language organisation in left perinatal stroke

Original Article 157

Guzzetta A et al. Language Organization in Left Perinatal Stroke. Neuropediatrics 2008 ; 39: 157 – 163

received 29.12.2007 revised 28.04.2008 accepted 07.07.2008

Bibliography DOI 10.1055/s-0028-1085465 Neuropediatrics 2008 ; 39: 157 – 163 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0174-304X

Correspondence Dr. A. Guzzetta Department of Developmental Neuroscience Stella Maris Scientifi c Institute Via dei Giacinti 2 56018 Calambrone Pisa Italy Tel.: + 39 / 050 / 886 230 Fax: + 39 / 050 / 30 056 [email protected]

Key words � � childhood stroke � � neonatal stroke � � fMRI

Language Organisation in Left Perinatal Stroke

dysfunction [25] , or to the exact type and timing of the insult. Most studies exploring the eff ects of early LH brain injury on language organisation have dealt with young individuals with intractable epilepsy, who underwent sodium amobarbital injection [12] , fMRI [13] or PET [23 – 25] as part of their pre-surgical evaluation. In most cases the under-lying pathologies consisted of brain cortical mal-formations, highly epileptogenic lesions occurring during the fi rst half of gestation. More recently, RH organisation of language was also demon-strated in subjects with deep white matter lesions of the early third trimester of gestation and no history of epileptic seizures [32, 33] . Little is still known on the mechanisms of language organiza-tion in subjects with gray matter lesions occur-ring later in gestation and not associated to persistent epileptic activity. This would provide a better understanding of the correlations between location of damage and language organisation. In the present study, we used fMRI to explore language representation in subjects with LH arte-rial stroke occurring around the term of gesta-tion. Inclusion criteria were term birth, clinical

Introduction & In vivo techniques of brain mapping have shed light on the mechanisms underlying language (re-)organisation in subjects with early left focal lesions. In this condition the laterality of lan-guage may be reduced or even reversed with function fully taken over by homotopic regions of the undamaged right hemisphere (RH) [21, 25, 32, 35] . The direct damage of language areas has been called upon as a possible determinant of the right lateralisation of language representation following early brain insult [1, 5, 16, 22, 29, 32] . However, there are reports showing that subjects with early lesions within the language circuit do not always show inter-hemispheric organisation of language [8] , or even that they can show a paradoxical predisposition towards intra-hemi-spheric organisation, as opposed to subjects with lesions remote from it [21] . These controversial fi ndings are likely to be related to the infl uence of other important factors and, in particular, to the presence and course of ictal and inter-ictal epi-leptic activity in the LH [4, 17, 18] , to the pres-ence of overt or covert sensori-motor hand

Authors A. Guzzetta 1 , C. Pecini 1 , L. Biagi 1 , M. Tosetti 1 , D. Brizzolara 1 , 2 , A. Chilosi 1 , P. Cipriani 1 , E. Petacchi 1 , G. Cioni 1 , 2

Affi liations 1 Department of Developmental Neuroscience, Stella Maris Scientifi c Institute, Calambrone, Pisa, Italy 2 Division of Child Neurology and Psychiatry, University of Pisa, Calambrone, Pisa, Italy

Abstract & Right-hemispheric organisation of language has been observed following early left-sided brain lesions. The role of the site of damage is still con-troversial, as other aspects infl uence the pattern of speech organisation including timing of the lesion and the presence of epilepsy. We studied a group of 10 term-born children homogeneous for timing / type of lesion and clinical picture. All subjects had left perinatal arterial stroke, right hemiplegia, normal cognitive functions and no or easily controlled epileptic seizures. In half the patients, the lesion clearly involved Broca ’ s area, in the other half it was remote from it. Language

lateralization was explored by an fMRI co vert rhyme generation task. Eight of 10 subjects showed a right lateralisation of language, includ-ing all fi ve patients with a damaged left Broca and 3 / 5 of those without it. Group analysis in patients with right hemispheric organisation showed brain activations homotopic to those found in the left hemisphere of a matched control group. Our fi ndings confi rm that, at the end of gestation, the human brain exhibits extraordinary (re-)organi-sational capabilities. Language organisation in the right hemisphere is favoured by the presence of destructive lesions of the left Broca ’ s area at birth, and occurs in brain regions homotopic to those usually involved in language processing.

