Cortical somatosensory processing measured by magnetoencephalography predicts neurodevelopment in extremely low-gestational-age infants

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1 nture publishing group Clinicl Investigtion Corticl somtosensory processing mesured by mgnetoencephlogrphy predicts neurodevelopment in extremely low-gesttionl-ge infnts Petri Rhkonen 1, Päivi Nevlinen 2, Leen Luronen 3, Elin Pihko 4, Aulikki Lno 5, Smps Vnhtlo 3, Anu-Ktriin Pesonen 6, Kti Heinonen 6, Ktri Räikkönen 6, Leen Vlnne 7, Tin Autti 7, Sture Andersson 1 nd Mrjo Metsärnt 1 Bckground: Higher corticl function during sensory processing cn be exmined by recording specific somtosensoryevoked mgnetic fields (SEFs) with mgnetoencephlogrphy (MEG). We evluted whether, in extremely low-gesttionlge (ELGA) infnts, bnormlities in MEG-recorded SEFs t term ge re ssocited with dverse neurodevelopment t 2 y of corrected ge. Methods: SEFs to tctile stimultion of the index finger were recorded t term ge in 30 ELGA infnts (26.5 ± 1.2 wk, birth weight: 884g ± 181 g). Neurodevelopment ws evluted t 2 y of corrected ge. Controls were 11 helthy term infnts. Results: In nine of the ELGA infnts (30.0%), SEFs were ctegorized s bnorml on the bsis of lck of response from secondry somtosensory cortex (SII). At 2 y, these infnts hd significntly worse men developmentl quotient nd locomotor subscle on the Griffiths Mentl Development Scles thn the ELGA infnts with norml responses. Mild white mtter bnormlities in mgnetic resonnce imging t term ge were detected in 21% of infnts, but these bnormlities were not ssocited with dverse neurodevelopment. Conclusion: Abnorml SII responses t term predict dverse neuromotor development t 2 y of corrected ge. This dverse development my not be foreseen with conventionl neuroimging methods, suggesting role for evluting SII responses in the developmentl risk ssessment of ELGA infnts. Becuse of the incresing number of extremely low-gesttionl-ge (ELGA) survivors, more ttention is being pid to erly detection of brin injury nd bnorml brin development to enble erly interventions for the prevention of longterm morbidity (1). At present, however, ELGA infnts often develop with motor, sensory, cognitive, nd behviorl impirments (2 4). Grde III nd IV intrventriculr hemorrhges (IVHs) nd cystic periventriculr leukomlci re ssocited with dverse neurodevelopmentl outcome. However, neurodevelopmentl problems re frequently encountered in infnts with norml crnil ultrsonogrphy (US) (5). Compred with US, conventionl mgnetic resonnce imging (MRI) provides more informtion on white mtter (WM) (6), nd moderte to severe WM injury predicts dverse neurodevelopmentl outcome (7 10). However, neurodevelopmentl problems lso occur in preterm infnts with norml MRI (10,11). Becuse the structurl imging methods prtly fil in detecting the milder bnormlities tht my compromise lter neurocognitive development of ELGA infnts, dditionl methods re needed to predict neurodevelopmentl outcome nd llow the erly commencement of pproprite rehbilittion. Previous neurophysiologicl studies ssessing the functioning of the somtosensory system in preterm infnts hve focused on the first corticlly generted component in the somtosensory-evoked potentils (SEPs) with the im of ssessing the integrity of the pthwys from the periphery to the cortex (12 15). These studies hve been motivted by the ide tht somtosensory pthwys run through the vulnerble periventriculr zone nd hence the SEPs could reflect the otherwise elusive functionl integrity in tht structure. It hs recently become pprent, however, tht prevlent type of preterm brin injury is diffuse WM injury ssocited with vriety of secondry disturbnces in the structurl nd functionl brin orgniztion (16). This hs led to cll for methods tht would directly ssess integrity of corticl functions beyond the primry sensory res, thereby providing more elborte informtion on the functionl intctness of developing corticl networks. Mgnetoencephlogrphy (MEG) is noninvsive method for detecting wek extrcrnil mgnetic fields produced by currents generted in the cerebrl cortex. Activity from both the primry somtosensory cortex (SI) nd the secondry somtosensory cortex (SII) cn be detected nd modeled in both newborn term infnts nd ELGA infnts t term 1 Deprtment of Peditrics, Children s Hospitl, Helsinki University Centrl Hospitl, University of Helsinki, Helsinki, Finlnd; 2 BioMg Lbortory, Helsinki Medicl Imging Center, Helsinki University Centrl Hospitl, University of Helsinki, Helsinki, Finlnd; 3 Deprtment of Clinicl Neurophysiology, Children s Hospitl, Helsinki University Centrl Hospitl, University of Helsinki, Helsinki, Finlnd; 4 Brin Reserch Unit, O.V. Lounsm Lbortory, Alto University School of Science, Espoo, Finlnd; 5 Deprtment of Child Neurology, Children s Hospitl, Helsinki University Centrl Hospitl, University of Helsinki, Helsinki, Finlnd; 6 Fculty of Behviorl Sciences, University of Helsinki, Helsinki, Finlnd; 7 Helsinki Medicl Imging Center, University of Helsinki, Helsinki, Finlnd. Correspondence: Petri Rhkonen (petri.rhkonen@hus.fi) Received 20 July 2012; ccepted 19 December 2012; dvnce online publiction 24 April doi: /pr Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc. Volume 73 Number 6 June 2013 Peditric Reserch 763

