Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
FULL-LENGTH ORIGINAL RESEARCH
Language lateralization correlates with verbal memory performance in children with focal epilepsy *yRegula Everts, zxA. Simon Harvey, yLeasha Lillywhite, {Jacquie Wrennall, y**David F. Abbott, *{Linda Gonzalez, yyMichael Kean, y**zzGraeme D. Jackson, and *{xxVicki Anderson *Critical Care and Neuroscience, Murdoch Children’s Research Institute, Melbourne, Australia; yBrain Research Institute, Florey Neuroscience Institutes (Austin), Melbourne, Australia; zDepartment of Neurology, The Royal Children’s Hospital, Melbourne, Australia; xDepartment of Paediatrics, The University of Melbourne, Melbourne, Australia; {Department of Psychology, The Royal Children’s Hospital, Melbourne, Australia; **Department of Medicine, The University of Melbourne, Melbourne, Australia; yyMedical Imaging, The Royal Children’s Hospital, Melbourne, Australia; zzDepartment of Radiology, The University of Melbourne, Melbourne, Australia; and xxDepartment of Psychology, The University of Melbourne, Melbourne, Australia
SUMMARY Purpose: Assessment of language dominance with functional magnetic resonance imaging (fMRI) and neuropsychological evaluation is often used prior to epilepsy surgery. This study explores whether language lateralization and cognitive performance are systematically related in young patients with focal epilepsy. Methods: Language fMRI and neuropsychological data (language, visuospatial functions, and memory) of 40 patients (7–18 years of age) with unilateral, refractory focal epilepsy in temporal and/or frontal areas of the left (n = 23) or right hemisphere (n = 17) were analyzed. fMRI data of 18 healthy controls (7–18 years) served as a normative sample. A laterality index was computed to determine the lateralization of activation in three regions of interest (frontal, parietal, and temporal). Results: Atypical language lateralization was demonstrated in 12 (30%) of 40 patients. A correlation between language lateralization and verbal memory performance
Language lateralization using functional magnetic resonance imaging (fMRI) and neuropsychological assessment is regularly performed in children and adults prior to epilepsy surgery. Language fMRI is used to identify the language-dominant hemisphere and to help interpret cognitive findings with knowledge of the side of lesion and seizures. The interpretation of presurgical fMRI findings and cognitive data is important to minimize the risk of functional loss after surgery. However, the relationship between language Accepted September 30, 2009; Early View publication November 16, 2009. Address correspondence to Regula Everts, PhD, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, 3052 VIC, Australia. E-mail:
[email protected] Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy
occurred in patients with left-sided epilepsy over all three regions of interest, with bilateral or right-sided language lateralization being correlated with better verbal memory performance (Word Pairs Recall: frontal r = )0.4, p = 0.016; parietal r = )0.4, p = 0.043; temporal r = )0.4, p = 0.041). Verbal memory performance made the largest contribution to language lateralization, whereas handedness and side of seizures did not contribute to the variance in language lateralization. Discussion: This finding reflects the association between neocortical language and hippocampal memory regions in patients with left-sided epilepsy. Atypical language lateralization is advantageous for verbal memory performance, presumably a result of transfer of verbal memory function. In children with focal epilepsy, verbal memory performance provides a better idea of language lateralization than handedness and side of epilepsy and lesion. KEY WORDS: Language lateralization, fMRI, Verbal memory performance, Children with epilepsy.
lateralization and cognitive performance (i.e., language, visuospatial functions, and memory) is still unclear, particularly in the developing brain. A link between language lateralization and cognitive performance has been demonstrated previously, in pediatric and adult studies of normal subjects and patients with epilepsy. Atypical (bilateral or right-sided) language lateralization appears to be related to weaker language performance in healthy children (Everts et al., 2009) and worse visuospatial memory performance in children (Gleissner et al., 2003) and adults (Loring et al., 1999) with lefthemisphere epilepsy. Furthermore, a relationship between language lateralization and medial temporal lobe verbal memory performance is reported in adults with temporal epilepsy (Kim et al., 2003; Helmstaedter et al., 2004). These latter studies demonstrated by means of the
627
628 R. Everts et al. intracarotid amobarbital procedure (IAP) that patients with left lateral epilepsy focus with atypical language dominance (bilateral or right) had significantly better verbal memory than patients with typical (left) language dominance. Further evidence for an association between language lateralization and verbal memory comes from a diffusion tensor imaging (DTI) study (Catani et al., 2007) in which healthy adults with symmetrical perisylvian language pathways (connection between Broca’s and Wernicke’s territories) performed better on a verbal memory task than individuals with strong asymmetrical left-hemisphere language pathways. Hence, there seems to be a complex interaction among language lateralization, the functionality of the medial temporal lobe (memory), and neocortical functions (language, visuospatial performance), which has not yet been investigated in children and adolescents. Given that young patients with epilepsy are more likely to present atypical language patterns compared to healthy individuals (Saltzman et al., 2002), an examination of this group provides an opportunity to enhance our understanding of the relationship between language lateralization and cognitive performance, and, in particular, verbal memory. We studied children and adolescents with unilateral, refractory focal epilepsy arising from the left or right frontal and/or temporal lobes. Based on previous studies, mostly in adults, we hypothesised that children with atypical language will have better verbal memory than children with typical language lateralization. The existence of a systematic link between language lateralization and cognitive performance would contribute to a better understanding and strengthened interpretation of the presurgical language fMRI and neuropsychological assessment.
