NTNU Det medisinske fakultet White Matter Abnormalities seen on Diffusion Tensor Imaging Relate to Neuroimpairments in VLBW Children at 15 Years of Age

NTNU Det medisinske fakultet

White Matter Abnormalities seen on Diffusion Tensor Imaging Relate to Neuroimpairments in VLBW

Children at 15 Years of Age

Jon Skranes1, Torgil R Vangberg2, Arild Kristoffersen2, Siri Kulseng1, Marit Indredavik3, Kari Anne I. Evensen1, Marit Martinussen2, David Tuch5, Anders Dale5, Olav Haraldseth2, Torstein Vik4 and Ann Mari Brubakk1

1Dep of Laboratory Medicine, Children’s and Woman’s Health; 2Dep of Circulation and Medical Imaging; 3Dep of Neuroscience; 4Dep of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 5Martinos Center, MGH, Boston, USA


BACKGROUND • VLBW (birth weight < 1500 grams) children are at increased risk of neuroimpairments caused by perinatal injury like

periventricular leukomalacia (PVL). • Brain DTI may detect subtle changes in white matter microstructure

that is not seen on conventional MRI.

OBJECTIVE• To compare cerebral DTI findings with the results from extensive psychiatric, behavioural, cognitive and motor assessments in VLBW adolescents at age 15.• We hypothesized that reduced fractional anisotropy in specific areas of white matter was related with abnormal test results.


MATERIAL• 34 VLBW children • 49 non-SGA term controls • Examined at 15 years of age in a population based study

METHODS• Movement-ABC • Developmental test of Visual-Motor Integration (VMI) with

supplementary tests: Visual perception and Motor coordination • Psychiatric interview (Kaufman-SADS), ADHD rating scale• Subtests from WISC-III: Arithmetic, Vocabulary, Picture arrangement,

Block design


Child characteristics

VLBW Control

Child characteristics Mean (SD) Mean (SD)

n=34 n=49

Birth weight (g) 1232* (217) 3631 (472)

Gestational age (weeks) Male Female

29.3* 16 18

(2.7)

39.3 18 31

(1.4)

MRI assessment age (years) 15.1 (0.6) 15.3 (0.5)

* p <0.05 versus controls. SD: standard deviation


Diffusion-Tensor Imaging

• MRI technique for in-vivo characterization of 3D white matter microstructure. – Measures magnitude and direction of water diffusion in

biological tissue in 3D.• DTI scans were performed for calculation of fractional

anisotropy (FA) maps for each individual and for group comparisons.


METHODS cont.

• Fractional Anisotropy (FA): The extent to which diffusion is directionally restricted, i.e. anisotropic. Scalar measure: 0 to 1

• For isotropic diffusion (λ1 = λ2 = λ3), FA is zero, and in the case where there is a strongly preferred direction of diffusion (λ1 >> λ2 = λ3), FA approaches one.

• Mean FA values for anatomical areas of significant differences between VLBW and controls were identified and then compared with clinical data for the VLBW adolescents (low performers vs. normal performers).


(A) Water molecules in the brain are constantly moving (i.e., in Brownian motion). When motion is unconstrained, as in the ventricles, seen in the MR image on the left, diffusion is isotropic, i.e. motion occurs equally and randomly in all directions. (B) When motion is constrained, as in white matter tracts (right), diffusion is anisotropic, i.e. motion is oriented more in one direction than another (e.g., along the y axis rather than along the x axis).

Margaret Rosenbloom et al. July 2004


Image Acquisition

Scanner: – 1.5 T Siemens Symphony

Structural scan: – T1-weighted MPRAGE-sequence– in-plane resolution 1 x 1 mm– Slice thickness 1.33 mm

DTI scans:– Twice-refocused spin echo sequence– 6 directions with b = 1000 s/mm2

– in-plane resolution 1.78 x 1.78 mm – 20 contiguous slices, 5 mm thick– Repeated 6 times

T1-weighted MPRAGE scan,showing approximate location of DTI slice packet (black lines).


Diffusion Tensor Calculation

• Motion correction of DTI series using 12-parameter affine transform

• The six DTI acquisitions are averaged

• Diffusion tensor and FA maps calculated from averaged DTI volume.