Original Article158


and neuroimaging (brain ultrasounds or MRI) evidence of peri-natal arterial stroke and right hemiplegia; patients showed no or easily controlled epileptic seizures. The specifi c aim was to investigate in this population, homogeneous for timing of lesion and clinical picture, the presence of atypical RH organisation of language, its relation to lesion location and its topographical dis-tribution.

Patients and Methods & Subjects Ten young subjects, aged 7 – 19 years (mean age: 11 years and 6 months), with perinatal stroke of the LH on MRI ( � � Fig. 1 ) and hemiplegia participated in the study. They were randomly selected from the subjects referred to our institution. In all patients neonatal imaging was available, brain MRI in 3 and cranial ultrasound in the remaining 7. Imaging fi ndings were always suggestive of focal acute damage (transient focal unilat-eral echogenicity or focal abnormal signal at the conventional or diff usion-weighted MR images). To assess the quality of upper limb motor function, we administered to all patients the Melbourne Assessment of Unilateral Upper Limb Function [28] . Scoring ranges from 0 to 100 % , the latter indicating the best performance. Ten healthy subjects with Italian as fi rst language, aged between 11 and 19 years (mean age: 13 years and 8 months), were recruited as controls. Informed written consent was obtained from all participants or from their parents. The study was approved by the ethical committee of the Stella Maris Foundation.

fMRI data acquisition An MR system (1.5-T. LX-SIGNA, HealthCare GE Systems), equipped with Echo-speed gradient coils and amplifi er hard-ware was used. Images were acquired by an EPI gradient-recalled echo sequence (fl ip angle 90 ° , TE = 50 msec, TR = 3 000 msec,

matrix: 128 × 128, FOV = 28 cm × 28 cm, spatial resolution in-plane = 2.2 mm). Each volume consisted of 13 – 15 contiguous axial slices 5 – 6 mm thick. A volumetric set of anatomic high resolution 3D FSPGR images (124 axial images, 1.1 × 1.1 × 1.1 mm 3 voxels) was acquired at the end of the session in order to generate a 3-dimensional whole brain reconstruction and to estimate the anatomic localisation of activated regions. The paradigm consisted of repeated cycles of “ on ” and “ off ” peri-ods of a single task (block design, time-course series of 30 s each, repeated 6 times). Stimuli were generated as AVI movies in MAT-LAB and displayed through liquid crystal goggles (VisuaStim XGA – Resonance Technology at a resolution of 800 × 600 voxels, subtending 30 ° × 22.5 ° at an apparent distance of 1.5 m, with mean luminance of 30 cd / m 2 ). Luminance, colour, shapes (Arial font) and size (font 96) were carefully balanced between task and rest. The organization of language was studied by fMRI using a co vert rhyme generation task. The participants were asked to silently generate a word rhyming with a two-syllable word presented on the screen. Stimuli were presented at 0.2 Hz (1 / 5 s), 6 words per block, for a total of 18 words. Rest condition consisted of passive watching of a string of capital x letters (XXXX) presented at the same time frequency as the task stim-uli. All subjects received detailed instructions and a short training prior to the experiment.

fMRI data analysis Post-processing and statistical analysis of the functional images were performed using the software package Brain Voyager QX (Brain Innovation, Maastricht, the Netherlands). After the realignment of all volumes, the data were pre-pro-cessed (spatial and temporal smoothing, linear trend removal) and the fi rst functional volume was co-registered to the respec-tive high resolution T 1 anatomic images of each subject. Then, the process of normalisation to a standard brain in Talairach space was conducted on the two groups of subjects. For the con-

Fig. 1 Lesion location (circled) in each patient, as shown on T 1 -weighted images. ( A ) Lesions involving the anterior language cortex. ( B ) Lesions remote from the anterior language cortex. In axial images the left hemisphere is on the right; in sagittal images the left is shown. The patient number is indicated in the left-hand corner in each case.



trol group we transformed each T 1 anatomic data set in Talairach space. For the patient group a diff erent procedure was applied to limit the error deriving from the presence of cortical brain dam-age. Firstly, the healthy right hemisphere of each subject was manually realigned to the right hemisphere of a control brain matched for sex and age. Then the control brain was normalised to Talairach space and the double transformation was applied to the functional data set of the matching patient. Two types of analysis were performed, a single subject analysis and a group analysis.

