There is a high incidence of periventricular leukomalacia, caused by hypoxia-ischemia, in preterm infants. These lesions
damage the periventricular crossroads of commissural, projection and associative pathways, which are in a close
topographical relationship with the lateral ventricles. We explored to what extent abnormalities of echogenicity of the
periventricular crossroads correlate with changes in size of the corpus callosum. Our study included nine infants (gestation
from 26–41 weeks; birth weight between 938–4450 grams) with perinatal brain injury. Periventricular areas, which
topographically correspond to the frontal, main and occipital crossroad, were readily visualized by cranial ultrasound
scans, performed during the first two weeks after birth. Corpus callosum mediosagittal area measurements were performed
using magnetic resonance images, acquired between the first and sixth postnatal month (postmenstrual age
40–49 weeks). We found a statistically significant correlation between the increased echogenicity in the crossroad areas
and the decrease of the corpus callosum midsagittal area (p<0.05). This supports the hypothesis that callosal fibers can
be damaged, during growth through the periventricular crossroads of pathways

Maja Pavlović

Marko Čuljat

Mirna Kostović-Srzentić

Vesna Benjak

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Coll. Antropol. 32 (2008) Suppl. 1: 25–29Original scientific paperChanges of the Corpus Callosum in Children whoSuffered Perinatal Injury of the PeriventricularCrossroads of PathwaysVesna Benjak1, Marko ^uljat2, Maja Pavlovi}1 and Mirna Kostovi}-Srzenti}31 Department of Neonatology and Pediatric Intensive Care, University Hospital Center »Zagreb«, School of Medicine,University of Zagreb, Zagreb, Croatia2 Section for Developmental Neuroscience, Croatian Institute for Brain Research, School of Medicine, University of Zagreb,Zagreb, Croatia3 Department of Health Psychology, University of Applied Health Sciences, Zagreb, CroatiaA B S T R A C TThere is a high incidence of periventricular leukomalacia, caused by hypoxia-ischemia, in preterm infants. These le-sions damage the periventricular crossroads of commissural, projection and associative pathways, which are in a closetopographical relationship with the lateral ventricles. We explored to what extent abnormalities of echogenicity of theperiventricular crossroads correlate with changes in size of the corpus callosum. Our study included nine infants (gesta-tion from 26–41 weeks; birth weight between 938–4450 grams) with perinatal brain injury. Periventricular areas, whichtopographically correspond to the frontal, main and occipital crossroad, were readily visualized by cranial ultrasoundscans, performed during the first two weeks after birth. Corpus callosum mediosagittal area measurements were per-formed using magnetic resonance images, acquired between the first and sixth postnatal month (postmenstrual age40–49 weeks). We found a statistically significant correlation between the increased echogenicity in the crossroad areasand the decrease of the corpus callosum midsagittal area (p<0.05). This supports the hypothesis that callosal fibers canbe damaged, during growth through the periventricular crossroads of pathways.Key words: human, development, magnetic resonance, ultrasoundIntroductionPeriventricular lesions caused by hypoxia-ischemiaare the major cause of motor, sensory and cognitivedeficits1–4 in infants, who were born prematurely. Twobasic forms of periventricular leukomalacia were de-scribed: focal and diffuse5,6. The focal lesions affect thefetal »white matter« in the strategic periventricular zo-nes7. Judas et al. 20058 have proposed that damage of thecrossroads of periventricular projection, associative andcommissural pathways may explain frequent