Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 6 ) 1 e9

Official Journal of the European Paediatric Neurology Society

Original Article

Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study Maximilien Perivier a,b, Matthieu Delion c,d, Eva Chinier e, Sebastien Loustau f, Sylvie Nguyen a,b, Aram Ter Minassian a,g, Isabelle Richard h,i, Mickael Dinomais a,i,* a LUNAM, Universit
e d'Angers, Laboratoire Angevin de Recherche en Ing
enierie des Systemes (LARIS), EA7315, F-49000, France b LUNAM Universit
e d'Angers, CHU Angers, d
epartement de neurop
ediatrie, F-49933, France c LUNAM Universit
e d'Angers, CHU Angers, d
epartement de neurochirurgie p
ediatrique, F-49933, France d LUNAM Universit
e d'Angers, Laboratoire d'anatomie, Facult
e de m
edecine Angers, F-49045, France e Department of Physical Medicine and Rehabilitation, University Hospital, H^opital Saint-Jacques, Nantes, Cedex 01, France f Universit
e d'Angers, Laboratoire Angevin de Recherche en Maths (LAREMA), UMR CNRS 6093, France g LUNAM Universit
e d'Angers, CHU Angers, P^ole d'anesth
esie r
eanimation, F-49933, France h LUNAM, Universit
e d'Angers, Laboratoire d'
epid
emiologie, ergonomie et sant
e au travail, EA 4626 F-49000, France i LUNAM, Universit
e d'Angers, CHU Angers D
epartement de M
edecine Physique et de R
eadaptation, F-49933, France

article info

abstract

Article history:

Cerebral Palsy (CP) is a group of permanent motor disorders due to non-progressive

Received 8 June 2015

damage to the developing brain. Poor tactile discrimination is common in children with

Received in revised form

unilateral CP. Previous findings suggest the crucial role of structural integrity of the pri-

16 November 2015

mary (S1) and secondary (S2) somatosensory areas located in the ipsilesional hemisphere

Accepted 26 November 2015

for somatosensory function processing. However, no focus on the relationship between structural characteristics of ipsilesional S1 and S2 and tactile discrimination function in

Keywords:

paretic hands has been proposed. Using structural MRI and a two-point discrimination

Cerebral palsy

assessment (2 PD), we explore this potential link in a group of 21 children (mean age 13

Somatosensory system

years and 7 months) with unilateral CP secondary to a periventricular white matter injury

Morphometry

(PWMI) or middle cerebral artery infarct (MCA). For our whole sample there was a signif-

MRI

icant negative correlation between the 2 PD and the gray matter volume in the ipsilesional

Sensory function

S2 (rho ¼ 0.50 95% confidence interval [0.76, 0.08], one-tailed p-value ¼ 0.0109) and in the ipsilesional S1 (rho ¼ 0.57, 95% confidence interval [0.81, 0.19], one-tailed pvalue ¼ 0.0032). When studying these relationships with regard to the lesion types, we found these correlations were non-significant in the patients with PWMI but stronger in patients with MCA. According to our results, the degree of sensory impairment is related to the spared gray matter volume in ipsilesional S1 and S2 and is marked after an MCA stroke.


partement de me
decine physique et re
adaptation, CHU-Les Capucins, 3 rue des capucins, BP 40329, 49103 * Corresponding author. De Angers cedex 02, France. Tel.: þ33 2 41 35 18 04; fax: þ33 2 41 35 18 05. E-mail address: [email protected] (M. Dinomais). http://dx.doi.org/10.1016/j.ejpn.2015.11.013 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

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Our work contributes to a better understanding of why some patients with CP have variable somatosensory deficit following an early brain lesion. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1.

