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- MATERIALS AND METHODS
Summary: Purpose: Lateralization of language function is crucial to the planning of surgery in children with frontal or temporal lobe lesions. We examined the utility of functional magnetic resonance imaging (fMRI) as a determinant of lateralization of expressive language in children with cerebral lesions.
Methods: fMRI language lateralization was attempted in 35 children (29 with epilepsy) aged 8–18 years with frontal or temporal lobe lesions (28 left hemisphere, five right hemisphere, two bilateral). Axial and coronal fMRI scans through the frontal and temporal lobes were acquired at 1.5 Tesla by using a block-design, covert word-generation paradigm. Activation maps were lateralized by blinded visual inspection and quantitative asymmetry indices (hemispheric and inferior frontal regions of interest, at p < 0.001 uncorrected and p < 0.05 Bonferroni corrected).
Results: Thirty children showed significant activation in the inferior frontal gyrus. Lateralization by visual inspection was left in 21, right in six, and bilateral in three, and concordant with hemispheric and inferior frontal quantitative lateralization in 93% of cases. Developmental tumors and dysplasias involving the inferior left frontal lobe had activation overlying or abutting the lesion in five of six cases. fMRI language lateralization was corroborated in six children by frontal cortex stimulation or intracarotid amytal testing and indirectly supported by aphasiology in a further six cases. In two children, fMRI language lateralization was bilateral, and corroborative methods of language lateralization were left. Neither lesion lateralization, patient handedness, nor developmental versus acquired nature of the lesion was associated with language lateralization. Involvement of the left inferior or middle frontal gyri increased the likelihood of atypical language lateralization.
Conclusions: fMRI lateralizes language in children with cerebral lesions, although caution is needed in interpretation of individual results.
Standard methods of language lateralization, including intracarotid amytal (ICA) testing and cortical stimulation, are often difficult to perform in children, and their invasive nature limits repeated assessments and study of normal children. In contrast, functional magnetic resonance imaging (fMRI) is relatively noninvasive and, in spite of several challenges in its application to children, has been used to lateralize language in children by several groups (1–13). Word-generation paradigms used to study expressive language in normal children produce consistent left-lateralized activation, primarily in the inferior frontal gyrus and middle frontal gyrus (2,3,5,6,10–12).
Lateralization of language function is crucial to the planning of epilepsy, tumor, and vascular surgery and to the understanding of patients' baseline and postoperative language deficits. Cortical organization of language function is more likely to be aberrant in children with epilepsy and brain lesions (14,15). The application of fMRI to pediatric patients with neurologic conditions has not been extensively studied. Contributing reasons include the practical difficulties inherent in the use of fMRI in children, neurobehavioral disabilities prevalent in pediatric neurology patients, and organizational hurdles encountered by clinical departments associated with implementation of protocols developed largely for research. Reports of fMRI of language in pediatric patients are presently limited to case studies (16–20) and series of seven to 14 patients (1,4,9,13,21,22). These studies demonstrate that fMRI is feasible in children and valid as a measure of language lateralization when assessed against the gold standards of cortical stimulation or ICA testing (1,4,9,13,18,20), irrespective of the specific language paradigm, imaging techniques, or quantitative assessments used. One of the larger series considered issues of cerebral plasticity and reported that lateralization cannot be inferred from the proximity of lesions to language cortex, highlighting the complexity inherent in predicting language lateralization (4). Case studies are helpful in understanding concepts of plasticity and critical periods for language acquisition (17), as well as questioning the meaning of fMRI activation in clinical subjects (16–18).
Given the relatively limited clinical experience with fMRI in children with cerebral lesions, we aimed to examine language lateralization by using fMRI in a large sample of children with cerebral lesions and to analyze the results from a clinical perspective. Secondary aims were to evaluate the results in relation to corroborative evidence from other modalities, to compare visual and quantitative methods of lateralization, and to examine the need for Bonferroni correction in data analysis.