occurrenceof combination of motor, sensory and cognitive deficits(for detailed description of periventricular crossroads seeJudas et al. 20058). Diagnosis of periventricular lesionscan be performed by magnetic resonance imaging (MRI)and ultrasound (US) examination. It was shown that USwas not a completely reliable method in diagnosis ofperiventricular leukomalacia9,10. However, US is still thebasic clinical method for screening preterm infant brain.In order to evaluate the potential of the ultrasoundmethod for analysis of periventricular crossroads, wehave compared early ultrasound findings with postnatalvalues of mediosagittal area of corpus callosum. This ini-tial study will allow us to develop a new approach to testthe hypothesis whether corpus callosum can be damagedwhile passing through the periphery of periventricularcrossroads. The additional goal was to determine the de-velopmental window of vulnerability of developing cor-pus callosum.Materials and MethodsNine preterm and term infants, who suffered peri-natal brain injury, were included in the research. Thegestational age ranged from 26 to 41 gestational weeks25Received for publication June 1, 2007.(GW), median 38 GW (Table 1). They were treated in theIntensive Care Unit of the University Hospital CenterZagreb, and underwent a series of US examinations andMRI procedures. The Internal Review Board of the Ethi-cal Committee at the School of Medicine, University ofZagreb, gave ethical approval for the research, and pa-rental consent was obtained for each infant.Cranial US scans were obtained using a GE MedicalSystems LogiqTM a 200 machine, with 6.5 and 5 MHztransducers. Paper copies of the images were made usinga Sony UP-895 MDV printer on Mitsubishi K 65 HM-CEhigh-quality paper, for later analysis.The US scans were performed through the anteriorfontanel using the standard five coronal and five sagittaland parasagittal sections. The second and third coronalsections were used for the analysis. The US scans usedwere performed in the first two postnatal weeks. Two ob-servers performed the analysis of the US scans, and aconsensus was reached concerning the analysis.The degree of echogenicity of white matter on USscans was analyzed as follows. The intensities were sco-red on a linear analog scale9 from 0 to 3 compared to theechogenicity of the plexus choroideus, the grade 3 beinggiven to the areas with the same echogenicity as theplexus (0 – normal echogenicity, 1 – mild increase inechogenicity, 2 – moderate increase in echogenicity, 3 –severe increase in echogenicity). The grade 3 was alsogiven to areas that had cysts in the white matter. Thethree crossroad areas were analyzed, according to topo-graphical criteria given by Judas et al. 20058. The frontalcrossroad area, situated dorsally and the main, situatedlaterally to the angles of the frontal-central portion ofthe lateral ventricles, and the occipital situated laterallyto the trigonum of the lateral ventricle (Figure 1b and2c).V. Benjak et al.: Relationship of Callosal Area and Crossroad Echogenicity, Coll. Antropol. 32 (2008) Suppl. 1: 25–2926TABLE 1CHARACTERISTICS OF INFANTS INCLUDED IN THE STUDYInfants GWWeight(g)Chronolo-gical age atUS scanChronologicalage at MRIscanPostmenstrualage at MRIscanScores of crossroadechogenicity CC area(mm2)Main CombinedK.D. 41 3800 1 d 1m 2w 47 w 4 NA 165.98R.T. 41 4450 6 d 1m 45 w 5 12 141.54^.M. 39 3190 9 d 3w 42 w 5 8 183.16K.A. 39 3050 1 d 1m 3w 45 w 4 NA 150.91T.J. 37 2800 1 d 1m 1w 42 w 5 8 156.82P.N. 33 2210 5 d 1m 3w 40 w 3 10 175.02B.M. 31 2240 10 d 2m 2w 41 w 6 14 128.94V.M. 27 970 2 d 3m 3w 42 w 5 11 156.51D.E. 26 938 1 d 5m 3w 49 w 1 6 180.52GW – gestational weeks, CC – corpus callosum, m – month, w – week, d – dayFig. 