Introduction

Cerebral Palsy (CP) is a group of permanent motor disorders due to non-progressive damage to the developing brain. CP is a major cause of motor disability in children. Among these CP children, approximately one third have unilateral CP (UCP) resulting in abnormal motor function of one upper limb, and normal motor function of the other. Poor tactile discrimination is common in children with UCP.1 Perception and tactile discrimination deficit is believed to contribute to reduced dexterity, impaired motor learning2,3 and motor planning.4e6 Conflicting results have been reported for a correlate with the global motor function.7 It has been suggested that a somatosensory deficit could behind the prominent motor impairment in certain cases of subjects with UCP8 (for a commentary see9). Conventional structural Magnetic Resonance Imaging (MRI) is increasingly performed in children with CP. This allows structural and volumetric analysis and could provide critical insights into the relationship between function and underlying cortical changes or damage. Regarding the anatomical and topographical study, primary (S1) and secondary (S2) sensory areas and the inferior parietal cortex directly neighboring S1 and S2 located in the ipsilesional postcentral gyrus (i.e., contralateral to the paretic hand) were shown to be determinant for the somatosensory function following a middle cerebral artery (MCA) infarct: typically damaged in children with UCP with a somatosensory deficit but typically spared in those without a somatosensory deficit.10 Using structural analysis of the somatosensory system, we have also suggested11 that a more pronounced affection of ipsilesional S2, located on the parietal operculum,12 may underlie the stronger tactile discrimination deficit. These findings suggest a crucial role for structural integrity of ipsilesional S1 and S2 for somatosensory function processing. Functional outcomes have already been shown to be linked to gray matter volume13 in healthy subjects but also in pathology.14 For example, Ku¨hn et al.15 found a positive correlation between manual dexterity and GM volume notably in the supplementary motor area and the cerebellum. To date, no focus on the relationship between volumetric characteristic of ipsilesional S1 and S2 and somatosensory function has been proposed in children with UCP. The purpose of our study was to define how the sensory deficit is related to structural brain modifications defined by gray matter volume in children with UCP secondary to white matter (WM) lesion (PWMI) or MCA infarct. Since the structural integrity of S1 and S2 in the ipsilesional hemisphere seems crucial in preserving the somatosensory function of the paretic hand, as demonstrated by previous research,10 it should be possible to find a negative correlate

between the remaining GM volume of S1 and/or S2 and the somatosensory function as assessed by the two point discrimination task (2-PD). Therefore, we tested the hypothesis that the more severe the somatosensory deficit (i.e. the higher the value of 2 PD) the more a reduced volume (i.e. the lower the value of GM volume) would be found for S1 and S2 located in the ipsilesional hemisphere (see the method part for a detailed explanation).

2.

Materials and methods

2.1.

Participants

Twenty-one children ((seventeen males, mean age 13 years and 7 months, aged 6 years 10 monthse20 years 10 months) with clinical apparent UCP were included as part of an ongoing study16e18) (Table 1). The population analyzed here is made up of from 12 subjects suffering from right UCP (left brain lesions) and 9 from left UCP (right brain lesions). 10 subjects suffered from MCA and 11 from PWMI. Subjects 20 and 21 presented pure left UCP despite some MRI signal abnormalities in the left hemisphere which are not clinically relevant. All participants were born after 35 weeks of gestation. The Bimanual Fine motor function was used to categorize children into five levels according to their ability to perform fine motor function.19 Approval was given by the local Ethics' Committee. All subjects and parents gave written, informed consent. Exclusion criteria were as follows: severe mental retardation, severe vision impairment, severe attention disorders.

2.2.

Sensory assessment

Neurological examination was performed in all participants by the last author (MD). Discriminative somatosensory function was characterized by the minimal distance between two points of tactile stimulation on the thumb that render them distinguishable. (2-Point Discrimination, 2-PD). The 2-point aesthesiometer (Aesthesiometer Lafayette®) was used to determine this distance on the paretic hand (affected hand) and the non paretic hand (unaffected hand) using the thumb pad on the palm. Each subject was instructed to close their eyes while the examiner (MD) applied the two contact points. The subject was asked to report whether they felt one or two points. Two trials were performed for each hand. The trial was performed by increasing the aesthesiometer distance from 0 cm in 1 mm steps until the subject was able to successfully resolve two points. The average of these two discrimination trials was recorded. Higher values reflect stronger

Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

Subj

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Sex

Age [yr]

Lesion side [L/R]

Lesion type

BFMF [1e5]

2 PD [ph/nph]

TIV [ml]