Single subject analysis For each individual subject, the statistical analysis in each voxel was performed using a general linear model. As basic function, we chose a box-car waveform, synchronous with the stimulus presentation and convoluted with a synthetic haemodynamic response function. The pattern of activation for each patient was analysed individually applying a threshold of p < 0.005 uncor-rected [q(FDR) < 0.01], and the numbers of activated voxels in both the left and the right cerebral hemispheres were deter-mined. For each participant, a lateralisation index was calculated on the basis of fMRI activation in the inferior frontal gyrus, as this area was shown to be most reliable for assessment of language later-alisation [19] . Firstly, the number of signifi cantly activated vox-els within the inferior frontal gyrus of each hemisphere was determined. Then a lateralisation index was obtained by com-puting (nR – nL) / (nR + nL), where nL and nR are the number of activated voxels in the LH and in the RH, respectively [9] . Par-ticipants with a negative lateralisation index were considered left lateralised for language, while those with a positive laterali-sation index were considered right lateralised.

Group analysis To obtain activation maps across the two groups of subjects, the functional data within both groups were combined in a “ fi xed-eff ect ” analysis, the most sensitive approach to identify areas involved in language processing. For this kind of analysis we restricted our sample to the eight patients who presented an RH organisation of language (see results), and to eight age-matched controls [note: for the patients, only activations of the RH were considered as group analysis produced unreliable results in the LH due to the extensive tissue loss]. An uncorrected activation threshold of p < 0.0001 at the voxel level [q(FDR) < 0.001] was applied for this analysis. Statistical analysis was performed by L. Biagi, physicist.

Results & All patients had Italian as fi rst language. They had normal verbal IQ (mean: 97; range: 89 – 112) at the Wechsler scales [38] and presented with no dysphasic symptoms at the time of scanning. In fi ve patients, the lesion was remote from classical language areas, in the mesial cortex, the centrum semiovale or in the sub-cortical nuclei and internal capsule; in the remaining fi ve patients, the lesion involved Broca ’ s area, entirely in four and partially in one. Details on the type of arterial stroke, severity of motor impairment and fMRI language lateralisation are reported in � � Table 1 . All control subjects showed on fMRI a clear LH lateralisation for language ranging from 0.8 to 1. According to the Edinburgh Ta

ble

1 Pa

tient

det

ails

.

Patie

nt

Sex

Terr

itory

dis

trib

utio

n Br

oca’

s ar

ea

Seiz

ure

type

Epile

psy

Pres

ent

trea

tmen

t

Age

at fM

RI

Lang

uage

late

ralis

atio

n (in

dex)

Han

d m

otor

impa

irm

ent (

MAU

ULF

)

Fi

rst

epis

ode

Last

epis

ode

1 M

LM

CA, m

ain

bran

ch

invo

lved

PS

2m

o 3m

o –

7 yr

, 9 m

o rig

ht (1

) 58

2

M

LMCA

, mai

n br

anch

in

volv

ed

–

–

10 yr

, 9 m

o rig

ht (1

) 44

3

M

LMCA

, cor

tical

bra

nch

invo

lved

PS

7

yr

7 yr

10m

o –

16 yr

, 1 m

o rig

ht (1

) 97

4

M

LMCA

, mai

n br

anch

in

volv

ed

–

–

7 yr

, 4m

o rig

ht (1

) 65

5

M

LMCA

, cor

tical

bra

nch

part

ially

invo

lved

–

– 16

yr

right

(1)

49

6 M

LM

CA, d

eep

wat

ersh

ed

not i

nvol

ved

PS

4 yr

7

yr 8

mo

CBZ

8 yr

, 4 m

o le

ft (

− 1)

96

7

M

LMCA

, len

ticul

o-st

riata

l bra

nch

not i

nvol

ved

–

–

19 yr

, 2 m

o rig

ht (1

) 73

8

F LA

CA, c

ortic

al b

ranc

h no

t inv

olve

d –

– 9

yr, 4

mo

left

( −

1)