Participants and Methods Patients Patients with refractory, symptomatic, focal epilepsy aged 7–18 years who underwent language fMRI for presurgical examination at the Brain Research Institute (April 2001 to February 2006) or Royal Children’s Hospital (July 2006 to July 2008) in Melbourne, Australia, were eligible for recruitment. Inclusion criteria were (1) well-characterized focal epilepsy with seizure focus in the temporal or frontal lobe, with or without involvement of other ipsilateral regions; and (2) available neuropsychological data assessed within 1 year from fMRI. Exclusion criteria were patients with partial seizures arising solely in brain areas remote from the temporal or frontal lobe, patients with generalized epilepsy, and patients with tuberous sclerosis. Children with intellectual disability were automatically excluded due to inability to perform functional MRI and complete a neuropsychological assessment. From 65 patients who underwent language fMRI during the study period, 40 patients (18 female, 22 male) between Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
7.2 and 17.9 years [mean age 12.3 years, standard deviation (SD) 3.1] fulfilled the inclusion criteria and were included in the study (for patients’ details see Table 1). Twenty-nine patients were right-handed; 11 patients were left-handed. Epilepsy onset varied between 5 months and 13.0 years of age (mean 7.0 years, SD 3.2). Mean general intelligence (Full Scale IQ, WISC-III and WISC-IV) was 92.1 (range 63–128, SD 15.3).The lateralization and localization of the seizure focus, and the underlying pathology varied among patients (Table 1). Twenty-three patients had a left-hemisphere seizure focus, 17 patients had a right-hemisphere onset, based on ictal EEG recordings. The majority of the patients had temporal lobe seizures (n = 26), most often occurring in the left temporal (n = 13) or the right temporal (n = 13) region. The remaining patients had frontal seizures (n = 9) or seizures within multiple areas (n = 5). Nine patients had no apparent lesion on MRI, 10 patients had focal cortical dysplasia, 9 patients had a tumor, and 12 patients had other lesions (Table 1). Thirty-one patients underwent epilepsy surgery. Controls fMRI data of healthy children and adolescents (aged 7–18 years) assessed at the Brain Research Institute (October 2004 to September 2006) were included. Participants met the following inclusion criteria: right-handed, native English-speaking, normal hearing, normal or corrected-to-normal vision, free of neurologic diseases or psychiatric disorders, not taking medication affecting the central nervous system, and no history of cognitive deficits (intelligence, reading, or language). A total of 18 controls (14 male, 4 female) between 7.5 and 17.5 years (mean age 11.2 years, SD 2.9) were recruited. Experiments were undertaken with the understanding and written assent of each control participant and patient and with the written consent of their parent from the Brain Research Institute, Melbourne, according to the Code of Ethics of the World Medical Association (Declaration of Helsinki) and were approved by the Austin Health Human Research Ethics Committee, Melbourne. The review of the patients’ data from the Royal Children’s Hospital was conducted in accordance with the national guidelines pertaining to audit and quality assurance studies (NHMRC 2003) and was approved by the Chair of the Human Research Ethics Committee, Royal Children’s Hospital Melbourne. fMRI paradigm Participants performed a verbal fluency task in the scanner (orthographic-lexical retrieval task, OLR). They were asked to think of as many different words beginning with a letter presented on the screen (i.e., ‘‘a’’; possible answers include apple, ant, alike). Participants were told to think of possible answers in their head and not say the words aloud, not to repeat words, and not to use proper nouns. The
F
F F F
M M
F M M M
F F M M M F F M
F M
M
F M M
M M F F M F
1
2 3 4
5 6
7 8 9 10
11 12 13 14 15 16 17 18
19 20
21
22 23 24
25 26 27 28 29 30
r 1 1 r 1 r
r r r
r
r r
1 r 1 r r r r r
r 1 r r
r 1
r 1 r
r
12.9 9.2 15.6 9.5 7.9 13.3
12.9 8.6 16.2
11.4
13.2 13.9
15.7 17.7 12.9 17.4 16.3 14.1 10.1 12.2
13.2 9.1 9.6 9.8
17.1 13.5
14.4 8.0 9.7
14.2
5 3 8 5 5 11
7 7 11
2
6 13
1 8 7 10 4 5 7 11
13 8 9 8
9 8
11 4 1
10
7.9 6.2 7.6 4.5 2.9 2.3
5.9 1.6 5.2
9.4
7.2 0.9
14.7 9.7 5.9 7.4 12.3 9.1 3.1 1.2
0.2 1.1 0.6 1.8
8.1 5.5
3.4 4.0 8.7
4.2
R R R L R R
L L R
R
L L
R R L R R R L L
L L R L
L L
R L R
R