GM in ipsilesional S1 [ml]

GM in contralesional S1 [ml]

GM in ipsilesional S2 [ml]

GM in contralesional S2 [ml]

Ipsilesional S1r [%]

Ipsilesional S2r [%]

M F M M M M M M M M M M M F F M M F M M M

16 12 10 9 13 11 12 20 21 10 16 15 11 18 15 16 6 7 13 10 9

L L L L L L L L L L L R R R R R R R L R>L R>L

PWMI MCA MCA MCA MCA PWMI MCA MCA MCA PWMI PWMI PWMI PWMI PWMI PWMI MCA MCA MCA PWMI PWMI PWMI

1 1 2 1 3 1 1 2 3 1 2 2 1 2 1 2 1 1 2 1 1

1/1 12/2 2/1 1/1 3/2 1/1 1/1 3/2 7/3 1/1 1/1 1/1 3/2 3/2 1/1 1/2 2/2 2/2 3/1 4/3 1/1

1460.16 1131.3 1065.76 1334.3 1086.4 1408.07 1311.25 1395.2 1368.47 1481.56 1452.21 1516.6 1277.16 1418.34 1387.26 1282.3 1289.97 1271.12 1599.96 1316.67 1536.91

9.59 3.09 3.11 10.02 1.89 9.42 9.46 7.28 4.21 10.52 8.55 9.42 10.25 4.05 7.99 7.37 7.81 9.31 8.76 5.44 7.97

10.81 9.32 9.53 10.09 9.23 11.60 8.56 8.53 10.19 10.79 9.21 7.41 8.44 6.73 8.14 6.72 10.90 8.93 9.68 6.46 8.15

2.29 0.00 0.00 2.73 0.00 2.33 2.15 1.43 1.55 3.27 2.34 2.13 2.25 1.35 2.16 1.63 2.15 2.60 2.14 2.15 2.52

2.30 2.23 2.02 2.64 1.97 2.89 2.19 2.36 2.67 2.67 2.54 2.20 2.05 2.29 2.27 1.98 2.55 2.45 2.85 2.35 2.64

0.66 0.27 0.29 0.75 0.17 0.67 0.72 0.52 0.31 0.71 0.59 0.62 0.80 0.29 0.58 0.58 0.61 0.73 0.55 0.41 0.52

0.16 0.00 0.00 0.20 0.00 0.17 0.16 0.10 0.11 0.22 0.16 0.14 0.18 0.09 0.16 0.13 0.17 0.20 0.13 0.16 0.16

Subj, subject number; yr, years; L/R, left/right; PWMI, periventricular white matter injury; MCA, middle cerebral artery; BFMF, bimanual fine motor function; 2 PD, 2 point discrimination in millimeter; ph/nph, paretic hand/nonparetic hand; GM, Gray matter; ml, milliliter; TIV, total intracranial volume; ipsilesioned S1r, ratio of GM volume in ipsilesioned S1 divided by the TIV, expressed in percentage [%]; ipsilesioned S2r, ratio of GM volume in ipsilesioned S2 divided by the TIV, expressed in percentage [%]; See text for details.

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Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

Table 1 e Demographic data and volumetric values.

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impairment. This 2-PD was shown to correlate well with extensive sensory assessment batteries.20

2.3.

Imaging procedure

All datasets were acquired on a 1.5 T MR scanner (MagnetomAvanto, Siemens). A T1-weighted anatomical 3D data set was obtained (176 contiguous sagittal slices, in-plane matrix 256  256, yielding a voxel size of 1  1  1 mm3).

2.4.

Image data processing

2.4.1.