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- MATERIALS AND METHODS
The demographic and lesion characteristics of the 35 recruited children (19 boys) age 8–18 years (mean age, 12 years) are summarized in Table 1. Although a specific language concern was not an inclusion criterion, the source of patients resulted in a bias toward patients with seizures, left-hemisphere lesions, and right-hemisphere lesions associated with left-handedness. Twenty-nine (83%) children had epilepsy, and two had a single seizure. Twenty-eight (80%) children had lesions confined to the left hemisphere, five had right-hemisphere lesions, and two children had lesions with considerably greater involvement on the left. Twenty children had developmental tumors or dysplasias, and 15 had acquired lesions with a variety of antecedents including febrile convulsions, stroke, and encephalitis. Seven children underwent frontal lobe cortical stimulation or ICA testing, and 19 children underwent epilepsy surgery. The children varied considerably in general intelligence (mean IQ, 86; range, 59–117), receptive vocabulary (mean PPVT-R standard score, 83; range, 46–124), and ability to perform the standardized version of the COWAT (mean number of words, 20; range, 5–40).
Table 1. Patient demographic and lesion data
|Patient data||Lesion data|
|Pt||Age Sex||Handed||Epilepsy||FSIQ||PPVT||COWAT||MRI findings (pathology of resected tissue)||Etiology (antecedent) [age acquired in yr]|
|Successful fMRI studies|
| 1||13, M||R||Y||86||83||28||R gyrus rectus FCD (dysplasia)||Developmental|
| 2||10, M||L||Y||84||92||18||R temporoparietooccipital atrophy/gliosis & HS||Acquired (chemotherapy) [3.5]|
| 3||14, M||L||Y||78||67||19||L HS||Acquired (nil antecedent) [?<4]|
| 4||14, M||R||1 seizure||90||104 ||21||L IFG + MFG calcified tumor||Developmental|
| 5||11, F||L||Y||91||79||12||R HS (HS)||Acquired (febrile seizures) |
| 6||14, F||R||Y||108 ||94||25||L temporal FCD 2° to tuberous sclerosis (dysplasia)||Developmental|
| 7|| 8, F||L||Y||81||52|| 6||L temporal encephalomalacia/gliosis & HS (no pathology)||Acquired (HSVE) [0.5]|
| 8||18, M||L||Y||94||n/a||26||L hemisphere atrophy & HS (HS)||Acquired (nil antecedent)|
| 9||10, F||R||Y||92||100 ||22||L STG tumor (dysembryoplastic neuroepithelial tumor)||Developmental|
| 10|| 8, F||R||Y||90||88|| 5||L IFG tumor (ganglioglioma, later malignant transformation)||Developmental|
| 11||14, M||R||N||71||78|| 5||L temporal tumor with hemispheric edema (glioblastoma)||Acquired (tumor growth) |
| 12||14, F||R||Y||99||80||40||L parahippocampal FCD (dysplasia) & hypothalamic hamartoma||Developmental|
| 13||12, F||L||1 seizure||85||99||20||L IFG porencephalic cyst & small hemisphere||Acquired (nil antecedent)|
| 14||12, M||L||Y||88||90||21||L MFG FCD (dysplasia)||Developmental|
| 15||10, F||R||Y||59||47||25||L SFG FCD||Developmental|
| 16||10, M||L||Y||69||58||10||L STG tumor ?dysembryoplastic neuroepithelial tumor||Developmental|
| 17|| 9, M||L||N||113 ||105 ||26||L MCA territory atrophy/gliosis||Acquired (stroke) |
| 18|| 9, M||R||Y||87||92||14||L hippocampal & parahippocampal FCD (dysplasia)||Developmental|
| 19||13, M||R||Y||97||98||21||L IFG tumor (dysembryoplastic neuroepithelial tumor)||Developmental|
| 20||18, F||R||Y||94||77||36||L occipitotemporal atrophy/gliosis & HS (HS, atrophy)||Acquired (nil antecedent)|
| 21|| 9, M||R||Y||84||78||15||L hemisphere atrophy/gliosis & HS (encephalomalacia)||Acquired (HSVE) |
| 22||13, M||R||Y||76||90||18||L SFG + MFG FCD (dysplasia)||Developmental|
| 23||13, F||L||Y||117 ||124||30||L inferior temporal tumor (ganglioglioma)||Developmental|
