Reorganisation of the sensorimotor cortex following early unilateral brain damage

Hemiplegic cerebral palsy is the most common form of cerebral palsy (CP) with a
prevalence of 1:3000 livebirths.1 Perinatal arterial ischemic stroke (PAIS) is
responsible for more than 70% of moderate to severe hemiplegic CP.2
Malformations or unilateral parenchymal haemorrhage (PH) and unilateral
periventricular leukomalacia (PVL) in preterm infants are responsible for the
remaining 30%. While the diagnosis of brain injury in preterm infants is mostly
made using routine neurosonography, PAIS is often considered to be present when
full-term infants present with (hemi)convulsions within the first 24-48 hours
after birth. The diagnosis is subsequently confirmed with neonatal MRI, rather
than neurosonography. Not all children with unilateral brain injury will
however go on to develop hemiplegic CP. This seems to depend on the size, but
especially the site of the lesion. Neuroimaging, cranial ultrasound and
especially MRI have been shown to be extremely helpful for early prediction of
subsequent motor outcome.3,4,5,6 The number of important structures that are
involved (basal ganglia, internal capsule and cerebral cortices) have been
shown to accurately predict subsequent development of hemiplegic CP.7 More
recently our group has shown that abnormal signal intensity on diffusion
weighted imaging (DWI) in the descending corticospinal tracts will even more
precisely predict hemiplegic CP, within days of occurrence of the insult.6
Hemiplegic motor signs tend to be recognised after the first six months up to
two years, with delayed onset in those with milder hemiplegic CP. Although the
main lesion determines subsequent motor outcome, smaller lesions may be present
in the contralateral hemisphere (15-25% on neonatal MRI). In 64% of the 22
children studied by Mercuri et al.8 some degree of functional impairment of the
non-hemiplegic hand was found. It was of interest that the severity of the
impairment on the non-hemiplegic side was not significantly related to the
severity of impairment in the hemiplegic hand but it was due to milder
abnormalities of the hemisphere contralateral to the side of the PAIS/PH, as
can nowadays be better visualised using high quality MRI-DWI performed in the
neonatal period.
To address the issue of potential involvement of both hemispheres, we will
assess integrity of both hemispheres using a variety of structural and
functional methods evaluating the gray matter volume, the integrity of the
white matter and the resulting pattern of reorganisation.
Reorganisation of the sensorimotor system has recently been studied in small
groups of children and adolescents with a variety of underlying problems. These
studies have shed light on differences between the reorganisation of
somatosensory and motor pathways. While reorganisation of the somatosensory
system usually takes place in the ipsilesional hemisphere, reorganisation of
the primary motor function may occur in the contralesional hemisphere as a
result of preservation of ipsilateral corticospinal projections.9,10,11,12,13
Interhemispheric dissociation between motor and sensory representation can
therefore be seen. The difference between motor- and sensory representation may
be due to the fact that spino-thalamic sensory fibres only reach the cortical
level after the first weeks after birth.14 The thalamo-cortical fibres
therefore still bypass the lesion, which occurred before the thalamo-cortical
fibres have fully developed. While contralesional reorganisation could be
considered to be a result of brain plasticity, ipsilesional reorganisation has
been shown to be more effective in the preservation of motor function than
contralesional reorganisation.
Preterm infants with unilateral PH and full-term infants with PAIS, born
between 1990-2005 and who were admitted to the level III neonatal intensive
care unit at the Wilhelmina Children*s Hospital/University Medical Centre
Utrecht will be eligible for the study. Both infants with and without
development of hemiplegic cerebral palsy will be invited to participate.
Altogether 62 infants with PH and 69 full-term infants with PAIS who are now
eight years or above will be approached and invited to participate in the
study. These children have at least been seen in our follow-up clinic till an
age of 5 years.

1- to describe the presence and severity of hemiplegic CP on the basis of
neonatal MRI findings and correlate the involvement of different structures
(basal ganglia, posterior limb of the internal capsule and hemisphere) with the
size of the lesion
2- to correlate the structural characteristics of a lesion with the pattern of
subsequent sensorimotor reorganisation.