Structural MRI

Processing of the T1-weighted 3D volume was performed using the New segmentation toolbox in the statistical parametrical mapping software, SPM8 (Wellcome Department of Imaging Neuroscience, University College, London, UK; http://www.fil.ion.ucl.ac.uk/spm) running in Matlab R2011a (The MathWorks, Natick, MA, USA). Processing involved bias correction and iterative normalization and segmentation of the 3D original anatomic images into distinct tissue classes. The algorithm is essentially the same as that described in the unified Segmentation paper.21 Gray Matter (GM), White Matter (WM) and segmented cerebrospinal fluid (CSF) tissues were normalized according to the MNI template. Default values were used (12-parameter affine transformation and nonlinear deformation with a warp frequency cutoff of 25 mm). A modulation of the segmented and normalized GM (modulated GM) was undertaken in order to compensate for the effect of spatial normalization and preserve actual GM values locally by multiplying the voxel values by the jacobian determinants derived from the spatial normalization step.22 The final result of the structural MRI processing was a modulated GM probability map for each participant in which the total amount of GM remained as in the original images. Thus, modulated images reflect the GM volumes before spatial normalization and allow testing for “regional differences in the absolute amount “volume” of gray matter …”.22 All images were visually inspected to ensure that the steps described above were successful and that each modulated GM map covered the whole brain.

2.4.2.

Defining somatosensory cortex

The somatosensory cortex was defined as the primary somatosensory cortex (S1), which includes the Brodmann areas (BA) 3a, 3b and 1 on the postcentral gyrus,23 as well as the secondary somatosensory cortex (S2) located in the subcentral section lateroventral to the post central gyrus on the parietal operculum 1 (OP1).24 This description corresponds to the same technique used in our previous work11 which studied the functional connectivity in the somatosensory system. Thus the same S1 and S2 region of interest (ROIs) already generated and used in our previous work11 was again applied here (see Fig. 1).

2.4.3.

Defining control brain areas

We also defined two brain regions located in the ipsilesional hemisphere but not involved in discriminative somatosensory processing and localized far enough from S1 and S2 to avoid

neighboring effect. Thus, we generated two distinct brain regions: 1 e the inferior temporal gyrus and 2 e the middle frontal orbicular gyrus (see Fig. 2). These regions were defined using standard anatomical delineations available within WFU_Pickatlas version 2.4 software. As for S1 and S2 ROIs (see paragraph 2.4.2 Defining somatosensory cortex), these ROIs were smoothed by 6-mm FWHM and then binarized in order to render them slightly more inclusive.

2.5.

Data analysis

2.5.1.

Volume of GM calculation in somatosensory system

The volume of GM was calculated by summing the GM voxel values from modulated GM maps in each ROIs for each participant. Total intracranial volume (TIV) was approximated for each participant by calculating the sum of modulated GM, WM and CSF maps obtained from the segmentation and normalization processing (see section above). A ratio was calculated for each S1 (S1r) and each S2 (S2r) as: ipsilesionalS1r ¼ (GMipsilesionalS1/TIV)*100, where GMipsilesionalS1 refers to the volume of GM calculated in the S1 ROI located in the ipsilesional hemisphere and TIV refers to the total intracranial volume. IpsilesionalS2r was calculated in the same manner using the respective S2 ROI located in the ipsilesional hemisphere. Lower ipsilesionalS1r or ipsilesionalS2r represent reduced GM volume respectively in S1 or S2 located in the ipsilesional hemisphere. In the same way, ratios volume of GM were calculated for ipsilesional inferior temporal gyrus and for ipsilesional middle frontal orbicular gyrus.

2.5.2.

Statistical analysis

Relationships between 2PD and ispilesionalS1r and ipsilesionalS2r are computed separately. Because of the small size of our sample, nonparametric statistical dependences were assessed using Spearman's rank coefficients. To analyze a specific effect of the lesion type (MCA or PWMI) on the correlations found, we performed a secondary analysis for the MCA group and the PWMI group. Based on our a priori hypothesis (see Section 1), we considered negative correlations for ipsilesionalS1r and ipsilesionalS2r if they reached the p < 0.05, one-tailed cut-off. We also suggested a graphical representation to get a clear picture of how the data behaves. In this case, we performed two linear regressions of 2PD against ipsilesionalS1r and ipsilesionalS2r for each MCA and PWMI group. Finally, we assess the statistical dependences between 2PD and volume in the ipsilesional control brain areas using Spearman's rank coefficients. Because of lack of prior hypothesis on the direction of the correlation (negative or positive) for these brain regions, correlations were considered as significant if they reached the p < 0.05, two-tailed cut-off. We compare the strength of these two latter correlations with the strength of the correlations with ipsilesional S1 and S2 by comparing the rho value of each correlations. Higher rho value of correlations with ipsilesional S1 and S2 compared to correlations with control brain areas indicate that tactile discrimination deficit correlate specifically with reduced GM volume in ipsilesional S1 and S2.

Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

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Fig. 1 e This figure illustrates the ROIs used in this study to examine somatosensory brain areas. S1 ¼ primary somatosensory cortex, S2 ¼ secondary somatosensory cortex. See Section 2 for details.

3.

Results

3.1. Characteristics for 2PD, volume of gray matter in S1 and S2 Somatosensory characteristics for each patient are shown in Table 1. The median value of the 2PD measured in paretic thumb was 2 mm (95% confidence interval CI [1e3]). There is no difference between the MCA group and PWMI group,

respectively the median 2PD was 2 mm (95%CI [1e7]) and 1 mm (95%CI [1e3]), (p-value ¼ 0.26, ManneWhitney U test). The GM volume in S1 and in S2 for each patient is shown in Table 1. The median values of GM in ipsilesional S1 and in ipsilesional S2 were respectively 7.41 ml (range (95%CI [5.44, 9.42]) and 1.86 ml (95%CI [1.55, 2.33])). Although the differences did not reach statistical significance, GM volumes appear higher in the MCA group than in PWMI group in S2 (respectively the median values were 1.59 ml (95%CI [0.00, 2.60]) and

Fig. 2 e This figure illustrates the ROIs used in this study to examine control brain areas and somatosensory brain areas. Blue color represents S1, red color ¼ S2, green ¼ inferior temporal gyrus, yellow ¼ middle frontal orbicular gyrus. See Section 2 for details. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

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2.25 ml (95%CI [2.13, 2.52]), p-value ¼ 0.08, ManneWhitney U test) and in S1 (respectively the median values were 7.33 ml (95%CI [3.09, 9.46]) and 8.76 ml (95%CI [5.44, 10.25]), pvalue ¼ 0.08, ManneWhitney U test). The median value for ipsilesionalS1r was 0.58% (95%CI [0.41, 0.67]). There was no significant difference between the MCA group and the PWMI group, respectively the median values were is 0.55% (95%CI [0.27, 0.73]) and 0.59% (95%CI [0.41, 0.71]), (p-value ¼ 0.48, ManneWhitney U test). The median value for ipsilesionalS2r was 0.16% (95%CI [0.11e0.17]). There was no significant difference between the MCA group and the PWMI group, respectively the median values were 0.12% (95% CI [0.00, 0.20]) and 0.16% (95%CI [0.13, 0.18]), (p-value ¼ 0.22, ManneWhitney U test).

3.2. Correlation between 2PD and ipsilesional ratio volume in S1 and S2 The relationships between 2PD and ipsilesionalS1r and ipsilesionalS2r are studied with the one-tailed Spearman's rank correlation test. For our whole sample, there was a significant negative correlation between the 2PD and the ipsilesionalS2r (rho ¼ 0.50 95% confidence interval [0.76, 0.08], one-tailed pvalue ¼ 0.0109) and the ispilesionalS1r (rho ¼ 0.57, 95% confidence interval [0.81, 0.19], one-tailed p-value ¼ 0.0032) (Fig. 3). When studying these relationship with regard to the lesion types, we found these correlations were non-significant in patients in the PWMI group (rho ¼ 0.28 95%, CI [0.75, 0.38], one-tailed p-value ¼ 0.2026, for ipsilesionalS2r; rho ¼ 0.41, 95% CI [0.8, 0.28], one-tailed p-value ¼ 0.1082, for ipsilesionalS1r). Inversely negative correlations between 2PD and ipsilesionalS2r and ipsilesionalS1r were stronger in patients with MCA with respectively rho ¼ 0.63 (95% CI [0.9, 0.01],

one-tailed p-value ¼ 0.0247) and rho ¼ 0.73 (95% CI [0.93, 0.18], one-tailed p-value ¼ 0.0083). This phenomenon is depicted in Fig. 3 with simple linear regressions. In Fig. 3A (resp. 3B), two linear regressions of 2PD against ipsilesionalS1r (resp. IpsilesionalS2r) are computed for patients with PWMI (represented by X) and MCA (represented by open triangles).