R temp—sclerosis, atrophy (atrophy) Temp Normal (G) Front L front—dysplasia (FCD) Temp R temp—HS, dysplasia (HS, FCD) Temp L temp—tumor (GNT) TPO L TPO—atrophy, sclerosis (G) Temp L temp—tumor (DNET) Front Normal Temp R temp—tumor (PXA) Front L front & temp— atrophy, signal change (G) Front R front—dysplasia (FCD) Temp R temp—dysplasia (FCD) Temp Normal Front Normal (no abnormality) Front, Cent R front & cent—PMG (G) Temp R temp—dysplasia (FCD) Front L front—dysplasia Front L front—cavernoma (cavernoma) Temp L temp—tumor (DNET) Temp L temp—cavernoma (cavernoma) TPO, Cent R TPO & cent—dysplasia (FCD) Temp Normal Front Normal (no abnormality) Temp R temp—tumor (ganglioma) Temp R temp—dysplasia (FCD) Temp Normal Temp R temp—dysplasia (FCD) Temp L temp—tumor Temp R temp—tumor (PXA) Temp Normal (chronic encephalitis)
Temp
MRI finding (pathology of resected tissuea)
Age onset Duration (years) (years) Side
ID Gender Handed Age
Location
Lesion data
Seizure data
Patients
0.84 )0.73 )0.71 0.65 0.85 0.76
0.76 )0.71 )0.31
0.19
0.19 0.87
0.29
)0.38
0.25 )0.64 )0.05 0.70 0.39 0.70
0.11 )0.20 )0.05 0.66 0.74 0.36
0.55 )0.87 0.53
)0.22 0.72
)0.27 0.34
0.68 0.38 0.44
0.34 0.05 0.62 0.70 )0.42 )0.85 0.32 0.67
)0.34 )0.31 0.50 0.64
0.21 )0.01
0.67 0.54 0.69
0.63
0.21 0.12 0.65 0.61 )0.59 0.75 0.65 0.82
)0.57 0.71 0.73 0.66
)0.12 0.79 0.80 0.69 0.92 0.09 0.78 0.75 0.03 )0.27 0.74 0.78
0.56 0.63
0.78 0.83 0.47
0.81
0.46 )0.05
0.80 0.87 0.50
0.90
Typical Atypical Atypical Typical Typical Typical
Typical Atypical Typical
Atypical
Atypical Typical
Typical Atypical Typical Typical Atypical Atypical Typical Typical
Atypical Typical Typical Typical
Typical Atypical
Typical Typical Typical
Typical
0.3 1.1 3.0 0.6 2.3 0.4 0.7 0.6 )0.3 )0.1 1.0 )1.4 0.3 1.0 0.9 )0.3 )0.3 0.6
)1.7 )0.3 0.3 )1.0
0.8 1.1 0.2 1.4
)0.9
)0.2 0.4
Continued
0.7 1.3 )3.0
0.0 1.3 )3.0 )0.5 0.5
)1.7 0.9 )1.2 0.0 )2.0 )1.6 0.7 )0.7 0.0 0.0 )0.7 0.0 0.8 0.3 0.3 0.7 )0.3 )0.7 1.0 )0.3 )0.3 0.9
)2.7 0.9 )1.1
1.0 )0.6
)1.0 )1.1 )1.8 0.3
)1.1 )2.1 )1.8 )1.7 0.6 )0.7
)0.7 0.6 )2.0
0.0 0.5 0.4 )3.0
)1.3
)1.2 0.3
)1.7 1.2 )2.2
)0.7 )1.0 1.0 )2.8
)1.2
)2.7 0.0
)2.0
0.1 )0.3 )1.2
)1.3
)1.7 )0.3
0.5 0.8 )0.7 0.6 0.8 )0.8 )0.4 0.4
0.1 )0.1 0.0 )0.7
)2.3
1.4 )0.9
)1.7
)0.7 )1.3 )1.7 0.4 0.7 0.3 0.7 )3.0 )3.1
)1.7
)1.3 0.7 )2.0 )1.2 )0.3 )2.3 )0.7 0.7
)1.0 3.0 )0.3 )0.3 )2.3 )0.7 0.0 1.0
)1.0 )0.7 1.3 )0.7 )0.7 1.0 1.0 0.7 2.0 1.0 0.0 )0.3
0.0 0.7 )1.7 )2.3 )1.3 )3.0
1.0 0.9
)3.0
Rey Rey Word Pairs Word Pairs Copy Recall Learn Recall
)1.0 )0.8
1.0 )1.7 )1.3 0.7 0.3 )0.3 0.3 )1.0
)1.3
BD
Cognitive Performance
LI LI LI Language frontal parietal temporal lateralizationb Sim FAS
Language lateralization (LI)
Table 1. Patients’ data
629
Language Lateralization and Verbal Memory
Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
Seizure data
F
M
F
M
M
M
35
36
37
38
39
40
r
1
r
r
1
r
r r r 1
7.9
13.0
10.0
14.8
17.9
10.0
10.5 7.9 7.2 14.1
0.5
9
8
7
8
7
5 7 3 10
7.4
4.0
2.0
7.8
9.9
3.0
5.5 0.9 4.2 4.1
R
L
L
L
L
L
L L L L
Temp
Temp
Temp
Temp
Temp
Temp
Front Front Temp Front, Temp
Location
0.39
0.51
0.88
0.61
0.51
0.47
0.81 0.01 0.67 )0.72
0.63
0.16
Typical
Typical
Typical
Atypical
)0.38 0.89
Typical
Typical
)0.31 0.54
Typical typical Typical Atypical
)0.26 0.63 0.57 0.48
1.7 )0.3 )3.0
0.3
0.3
0.0
)1.0 )1.0
1.3
0.7
1.0
1.0
0.7
0.9
)1.7 )1.0 )0.3 )0.8
)1.0
)1.7 )0.3
)1.7 )0.7 )0.3 )0.3 0.0 )1.0 )0.2 )2.0 )0.7 )0.3 )1.6 )1.3 )1.7 0.0 )0.2
)1.5
)1.0
)0.5
)1.0
)0.2
)1.5
0.1
)0.3 0.0 )1.3 )1.1
)3.0
)2.6
2.1
0.3
)1.7
)1.3
)0.8
)1.2
)1.8
)0.9
0.7 0.7 )1.0 )1.3
Rey Rey Word Pairs Word Pairs Copy Recall Learn Recall
Cognitive Performance
LI LI LI Language frontal parietal temporal lateralizationb Sim FAS BD
Language lateralization (LI)
L front—dysplasia (FCD) 0.29 Normal 0.25 L temp—tumor (DNET) 0.79 L front & temp—atrophy, )0.17 HS, probable RE L temp—atrophy, 0.83 sclerosis, hemosiderin (G) L temp—tumor, 0.45 dysplasia (GNT) L temp—atrophy, 0.12 gliosis (chronic encephalitis) L temp—atrophy, 0.91 signal change, probable RE L temp—atrophy, 0.69 sclerosis, hemosiderin (G) R temp—dysplasia (FCD) 0.66
MRI finding (pathology or resected tissuea)
Lesion data
FCD, focal cortical dysplasia; GNT, glioneuronal tumor; HS, hippocampal sclerosis; DNET, dysembryoplastic neuroepithelial tumor; PXA, pleomorphic xanthoastrocytoma; G, gliosis; RE, Rasmussen encephalitis; TPO, temporo-parietal-occipital; PMG, polymicrogyria; Sim, Similarities; FAS, verbal fluency task; BD, Block Design; LI, language lateralization. a All patients with pathology information underwent surgery. b Atypical language is assumed if laterality index (LI) < 0.2 in two or more regions of interest (ROIs).