98

9 F

LMCA

, len

ticul

o-st

riata

l bra

nch

not i

nvol

ved

–

–

9 yr

, 7 m

o rig

ht (1

) 66

10

M

LM

CA, c

ortic

al b

ranc

h no

t inv

olve

d –

– 8

yr, 6

mo

right

(0.8

) 80

M

= m

ale;

F =

fem

ale;

LM

CA =

left

mid

dle

cere

bral

art

ery;

LAC

A =

left

ant

erio

r cer

ebra

l art

ery;

PS

= pa

rtia

l sei

zure

s; y

r = ye

ars;

mo

= m

onth

s; C

BZ =

carb

amaz

epin

e; M

AUU

LF =

Mel

bour

ne A

sses

smen

t of U

nila

tera

l Upp

er L

imb

Func

tion

[28]

Original Article160


Handedness Inventory Laterality Quotients [26] , or the Longoni test [30] for children younger than 12 years, they were all right-handed but one.

Language lateralisation and lesion location All fi ve patients with lesions involving Broca ’ s area showed an RH lateralisation for language ( � � Fig. 2a ). Only the anterior lan-guage areas of the RH were activated in the fi ve patients, result-ing in a lateralisation index of 1 in all. In three cases (patients 1, 2 and 5) fMRI activation was located in regions of the RH clearly homotopic to language areas found in the LH of the control sub-jects. In patients 3 and 4 the activations of the inferior frontal gyrus were more dorsal, and extended into the right dorso lateral prefrontal cortex. Out of the fi ve patients with lesions remote from the language areas, two showed an LH and three an RH lateralisation of lan-guage ( � � Fig. 2b ). fMRI activations were located in the left lan-guage areas in the fi rst two and in homotopic regions of the RH

in the remaining three. The only patient with a bilateral activa-tion of Broca ’ s area was subject 10 who, however, showed a lat-eralisation index of 0.8 consistent with a high degree of RH lateralisation.

Topography of RH language representation The group analysis of the control subjects showed a pattern of activation mainly involving the left inferior frontal gyrus, dorso-lateral pre-frontal cortex and posterior middle temporal region and the supplementary motor area. Group analysis of the eight patients with RH lateralisation showed activations of the right unaff ected hemisphere ( � � Fig. 3 ). A comparison of the activa-tions in the two groups revealed a high degree of similarity between the LH in controls and the RH in patients, with slightly larger activations in the latter. The homotopy of RH topography was confi rmed when comparing local maxima of activation ( � � Table 2 ).

Fig. 2 Sagittal and axial views of fMRI activation in the frontal cortex during the task of covert rhyme generation, displayed at a threshold of p < 0.005, uncorrected for multiple comparisons. Stereotactic coordinates of local maxima in Broca ’ s area (crossairs) are indicated for each patient. Activation maps are superimposed on each patient ’ s T 1 -weighted image. The patient number is indicated in the upper part of each half column. L = left hemisphere; R = right hemisphere.



Discussion & In the present study we explored language lateralisation in ten young patients with perinatal stroke and hemiplegia and found a right lateralisation in 80 % of them. These fi gures are higher than what was found in previous large studies in subjects with early left damage using intracarotid amobarbital (55 % in Ras-mussen et al. [29] ), in patients with congenital right hemiple-gia using dichotic listening (60 % in Isaacs et al. [16] ) or in patients with early epileptic seizures using fMRI (22 % in Springer et al. [31] ; 20 % in Anderson et al. [1] ), intracarotid