3.3. Relation between 2PD and ipsilesional ratio volume in control brain areas For our whole sample, there was a trend for negative correlation between the 2PD and the ipsilesional inferior temporal gyrus (rho ¼ 0.40, 95% confidence interval [0.72, 0.05], twotailed p-value ¼ 0.0729). No statistical correlation was found between the 2PD and the ipsilesional middle frontal orbicular gyrus (rho ¼ 0.30, 95% confidence interval [0.65, 0.17], twotailed p-value ¼ 0.19). These two latter rho values (rho ¼ 0.40 for ipsilesional inferior temporal gyrus, rho ¼ 0.30 for ipsilesional middle frontal orbicular gyrus) were weaker than the rho value for ipsilesional S1 and ipsilesional S2 (respectively rho ¼ 0.57 and rho ¼ 0.50).

4.

Discussion

In this study, we demonstrate that the degree of somatosensory impairment is directly linked to the volume of spared GM in the ipsilesional postcentral gyrus (S1 and S2). In order to show that these correlations of 2PD with S1 and S2 GM volume were indeed specific we defined two control brain areas and showed that correlations were indeed weaker. Moreover, we observed a significant correlation between

Fig. 3 e Correlation between 2PD (y-axis in millimiter) and the ipsilesionalS1r (x-axis in %) on the left panel (Fig. 3A) and the ipsilesionalS2r (x-axis in %) on the right panel (Fig. 3B). The correlation was significant for ipsilesionalS2r and ipsilesionalS1r. Open triangles represent subjects with a middle cerebral artery (MCA) stroke, X represent subjects with a periventricular white matter injury (PWMI). See Section 3 for details. Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

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tactile discrimination deficit and reduced GM volume in S1 and S2 in children with UCP due to an MCA infarct. This was not the case when the UCP was due to PWMI. Previous studies have suggested similar results. Guzzetta et al.25 reported a correlation between the number of activated voxels in the ipsilesional perirolandic region (S1M1) and sensory impairment in their patients. There is sufficient evidence to indicate that the number of activated voxels in an ROI may depend on the remaining GM volume. Thus, we could interpret Guzzetta's results as an indirect marker of the influence of GM volume remaining in the postcentral gyrus on sensory processing. From our point of view, the correlation found between sensory impairment and GM volume in S1/S2 located in the ipsilesional hemisphere could also explain why degrees of tactile discrimination impairment are variables in patients with UCP. Our results underline the crucial role of ipsilesional S1 and S2 to preserve the tactile discrimination function of the paretic hand and are in line with our previous results.11 S1 is the main cortical region for sensory-discriminative processing,26 but S2 also represents the anatomical substrate of various sensory functions such as stimulus discrimination.27 In the case of an early brain lesion, it is well known that the brain somatosensory representation of the paretic hand (S1 and S2) still remains in the ipsilesional hemisphere.28,29 Recent neurophysiological studies have highlighted the malfunctioning of these postcentral areas in the somatosensory process30e32 in children with CP. Diminished GM volume in ipsilesional S1 and S2 constitutes a negative contributor to the clinically evident somatosensory impairment. As we found strong a correlation between GM volume in S1 and S2 and sensory function, we believe that this further argues in favor of the limited potential for compensatory and reorganization processes in the sensory system after an early brain lesion, especially after an early MCA infarct.33,10 The limited plasticity of the sensory system should be considered in line with the fact that the more mature and determined a brain system is, the less plastic it is. If a lesion occurs after the full determination of the topographical specificity for sensory function, cortical representations cannot develop in other brain regions. The sensory system is one of the first to mature during the last trimester of gestation and the first weeks of life34 and confirmed by structural study.10 Since the sensory system in the human brain is early determined during the fetal life. The cortical map is genetically determined before thalamo-cortical connections have been established. Even in the case of large WM early-gestation lesions, the thalamo-cortical axons can bypass the lesion and reach the postcentral gyrus.35 In patients with PWMI, there was no significant relationship between sensory impairment and GM volume even though 4 out of 11 children had abnormal 2PD scores. In these patients, lesions are mainly subcortical and usually do not involve the cortex as we found higher GM volume in this latter group compared to the MCA group. Somatosensory deficit in patients with PWMI may be better explained by loss of integrity of thalamo-cortical pathways than by loss of GM volume in ipsilesional S1 and/or S2. In case of PWMI, the ascending somatosensory fiber tracts may bypass white-