F M F M
31 32 33 34
Age onset Duration ID Gender Handed Age (years) (years) Side
Patients
Table 1. Continued
630 R. Everts et al.
631 Language Lateralization and Verbal Memory task was presented in a block design, with three (Royal Children’s Hospital) or four (Brain Research Institute) activation conditions (each 36 s) alternating with four (Royal Children’s Hospital) or five (Brain Research Institute) rest conditions (each 36 s). In each of the tasks conditions, two letters were projected (each for 18 s). During the practice trial outside the scanner, participants were asked to say the words aloud, enabling the examiner to correct errors and ensure that the participant could perform the task. All participants were able to perform the task before entering the scanner. This OLR task relates to the Controlled Oral Word Association Test (COWAT, Spreen & Strauss, 1998) used in clinical neuropsychological practice to assess verbal fluency. Previous studies present fMRI results of the OLR task performed in healthy participants (i.e., Cuenod et al., 1995; Jackson et al., 1997; van der Kallen et al., 1998; Wood et al., 2004) and young patients with cerebral lesions (Briellmann et al., 2002; Anderson et al., 2006). Studies of healthy participants report activation in the middle frontal gyrus and/or inferior frontal gyrus predominantly, with activation less often observed in the anterior cingulate region, inferior parietal lobe, supplementary motor area, premotor cortex, anterior insula, and a variety of regions in the left temporal lobe (Cuenod et al., 1995; van der Kallen et al., 1998; Wood et al., 2004). Characteristically, activation in response to OLR is left-hemisphere biased, with predominant involvement of left frontal brain areas. Neuropsychological protocol An individualized neuropsychological examination was performed with all patients as part of routine clinical evaluation. Considering our study hypotheses and the availability of test scores (retrospective study design), performance on tasks tapping language, visuospatial performance, and verbal as well as visuospatial memory was included (Table 2). Verbal memory was assessed using the ‘‘Word Pairs Learning’’ and ‘‘Word Pairs Recall’’ of the Wechsler Memory Scale (WMS) and Children’s Memory Scale (CMS). For the WMS, only the learning and recall scores of Word Pairs without semantic relationship (‘‘hard pairs’’) are included, since the associative learning required when encoding ‘‘hard pairs’’ is known to tap hippocampal functioning (Gonzalez et al., 2007). The CMS included only semantically unrelated word pairs (‘‘hard pairs,’’ unpublished norms from Gonzalez et al. 2003); therefore, all word pairs were included. Raw scores of cognitive tests were transformed to standard scores using age norms from the test. In order to make results comparable, z-scores were constructed from the respective transformed test score according to the formula ½z ¼ X l=r. Data acquisition At the Brain Research Institute, MRI experiments were performed on a 3T GE Signa LX scanner (GE Medical Systems, Milwaukee, WI, U.S.A) using a standard birdcage
quadrature head coil. Data were acquired in an axial plane tilted 30 degrees toward coronal to minimize susceptibility artifact. At the Royal Children’s Hospital, a 3T whole body scanner (Siemens, Erlangen, Germany) was used equipped with the Syngo MR 2002B (VA21B) software release. Whole-brain gradient-recalled, functional echo planar images were acquired for both centers (Brain Research Institute: TR = 3,600 ms, TA = 5 min 24 s/90scans, TE = 40 ms, 22 axial slices, 2 · 2 · 4 mm3 voxel size, 4 mm thick slices with 1 mm gap; Royal Children’s Hospital: TR = 3,000 ms, TA = 3 min 58 s/198 scans, TE = 60 ms, TE = 60 ms, 45 axial slices, 1.6 · 1.6 · 3 mm3 voxel size). To aid interpretation of activation maps, a set of T1-weighted and MR angiographic images were collected in the same plane as the fMRI data. Data analysis fMRI data were analyzed using SPM2 (Wellcome Department of Imaging Neuroscience, University College London, United Kingdom) with the assistance of iBrain (Brain Research Institute, Melbourne, Australia) (Abbott & Jackson, 2001). During preprocessing, images of each participant were slice-time corrected and spatially realigned to eliminate movement artifacts. To allow for the calculation of a laterality index, data were spatially normalized to the SPM2 EPI template. Visual inspection of the spatially normalized data enabled the verification of successful normalization and signal homogeneity in the left and right hemispheres. An automated motion rejection scheme was used to remove the effect of volumes with excessive movement relative to the previous volume by including delta function regressors centered on the volumes to be rejected; specifically, if the relative motion of a volume exceeded 1 mm, then that volume and the following three were rejected (Lemieux et al., 2007). If >25% rejected volumes occurred, scans were excluded from analysis; however, no scan was excluded due to movement in this study. After smoothing with a Gaussian filter of full width at half maximum (FWHM) =8 mm, the functional data were subjected to voxel-based statistics according to the general linear model (Friston et al., 1995) to assess activation contrasts for the different tasks. First-level single-subject statistics were assessed by contrasting the activation condition with the contrast condition, treating the contrast condition as a condition of no interest. For modeling, basic box-car functions were convolved with the hemodynamic response function. To reduce the effects of low frequency scanner or physiologic noise and intersubject activation variability, the functional data were subjected to a highpass filter (cutoff period of 128 s). For the description of differences between activation and control conditions in single-subject data, a height threshold of p < 0.001, uncorrected for multiple comparisons, and an extent threshold k > 50 voxels were chosen. Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
Word Pairs Learning
Verbal Memory
Copying a complex geometric figure from a template Recalling the complex geometric figure without template after 5 min Learning a list of semantically unrelated word pairs (e.g., school – grocery) Recalling a list of semantically unrelated word pairs from memory
Explaining how two different things (e.g., horse, cow) or concepts (e.g., hope, fear) could be alike Naming as many words as possible that begin with the given letters (F, A, and S) Copying small geometric designs with plastic cubes
Task
SE, standard error of the mean; n, number of patients. a Wechsler Intelligence Scale for Children. b Wechsler Adult Intelligence Scale. c Rey Complex Figure. d Wechsler Memory Scale. e Children’s Memory Scale. f Analyses of all patients: v2-test, group comparison: Mann-Whitney U test.
