Trondheimsstudien: Quantitative MR imaging used to gain new knowledge of perinatal brain injury: from a newborn animal model to young adults born

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1 Trondheimsstudien: Quantitative MR imaging used to gain new knowledge of perinatal brain injury: from a newborn animal model to young adults born preterm with very low birth weight Jon Skranes, Department of Laboratory Medicine, Children's and Women's Health

2 Research group Project management: Profs Ann-Mari Brubakk 1 and Jon Skranes 1 Senior researchers: Prof Torstein Vik 1, Assoc. Prof Marit S. Indredavik 2, Assoc. Prof Marit Martinussen 1, Assoc. Prof Susanne Lindqvist 1, Assoc. Prof Asta Håberg 2, Prof Ingrid Gribbestad 3, Assoc Prof Tone Bathen 3, Prof Olav Haraldseth 3, Assoc. Professor Ragnhild Støen 1, Senior researcher Lars Adde 1 Post docs: Kari Anne I. Evensen 1, Ole Chr. Eidheim 1, Live Eikenes 3 PhD students: Gro Løhaugen 1, Line Knutsen Lund 2, Marius Widerøe 1, Tora Morken 1, Kristine Grünewaldt 1 International: Prof Torkel Klingberg 4, Prof Coby Heinen 5, Prof Floris Groenendal 5, Prof Anders Dale 6, Prof Linda Chang 7 1 Dept of Laboratory medicine, Children s and Women s Health, 2 Dept of Neuroscience, 3 Dept of Circulation and Medical Imaging, 4 Karolinska institute, Stockholm, Sweden, 5 University of Utrecht, Utrecht, Holland, 6 Martinos Center, University of California, San Diego, USA, 7 University of Hawaii, HI, USA

3 Projects Project 1: Animal study: Cerebral Manganese-Enhanced MRI, histology and histochemistry of brain injury following hypoxic ischemia and treatment with hyperbaric oxygen in the newborn rat. Project 2: Clinical study: Clinical functions and cerebral MR in children, adolescents and young adults with low birth weight (born ) 56 very low birth weight (VLBW: bw < 1500g) from Sør/Nord T.lag/Møre og Romsdal) 60 term born small for gestational age (SGA: bw < 10 th percentile)) 83 term born controls (bw> 10 th percentile) compare clinics with perinatal and MR findings compare with earlier results change/development Project 3: Intervention study: The effect of RoboMemo - a training program for working memory, on higher cognitive function and brain activation in ELBW 14 years old children. Investigation with fmri.

4 Trondheim study Objectives of study The aim of this study was to compare MRI findings and clinical function in VLBW prematures and SGA (birth weight < 10 th percentile at term) children with non-sga term controls in childhood and adolescence. The first high five - survival!

5 Clinical assessments years of age: Motor, ophthalmologic, cognitive, perceptual, behavioral, psychiatric assessments 3 PhD projects: Marit S Indredavik, Kari Anne Indredavik Evensen, Susanne Lindqvist years of age Physical, neuropsychological, psychiatric assessments 2 PhD projects: Gro Løhaugen, Line Knudsen Lund

6 MR evaluations Conventional MRI: T1, T2, PD MR spectroscopy Diffusion Tensor Imaging Quantitative / morphometric evaluations MR Center, Massaschusets /San Diego Cortical thickness and surface area Absolute volumes: gray & white matter, ventricles, basal ganglia Anders Dale, Ph.D. Professor of Radiology/Neurosciences, Co-Director of Multimodal Imaging Lab, University of California, Ja Jolla, San Diego, CA, USA

7 Sample at age investigation in Trondheim VLBW group: 56 adolescents born preterm with very low birth weight (VLBW), BW 1500g SGA group: 60 adolescents born small for gestational age (SGA) at term with birth weight < 10th centile VLBW SGA Control group: 83 adolescents born at term with birth weight 10th centile control 10

8 Ungdommene VLBW (56) SGA (60) Control (83) Gj.snitt Gj.snitt Gj.snitt Fødselsvekt (gram) Svangerskapslengde (uker) Alder ved undersøkelse (år)

9 Øye-hånd koordinering, figurgjenkjenning og motorisk koordinering ** ** ** VLBW SGA Controls 5 0 VMI Visuell pers Motor koord Psykolog Siri Kulseng

10 Grooved pegboard (nøkkelhull)(sek) ** 90 ** Skrive-hand Ikke skrivehand **P<0.01 VLBW vs kontroller VLBW SGA Kontroll

11 Movement ABC 8 forskjellige oppgaver 3 manuelle oppgaver (finmotorikk) 2 balloppgaver (fin/grovmotorikk) 3 balanseoppgaver (grovmotorikk)