amobarbital (24 % in Helmstaedter [12] ) or subdural electrical stimulation (32 % in Duchowny [8] ). In these studies, however, patients presented with diff erent types of early brain damage, mainly consisting of brain malformations that occurred during early gestation. The few reports specifi cally exploring language organisation following perinatal stroke are more consistent with our fi ndings. Tillema et al. [35] recently reported an atyp-ical RH organisation in 8 of 10 subjects with perinatal left arte-rial stroke. Booth et al. [3] and Heller et al. [11] studied two single cases of perinatal left hemisphere stroke and reported an inter-hemispheric organisation in both. A high rate of inter-hemispheric organisation of language in children with arterial stroke was also reported by Brizzolara et al. [6] , who found a right lateralisation at the dichotic listening in 4 / 5 term born children with stroke, as opposed to only 2 / 5 preterm children with periventricular damage at the early third trimester of ges-tation. Altogether, these fi ndings point to the direction of a cer-tain predisposition of patients with arterial stroke to exhibit inter-hemispheric organisation of language. Furthermore, our fi ndings suggest that this is to some extent independent from the presence of persistent epileptic activity, as in our cohort only one subject had persistent epileptic seizures, and despite that showed an LH lateralisation. Studies exploring language representation in left perinatal stroke have not specifi cally addressed the relation between damage location and type of organisation. In the study by Tillema et al. [35] no relation was found between size of lesion and language organisation, however, no mention is made about the arterial distribution of the infarction or to its location. Also, more than half of the subjects studied were reported to be epileptic, while no information was available about their motor function, thus making it hard to extrapolate the specifi c role of the brain lesion in driving language organisation. To explore this issue we exam-ined our cohort on the basis of the presence / absence of a direct involvement of left Broca ’ s area. All subjects with a clear damage of Broca ’ s area showed an inter-hemispheric shifting of language. In three of them, the lesions were very extensive, involving the entire territory of distribution of the middle cerebral artery, and one would argue that not enough unaff ected tissue was left for intra-hemispheric organisation. Interestingly, however, the remaining two subjects showed a more localised damage that in one case involved only the posterior aspects of Broca ’ s area. Our fi ndings are in contrast with those of Liegeois and co-workers [21] , who studied with a similar approach ten subjects with con-genital LH lesions and intractable epilepsy, reporting a paradox-ical tendency to intra-hemispheric organisation in subjects with lesions within or adjacent to Broca ’ s area as opposed to those with lesions remote from it. It might be suggested that other fac-tors contributed to the diff erent results. One is the nature of the insult, that was destructive in our subjects and mainly dysplastic or compressive in Liegeois ’ cohort; this may have determined in the latter either a physical displacement or a survival within the malformed cortex of functioning tissue. This is also supported by the fact that in Liegeois ’ study the coordinates of brain activa-tion corresponding to Broca ’ s area were apparently not dissimi-lar (with opposite values in the x axis) in patients with intra- and inter-hemispheric organisation, suggesting the presence of some functional tissue in left anterior language regions also in patients with damaged Broca areas. Unexpectedly, 3 / 5 patients with small lesions remote from Bro-ca ’ s area showed an inter-hemispheric organisation of language. This is more consistent with the fi ndings of Liegeois and co-

Fig. 3 Fixed-eff ect analysis for the 8 patients with RH organisation of language (right) and controls (left), using a p < 0.0001 activation threshold, uncorrected for multiple comparisons. Activation maps were rendered onto a set of normalised high resolution anatomic T 1 -weighted images from a single control subject.

Original Article162


workers who reported atypical RH lateralisation in 4 / 5 subjects with LH damage remote from anterior language areas. Neverthe-less, in that study lesions were located in the temporal pole or in the hippocampus, and were associated to epileptic discharges that are likely to have spread to relevant language regions of the left temporal cortex [11] . In our study, only one of the fi ve showed epileptic seizures and, in spite of that, he presented a typical left language representation. Also, none of the three patients with lesions remote from Broca ’ s area and RH organisa-tion showed a damage to other relevant language areas and, in particular, to the temporal lobe. Diff erent mechanisms are thus involved in our patients. One possible explanation of our fi nd-ings is that RH organisation was induced by the presence, in the early phases, of associated cortical dysfunction not visible at later conventional MRI. In adults, subcortical stroke was found to be associated to cortical hypo-perfusion using SPECT [27, 40] or MRI diff usion-weighted imaging [14] , and resolution of hypo-perfusion was shown to parallel recovery from aphasia [15, 36, 39] . It might be hypothesised that, in the early stages of development, the presence of cortical dysfunction in the terri-tory of the middle cerebral artery, even when no longer present or visible at later stages, can induce an atypical RH representa-tion of language. We also cannot exclude, however, the possibil-ity that subcortical lesions may have a direct eff ect on language impairment, as previously suggested [7] . Another possible interpretation of our fi ndings, not necessarily in contrast with the previous one, is that the pattern of language representation was infl uenced in our patients by the degree of impairment of hand motor function, which was indeed greater in the three subjects with small lesions and atypical RH organi-sation. This would be consistent with the motor theory of lan-guage development (see [10] , for a review), based on the strict relationships existing between early gesture and speech devel-opment [2, 37] , and also with the recent fi ndings of Sveller et al. [34] who reported in a large cohort of subjects with left focal seizures a strong correlation between shift of language function and handedness. Similarly, RH activation during language pro-duction was found to be correlated with the degree of pyramidal tract involvement and, in particular, its facial part, in subjects with periventricular lesions, suggesting that an impairment of motor output from the left hemisphere can infl uence the pat-tern of language organisation [32] . Larger studies including the