Word Pairs Recall
Rey Recall
Rey Copy
Block Design
FAS (verbal fluency task)
Similarities
Subtest
Visuospatial Memory
Visuospatial Construction
Language
Function
33
31
33
CFRc
CFRc
WMSd (semantically unrelated pairs) CMSe 33
40
WISC-III, IVa WAISb
38
n
28
b
FAS
WISC-III, IV WAIS
a
Test
SE 0.18
0.16
0.19
0.22
0.22
0.20
0.20
mean )0.35
)0.58 )0.05 )0.01 )0.47 )0.89 )0.67
14 (44%) p = 0.000
16 (48%) p = 0.000
8 (26%) p = 0.130
7 (21%) p = 0.400
7 (18%) p = 0.776
6 (21%) p = 0.420
10 (26%) p = 0.078
All patients
Table 2. Neuropsychological tests and performance of patients Left- versus right-handers
Left = 4, Right = 2 p = 0.885 Left = 3, Right = 4 p = 0.432 Left = 4, Right = 3 p = 0.619 Left = 5, Right = 3 p = 0.746 Left = 11, Right = 5 p = 0.125 Left = 10, Right = 4 p = 0.349
Left = 7, Right = 3 p = 0.201
Left = 3, Right = 3 p = 0.224 Left = 1, Right = 6 p = 0.307 Left = 2, Right = 5 p = 0.753 Left = 2, Right = 6 p = 0.928 Left = 5, Right = 11 p = 0.762 Left = 4, Right = 10 p = 0.746
Left = 2, Right = 8 p = 0.309
n below normal rangef (p-value)
Left versus right epilepsy
Male = 3, Female = 3 p = 0.676 Male = 4, Female = 3 p = 0.967 Male = 4, Female = 3 p = 0.220 Male = 5, Female = 3 p = 0.429 Male = 7, Female = 9 p = 0.652 Male = 7, Female = 7 p = 0.926
Male = 4, Female = 6 p = 0.323
Male versus female
632 R. Everts et al.
633 Language Lateralization and Verbal Memory Laterality index A laterality index (LI) was computed for each participant to describe the laterality of activation over three different brain regions using the SPM2 LI-toolbox (Wilke & Lidzba, 2007). Regions of interest (ROI) were chosen based on findings from previous research using the OLR task (Cuenod et al., 1995; van der Kallen et al., 1998; Wood et al., 2004). A frontal region (superior, middle, and inferior frontal gyrus), a parietal region (superior and inferior parietal gyrus, angular gyrus, and supramarginal gyrus), and a temporal region (superior, middle, and inferior temporal gyrus) were included, disregarding 5 mm left and right of the interhemispheric fissure. To calculate the laterality index, a bootstrapping approach was employed as suggested recently (Wilke & Schmithorst, 2006). This approach avoids the issue of using a fixed threshold, which has been recognized as one of the main drawbacks when assessing laterality (Wilke & Lidzba, 2007), by applying the concept of threshold-dependent laterality curves (Deblaere et al., 2004). An LI based on the weighted mean value as computed for each of the three ROIs during the iterative thresholding steps was used in this study. The LI was calculated based on the formula [LI = (left ) right)/(left + right)], resulting in positive values for predominantly left-hemisphere lateralization (+1) and negative values for right-hemisphere lateralization ()1). Typical left-hemisphere dominance was assumed at LI > 0.2, whereas atypical language lateralization (bilateral and right-hemisphere) was assumed at LI < 0.2. Language lateralization was regarded as left dominant if two of the three ROIs showed left-sided lateralization, right-sided dominance was assumed if two of the three ROIs were right lateralized, and bilateral language dominance was defined if two of the three ROIs were bilateral or if right, left, and bilateral dominance occurred over the three ROIs. Because we chose a quantitative approach to lateralize language activation, no additional standardized visual inspection of language lateralization was performed. Statistical analysis of behavioral data Statistical analyses were conducted using SPSS (version 14.0). Because LIs were not normally distributed, nonparametric testing was conducted whenever analyses included laterality indices. The relationship between continuous LIs and variables with two categories (handedness, gender, and side of seizures) was analyzed using the nonparametric Mann-Whitney U test. The association between continuous LIs and variables with three categories (location of seizures) was analyzed using the nonparametric Kruskal-Wallis test. The strength of the relationship between continuous LIs and continuous variables (neuropsychological test scores, age at scan, age at epilepsy onset, and duration of epilepsy) was investigated using Pearson product-moment correlation coefficient. The comparison of neuropsychological scores between
patients with typical and atypical language lateralization was performed using the independent Student’s t-test. To detect the predictive value of a set of variables (handedness, lateralization of epilepsy, and neuropsychological performance) on language lateralization, a standard multiple regression analysis was performed, where all independent variables were entered into the equation simultaneously. Chi-square-test was applied to compare the number of patients with below-average neuropsychological scores (z < )1) with the number of individuals expected to deviate from the normal range in a healthy population (15.86%).