12 Resultater av Movement ABC (prosentandel med motoriske problemer) * * * * * VLBW SGA Kontroll 5 0 Total ABC Manuelle ferdigheter Ballferdigheter Balanse * p < 0.05 vs. kontroller

13 Ventricular dilatation White matter reduction CC pathology Gliosis VLBW (n=49) 40* (82%) 26* (53%) 23* (47%) 15* (31%) SGA (n=42) 8 (19%) 2 (5%) 0 2 (5%) Controls (n=61) 13 (21%) 1 (2%) 4 (6.5%) 5 (8%) * p <.01 (VLBW vs. SGA, VLBW vs. controls) 14

14 Diffusion tensor imaging Brain microstructure, especially white matter trajectories Measures the diffusion of water molecules Diffusion is described in three dimensions by the eigenvalues: l 1, l 2, l 3 FA measures the degree of directionality of diffusion within a voxel λ 2 λ 1 λ 3

15 Results The VLBW teenagers had significantly lower mean FA values in several anatomical white matter areas compared with controls: internal capsule (mainly PLIC) external capsule corpus callosum (anterior and posterior) long association tracts cingulum periventricular occipital white matter

16 Avvik i hvit substans hos VLBW barn Vangberg T, Skranes J et al. Neuroimage 2006

17 An overview of the different neuroimpairments and the corresponding strongest related anatomical areas with reduced fractional anisotropy values in the VLBW group 18

18 Automated surface reconstruction model 20

19 In the VLBW group: Smaller cortical surface area Reduced cortical volume No change in mean global hemispheric cortical thickness Areas of significant cortical thinning and thickening Most pronounced in those with lowest SGA / BW Marit Martinussen et al. Brain

20 Areas of significant differences in cortical thickness between VLBW and controls Marit Martinussen et al. Brain

21 Follow-up at years of age Just finished the 19-year follow up (198 persons) Gro Løhaugen: PhD neuropsychology and MR Line K Lund: PhD psychiatry and MR Two Post docs: MR changes from age 14 to 19 years More advanced DTI tractography MR surface area MR spectroscopy Follow up as adults?

22 Abnormal brain connectivity in very low birth weight (VLBW) CP adolescents at 15 and 19 years of age. J Skranes 1,3, GC Lohaugen 1,4, T Vangberg 5, L Eikenes 2, M Martinussen 1,3, O Haraldseth 2,3, A Håberg 2,3, B Fischl 6, AM Dale 7, A-M Brubakk 1,3 1 Dept of Lab Medicine, Children's and Women's Health, 2 Dept of Circulation and Medical Imaging, Norwegian University of Science and Technology; 3 St Olav University Hospital, Trondheim; 4 Dept of Pediatrics, Sorlandet Hospital, Arendal; 5 University of Tromso, Tromso, Norway; 6 Nuclear Magnetic Resonance Center, MGH, Harvard Medical School, Boston, MA; 7 MIL, Dept of Neurosciences and Radiology, University of San Diego, La Jolla, California, USA. 3 rd International Cerebral Palsy Conference 2009

23 Tractography at age 19 years Disruptions in corpus callosum in two CP adolescents. Clinics: Triplegia (combined diplegia and hemiplegia) Patient 1 Patient 2

24 Tractography at age 19 years CP adolescents: Abnormal tractography findings in commissural, association and projection tracts indicating loss and disorganization of nerve fibres.

25 CP adolescents: Affection of optical tract in one of the CP children Term control CP VLBW without CC disruption CP VLBW with CC disruption 3 rd International Cerebral Palsy Conference 2009

26 1. Fractional Anisotropy Correlates with Total IQ and Visual Perception in Young Adults Born with Very Low Birth Weight 2. Young Adults Born with Very Low Birth Weight Demonstrate Widespread White Matter Abnormalities on Brain DTI Live Eikenes 1, Jon S Skranes 2,5, Gro CC Løhaugen 2,5, Kjerstin Bjørlykke 2, Ann-Mari Brubakk 2,4, Asta Håberg 1,3,4 1 Dept of Circulation and Medical Imaging; 2 Dept of Lab Medicine, Children's and Women's Health; 3 Dept of Neuroscience, Norwegian University of Science and Technology; 4 St Olav University Hospital, Trondheim; 5 Depts of Pediatrics and Research, Sørlandet Hospital, Arendal, Norway.

27 DTI results: Reduced FA in VLBW group

28 FA in the VLBW group correlated positively with BW and GA, and negatively with days in NICU and days on mechanical ventilator.

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30 Veien videre.. Sammenlikne MR og klinikk ved 19 år Sammenlikne med tidligere kliniske data Se på hjerneutvikling fra 14 til 19 år ved MR Hjernebarktykkelse, overflate, volumer, mikrostruktur hvit substans etc. Nye studier: ELBW åringer RoboMemo på førskolebarn