2 Rhkonen et l. equivlent ge (TEA) (17 19). Becuse MEG cn detect somtosensory processing beyond primry res, we wnted to test whether the bnormlities in corticl processing of somtosensory informtion in ELGA infnts, reflected s SI SII 10 nam ms Figure 1. Strength nd loction of ctivity in the right primry (SI) nd secondry (SII) somtosensory cortices to stimultion of the left index finger. The open spheres indicte the SI source nd the open squres indicte the SII source in one extremely low-gesttionl-ge infnt. The upper line shows how the strength of ctivity in SI chnges in time with its pek t ~60 ms (rrow), nd the lower line shows the strength of the ctivity in SII with its pek t 240 ms. The verticl line denotes the time of stimultion. bnorml somtosensory-evoked mgnetic fields (SEFs) t TEA, re ssocited with dverse neurodevelopmentl outcome t 2 y of corrected ge. RESULTS MEG nd Neurodevelopmentl Outcome The SEF response from the contrlterl SI, peking t ~60 ms fter tctile stimultion, ws detectble in ll ELGA infnts nd controls (Figure 1). The M60 pek ltencies nd source strengths were norml (within 2.5 SD from the men reported in full-term newborns) (20) in ll but one preterm infnt, who showed slightly delyed M60. The response from the contrlterl SII (Figure 2), peking t ~200 ms fter stimulus, ws bsent in nine ELGA infnts in the right hemisphere nd eight in the left hemisphere. To ipsilterl stimultion, the SII response ws visible in the right hemisphere in three of the nine infnts nd in the left hemisphere in three of the eight infnts with response missing to contrlterl Originl Ptient 1 SI source subtrcted Originl Ptient 2 SI source subtrcted b 500 ms 100 ft/cm c d SI SII SI Figure 2. Exmples of preterm infnts with norml secondry somtosensory cortex (SII) response (Ptient 1) nd missing SII response (Ptient 2). () For both infnts, the upper left hnd pnel shows the responses of subset of mgnetoencephlogrphy grdients over the mesured hemisphere. (b,c) In both infnts, the first deflection cn be modeled with n equivlent current dipole (ECD) displyed in c, where the mgnetic contour mps re reflected on sphericl surfce. The red lines indicte mgnetic field exiting the hed, nd blue lines indicte mgnetic field entering the hed. The rrow represents the ECD. Note tht the ECD for the first deflection hs horizontl orienttion nd is locted centrlly. The ECD orienttion nd loction gree with source loction t the primry somtosensory cortex (SI). When this SI source is subtrcted from the dt (: on the upper right hnd pnel for both infnts), nother deflection cn be seen in the dt of Ptient 1 (s in,b), but not in Ptient 2. (c) This lter deflection cn be modeled with n ECD with upright orienttion nd loction more inferiorly nd lterlly (s compred with the SI ECD), greeing with source loction t the SII in the prietl operculum. (d) The modeled wveforms (red: one-dipole model including SI ECD, green: two-dipole model including SI nd SII ECDs) re on top of the mesured wveforms (blck). Note tht the one-dipole model (red) fits well with the dt of Ptient 2 but does not explin the lter deflection for Ptient 1, wheres the two-dipole model (green) lso explins the lter deflection for Ptient 1 (red vs. green line on circled chnnel). 764 Peditric Reserch Volume 73 Number 6 June 2013 Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc.