Results Language lateralization Atypical (bilateral or right) language dominance in at least two of the three ROIs occurred in 12 (30%) of 40 patients, being bilateral in 6 and right lateralized in 6 patients. All controls demonstrated typical left-sided language in at least two of the three ROIs. Language lateralization differed significantly between patients and controls (parietal z = )2.4, p = 0.017; temporal z = )2.7, p = 0.007), with patients showing weaker lateralization in the parietal and temporal region than controls. Language lateralization in the frontal area did not differ between patients and controls (frontal z = )0.7, p = 0.454). There was no difference in language lateralization between patients with left-sided epilepsy and patients with right-sided epilepsy. Furthermore, language lateralization in patients did not differ between left- and right-handers and patients showed no difference in language lateralization when considering the gender. In controls, female subjects (n = 4) showed significantly weaker frontal language lateralization than did male subjects, whereas there was no lateralization difference in parietal and temporal regions. Language lateralization did not differ among patients with seizure location within frontal, temporal, or multiple brain areas. There was no correlation between age at scan and language lateralization in patients or controls. The age at epilepsy onset and the duration of epilepsy did not relate to language lateralization. All statistical data of variables expected to influence language lateralization are presented in Table 3. Neuropsychological data Mean scores of neuropsychological tests in patients were within the average range. Despite this, significantly more patients showed below-average verbal memory performance than expected in a healthy population (Word Pairs Learning p = 0.000; Word Pairs Recall p = 0.000, Table 2). There was no difference in neuropsychological performance between patients with left-sided epilepsy and patients with right-sided epilepsy, no significant gender difference occurred, and neuropsychological performance did not Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
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differ significantly between left- and right-handers (statistics are presented in Table 2). Patients with seizures in multiple brain areas showed worse language performance (Similarities v2 = 7.7, p = 0.021) when compared to patients with frontal or temporal seizures. The age at assessment correlated with language performance (FAS, verbal fluency task r = )0.5, p = 0.007) and visuospatial memory (Rey Recall r = )0.4, p = 0.039), with older age at assessment relating to worse performance. This correlation could reflect a longer duration of epilepsy or younger age at epilepsy onset. However, neither of these two variables (duration of epilepsy, age at epilepsy onset) correlated with any of the neuropsychological measures assessed.
r = )0.3, p = 0.070/r = )0.4, p = 0.028
c
b
Mann-Whitney U test. Chi-square test. Pearson correlation analysis.
Correlation between neuropsychological data and lateralization index Whole group analysis of patients showed that there was a strong correlation between verbal memory performance and language lateralization in patients with left-sided epilepsy (Table 4, Fig. 1). Atypical language lateralization related to better verbal memory performance. Even after controlling for the age at epilepsy onset, the duration of epilepsy and the age at assessment, a significant correlation between language lateralization and verbal memory performance (verbal learning and verbal recall) remained in patients with left-sided epilepsy, indicating that these other variables are not significant contributors to the relationship between language lateralization and verbal memory (Table 3). When patients were separated by side of epilepsy, the correlation between language lateralization and verbal memory performance was present in patients with left-sided, but not in patients with right-sided epilepsy (Table 4). When patients were separated by language dominance (typical vs. atypical language lateralization), patients with typical language lateralization (n = 21) had lower verbal memory scores when compared to patients with atypical language lateralization (Word Pairs Learning z = 2.0, p = 0.050; Word Pairs Recall z = 1.9, p = 0.084, Fig. 2).
a
r = )0.4, p = 0.035/r = )0.4, p = 0.033 r = )0.4, p = 0.019/r = )0.4, p = 0.012
r = )0.3, p = 0.050/r = )0.4, p = 0.027 r = )0.4, p = 0.022/r = )0.4, p = 0.036 r = )0.4, p = 0.013/r = )0.4, p = 0.014
Temporal Parietal
z = )1.3, p = 0.194 z = )0.9, p = 0.340 z = )1.3, p = 0.183 z = )0.1, p = 0.915 v2 = 3.9, p = 0.139 r = )0.2, p = 0.339 r = 0.2, p = 0.373 r = 0.1, p = 0.435 r = )0.3, p = 0.106 r = )0.03, p = 0.030/r = )0.3, p = 0.046
Frontal
z = )0.2, p = 0.848 z = )0.1, p = 0.952 z = )0.3, p = 0.714 z = )2.1, p = 0.038 v2 = 3.7, p = 0.154 r = )0.2, p = 0.250 r = )0.4, p = 0.072 r = 0.01, p = 0.929 r = )0.2, p = 0.259 r = )0.4, p = 0.017/r = )0.4, p = 0.018
Lateralization of epilepsy (left vs. right)a Handednessa Gender (patients)a Gender (controls)a Seizure location (frontal, temporal, multiple)b Age at scan (patients)c Age at scan (controls)c Age at epilepsy onsetc Duration of epilepsyc Verbal Learning/Recall performancec (controlling for age at onset) Verbal Learning/Recall performancec (controlling for duration of epilepsy) Verbal Learning/Recall performancec (controlling for age at assessment)
Table 3. Statistical data of variables, expected to influence language lateralization
z = )0.3, p = 0.743 z = )0.4, p = 0.649 z = )1.1, p = 0.248 z = )0.2, p = 0.832 v2 = 0.6, p = 0.729 r = )0.1, p = 0.536 r = 0.2, p = 0.514 r = 0.1, p = 0.547 r = )0.2, p = 0.258 r = )0.3, p = 0.054/r = )0.3, p = 0.033