1. a) Coronal section on an ultrasound image of a 2 month- old infant. The area that encompasses both the frontal and the maincrossroads is indicated by the dotted line. v – lateral ventricle; p – plexus choroideus. b) Coronal section through the telencephalon of 20week-old fetus, as revealed by fibronectin immunocytochemistry. The position of the frontal crossroad, situated dor- sally to the anteriorhorn of the lateral ventricle, and the main crossroad, situated laterally to the lateral ventricle, is indicated. The Zagreb Neuroem-bryological Collection. cp – cortical plate; sp – subplate; iz – intermediate zone; cc – corpus callosum; ic – internal capsule, F – frontalcrossroad, M – main crossroad.Two scales were calculated from these grades. Thefirst one was the scale for the main crossroad areas,which was calculated by adding the intensity grade of theright and left main crossroad areas, thus giving the rangefor this scale from 0 (normal echogenicity of the maincrossroad areas on both sides) to 6 (severely increasedechogenicity of the main crossroad areas on both sides).The second scale was calculated by adding the ultra-sound intensity grades of all three crossroad areas ofboth sides, thus giving the range for this scale from 0(normal echogenicity in all three crossroad areas on bothsides) to 18 (severely increased echogenicity in all thecrossroads on both sides). It was possible to determinethe echogenicity of the main crossroad areas in all nineinfants included in the study. We were able to determinethe echogenicity of all the crossroad areas of both sides inseven of the nine infants (Table 1).The MR images used for the measurements of themediosagittal cross-section of the corpus callosum, were3D spoiled gradient-echo (3D-GRE) T1-weighted MR im-ages obtained with the high-field 2T MR imaging system(Gyrex Prestige, GEMS/Elscint, Haifa, Israel) and thefollowing parameters: repetition time (TR) 650 ms, echotime (TE) 12 ms, number of excitations (NEX) 1, flip an-gle 180°, and section thickness of 5 mm. The matrix sizeand the field of view were adjusted to obtain a spatial res-olution of at least 0.898 x 0.898 mm2. The MR scan wasperformed between 40–49 postmenstrual weeks, at theSection of Neuroimaging, Croatian Institute for BrainResearch, School of Medicine, University of Zagreb.The pictures were analyzed using the Analyze 6.0software package (Biomedical Imaging Resource, MayoClinic, Rochester, MN). The parameters for recognizingthe mediosagittal section were previously established,V. Benjak et al.: Relationship of Callosal Area and Crossroad Echogenicity, Coll. Antropol. 32 (2008) Suppl. 1: 25–2927Fig. 2. a) Coronal section on an ultrasound image of a 2 month- old infant. The area of the occipital crossroads, indicated by the square,can be readily visualized on this section, localized lateral to the lateral ventricle, at the level of the trigonum. O – occipital crossroadarea. b) Mediosagittal section on an ultrasound image of the same infant. The corpus callosum is easily visualized on this section. Theposition of the occipital crossroad is indicated by the asterix (*). c) Coronal section through the telencephalon of 26 week-old fetus,AchE-stained. The occipital crossroad is located dorsolateral to the posterior horn of the lateral ventricle, at the level of the trigonum. cp– cortical plate; sp – subplate; fc – fissura calcarina, O – occipital crossroad.Fig. 3. The mediosagittal slice of a T1-weighted image of a 1 month-old infant, acquired with a 2T imaging system. The corpus callo-sum (arrows) in the picture is of reduced size.and include a visible interhemispheric fissure, fully de-picted corpus callosum and visible cerebral aqueduct11–14(Figure 3). The voxel size of the mediosagittal sectionwas reduced to 0.1x0.1x0.1, to minimize the voxelisationeffect in order to obtain more precise area measure-ments. The corpus callosum was manually delineated,and