3 MEG nd neurodevelopment 100 Tble 1. Chrcteristics of ELGA infnts with norml nd bnorml SII response in MEG Norml SII SEF ** Abnorml SII SEF Figure 3. Griffiths Mentl Development Scles (29) quotients in extremely low-gesttionl-ge infnts with norml (left) nd bnorml secondry somtosensory cortex (SII) response in mgnetoencephlogrphy (MEG). White boxes: developmentl quotient; drk gry boxes: locotomor subscle; lighter gry boxes: eye hnd coordintion. The drk lines in the middle of the boxes depict the medin, nd open circles show outliers. **P < SEF, somtosensory-evoked mgnetic field. stimultion. When, in either hemisphere (right or left), both contr- nd ipsilterlly evoked SII responses were bsent, the SEF ws considered to be bnorml. Consequently, the SII SEF ws bnorml in nine of 30 ELGA infnts. Of the control infnts, one showed n bsence of SII responses in the right hemisphere (left not recorded), nd this infnt lso showed minor WM bnormlity in MRI (focl regions of high T1- or T2-weighted signl). His developmentl quotient (DQ) on the Griffiths Mentl Development Scles (GMDS) nd cognition nd lnguge development on the Byley Scles of Infnt nd Toddler Development, Third Edition (BSID-III), were lower thn those of controls on verge. In infnts in whom SII responses were present, the pek ltencies nd source strengths were within norml limits (men ± 2.5 SD) (20). The ELGA infnts with bnorml SII SEF responses hd lower totl DQ nd locomotor subscle quotient (SQ) in GMDS (P < 0.01) thn the ELGA infnts with norml SII responses (totl DQ: 82.8 ± 11.2 vs ± 4.6; locomotor subscle: 78.6 ± 14.8 vs ± 4.8, respectively; Figure 3). The difference in eye hnd coordintion pproched significnce (P = 0.07). There ws no difference in cognition nd lnguge skills in ELGA infnts with norml or bnorml SII response (BSID-III). Clinicl chrcteristics nd previous medicl history of ELGA infnts with norml nd bnorml SII response in MEG did not differ significntly (Tble 1). The neurologicl exmintion ws norml significntly more often in the ELGA infnts with norml (13/21, 62%) thn in those with bnorml (2/9, 22%) SII response (P < 0.05). The one infnt with delyed M60 pek ltency hd norml 2 y outcome exmintion. The results of GMDS nd BSID-III t 2 y of corrected ge re shown in Tble 2. ** Norml SII response (n = 21) Abnorml SII response (n = 9) P Gesttionl ge 26.5 (1.3) 26.5 (0.8) 0.98 t birth (wk) Birth weight (g) 841 (184.9) 895 (159.0) 0.46 Mle 8 [38.1] 7 [77.8] 0.11 Cesren section 11 [52.4] 5 [55.6] 0.87 Choriomnionitis 7 [33.3] 5 [55.6] 0.42 Prentl 21 [100] 9 [100] 1.00 betmethsone (t lest one dose) Prentl 16 [76.2] 8 [88.9] 0.63 betmethsone (two doses) Smll for gesttionl ge 8 [38.1] 2 [22.2] 0.67 RDS 15 [71.4] 4 [44.4] 0.23 BPD t hours [38.1] 4 [44.4] 0.75 Septicemi 6 [28.6] 3 [33.3] 0.79 IVH grde III IV 2 [9.5] 1 [11.1] 0.89 PVL in US 0 [0] 0 [0] 1.00 NEC 1 [4.8] 0 [0] 0.50 ROP 4 [19.1] 2 [22.2] 0.84 Hemodynmiclly 15 [71.4] 5 [55.6] 0.40 significnt PDA Postntl use of dexmethsone 1 [4.8] 1 [11.1] 0.52 Dt shown s men (SD) or n [%]. BPD, bronchopulmonr dysplsi; ELGA, extremely low gesttionl ge; IVH, intrventriculr hemorrhge; MEG, mgnetoencephlogrphy; NEC, necrotizing enterocolitis; PDA, ptent ductus rteriosus; PVL, periventriculr leukomlci; RDS, respirtory distress syndrome; ROP, retinopthy of premturity; SII, secondry somtosensory cortex; US, ultrsonogrphy. MRI, US, nd Neurodevelopmentl Outcome The neurodevelopmentl outcome of infnts with WM bnormlities in MRI or IVH grdes III IV in US is shown in Tble 3. WM in MRI ws defined s norml in 23 ELGA infnts (79%) nd mildly bnorml in 6 infnts (21%). There were no moderte-to-severe WM bnormlities in the study popultion. Neurodevelopmentl outcome t 2 y of corrected ge did not differ between ELGA infnts with or without mild WM bnormlities. Among six ELGA infnts with WM bnormlities, only one hd bnorml SII response in MEG. His DQ 91.5 ws the second lowest of these six (rnge: ) nd locomotor SQ 85.0 ws the lowest (rnge: ). He hd complex minor neurologicl dysfunction (MND-2), wheres of the ELGA infnts with WM bnormlities but norml SII response, three hd norml neurologicl exmintion nd two hd simple minor neurologicl dysfunction (MND-1). Gry mtter in MRI ws clssified s norml in ll ELGA nd term infnts ccording to Woodwrd et l. (5). However, more Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc. Volume 73 Number 6 June 2013 Peditric Reserch 765

4 Rhkonen et l. Tble 2. MEG nd neurodevelopmentl outcome t 24 mo of corrected ge ELGA infnts Norml SII response (n = 21) Abnorml SII response (n = 9) P Term controls (n = 11) GMDS DQ score 91.8 (4.6) 82.8 (11.2) < (3.7) GMDS locomotor SQ 90.0 (4.8) 78.7 (14.8) < (2.6) GMDS personl nd socil SQ 91.3 (6.5) 84.2 (9.9) (5.1) GMDS hering nd lnguge SQ 91.5 (8.0) 78.4 (18.9) (9.2) GMDS eye hnd coordintion SQ 92.3 (6.0) 84.6 (14.6) (4.5) GMDS performnce SQ 93.8 (4.2) 88.3 (9.9) (2.3) BSID-III cognition 10.8 (1.7) 9.4 (3.9) (3.2) BSID-III lnguge receptive b 12.6 (2.2) 10.4 (4.9) (3.1) BSID-III lnguge expressive c 11.3 (2.7) 8.5 (5.2) (4.5) Neurologicl exmintion norml 13 [61.9] 2 [22.2] < (83.3) Dt shown s men (SD) or n [%]. BSID-III, Byley Scles of Infnt nd Toddler Development, Third