assessment of sensori-motor reorganisation and a more sensi-tive measure of hand motor function are necessary to explore the plausibility of this hypothesis. Our results support the hypothesis of a substantial equipotenti-ality of the two hemispheres as to language function at term age. Mechanisms of (re-)organisation seem to diff er to some extent from those present after lesions occurring only few weeks earlier (e.g., in case of preterm lesions or cortical dysplasias), when the likelihood of having a full shift of language function is apparently lower [21, 32] . When this happens however, activated areas of the RH are mostly homotopic to the language zones in the LH of healthy controls, in subjects with brain malformations [25] , with periventricular damage [32] and in those with cortico-subcorti-cal damage at term ( [35] and the present study). Nevertheless, as in children with periventricular damage [32] , we observed larger activations in patients than controls, suggesting some degree of variability in RH language topography. This is more evident at a single-subject level, where the activation of slightly diff erent aspects within the inferior frontal gyrus was found. In conclusion, the results from the present study confi rm that right language lateralisation is common in patients with perina-tal arterial stroke. Lesion proximity to anterior language regions seems to be associated to atypical RH lateralisation, but other factors play a role, as it can be also found in subjects with lesions remote from Broca ’ a area and no persistent epileptic activity. These fi ndings may be important for the correct interpretation of neuropsychological profi les in patients with perinatal stroke, since atypical lateralisation of language is known to be associ-ated to visuo-spatial defi cits as a possible eff ect of functional ‘ crowding ’ of the RH [20] . Further knowledge on the mecha-nisms underlying early (re-)organization of language networks and their relation to other high cortical functions, will be obtained from studies based on a strict case selection, control-ling for timing of the insult, epileptic activity, nature and loca-tion of the insult, and employing longitudinal approaches based on both neuroimaging and electrophysiological techniques.

Acknowledgements & This work was supported by grants FIRB 2001 from the Italian Ministry of University and Scientifi c Research and RC 1 / 2007 of

Table 2 Comparison of all major activation sites (fi xed-eff ect analysis; uncorrected p < 0.000; cluster size > 200 voxels), including T-values, stereotactic coordinates (in Talairach space) for all local maxima.

Controls Patients

Brain Region cluster size in voxels T max Talairach (x,y,z) cluster size in voxels Tmax Talairach (x,y,z)

lateral frontal lobe 8829 6.75 ( − 44, 4, 38) 10017 8.41 (48, 2, 36) 5.13 ( − 43, 19, 4) 7.6 (48, 15, 2) 7.54 (45, 31, 26) 6.75 ( − 45, − 2, 44) 7.44 (44, − 4, 46) 7.44 (44, 29, 30) 6.07 ( − 53, 13, 6) 6.98 (49, 13, 6) 6.31 (57, 1, 18) 5.72 ( − 43, 25, 11) 5.87 (43, 22, 12) 6.15 ( − 46, 11, 23) 5.65 (46, 10, 20) mesial frontal lobe 2406 7.71 (0, 7, 47) 5921 9.83 (4, 4, 46) 5.84 ( − 3, 15, 41) 7.53 (5, 19, 42) 7.06 (0, − 2, 56) 7.47 (3, − 5, 56) temporal lobe 600 5.76 ( − 49, − 39, 5) 956 6.75 (55, − 37, 4) Data are sorted by cluster size and T values in the patients



the Italian Ministry of Health. The authors gratefully acknowl-edge the participation of P. Brovedani, G. Ferretti and L. Pfanner to clinical testing of the patients.

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