| 24||15, M||L||Y||83||80||19||L perisylvian (insula, STG, IFG, MFG) FCD (dysplasia)||Developmental|
| 25||16, M||L||Y||71||54||18||L > R HS & white-matter abnormalities||Acquired (head injury) |
| 26||14, F||R||Y||84||98||17||R posterior temporal angiomas (cavernoma)||Developmental|
| 27|| 9, M||R/Mixed||N||87||113 ||13||R MCF arachnoid cyst and R temporal hypoplasia||Developmental|
| 28|| 8, M||R||Y||107 ||90||25||L amygdala & STG hyperintensity (chronic encephalitis)||Acquired (Rasmussen) |
| 29||14, F||R||N||106 ||97||26||L inferior frontal atrophy/gliosis||Acquired (stroke) |
| 30||14, F||R||Y||64||46||28||L mesial occipitotemporal FCD (dysplasia)||Developmental|
|Unsuccessful fMRI studies|
| 31||15, F||R||Y||77||71||23||L HS (HS)||Acquired (febrile seizures) [1.4]|
| 32||11, M||L||Y||62||80||12||L HS (HS)||Acquired (meningitis) [0.5]|
| 33||18, F||R||Y||83||65||19||L ITG tumor (ganglioglioma)||Developmental|
| 34||10, M||R||Y||85||89||17||L > R multiple FCD 2° to tuberous sclerosis||Developmental|
| 35||14, F||L||Y||83||62||11||L inferior temporal granuloma (meningioangiomatosis)||Developmental|
fMRI language lateralization
The results of fMRI are shown in Table 2. Significant activation (p < 0.0001, uncorrected) was seen in all but one patient (patient 33) on coronal examination. Three studies with activation were also considered unsuccessful, as no activation was noted in the inferior frontal region (patients 31, 32, 34). Thus 30 (86%) of the 35 studies were considered successful in terms of activating inferior frontal regions. Activation remained significant at the p < 0.05 Bonferroni corrected level in all but one (patient 26) of the 30 successful studies.
Table 2. Functional MRI language lateralization and corroborative data
|Pt||Visual inspection Side Gyri activated (p < 0.0001, warm colors)||Asymmetry indices||Best corroborative evidence of language lateralization|
| ||LIFG||RIFG||LMFG||RMFG||LSFG||RSFG||(p < 0.001) hemisphere inf. frontal||p < 0.05 Bonferroni hemisphere inf. frontal|
|Successful fMRI studies|
| 1||L||+|| ||+|| ||0.82||0.91||1 ||1 || |
| 2||L||+||+||+|| ||+|| ||0.52||0.37||0.61||0.5|| |
| 3||L||+|| ||+||+||+|| ||0.43||0.61||0.71||0.96|| |
| 4||L||+|| ||+|| ||+|| ||0.61||0.35||1 ||1 || |
| 5||L||+|| ||+|| ||+||+||0.88||0.85||0.75||0.75|| |
| 6||L||+|| ||+||+||+||+||0.79||0.90||0.64||0.79||L frontal & temporal stimulation: aphasic|
| 7||L||+||+||+|| ||+||+||0.53||0.54||0.65||0.88||L frontal & temporal stimulation: aphasic|
| 8||B||+||+||+||+||+||+||−0.19 ||−0.17 ||−0.15 ||−0.19 ||L frontal & temporal stimulation: not aphasic|
| 9||L||+|| ||+||+||0.87||0.94||0.97||1 ||Ictal aphasia|
| 10||B||+||+||+||+||+||+||0.16||0.08||0.18||0 ||Ictal aphasia|
| 11||L||+|| ||+||+||+||+||0.39||0.60||0.57||0.63||Aphasia with tumor enlargement|
| 12||L||+||+||+||+||+||+||0.64||0.68||0.9 ||0.87||L frontal & temporal stimulation: aphasic|
| 13||R|| ||+|| ||+||−0.50 ||−1 ||−1 ||−1 || |
| 14||L||+||+||+||+||+||+||0.28||0.31||0.49||0.47||L frontal stimulation: aphasic|
| 15||L||+||+||+||+||+||+||0.35||0.44||0.31||0.68||Ictal aphasia|
| 16||R||+||+||+||+|| ||+||−0.64 ||−0.59 ||−0.62 ||−0.27 || |
| 17||R|| ||+|| ||+|| ||−0.33 ||−0.38 ||−1 ||−1 ||Not aphasic with acute L MCA stroke|
| 18||L||+|| ||+|| ||0.86||1 ||1 ||1 || |
| 19||B||+||+||+|| ||+||+||0 ||0.31||0.08||0.72||L frontal stimulation: aphasic|
| 20||L||+|| ||+|| ||+|| ||0.39||0.8 ||1 ||1 ||Ictal aphasia|
| 21||L||+|| ||+|| ||+||+||0.92||0.93||0.98||0.98|| |
| 22||L||+|| ||+|| ||0.78||0.87||1 ||1 || |
| 23||R|| ||+|| ||+|| ||+||−0.94 ||−0.93 ||−1 ||−1 || |
| 24||R|| ||+|| ||+||+||+||−0.88 ||−1 ||−0.78 ||−1 ||L ICA testing: not aphasic|