Edition; DQ, developmentl quotient; ELGA, extremely low gesttionl ge; GMDS, Griffiths Mentl Development Scles; MEG, mgnetoencephlogrphy; SQ, subscle quotient; SII, secondry somtosensory cortex. Dt for six ELGA infnts nd two helthy term infnts missing. b Dt for seven ELGA infnts nd two helthy term infnts missing. c Dt for eight ELGA infnts nd two helthy term infnts missing. Tble 3. WM in MRI, IVH grdes III IV in US, nd neurodevelopmentl outcome t 24 mo of corrected ge ELGA infnts WM norml in MRI (n = 23) WM bnorml in MRI (n = 6) P No IVH or grde I II IVH (n = 27) Grde III IV IVH (n = 3) Term controls (n = 11) GMDS DQ score 88.1 (8.9) 93.4 (3.6) (5.7) 83.0 (22.0) 91.1 (3.7) GMDS locomotor SQ 86.6 (9.4) 91.5 (4.5) (7.9) 77.5 (23.6) 90.0 (2.6) GMDS personl nd 87.7 (8.5) 93.8 (5.3) (7.5) 88.3 (15.4) 90.8 (5.1) socil SQ GMDS hering nd 85.8 (14.3) 92.4 (9.2) (12.3) 82.9 (24.6) 88.4 (9.2) lnguge SQ GMDS eye hnd 89.2 (10.9) 92.8 (4.5) (5.5) 79.5 (28.8) 92.2 (4.5) coordintion SQ GMDS performnce SQ 90.9 (7.4) 96.2 (1.4) (4.9) 86.9 (17.7) 94.2 (2.3) BSID-III cognition 10.4 (2.9) 10.3 (1.6) (1.6) 7.3 (5.7) 13.3 (3.2) BSID-III lnguge 11.8 (3.8) 12.2 (1.1) (2.3) 10.0 (7.9) 14.3 (3.1) receptive b BSID-III lnguge 10.0 (3.9) 12.2 (1.6) (2.7) 9.0 (6.2) 10.4 (4.5) expressive c Neurologicl exmintion norml 12 [52.2] 3 [50.0] [51.9] 1 [33.3] 10 [83.3] Dt shown s men (SD) or n [%]. BSID-III, Byley Scles of Infnt nd Toddler Development, Third Edition; DQ, developmentl quotient; ELGA, extremely low gesttionl ge; GMDS, Griffiths Mentl Development Scles; IVH, intrventriculr hemorrhge; MRI, mgnetic resonnce imging; SQ, subscle quotient; US, ultrsonogrphy; WM, white mtter. Dt for six ELGA infnts nd two helthy term infnts missing. b Dt for seven ELGA infnts nd two helthy term infnts missing. c Dt for eight ELGA infnts nd two helthy term infnts missing. subtle gry mtter chnges were found in 8 of 30 ELGA infnts nd 0 of 10 term infnts. Altogether, IVH in US ws found in 8 of 30 ELGA infnts; grde I II IVH ws present in five (16.7%) nd grde III IV IVH in three infnts (10%). Only two ELGA infnts with IVH hd bnorml SII response in MEG. Two ELGA infnts with grde III IV IVH hd norml SII response in MEG, nd their DQ ws 96.9 nd 94.5, locomotor SQ ws 94.0 nd 88.0, nd neurologicl exmintion norml nd MND-2, respectively. One infnt with grde III IV IVH nd bnorml SII response in MEG hd poor neurodevelopmentl outcome with DQ 57.7, locomotor SQ 50.4, nd neurologicl exmintion MND-2. The results of MEG, MRI, nd US t TEA or neontl period, nd neurologicl exmintion t 2 y of corrected ge in ELGA infnts re shown in Tble Peditric Reserch Volume 73 Number 6 June 2013 Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc.

5 MEG nd neurodevelopment Tble 4. MEG nd neurordiology t TEA nd neurologicl outcome t 2 y of corrected ge in ELGA infnts Gesttionl ge (weeks) SII in MEG WM in MRI US (IVH) Neurologicl exmintion b 25+0 Abnorml Norml Norml Norml 27+6 Norml Norml Norml Norml 27+0 Abnorml Norml Norml MND Norml Norml Norml Norml 24+3 Norml Norml Norml CP 24+1 Norml Norml Grde IV dx MND Norml Norml Norml Norml 27+3 Norml Mild bnormlity Norml MND Norml Norml Norml MND Norml Norml Norml Norml 27+6 Abnorml Norml Grde IV dx MND Norml Norml Norml Norml 25+4 Abnorml Mild bnormlity Norml MND Abnorml Norml Norml MND Norml Norml Grde II dx Norml 27+3 Norml Norml Grde I dx MND Norml Norml Norml Norml 26+3 Norml Norml Norml Norml 26+3 Abnorml Norml Norml Norml 27+2 Norml Mild bnormlity Norml Norml 27+2 Norml Mild bnormlity Grde III sin grde II dx Norml 27+1 Abnorml Norml Norml MND Norml Mild bnormlity Norml Norml 26+2 Abnorml Norml Grde I dx MND Norml Norml Grde I sin Norml 27+6 Norml Norml Norml MND Norml Norml Norml MND Norml Norml Norml Norml 27+6 Norml Mild bnormlity Norml MND Abnorml MRI missing Norml CP CP, cerebrl plsy; dx, dexter (right); ELGA, extremely low gesttionl ge; IVH, intrventriculr hemorrhge; MEG, mgnetoencephlogrphy; MND-1, simple minor neurologicl dysfunction; MND-2, complex minor neurologicl dysfunction; MRI, mgnetic resonnce imging; SII, secondry somtosensory cortex; sin, sinister (left); TEA, term equivlent ge; US, ultrsonogrphy; WM, white mtter. According to Woodwrd et l. (5). b According to Hempel (30). DISCUSSION We show tht lte somtosensory responses from SII, which re ssocited with higher level of somtosensory corticl processing, cn be relibly studied with MEG in ELGA infnts t term nd tht they my yield prognostic informtion overlooked by other neurophysiologicl nd neuroimging methods. We investigted whether bnormlities in SEFs re ssocited with problems in neurodevelopmentl