DTI scans 1 - 6

Motion correction and averaging

Averaged volume

Diffusion tensor

Calculation of diffusion tensor

FA map S0 volume


Image Post Processing

• SPM2 used for post processing and statistical analysis

• Custom template created from structural images of all subjects

• FA maps normalized to custom template

• Prior to statistical analysis FA maps smoothed with 4 mm FWHM Gaussian

FA S0Anatomical

3.Transformation

1. Coregister

Normalizedanatomical

2. Norm

alization

Normalized FA

4. Norm

alization


RESULTS

• The VLBW teenagers had significantly lower mean FA values in several anatomical white matter areas compared with controls: – internal capsule (mainly PLIC) – corpus callosum (anterior and posterior) – centrum semiovale (central parietofrontal w.m.) – peripheral parietofrontal white matter – periventricular occipital white matter


Location, size and mean FA values in clusters where the VLBW group had significantly lower FA values than controls (p<.05).

Location of significant

clusters cluster size(voxels)

Mean FA in cluster

VLBW Control

Capsula interna left 1659 0.388 0.440

Capsula interna right 1522 0.395 0.452

Corpus callosum post 429 0.439 0.515

Corpus callosum ant 505 0.430 0.505

Centrum semiovale left 710 0.396 0.446

Centrum semiovale right 395 0.406 0.457

Peripheral wm left 235 0.382 0.428

Peripheral wm right 144 0.371 0.415

Occipital wm left 212 0.414 0.469


Results VLBW < ControlCorpus callosum (green arrows)

RL

Regions with reduced FA in VLBW group. Underlay is average of anatomical images from VLBW and control group.


Results VLBW < ControlInternal capsule (mostly PLIC)

RL RL


Results VLBW < ControlOccipital white matter (green arrows)

RL RL


Results VLBW < Control

(right side)

Peripheral white matterCentrum semiovale


Relationship between motor test results and FA values in different anatomical regions in VLBW adolescents

Total ABC score Manual dext. score Ball skills score< 5th p. > 5th p. < 5th p. > 5th p. < 5th p. > 5th p. (8) (22) (3) (29) (4) (27)

Anatomical region

Capsula interna 0.358 0.400

Periph wm right 0.343 0.384 0.335 0.379

Posterior corpus call 0.370 0.454

P < .05


Relationship between visuo-perceptual and behavioural test results and FA values in different anatomical regions

VMI visual perc. ADHD / ADD < -1SD > -1SD yes no (7) (23) (8) (26)

Anatomical region

Capsula interna 0.355 0.407 Peripheral wm 0.367 0.396 0.346 0.393Post. corpus callosum 0.406 0.464 0.359 0.464Centrum semiovale 0.386 0.421Occipital wm 0.391 0.431 0.359 0.431


Correlations between WISC III subtest scores and FA values in different anatomical regions in 33 VLBW adolescents

WISC III subtest scores

Arithmetic Pict. arrangement Block design Anatomical region

Capsula interna ,416**

Corpus callosum post part ,381** ,344# ,399**

Centrum semiovale ,411**

Peripheral wm left ,571* ,418** ,472*

Occipital wm left ,388**

* p < 0.01, ** p < 0.05, # p = 0.05Abbreviations: wm: white matter; WISC: Wechsler Intelligence Scale; Pict.: pictureCorrelations by Spearman’s rho


Discussion• The VLBW group has reduced anisotropy in several wm

areas which are known to be affected by premature birth (PVL, asphyxia)

• periventricular occipital white matter• centrum semiovale• corpus callosum• posterior limb of internal capsule

• The reduced anisotropy may be due to:• reduced myelination• fiber disorganization• fewer axons


Conclusions / Speculations

• Low FA values in specific brain areas seem to relate to motor, cognitive, perceptual and behavioural impairments in VLBW adolescents.

• The neuroimpairments may be due to disturbed white matter microstructure and connectivity of commissural and association fibres between different cortical areas.

• The disrupted connectivity may influence neuronal networks and thereby neurodevelopment and higher cognitive functions in VLBW adolescents.


Documents

NTNU Det medisinske fakultet White Matter Abnormalities seen on Diffusion Tensor Imaging Relate to Neuroimpairments in VLBW Children at 15 Years of Age