R. Everts et al.
Predictors of language lateralization To detect the amount of variance in language lateralization explained by different independent variables, a standard multiple regression analysis was performed. Based on theoretical knowledge and the findings from our data, handedness, side of seizures, and verbal memory performance (Word Pairs Learning) were entered into the equation. A chi-square test revealed no relationship between handedness and side of seizure (v2 = 0.234, p = 0.629); therefore, their influence on language lateralization is independent. Language lateralization of the frontal, parietal, and temporal lobe was entered as dependent variables. The regression model explained 21.5% of the variance in language lateralization in frontal brain areas [R2 = 0.2, analysis of variance (ANOVA) F = 3.2, p = 0.038]. Of the three variables, ver-
635 Language Lateralization and Verbal Memory Table 4. Correlation coefficients for predictors of language lateralization Pearson correlation coefficient (p-value) All patients (n = 40) Function Language
Subtest Similarities FAS
Visuo-spatial Perception
Block Design Rey Copy
Visuo-spatial Memory
Rey Recall
Verbal Memory
Word Pairs Learning Word Pairs Recall
Left-sided epilepsy (n = 23)
Right-sided epilepsy (n = 17)
Frontal
Parietal
Temporal
Frontal
Parietal
Temporal
Frontal
Parietal
Temporal
0.060 (0.719) 0.126 (0.522) 0.074 (0.649) 0.309 (0.080) 0.199 (0.283) )0.420 (0.015)a )0.417 (0.016)a
0.221 (0.182) 0.104 (0.599) 0.091 (0.578) 0.019 (0.918) )0.108 (0.565) )0.382 (0.028)a )0.355 (0.043)a
0.268 (0.104) 0.045 (0.820) )0.136 (0.404) 0.087 (0.630) )0.035 (0.850) )0.334 (0.057) )0.377 (0.031)a
0.197 (0.379) 0.281 (0.259) 0.179 (0.413) 0.319 (0.170) 0.356 (0.135) )0.498 (0.022)a )0.370 (0.099)
0.293 (0.186) 0.107 (0.672) 0.122 (0.580) 0.098 (0.681) 0.048 (0.849) )0.436 (0.048)a )0.298 (0.190)
0.386 (0.076) 0.024 (0.925) )0.019 (0.932) 0.012 (0.959) 0.086 (0.726) )0.608 (0.003)a )0.490 (0.024)a
)0.250 (0.926) )0.440 (0.904) )0.020 (0.938) 0.292 (0.334) )0.024 (0.942) )0.233 (0.467) )0.454 (0.139)
0.249 (0.352) 0.111 (0.760) 0.033 (0.900) )0.149 (0.627) )0.434 (0.159) )0.140 (0.504) )0.409 (0.187)
0.136 (0.616) 0.077 (0.832) )0.254 (0.326) 0.217 (0.476) )0.270 (0.396) 0.138 (0.668) )0.128 (0.691)
a
p < 0.05.
Figure 1. Relationship between language lateralization (frontal region) and verbal memory performance (z-score Word Pairs Learning and Word Pairs Recall). Epilepsia ILAE
bal memory performance made the largest unique contribution (beta = )0.4, p = 0.032), whereas handedness (beta = )0.2, p = 0.347) and side of seizures (beta = )0.1, p = 0.460) did not contribute significantly. For language lateralization in parietal areas the model explained 19.7% of variance, and for temporal areas 11.9% of variance. Verbal memory performance made the largest unique contribution to language lateralization, not only in the frontal, but also in the parietal (beta = )0.4, p = 0.044) and temporal (beta = )0.4, p = 0.062) areas.
Discussion The present study demonstrates a strong correlation between language lateralization and verbal memory perfor-
Figure 2. Neuropsychological test scores (mean, standard error) in patients with typical and atypical language lateralization. *Word Pairs Learning z = 2.6, p = 0.016; Word Pairs Recall z = 2.1, p = 0.041. Epilepsia ILAE
mance in a large sample of children and adolescents with unilateral focal epilepsy within the temporal and/or frontal lobes. Specifically, bilateral or right-sided language lateralization is advantageous for verbal memory performance in patients with left-sided epilepsy. Furthermore, our data show that verbal memory performance predicts language lateralization better than handedness or the side of seizures and lesions. Previous studies describe the interaction between language lateralization and memory performance in adult patients (Kim et al., 2003; Helmstaedter et al., 2004; Thivard et al., 2005), healthy adults (Catani et al., 2007) or children and adolescents with epilepsy (Gleissner et al., 2003). Helmstaedter et al. (2004) highlighted the possible Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
636 R. Everts et al. relationship between language lateralization and verbal memory performance in a large sample of adults with leftsided temporal lobe epilepsy. Interestingly, the 75 female patients included in the sample showed stronger verbal memory performance when they had atypical language lateralization, whereas male patients did not, suggesting that gender is a crucial influencing variable. Our data could not replicate this relationship, although they are based on a smaller sample size with limited statistical power. Thivard et al. (2005) assessed language dominance (productive and perceptive language task) and neuropsychological performance in adults with left or right temporal lobe epilepsy. Patients with atypical language lateralization (n = 7) scored above patients with typical language lateralization (n = 29) on all neuropsychological variables, including verbal memory. The authors suggest that atypical language lateralization toward the right hemisphere facilitates successful adaptive compensational processes in all cognitive domains. Our results confirm the benefit of atypical language lateralization on cognitive functioning, but only for verbal memory. The literature suggests that the age at epilepsy onset (Springer et al., 1999; Gaillard et al., 2007) or the age at probable brain injury (Springer et al., 1999) might determine the relationship between language lateralization and verbal memory performance, with younger age at epilepsy onset or brain injury relating to an increased proportion of atypical language. However, the present data show that even after controlling for the age at epilepsy onset, the duration of epilepsy and the age at assessment, a significant correlation between language lateralization and verbal memory performance remained, indicating that these variables are not significant contributors to the relationship between language lateralization and verbal memory. Variations of study results can occur due to variability in the definition of age at onset, with some studies using the first febrile convulsion or other acute symptomatic seizures and some using the age at later recurrent seizures. There are two observations that suggest a possible mechanism for good verbal memory functions in patients with atypical language. First, language lateralization follows verbal memory lateralization in adults with left temporal lobe epilepsy (Binder et al., 2008) and in healthy participants (Weber et al., 2007). Second, patients with atypical verbal memory lateralization before temporal lobe surgery have better verbal memory performance after surgery when compared to patients with typical verbal memory lateralization (Janszky et al., 2005; Richardson et al., 2006; Binder et al., 2008). Hence, the co-occurrence of atypical language and atypical verbal memory lateralization is a plausible explanation for the preservation of verbal memory functions in our patients with atypical language dominance. Language is commonly understood as a neocortical frontotemporal brain function, whereas verbal memory is Epilepsia, 51(4):627–638, 2010 doi: 10.1111/j.1528-1167.2009.02406.x