outcome of ELGA infnts. Our results showed tht the bsence of SII responses t term ge in ELGA infnts is ssocited with poor men DQ nd locomotor subscle ssessed by GMDS t 2 y of corrected ge. Furthermore, in this regrd the SEF ssessment surpssed MRI nd crnil US in our study group. Previously, somtosensory functions in infnts hve minly been ssessed using SEPs. Most previous preterm SEP studies hve focused on the first corticl response s predictor of sensorimotor outcome becuse it reflects the integrity of the somtosensory pthwys from the periphery to the SI (21,22). In the current study, s in previous MEG study (18), SI response ws seen in every infnt, thus hving no predictive vlue in our study popultion consisting of ELGA infnts with reltively mild neuroimging bnormlities. Only few SEP studies hve pid ttention to lter corticl components. Using severl recording electrodes, Krniski et l. (23,24) noted tht some SEP components with longer ltencies were highly reproducible nd suggested the 200-ms component s possible cndidte in evluting the sttus of somtosensory Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc. Volume 73 Number 6 June 2013 Peditric Reserch 767

6 Rhkonen et l. MEG t term equivlent ge 39 ELGA infnts Nine drop outs First clinicl visit t 2 y of corrected ge 30 Neurologicl exmintion nd GMDS Three drop outs Second clinicl visit t 2 y of corrected ge 27 BSID-III Three excluded One excluded Two excluded 24 BSID-III Cognition scle 23 BSID-III Lnguge expressive 23 BSID-III Lnguge receptive Figure 4. Study protocol, drop outs, nd exclusions of extremely low-gesttionl-ge (ELGA) infnts. BSID-III, Byley Scles of Infnt nd Toddler Development, Third Edition (31); GMDS, Griffiths Mentl Development Scles (29); MEG, mgnetoencephlogrphy. Tble 5. Chrcteristics of study popultion ELGA infnts (n = 30) Term controls (n = 11) P Gesttionl ge t 26.5 (1.2) 40.3 (0.9) <0.001 birth (wk) Birth weight (g) 884 (181) 3,605 (482) <0.001 Mle 15 [50.0] 9 [81.8] 0.05 SGA 10 [33.3] Twins 7 [23.3] Mother s ge 32.5 [4.6] 32.6 [4.1] 0.94 Mother s eductionl ttinment Low 1 [3.8] Middle 15 [57.7] 4 [44.4] 0.49 High 10 [38.5] 5 [55.6] 0.37 Cesren section 16 [63.3] 2 [16.7] 0.03 Dt shown s men (SD) or n [%]. ELGA, extremely low gesttionl ge; SGA, smll for gesttionl ge. Dt for four ELGA infnts nd two helthy term infnts missing. system in preterm infnts (23,24). In ddition, in preliminry MEG study in preterm infnts, SII response ws often bsent t term in infnts with ntomicl lesion in the underlying hemisphere. However, in tht study, the neurodevelopmentl outcome of the infnts ws not vilble (18). In the current study, the bnorml SII response in MEG ws ssocited with poor totl DQ nd locomotor SQ in GMDS. Notbly, mong infnts with severe IVH, two ptients with norml SII response in MEG hd mrkedly better neurodevelopmentl outcome thn one ptient with severe IVH nd bnorml SII response in MEG. Correspondingly, one infnt with WM bnormlities in MRI nd bnorml SII response in MEG hd worse neurodevelopmentl outcome thn five infnts with bnorml WM but norml SII response. These results highlight the complementry vlue of functionl (neurophysiologicl) ssessments in predicting neuromotor development fter very preterm birth. Although SI response in MEG or electroencephlogrphy represents the intctness of pthwys from the periphery to the SI, the SII response cn be seen s n indictor of higher intrcorticl processing. Furthermore, the bsence of SII response my reflect not only dmge to the sensorimotor networks but possibly overll reduced corticocorticl connectivity, which could be reflected in the totl DQ. Behviorlly, SII neurons with bilterl receptive fields (25) hve been suggested to integrte somtosensory informtion from the two body hlves (26) nd to integrte somtosensory nd motor informtion (27), which mkes the study of SII responses interesting, s ELGA infnts hve high prevlence of minor neuromotor dysfunction nd poor coordintion (4). In our study group, mild WM bnormlities in MRI were found in 26% of the ELGA infnts, nd there were no moderte-to-severe WM lesions, which is less thn previously reported (mild: 58%, moderte: 15%, severe: 3% in infnts born <32 gesttionl weeks) (28). The lower number of WM lesions in our study group is probbly due to us being ble to perform MEG recordings only on infnts who did not require respirtory ssistnce or constnt monitoring t TEA. Second, prents whose infnts hve hd more complictions during neontl intensive cre might be less willing to ccept extr 768 Peditric Reserch Volume 73 Number 6 June 2013 Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc.