Methods
Functional and structural magnetic resonance imaging (fMRI) data will be
acquired on a 3-Tesla Philips scanner (Best, the Netherlands) in block designs.
Active movement will consist of repetitive opening and closing of the hand;
passive movement will consist of the same movement performed by the examiner.
Both hands will be assessed separately and in random order. During the active
hand movement they will be asked to exert, or not exert pressure. During the
passive movement task, the children are asked to relax, while the examiner
opens and closes their hand at a 1 Hz frequency. Postprocessing of fMRI data
and statistical analysis of the functional images will be performed using SPM2
(Statistical Parametric Mapping, Wellcome Department of Neuroscience, London,
UK). The pattern of brain activation (ipsi- and contralateral primary
sensorimotor cortex (SMC), supplementary motor area (SMA), and lateral premotor
cortex (PMC) will be studied to assess the degree of reorganization.
Gray matter density will be assessed using an automated voxel based structural
analysis (VBM, SPM2) using structural brain MRI. A cost-function approach will
ensure adequate hemisphere alignment, which will be followed by a voxel based
comparison of patients in groups A & B. A correlation analysis between the
performance on motor recovery and gray matter density will be performed. In
order to further ensure the authenticity of gray matter analyses and exclude
the possibility of differences between the groups being accounted by
deformation, deformations maps will extracted and the Jacobian determinants of
the normalization for every subject will be calculated. Using a two-sample
t-test we will then compare gray matter volumes for groups A & B. All analyses
will be corrected for multiple comparisons using a False Discovery Rate
(Genovese et al., 2002) with the threshold for statistical significance set at
p<0.05.
Diffusion Tensor Imaging (DTI) Diffusion images for thirty-two directions of
diffusion will also acquired using EPI. The diffusion images for each direction
will be realigned (SPM99/SPM2), and only the averaged image for each direction
is used to determine the diffusion tensor for each voxel and subsequent fibre
tracking. These procedures will be performed using DTI-Studio software

Navigated transcranial magnetic stimulation (TMS) will also be performed to
study ipsilesional or contralesional reorganisation (Guzzetta et al. 2007,
Staudt et al. 2004,2006). The TMS coil will be navigated to the individual
fMRI-activation maxima within the preselected regions of interest.

Guzzetta A, Bonanni P, Biagi L, Tosetti M, Montanaro D, Guerrini R, Cioni
G.Reorganisation of the somatosensory system after early brain damage. Clin
Neurophysiol. 2007;118:1110-21
Staudt M, Gerloff C, Grodd W et al reorganisation in congenital hemiparesis
acquired at different gestational ages. Neurology 2004, 56:854-63
Staudt M, Braun C, Gerloff C, Erb M et al. Developing somatosensory projections
bypass periventricular brain lesions. Neurology 2006; 67:522-5

Assessment of gross motor function and hand function
Gross Motor developmental status will be classified by the Gross Motor Function
Classification System (GMFCS) [Palisano 1997] and measured by the Gross Motor
Function Measure (GMFM) [Russell 1993].Fine Motor developmental status will be
classified by the Manual Ability Classification System (MACS) [Eliasson 2006]
and measured by the Assisting hand Assessment (AHA) [Krumlinde] for bilateral
activities (both affected and unaffected side) and the Abilhand for children
for unilateral assessment (affected side) [Arnould 2004]
GMFCS:
Palisano R., Rosenbaum P., Walter S., Russell D., Wood E., Baluppi B.
Development and reliability of a system to classify gross motor function in
children with cerebral palsy. Dev Med Child Neurol 1997; 39: 214-223.
GMFM:
Russell D.J., Rosenbaum P.L., Gowland C., Hardy S., Lane M., Plews N., McGavin
H., Cadman D., Jarvis S. Manual for the Gross Motor Function Measure (second
edition). Hamilton, ON: McMaster University; 1993.
MACS:
Eliasson AC, Krumlinde-Sundholm L, Rosblad B, Beckung E, Arner M, Ohrvall AM,
Rosenbaum P. The Manual Ability Classification System (MACS) for children with
cerebral palsy: scale development and evidence of validity and reliability. Dev
Med Child Neurol. 2006 Jul;48(7):549-54.
AHA:
Krumlinde-Sundholm L, Holmefur M, Kottorp A, Eliasson AC. The Assisting Hand
Assessment: current evidence of validity, reliability, and responsiveness to
change. Dev Med Child Neurol. 2007 Apr;49(4):259-64.
Abilhand:
Arnould C., Penta M., Renders A., Thonnard J.L. ABILHAND-Kids: A measure of
manual ability in children with cerebral palsy. Neurology 2004; 63: 1045-52.

A selection of Neuropsychological tests will be done by the department of
Neuropsychology:
- The Raven-C-NL (Intelligence)
- Thomal (Mnestic functions)
- Beery VMI 5th edition (graphic constructions)
- Bourdon-Vos test (attention/concentration)
- Trail Making, Balloon piercing, Sorting Task (executive functions)
- Reaction speed (npsyreact)

Magnetic resonance imaging (MRI) is performed for clinical purposes in many, if
not all, follow-up centers for many years. Over the last 15 years, we have
accumulated considerable collective expertise in MRI techniques, and its
associated practical issues in children aged between 8-10 years in previous
studies. We have used the MRI prototype scanner in the department of Psychiatry
to help the children get accustomed to the technique. We allow children to
bring their favourite CD to listen to and they can bring one of their parents
into the MRI room, whom they can see when looking in a mirror which is above
their head. The researcher will be with the child all day, which will also help
in not getting anxious about being in the MR scanner. There will not be a risk
for undergoing any of the tests mentioned in previous sections. It may be of
benefit to obtain detailed information about the brain lesion which can be of
use for the further rehabilitation process. For the children who did not
develop a hemiplegia but are also invited to take part in the present study
(group relatedness), other problems may be brought to light, which may help in
explaining certain problems which are experience at school and this may be of
help in improving the situation at school.