| 25||L||+|| ||+||+||+||+||0.72||0.80||0.82||0.80|| |
| 26||L||+|| ||+|| ||0.40||0.71||n/a ||n/a || |
| 27||L||+|| ||+|| ||+||+||0.57||0.47||1 ||1 || |
| 28||L||+||+||+|| ||+|| ||0.64||0.40||0.8 ||0.77||Ictal aphasia|
| 29||R||+||+||+||+||+||+||−0.22 ||−0.02 ||−0.67 ||−0.06 ||Aphasic with L MCA stroke|
| 30||L||+|| ||0.64||0.64||1 ||1 || |
|Unsuccessful fMRI studies|
| 31|| ||+|| ||Ictal aphasia|
| 32|| ||+|| |
| 33|| ||+|| |
| 34|| |
| 35|| |
Visual inspection revealed that inferior frontal activation was unilateral in 17 children and prominently asymmetrical in 10 children, leading to lateralized language in 27 children (21 left, six right). Three studies showed an equivalent degree of inferior frontal activation and were judged to have bilateral language. Activation was also present in the region of the middle frontal gyrus (three children), superior frontal gyrus (four children), or both (22 children). In the 27 lateralized studies, middle frontal and superior frontal activation was often bilateral, but where unilateral, activation was ipsilateral to the greater inferior frontal activation. Less-frequent regions of activation were the anterior cingulate (nine children) and insular cortex (six children). Cerebellar activation (seven children) and inferior or lateral temporal activation (eight children) also were seen, but these regions were not adequately imaged with the limited number of slices acquired. Figure 2 shows examples of typical lateralized and bilateral activation.
Figure 2. Typical examples of left-lateralized (patient 14), bilateral (patient 10), and right-lateralized (patient 23) frontal language activation. Activation thresholded at p < 0.005 (uncorrected probability of null hypothesis) and overlaid onto the average of the raw echoplanar imaging. Activity at p < 0.0001 is shown as bright white, whereas 0.0001 < p < 0.005 is shown in a dark shade of grey.
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Quantitative lateralization at each statistical threshold and for both hemispheric and inferior frontal regions of interest was concordant with lateralization from visual inspection in all but two children (patients 19 and 29; 93% concordant). Visual-inspection lateralization and hemispheric region-of-interest quantitative lateralization at both thresholds were bilateral for patient 19 but left lateralized based on the inferior frontal region of interest. Inferior frontal region of interest lateralization and hemispheric lateralization at p < 0.001 were bilateral for patient 29, whereas visual inspection and hemispheric lateralization at p < 0.05 Bonferroni corrected were right lateralized. No right–left discordance was seen.
Corroborative evidence of fMRI lateralization
Seven patients underwent language testing with ICA injection or electrical stimulation of the frontal cortex with results concordant with fMRI in six patients (patients 6, 7, 8, 12, 14, 24). Aphasia during left frontal cortical stimulation was potentially discordant with bilateral language activation on visual inspection and the hemispheric asymmetry index in patient 19 but concordant with left lateralization on the inferior frontal AI. Language deficits during seizures or in the course of disease were apparent in a further seven children and were concordant with fMRI lateralization in five (patients 9, 11, 15, 20, 28) and discordant in patients 10 and 29. In patient 17, the absence of a language deficit after an acute left middle cerebral artery (MCA) stroke was concordant with fMRI language lateralization to the right hemisphere. None of the 19 operated-on patients had a language deficit.