7 MEG nd neurodevelopment exmintions of their infnts thn prents of infnts without ny noticeble complictions. Consequently, more dt re needed to generlize our SEF findings to ELGA infnts with moderte-to-severe WM injury. Recent technicl dvnces, such s infnt-sized MEG devices nd the development of nlysis softwre to remove externl mgnetic rtifcts nd compenste for movements, should mke this method more pplicble in infnts nd perhps even in neontl intensive cre unit settings. A strength of our study is the homogeneous study popultion: ll were born t <28 gesttionl weeks. The study popultion represents ELGA infnts who received modern neontl intensive cre. Only 10% of infnts hd severe IVH, none hd cystic periventriculr leukomlci, nd 21% hd mild WM bnormlities in MRI t TEA. Therefore, mny of these ELGA infnts left the neontl intensive cre unit without ny visible morphologicl defects in US or MRI, but some of them still hd n dverse neurodevelopmentl outcome. Additionl mesures to recognize these infnts s erly s possible re needed. A limittion of the study is the use of GMDS for children up to 2 y of ge, which creted ceiling effect on our GMDS results. This hd no impct on results in infnts with developmentl impirments, but normlly developed infnts could hve hd better results if we hd used the scles for infnts older thn 2 y. Therefore, the difference between infnts with bnorml or norml SII response in DQ nd subquotients in GMDS could hve been lrger without this ceiling effect. Furthermore, we could not mesure ll 39 ELGA infnts using GMDS nd BSID-III. In the study group, 30% of ELGA infnts hd n bnorml SII response, wheres mong nine infnts excluded becuse of missing GMDS, five (55.6%) hd n bnorml SII response. Mesuring the outcome of these nine excluded infnts would hve been vluble. Furthermore, the lck of informtion of neurologicl sttus t term precludes the comprison of MEG nd clinicl exmintion s outcome predictors. It would lso hve been interesting to evlute the SII responses t 2 y of ge; however, t tht ge, MEG recordings, which require the subject to sty still, re extremely difficult to perform. Therefore, follow-up MEG mesurement is plnned closer to school ge. This study demonstrted tht the bsence of SII responses to tctile stimultion, s mesured by MEG, is ssocited with dverse neuromotor development t 2 y of corrected ge. The results suggest role for the evlution of the SII responses in the future s prt of developmentl risk ssessment for infnts born extremely preterm. METHODS Ptients The subjects were 39 ELGA infnts (born before 28 gesttionl weeks) recruited from the Neontl Intensive Cre Unit of the Helsinki University Centrl Hospitl between My 2006 nd September 2008 for lrger multimethodologicl study (84 ELGA infnts nd 22 term controls). The Ethics Committee of the Hospitl District of Helsinki nd Uusim pproved the study protocol. The prents signed n informed consent. Exclusion criteri were the need for respirtory support or constnt monitoring t TEA. Thirty-nine ELGA infnts were eligible to undergo MEG mesurement t to wk of gesttionl ge (men: 41.1 wk). Of these infnts, 30 lso underwent GMDS (29) nd structured neurologicl exmintion (30) t 2 y of corrected ge. We excluded two uncoopertive ELGA infnts from BSID-III (31) Cognition Scle nd one becuse the exmintion ws not possible in her ntive lnguge. In ddition, two inttentive children filed to complete the Receptive Lnguge Scle nd one child the Expressive Lnguge Scle. Figure 4 illustrtes the drop outs nd exclusions. Controls The controls were 11 helthy term infnts recruited from the mternity wrd of the Deprtment of Obstetrics, Helsinki University Centrl Hospitl. The controls underwent MEG recording 1 23 d fter birth t the gesttionl ge of to (men: 41.0 wk). All controls were ssessed t the ge of 2 y with GMDS nd structured neurologicl exmintion, nd nine of them lso with BSID- III. Tble 5 presents the chrcteristics of the study popultion. There were more mle infnts in the control group thn in the study group (Tble 5). Clinicl Dt Obstetric nd postntl dt of neontl clinicl course nd complictions were collected from the hospitl records. Gesttionl ge ws bsed on the first-trimester US when vilble. Birth weight z-scores for gesttionl ge nd sex were bsed on the Finnish growth reference dt (32). The highest grde of IVH in seril crnil US ws recorded. Socioeconomic sttus ws evluted with questionnire given to the child s prents when the infnt ws 2 y of ge. Mgnetoencephlogrphy Stimulus. The tctile stimulus ws given to the tip of the index finger by thin elstic membrne expnded by n ir pressure pulse delivered through plstic tube (Somtosensory Stimulus Genertor, 4-D NeuroImging, Sn Diego, CA). For more detils of the stimultion method, see Pihko et l. (33). The interstimulus intervl ws 2 s. Dt cquisition. MEG ws recorded in mgneticlly shielded room (ETS-Lindgren Euroshield Oy, Eur, Finlnd) with whole-hed helmet-shped sensor rry (Vector View,Elekt Neuromg Oy, Helsinki, Finlnd) consisting of 306 independent chnnels: 204 grdiometers nd 102 mgnetometers. Electroencephlogrphy with one to three electrodes nd electro-oculogrphy were simultneously recorded for sleep-stge monitoring. The helmet ws in supine position nd the infnt ly with one hemisphere downwrd over the occipitl prt of the helmet. The stimultion nd the recordings strted when the infnt fell sleep nd stopped when the infnt woke; the infnts were not sedted. In the beginning of ech dtset, the infnt s hed position inside the sensor rry ws estimted