the area size automatically calculated. The proce-dure was repeated five times by a single observer; themean value was calculated and used for subsequent sta-tistical analysis.The histological and immunocytochemical slices usedfor visualization of the periventricular crossroads, be-long to the Zagreb Neuroembryological Collection15 (Fig-ure 1b and 2c).ResultsWe were able to visualize all three crossroad areas ofboth sides by US in seven of the nine infants included inthe study (Figure 1a, 2a and 2b). The combined echoge-nicity scale was calculated, and the relationship betweenthe corpus callosum midsagittal area and the scale wasstatistically analyzed. The calculated Pearson's quotient(r) was –0.8574, showing that the higher combined echo-genicity of all the crossroad areas is in correlation withthe smaller mediosagittal area of corpus callosum, statis-tical significance of p<0.05 (Figure 4).All the infants included in the study had visible maincrossroad areas on both sides on US examination (Figure1a). The relationship between the scale and the corpuscallosum midsagittal area, as measured on MR images,was statistically analyzed using the Pearson’s correlationtest. The calculated quotient (r) of –0.6541 showed a neg-ative correlation between the main crossroad echogeni-city scale and the corpus callosum area, with p=0.056(Figure 5), indicating a need for a larger study sample.DiscussionThe results presented in this study have shown thatareas of the periventricular crossroads of pathways as de-scribed by Judas et al.8 can be readily located on conven-tional US scans in infants. Areas of frontal, main and oc-cipital periventricular crossroads, which contain a peri-ventricular contingent of growing callosal fibers8,16, inour material frequently show hyperechodensities. Theseabnormal changes of the periventricular crossroads werefrequently associated with a significant reduction ofcallosal cross-sectional area compared with normal in-fants17,18. Previous studies of infants, who suffered peri-natal hypoxia-ischemia during preterm period, have alsodemonstrated significant reduction of callosal cross-sec-tional area19–25, which was associated with marked cogni-tive deficit20,21. All authors agree that the final measure-ments of callosal cross-section area should be performedafter myelinization is finished, after 10 years of age.However, these studies did not explain why corpus callo-sum is damaged in lesions located lateral to the angle ofthe ventricles. We are inclined to accept the explanationof previous studies8,16 that callosal fibers grow throughthe frontal crossroad, the periphery of the main cross-road and through the occipital crossroad. Judas et al20058 proposed that developmental vulnerability ofperiventricular crossroads is related to the disturbanceof axonal guidance molecules and extracellular matrix.This pathogenetic mechanism may explain the lesion ofcorpus callosum. Our data supports the hypothesis thatcorpus callosum can be damaged during growth throughthe periventricular crossroad of pathways. Namely, cor-pus callosum fibers in preterm infants show intensivegrowth and remodeling26–29 and increased requirementfor axonal guidance with extracellular matrix molecu-les26. Therefore, late gestation and preterm period arevery likely vulnerable periods of callosal growth. Ourfindings are in accordance with this possibility.V. Benjak et al.: Relationship of Callosal Area and Crossroad Echogenicity, Coll. Antropol. 32 (2008) Suppl. 