An apparent discordance between fMRI lateralization and that from these other modalities was therefore present in three children (patients 10, 19, and 29). Timing of fMRI assessment in relation to an acquired lesion offered a plausible explanation in patient 29, who was aphasic after a left MCA territory stroke, suggesting preexisting left hemisphere dominance. fMRI showing bilateral (inferior frontal AI) or right hemisphere language lateralization (visual inspection and hemispheric AI) was conducted 6 months after the stroke when language function had recovered and may reflect reorganization in the right hemisphere. No plausible explanation was apparent for two patients who showed bilateral activation on visual inspection and hemispheric AI but had corroborative evidence of left hemisphere language dominance (cortical stimulation in patient 19, and ictal aphasia in patient 10). These children were both right-handed and had epileptogenic developmental tumors in the left inferior frontal gyrus. Repeated fMRI studies 2 years after the first examination (not analyzed in this series) in patient 19 showed left-hemisphere dominance consistent with the cortical-stimulation data, which were acquired at that time and left lateralization by inferior frontal asymmetry index in the present study. In patient 10, repeated fMRI studies (not analyzed in this series) showed right lateralized language, despite a deterioration of language function as the tumor increased in size and seizure control worsened (16).
Thus corroborative evidence from standard methods of language lateralization or aphasiology available in 15 patients was clearly consistent with fMRI language lateralization in 12 patients. A plausible explanation was apparent for the discrepancy in a further case. Discordance between fMRI and other methods of language lateralization could not be resolved in two patients (10 and 19).
fMRI language activation in relation to lesion characteristics
Classification of language lateralization as either typical (left) or atypical (right or bilateral) was based on visual inspection for the purpose of statistical calculations. Atypical lateralization was not associated with lesion lateralization, nature of lesion (developmental versus acquired), or timing of acquired lesions (Table 3). Atypical language lateralization was associated with lesion involvement of the left inferior or left middle frontal gyrus.
Table 3. Relation between lesion and patient variables and lateralization of language by fMRI (visual inspection)
| ||No.||“Typical” language (left) (left) (n = 21)||“Atypical” language (right or bilateral) (n = 9)||p Value|
|Left-sided lesion||25||16|| 9||0.3a |
|Left IFG/MFG lesion specifically|| 9|| 3|| 6||0.01a|
|Developmental lesion||17||12|| 5||1a |
|Late acquired (>6 yr) lesion|| 4|| 2|| 2||0.5a |
|Mean FSIQ (standard score)||30||85||95||0.07b|
|Mean COWAT (raw score)||30||20||20||1b |
|Mean PPVT (standard score)||29||81||94||0.1b |
|Mean age of patient (yr)||30||12||12||0.8b |
|Right-handed||18||15|| 3||0.1a |
Nine children had lesions in the left inferior frontal or middle frontal gyrus. fMRI language lateralization was left for three (patients 4, 14, 22), right for four (patients 13, 17, 24, 29), and bilateral for two (patients 10, 19). Six children had developmental lesions, three showed left lateralized activation (patients 4, 14, 22), and two showed bilateral activation (patients 10, 19) with activation overlying or abutting the lesion for all these cases (Figs. 3 and 4). One left-handed patient (patient 24) with a large dysplastic lesion involving the entire left perisylvian region, including frontal and temporal prototypic language regions, was right language lateralized. All three children with acquired lesions showed right lateralized language activation on fMRI (patients 13, 17, 29). These patients differed in terms of the timing of their lesions. Patient 13 had a presumed prenatal incident and was left-handed. Patients 17 and 29 had late acquired lesions, both having left MCA territory strokes. Patient 17 was left-handed and had no aphasia as a result of the stroke at age 9 years, whereas patient 29, as noted earlier, was right-handed and experienced aphasia after a stroke at age 13 years, with recovery of language function more than 6 months before fMRI investigation (Fig. 5).
Figure 3. Three axial anatomic MRI scans (top) and fMRI scans (bottom) showing language activation in left frontal cortex abutting an area of focal cortical dysplasia (arrows) (patient 14). Activation thresholded at p < 0.005 (uncorrected probability of null hypothesis) and overlaid onto the average of the raw echoplanar imaging. Activity at p < 0.0001 is shown as bright white, whereas 0.0001 < p < 0.005 is shown in a dark shade of grey.
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Figure 4. Two coronal fMRI scans showing bilateral language activation (insula, inferior frontal gyrus, superior frontal gyrus) in relation to a left inferior frontal developmental tumor (patient 19). Activation thresholded at p < 0.005 (uncorrected probability of null hypothesis) and overlaid onto the average of the raw echo-planar imaging. Activity at p < 0.0001 is shown as bright white, whereas 0.0001 < p < 0.005 is shown in a dark shade of grey.