using signls from position indictor coils ttched to the infnt s hed. For more detils of the recording settings nd procedure, see Nevlinen et l. (18). MEG dt from the right hemisphere were recorded during stimultion of the contrlterl left hnd in ll 30 ELGA infnts included in the finl study group nd in 10 of 11 controls. Recordings from the left hemisphere during stimultion of the right index finger were obtined in 24 of 30 ELGA infnts nd 9 of 11 controls. Recordings during stimultion of the ipsilterl hnd were obtined from the right hemisphere of 21 ELGA infnts nd from the left hemisphere of 20 of the 24 ELGA infnts with dt during contrlterl stimultion. All conditions could not be obtined in ll infnts owing to restlessness of the infnt nd/or mesurement time limittions. Dt nlysis. A single MEG resercher (P.N.), who ws blinded to the infnts neurodevelopmentl outcome, nlyzed ll MEG dt. The MEG dt were first preprocessed with sptiotemporl signl spce seprtion method (MxFilter,Elekt Neuromg Oy, Helsinki, Finlnd) to remove possible mgnetic rtifcts (8 s time window nd 0.9 correltion limit) (34,35). After sptiotemporl signl spce seprtion, periods Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc. Volume 73 Number 6 June 2013 Peditric Reserch 769

8 Rhkonen et l. with movement rtifcts were mnully discrded from the dt, nd quiet sleep periods were verged for further nlyses. For detils of the sleep-stge determintion, see Pihko et l. (33). The verged signls were bseline corrected ( 100 to 0 ms) nd low pss filtered t 90 Hz. From the quiet sleep dt, the contrlterl SI (M60) nd contrnd ipsilterl SII (M200) sources (17) were modeled with equivlent current dipoles using sphericl conductor model, which ws individully constructed bsed on ech infnt s ntomicl MRIs. When MRI ws not vilble (one ELGA infnt, one term infnt), the verge sphere origin, clculted from the other infnts MRIs, ws used. When there ws no cler pek or dipolr field pttern nd/or the dipole could not be modeled with the required goodness of fit of >70%, the response ws considered to be bsent. Moreover, pproprite loction of dipoles on individul MRIs ws required for cceptnce of SI nd SII dipoles. For detiled description of the dipole fitting procedure, see Nevlinen et l. (20). Mgnetic Resonnce Imging Brin MRI (1.5T) including T2-weighted xil nd T1-weighted three-dimensionl sgittl imges ws performed ner TEA on 29 of 30 ELGA infnts in the study group nd on 10 of 11 term controls. The imges were clssified by two experienced neurordiologists (L.V. nd T.A.) ccording to Woodwrd et l. (5). Neurodevelopmentl Assessments The neurodevelopmentl outcome ws mesured t 2 y of corrected ge by GMDS (29), structured neurologicl exmintion (30), nd BSID- III (31), which were dministered nd scored by certified exminers. Neurologicl sttus nd GMDS were ssessed by child neurologist (A.L.), who ws unwre of the MEG nd MRI clssifiction results. If there were unscorble items or judgment ws unrelible, the infnt ws clssified s nontestble on tht scle. GMDS provide n overll DQ nd the quotients of locomotor, personl nd socil, hering nd lnguge, eye hnd coordintion nd performnce subscles (SQ). On the bsis of neurologicl exmintion, infnts were divided into four ctegories: norml, simple minor neurologicl dysfunction (MND-1), complex minor neurologicl dysfunction (MND-2), nd cerebrl plsy (36). Three subscles of five in BSID-III were scored (cognition, receptive lnguge, nd expressive lnguge). Fine nd gross motor in BSID- III were omitted becuse the locomotor function (gross motor) nd eye hnd coordintion (fine motor) were ssessed in GMDS. Sttisticl Anlysis For continuous vribles, unpired comprisons were done with nonprmetric Mnn Whitney U test when dt did not follow norml distribution (e.g., GMDS quotients) nd with t-test when dt followed norml distribution (e.g., BSID-III results). Ctegoricl vribles were compred by χ² test. A P vlue < 0.05 ws considered sttisticlly significnt. ACKNOWLEDGMENTS We re deeply indebted to Mrit Suni for her excellence in cring for the very premturely born infnts during the MEG mesurements. Furthermore, we express our grtitude to ll our subjects nd their fmilies for prepring the wy for this study. Finlly, we thnk the personnel of the mternity wrd of the Deprtment of Obstetrics nd Gynecology nd the Neontl Intensive Cre Unit t the Helsinki University Centrl Hospitl, newborns wrd t Helsinki Mternity Hospitl, nd children s wrd t Jorvi Hospitl for their coopertion. STATEMENT OF FINANCIAL SUPPORT The study ws finncilly supported by the Jenny nd Antti Wihuri Foundtion, the Acdemy of Finlnd (Centre of Excellence Progrm), the Finnish Medicl Foundtion, the Helsinki University Centrl Hospitl Reserch Grnts, Foundtion for Peditric Reserch, the Päivikki nd Skri Sohlberg Foundtion, the Emil Altonen Foundtion, the Mud Kuistil Memoril Foundtion, nd the ivoaalto project of the Alto University. S.V. ws supported by the Europen Community s Seventh Frmework Progrm Europen Community FP7-PEOPLE-2009-IOF, grnt greement no Disclosure: The uthors declred no conflict of interest. References 1. Whittinghm K, Wee D, Boyd R. Systemtic review of the efficcy of prenting interventions for children with cerebrl plsy. Child Cre Helth Dev 2011;37: Mikkol K, Ritri N, Tommisk V, et l. Neurodevelopmentl outcome t 5 yers of ge of ntionl cohort of extremely low birth weight infnts who were born in Peditrics 2005;116: Slt A, Redshw M. Neurodevelopmentl follow-up fter preterm birth: follow up fter two yers. Erly Hum Dev 2006;82: Sigl