t h e mea n powe r p re cedin g burst onset (bl a ck vertical l i ne), w h e re in cre ased p o w er is re d a nd d ec r eas ed power is blue. Fig . 2: Co rtica l bur st r ate wa s depr e ss ed by GM-I VH . L eft: C e n tra l bu rst ra te o v er th e tw o hem i sp he r es w h e n i n j u ry is s y mm et r i c ( n = 1 4 E E G s) o r as y mm et r i c ( n = 3 3 EE G s ) . E ac h EE G i s r ep r e s e n t ed b y o n e l i n e . R i gh t : S cat t e r p lo t o f i n t e r - hemispheric burst rate ra tio ag ai n s t c orre ct ed gestati o n al ag e at EE G. F o r i n fa nts w it h sy mme tric injury, t h e h e misp h e ri c ratio is left: ri g h t hemisp h e re. Ea ch E EG is re p resen te d by one dot . Fig . 3: I n ter-hemispher ic cort i c al b urst d y n a mics wer e a l t er e d b y a symmetric GM-I VH . T h e re l a tive timi ng o f ce n tra l bu rst occurrence ove r the two h e misph e res when i njury is sym metric (n = 1 4 E EGs) o r a symm etric (n = 33 EE Gs). Centra l bursts over the worst-affec t ed h e misphere we r e l e ss l ikely to imme di a tely fo l low b u rsts ove r the lea st-aff ected h e misp h e re than vice ver sa . * = p < .05. 95% c o nf i dence in terva ls a r e deno te d by error b a rs. F i g. 4 : B u r st o c c u rre n c e r a t e a n d i n ci de n ce o f d e a t h o r s e ve re m o t o r i m p ai r me n t. a ) D istribut i o n o f stan dard i se d re sid ua l of b u rst occ urrence ra t e a f t er corr ect e d g esta ti on al a ge a nd m orphi n e e xpo sure con tro l led f or i n i nf ants w ho di d or di d no t surviv e wit hout sever e m o tor i m p a i rm ent. E ac h E E G is represented by a d o t (n = 4 1 ). The optima l cut-o ff threshold t o predi c t dea th or s ev e r e impairme n t is repre s e nte d by a bl a ck dashed line, a n d t h e a d ja cent R OC c u rv e il l ustrate s h ow t h is thresho l d w as d e riv ed. Da ta are co l ou r-co ded by whether the infant h a d i n tra p a renchyma l les i o n (s) (IP L ) , t o dem onstrate the d e gr ee to wh ich t h i s fa ctor co-va ri e d w it h b u r st ra te an d o u t com e. R igh t: F o r i llustrative purpose s, the cross-s e ctio nal dev e lo pme n t a l tra j e ctory o f burst rate i s fi tted separa tely fo r t hree subgroups t o demo nstrate ho w IPL a n d morp hin e e x p osure reduced b urst rate . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint

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(which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Worst- or equally-affected hemisphere Least- or equally-affected hemisphere Burst detected at this channel -3 -2 0 1 3 Sec -1 2 45 0.1 Hz2 6 Burst detected at this channel -3 -2 0 1 3 Sec -1 2 45 0.1 Hz2 6 Least- or equally-affected hemisphere Worst- or equally-affected hemisphere +2.81 -2.81 0 DECIBELS . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint 0 Central bursts per min 0 2 4 6 8 10 12 14 16 Worst-affected Least-affected Asymmetric injurySymmetric injury Equally-affected (Right) Equally-affected (Left) Hemisphere Hemisphere n.s. p = .001 Hemispheric ratio central bursts per min Asymmetric injury = Worst-affected: Least-affected 0.2 1.4 24 40 0.4 0.6 0.8 1.0 1.2 26 28 30 32 34 36 38 Symmetric injury Asymmetric injury Corrected gestational age . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Normalised cross-correlation Asymmetric injury Inter-central channels 0 0.35 0 1500-1500 Lag (msec) Worst-affected hemisphere bursts after least-affected hemisphere Worst-affected hemisphere bursts before least-affected hemisphere Symmetric injury Inter-central channels 0 1500-1500 Lag (msec) Equally-affected hemisphere bursts after equally-affected (left) hemisphere Equally-affected hemisphere bursts before equally-affected (right) hemisphere 0.05 0.10 0.15 0.20 0.25 0.30 0.40 Mean difference cross-correlation of positive vs. paired negative lag Lag (msec) 250 500 750 1000 1250 1500 0.06 0.04 0.02 0.00 -0.02 -0.04 -0.06 500 1000-1000 -500-500-1000 500 1000 0.45 * * * * . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint Central bursts per min (residual) Worst- or equally-affected hemisphere Death or severe impairment Survival without severe impairment Optimal cut-off threshold Optimal cut-off 2.4 -2.4 0 No IPL IPL Effect of CGA + morphine adjusted for Sensitivity (%) Specificity (%) 100 80 60 40 20 0 100 80 60 40 20 0 24 4026 28 30 32 34 36 38 Corrected gestational age 0 Central bursts per min Worst- or equally-affected hemisphere 0 2 4 6 8 10 12 14 16 No IPL IPL and morphine IPL no morphine b)a) . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 26, 2023. ; https://doi.org/10.1101/2023.04.25.23289131doi: medRxiv preprint