associated with medial temporal brain areas, in particular when assessed with an associative learning task as done in the present study (learning and recall of semantically unrelated word pairs; Gonzalez et al., 2007). Our findings demonstrate a correlation between language lateralization and medial temporal verbal memory functions, whereas more neocortical cognitive functions (such as language or visuospatial performance) were not related to language lateralization. Previous studies propose a close association between neocortical frontotemporal language areas and hippocampal verbal memory networks in healthy adults (Weber et al., 2007) and adults with epilepsy (Weber et al., 2006; Wagner et al., 2008). Wagner et al. (2008) used verbal memory fMRI and neuropsychological assessment before and after epilepsy surgery to examine correlations in signal fluctuations in the hippocampus and the superior temporal language area in both hemispheres. Patients who demonstrated a decrease in verbal memory postsurgically were found to have significantly higher intrahemispheric functional connectivity when examined presurgically. The authors suggest that a stronger hippocampal–neocortical link before surgery reflects higher functional network integrity relating to better verbal memory performance. These results support an association between neocortical language regions and hippocampal memory areas. Longer disease duration is suggested to correspond to more damage of cognition functions (Hermann et al., 2002) and a weaker hippocampal–neocortical connection (Wagner et al., 2008). Hence, in children with a comparatively short duration of disease, the interaction between hippocampal memory and neocortical language areas is possibly stronger than in adults with longer lasting disease. This might explain the tight correlation between language lateralization and verbal memory observed in our young epilepsy patients. Two other findings from the present study warrant comment. First, in contrast to studies that report reduced visuospatial function due to ‘‘crowding’’ in children and adults with atypical language lateralization (Loring et al., 1999; Kadis et al., 2009), we did not find an association between atypical language and reduced visuospatial performance in our pediatric patients, although visuospatial data were not available in seven patients. Two other pediatric epilepsy studies (Billingsley & Smith, 2000; Gleissner et al., 2003), did not find robust evidence for a ‘‘crowding effect’’ on visuospatial function in children, and some studies (Gonzalez et al., 2007) suggest that, other than face recognition, visuospatial functions are not lateralized until adulthood. Secondly, the present study revealed no significant difference between language lateralization in patients with left compared to right-sided epilepsy. This finding is surprising. Our sample is an unselected sample of focal epilepsy patients, including people with right-sided epilepsy whom other studies might not have included for fMRI. Due to the
637 Language Lateralization and Verbal Memory left-hemisphere speech dominance in left- and right-handers, the expectations for speech reorganization are greater following left-hemisphere injury (Knecht et al. 2000). Studies that have examined the relationship between language lateralization and language dominance have yielded mixed results. Several IAP studies support the relationship between left-hemisphere seizure activity and right-hemisphere language organization in children (Williams & Rausch, 1992; Westerveld et al., 1994) and adults (Rasmussen & Milner, 1977; Rausch & Walsh, 1984). On the other hand, Rey et al. (1988) found no relationship between patients with left- or right-hemisphere seizures after early brain lesions and language lateralization. DeVos et al. (1995) reported 10 cases of early low-grade left frontal or left temporal tumors that did not result in transfer of language dominance to the right hemisphere as measured by IAP. Similarly, Duchowny et al. (1996) presented results from subdural grid recordings in children, supporting the hypothesis that developmental pathologies may not result in a transfer of language dominance. Although it is well established that there is a high frequency of atypical language lateralization in children with epilepsy, this is not confined to patients with left-hemisphere seizures; reorganization of language in the right hemisphere seems to occur reliably only in children with early and extensive left-hemisphere destructive lesions (Duchowny et al., 1996; Anderson et al., 2006), such patients represented infrequently in pediatric epilepsy series. From a clinical perspective, an over-interpretation of our findings should be carefully avoided. Our findings come from group analysis, and extrapolation to individual patients in a clinical or surgical setting is problematic. In our patient sample, good verbal memory functions in children with leftsided epilepsy relate to atypical language lateralization. Still, there are occasional individual exceptions to this rule. Our data show that verbal memory performance can be considered a better clinical predictor for atypical language lateralization than handedness or side of seizures. However, our model is able to explain only a modest amount of variance in language lateralization, and the unique contribution of verbal memory to language lateralization is quite small. Hence it is premature to conclude that there is a causal relationship between language lateralization and verbal memory.
Acknowledgments This study was enabled by a fellowship from the Swiss Science Foundation. (PBBE1-11924) and funding from the National Health and Medical Research Council of Australia (NHMRC Project Grant 226100, Project Grant 368650, Project Grant 318900, and Program Grant 400121. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure: None of the authors has any conflict of interest to disclose
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