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matter insult to terminate in adjacent spared neuronal target regions (S1 and/or S2), which allows the ipsilesional hemisphere to support somatosensory functions of the paretic hand. However, the structural integrity and electrophysiological properties of these tracts could be deteriorated leading to abnormal transmission of sensory information along these injured pathways. Thus in patients with PWMI, tactile discrimination deficits could also be related to an injury to the thalamo-cortical pathways to parietal and sensory cortices36 as suggested by morphological studies.8,37,38 More recently, a diffusion MRI study confirmed a correlate between somatosensory impairment and the loss of WM integrity of the afferent thalamo-cortical projections on the ipsilesional hemisphere, especially the ones toward the primary sensorimotor cortex.39 It is noteworthy that a recent multimodal neuroimaging study40 in children with CP showed abnormal somatotopic organization within S1 and suggested a spatial reorganization within the precentral areas that was possibly a result of diminished thalamo-cortical projections.40 In this case thalamo-cortical projections by-pass the PWMI and they may project in different locations (like precentral areas) compared to healthy development. This remark could also explain why in case of PWMI we found a weak relationship between sensory impairment and GM volume in postcentral gyrus. Correlations between 2PD and GM in ipsilesional control brain areas were weaker than correlations between 2PD and GM volume in ipsilesional S1 and S2 and did not reach statistical significance. The trend observed for negative correlation between GM volume in inferior temporal gyrus and sensory deficit could be due to correlations between the GM volumes of different regions located in the ipsilesional hemisphere. Therefore correlation between sensory discrimination deficit and GM volume in ipsilesional S1 and S2 probably underlies specifically the neural substrate of sensory deficit in children with UCP notably after an MCA stroke. Previous work33,11,25 suggested that these somatosensory areas are the major contributors to restoring sensory function. A possible limitation of this study is the use of only the twopoint discrimination as the main measure. However this parameter was shown in previous studies to correlate well with extensive sensory assessment batteries.20 The absence of electrophysiological assessment did not allow for a reliable identification of somatosensory area and the drawing of further conclusions. We therefore believe that structural MRI is well suited to studying the structural properties of the sensory system, but other modalities may be useful to give a full understanding of the quality of neuronal reorganization following an early brain lesion. However, our main results (a correlation between GM volume and sensory outcome) remain valid.

5.

Conclusions

Our knowledge about pathophysiology of somatosensory impairment in UCP is increasingly developed these days, from structural data about the somatosensory cortex10 and structural connectivity41 to functional connectivity in resting state MRI, task-related MRI and neurophysiology.30 Our findings place another brick in the wall, highlighting the primary role of S1 and

Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013

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S2 in the somatosensory process in MCA patients. According to our results, the degree of sensory impairment is related to the spared GM volume in S1 and S2 located in the ipsilesional hemisphere and is marked after an MCA stroke. Our work contributes to a better understanding of why some patients have no mild to severe somatosensory deficit. The remaining volume of GM could be used as an indicator of the sensory outcome. If confirmed in a wider group of patients, our findings may help to establish the prognosis of sensory deficit following a unilateral brain lesion after a perinatal MCA stroke.

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Conflict of interest 13.

No party has direct interest neither a financial relationship nor will confer a benefit from the results of this research. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Thus the financial support of the study had no role in the study design data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Acknowledgments and fundings 18.

This research was supported by a grant from the University Hospital of Angers (France), AOI 2011-08, 2011-A0105635 (ANSM).

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Please cite this article in press as: Perivier M, et al., Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/j.ejpn.2015.11.013