S, Doyle LW. An overview of mortlity nd sequele of preterm birth from infncy to dulthood. Lncet 2008;371: Woodwrd LJ, Anderson PJ, Austin NC, Howrd K, Inder TE. Neontl MRI to predict neurodevelopmentl outcomes in preterm infnts. N Engl J Med 2006;355: Volpe JJ. Neurology of the Newborn, 5th edn. Phildelphi, PA: Sunders, 2008: Miller SP, Ferriero DM, Leonrd C, et l. Erly brin injury in premture newborns detected with mgnetic resonnce imging is ssocited with dverse erly neurodevelopmentl outcome. J Peditr 2005;147: Dyet LE, Kenne N, Counsell SJ, et l. Nturl history of brin lesions in extremely preterm infnts studied with seril mgnetic resonnce imging from birth nd neurodevelopmentl ssessment. Peditrics 2006;118: Brown NC, Inder TE, Ber MJ, Hunt RW, Anderson PJ, Doyle LW. Neurobehvior t term nd white nd gry mtter bnormlities in very preterm infnts. J Peditr 2009;155:32 8, 38.e Skiöld B, Vollmer B, Böhm B, et l. Neontl mgnetic resonnce imging nd outcome t ge 30 months in extremely preterm infnts. J Peditr 2012;160: e Mirmirn M, Brnes PD, Keller K, et l. Neontl brin mgnetic resonnce imging before dischrge is better thn seril crnil ultrsound in predicting cerebrl plsy in very low birth weight preterm infnts. Peditrics 2004;114: Klimch VJ, Cooke RW. Short-ltency corticl somtosensory evoked responses of preterm infnts with ultrsound bnormlity of the brin. Dev Med Child Neurol 1988;30: Willis J, Duncn MC, Bell R, Ppps F, Moniz M. Somtosensory evoked potentils predict neuromotor outcome fter periventriculr hemorrhge. Dev Med Child Neurol 1989;31: de Vries LS, Eken P, Pierrt V, Dniels H, Cser P. Prediction of neurodevelopmentl outcome in the preterm infnt: short ltency corticl somtosensory evoked potentils compred with crnil ultrsound. Arch Dis Child 1992;67(10 Spec No): Pierrt V, Eken P, de Vries LS. The predictive vlue of crnil ultrsound nd of somtosensory evoked potentils fter nerve stimultion for dverse neurologicl outcome in preterm infnts. Dev Med Child Neurol 1997;39: Volpe JJ. Brin injury in premture infnts: complex mlgm of destructive nd developmentl disturbnces. Lncet Neurol 2009;8: Nevlinen P, Luronen L, Smbeth A, Wikström H, Okd Y, Pihko E. Somtosensory evoked mgnetic fields from the primry nd secondry somtosensory cortices in helthy newborns. Neuroimge 2008;40: Nevlinen P, Pihko E, Metsärnt M, Andersson S, Autti T, Luronen L. Does very premture birth ffect the functioning of the somtosensory cortex? mgnetoencephlogrphy study. Int J Psychophysiol 2008;68: Pihko E, Luronen L, Kivistö K, Nevlinen P. Incresing the efficiency of neontl MEG mesurements by lternting uditory nd tctile stimultion. Clin Neurophysiol 2011;122: Nevlinen P, Pihko E, Metsärnt M, et l. Evoked mgnetic fields from primry nd secondry somtosensory cortices: relible tool for ssessment of corticl processing in the neontl period. Clin Neurophysiol 2012;123: Pike AA, Mrlow N. The role of corticl evoked responses in predicting neuromotor outcome in very preterm infnts. Erly Hum Dev 2000;57: Peditric Reserch Volume 73 Number 6 June 2013 Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc.

9 MEG nd neurodevelopment 22. Vnhtlo S, Luronen L. Neontl SEP - bck to bedside with bsic science. Semin Fetl Neontl Med 2006;11: Krniski W. The lte somtosensory evoked potentil in premture nd term infnts. I. Principl component topogrphy. Electroencephlogr Clin Neurophysiol 1992;84: Krniski W, Wyble L, Lese L, Blir RC. The lte somtosensory evoked potentil in premture nd term infnts. II. Topogrphy nd ltency development. Electroencephlogr Clin Neurophysiol 1992;84: Whitsel BL, Petrucelli LM, Werner G. Symmetry nd connectivity in the mp of the body surfce in somtosensory re II of primtes. J Neurophysiol 1969;32: Simões C, Hri R. Reltionship between responses to contr- nd ipsilterl stimuli in the humn second somtosensory cortex SII. Neuroimge 1999;10: Huttunen J, Wikström H, Korvenoj A, Seppäläinen AM, Aronen H, Ilmoniemi RJ. Significnce of the second somtosensory cortex in sensorimotor integrtion: enhncement of sensory responses during finger movements. Neuroreport 1996;7: Woodwrd LJ, Clrk CA, Pritchrd VE, Anderson PJ, Inder TE. Neontl white mtter bnormlities predict globl executive function impirment in children born very preterm. Dev Neuropsychol 2011;36: Brndt I, Sticker EJ. Griffiths Entwicklungssklen zur Beurteilung der Entwicklung in den ersten beiden Lebensjhren. Beltz Test GmbH, Göttingen, Hempel MS. The Neurologicl Exmintion for Toddler Age. Thesis, University of Groningen: Groningen, The Netherlnds, Byley N. The Byley Scles of Infnt nd Toddler Development, Third Edition. Sn Antonio, TX: The Psychologicl Corportion, Pihkl J, Hkl T, Voutilinen P, Rivio K. [Chrcteristic of recent fetl growth curves in Finlnd]. Duodecim 1989;105: Pihko E, Luronen L, Wikström H, et l. Somtosensory evoked potentils nd mgnetic fields elicited by tctile stimultion of the hnd during ctive nd quiet sleep in newborns. Clin Neurophysiol 2004;115: Tulu S, Simol J. Sptiotemporl signl spce seprtion method for rejecting nerby interference in MEG mesurements. Phys Med Biol 2006;51: Medvedovsky M, Tulu S, Bikmullin R, Ahonen A, Petu R. Fine tuning the correltion limit of sptio-temporl signl spce seprtion for mgnetoencephlogrphy. J Neurosci Methods 2009;177: Hdders-Algr M. Developmentl coordintion disorder: is clumsy motor behvior cused by lesion of the brin t erly ge? Neurl Plst 2003;10: Copyright 2013 Interntionl Peditric Reserch Foundtion, Inc. Volume 73 Number 6 June 2013 Peditric Reserch 771