1: 25–2928Fig. 5. The graph shows the relationship between the sum of echo-densities of the main crossroad areas of both sides and the mid-sagittal cross-sectional area of the corpus callosum. We see that thehigher overall echogenicity, indicating greater damage of the cross-roads, correlates with the smaller cross-sectional area of the cor-pus callosum (r=–0.6541, p=0.056). CC – corpus callosum.Fig. 4. The graph shows the relationship between the sum of echo-densities of the three crossroads of both sides (combined crossroadechogenicity) and the midsagittal cross-sectional area of the cor-pus callosum. We see that the higher overall echogenicity, indicat-ing greater damage of the crossroads, correlates with the smallercross-sectional area of the corpus callosum (r=–0.8574, p<0.05).CC – corpus callosum.AcknowledgementsThis research was supported by grant No. 108-1081870-1876 »Development of cortical networks in man«,from the Croatian Ministry of Science, Education andSports. We are grateful to Zdenka Cmuk, Danica Budin-{}ak, Bo`ica Popovi} and Maja Horvat for their techni-cal assistance and to Pero Hraba~ for the statisticalanalysis.R E F E R E N C E S1. VOLPE JJ, Pediatrics, 112 (2003) 176. — 2. JOHNSTONMV, TRE-SCHER WH, ISHIDA A, NAKAJIMA W, Pediatr Res, 49 (2001) 735. — 3.EVRARD P, Dev Neurosci, 23 (2001) 171. — 4. SMART IHM, DEHAY C,GIROUD P, Cereb Cortex, 12 (2002) 37. — 5. 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(University ofZagreb, Zagreb 2003). — 23. DE VRIES LS, WIGGLESWORTH JS, RE-GEV R, DUBOWITZ LMS Early Hum Dev, 17 (1988) 205. — 24. MOSESP, COURCHESNE E, STILES J, TRAUNER D, EGAAS B, EDWARDS E,Cereb Cortex, 10 (2000) 1200. — 25. MAÑERU C, JUNQUÉ C, SALGA-DO-PINEDA P, SERRA-GRABULOSA JM, BATRÉS-FAZ D, RAMIREZ-RUIZ B, BARGALLÓ N, TALLADA M, BOTET F, Brain injury, 17 (2003)1003. — 26. JOVANOV-MILO[EVI] N, BENJAK V, KOSTOVIC I, Colle-gium Antropol, 30 (2006) 375. — 27. JOVANOV-MILOSEVIC N, KOSTO-VIC I, Immunohistochemical characterization of midline cellular struc-tures assocated with growing corpus callosum in human fetus. In: FENSforum Abstr., vol2., A146.10. (FENS forum, 2004). — 28. PAUL LK,BROWNWS, ADOLPHS R, TYSZKA MJ, RICHARDS LJ, MUKHERJEEP, SHERR EH, Nat Rev Neurosci, 8 (2007) 287. — 29. TOVAR-MOLL F,MOLL J, DE OLIVEIRA-SOUZA R, BRAMATI I, ANDREIOULO PA,LENT R, Cereb Cortex, 17 (2007) 531.M. ^uljatCroatian Institute for Brain Research, School of Medicine, University of Zagreb, [alata 12, 10000 Zagreb, Croatia.e-mail: markoc@hiim.hrPROMJENE KORPUSA KALOZUMA U DJECE S PERINATALNIM O[TE]ENJEM U ODNOSUNA EHOGENOST PERIVENTRIKULARNIH KRI@ANJA PUTOVAS A @ E T A KKod nedono{~adi postoji visoka incidencija periventrikularne leukomalacije, uzrokovane hipoksijom-ishemijom. Ovelezije o{te}uju periventrikularna kri`anja asocijatvnih, komisuralnih i kalozalnih putova, koji su u bliskom topograf-skom odnosu sa postrani~nim komorama. Istra`ili smo u kojoj mjeri abnormalnosti ehogenosti periventrikularnih kri-`anja putova koreliraju sa promjenama veli~ine korpusa kalozuma. Na{a je studija obuhvatila devetoro djece (trajanjegestacije od 26–41 tjedana, te`ina pri ro|enju od 938–4450 grama) s perinatalnom ozljedom mozga. Podru~ja oko po-strani~nih komora, koja topografski odgovaraju frontalnom, glavnom i okcipitalnom kru`anju putova, su prikazanapomo}u kranijalnog ultrazvuka, obavljenog u prva dva tjedna nakon ro|enja. Mjerenja mediosagitalne povr{ine kor-pusa kalozuma su izvr{ena na slikovnim prikazima magnetske rezonance glave u dobi izme|u prvog i {estog mjesecaposlije ro|enja. Prona{li smo statisti~ki zna~ajnu povezanost izme|u pove}ane ehogenosti podru~ja periventrikularnogkri`anja putova i smanjene mediosagitalne povr{ine korpusa kalozuma (p<0.05). Na{i rezultati podupiru hipotezu dakalozalna vlakna mogu biti o{te}ena za vrijeme rasta kroz periventrikularna kri`anja putova.V. Benjak et al.: Relationship of Callosal Area and Crossroad Echogenicity, Coll. Antropol. 32 (2008) Suppl. 1: 25–2929

Changes of the Corpus Callosum in Children who Suffered Perinatal Injury of the Periventricular Crossroads of Pathways

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