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Figure 5. Two coronal fMRI scans showing right-lateralized language activation (insula, inferior frontal gyrus, superior frontal gyrus) in relation to a region of left inferior frontal atrophy and gliosis due to a left middle cerebral artery territory stroke (patient 29). Activation thresholded at p < 0.005 (uncorrected probability of null hypothesis) and overlaid onto the average of the raw echo-planar imaging. Activity at p < 0.0001 is shown as bright white, whilst 0.0001 < p < 0.005 is shown in a dark shade of grey.
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fMRI language activation in relation to neuropsychological and patient variables
Patients who showed successful language activation on visual inspection did not differ from those whose activation was unsuccessful in terms of their age [t(33) =−1.006; p = 0.322], ability to perform the COWAT [t(33) = 1.001; p = 0.320], intellect [IQ, t(33) = 1.516; p = 0.139], or language abilities [PPVT-R, t(32) = 1.244; p = 0.111].
Correlation between COWAT performance and Bonferroni-corrected hemispheric asymmetry index was not significant [r(27) =−0.037; p = 0.851], suggesting that language lateralization in fMRI scans showing activation was not related to level of proficiency on the activation task. Correlation between age and Bonferroni-corrected hemispheric asymmetry index was also not significant (r=−0.033; p = 0.866).
No significant differences between those whose language was left lateralized on visual inspection and those who showed atypical language lateralization were apparent in terms of IQ, COWAT performance, PPVT-R standard score or age (Table 3). However, there was a trend for IQ and PPVT-R scores to be higher in patients with atypical language lateralization, the lesions in these patients all being on the left. Language lateralization was not associated with handedness (Table 3).
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- MATERIALS AND METHODS
Consistent with previous studies, we have shown that it is possible to demonstrate language activation in children by using fMRI at 1.5 T in a clinical setting. Our study reports fMRI language lateralization in the largest group of pediatric patients to date. Patients were relatively heterogeneous with respect to the nature of their epilepsy, lesions, and neurobehavioral profiles, typical of pediatric clinical practice. The simple but robust paradigm successfully revealed language activation in children as young as 8 years of age, including those with intellectual disability and language impairment. Activation was consistently seen in the inferior frontal gyrus, as well as the middle and superior frontal gyri, consistent with previous reports of language fMRI using verbal fluency paradigms (4–6,11,13,28,29,31). As was the case in these studies, a degree of bilateral activation was present in about 60% of our patients. Nevertheless, lateralization could be easily determined by visual inspection. Visually rated lateralization was highly concordant with the quantitative AIs, regardless of region of interest used or whether the data were statistically corrected for multiple comparisons. In the majority of patients for whom data were available, fMRI lateralization was also concordant with lateralization determined on the basis of cortical stimulation, ICA testing, or aphasiology. Only two patients had seemingly unexplained discordance between visual-inspection lateralization (bilateral) and corroborative data (left), they being two children with developmental lesions in the left inferior frontal gyrus in whom different fMRI lateralization on follow-up imaging suggested possible influence of age, tumor change, and perhaps seizures.
The majority of children in the study were left lateralized for language despite the predominance of left-hemisphere lesions. Consistent with the epilepsy literature (14,32,33), however, the percentage of children who showed atypical language lateralization (20% right lateralized, 10% bilateral) was higher than for the normal population and indeed twice that found in a normative study of children by our group by using a visually presented version of the same orthographic lexical retrieval paradigm (2% right lateralized, 13% bilateral) in which lateralization was not related to subject age, gender, task proficiency, or handedness (5). Our clinical sample also included a higher incidence of left-handedness (41%) than the normal population. However, our sample could not be regarded as an unselected epilepsy sample, and both left-handedness and atypical language are probably overrepresented. Yet neither left-handedness nor the presence of a lesion in the left inferior or middle frontal gyrus, which was statistically associated with a greater likelihood of atypical language lateralization, was absolutely predictive of right-hemisphere language involvement, and clearly such indicators in isolation do not reliably predict language lateralization in patients.
Whereas our data could be considered from a number of perspectives, our interest was primarily in pragmatic clinical application of this technology in children with neurologic problems. Two subgroups of our sample were of particular clinical interest in this regard: first, the patients with lesions involving putative language cortex (inferior left frontal lobe), and second, the patients found to have atypical language lateralization.
An understanding of how lesions in language areas affect cortical organization and lateralization of language function may be important for the planning of surgery in children with tumors or refractory partial epilepsy. Destructive injury to language cortex before the end of a critical period for language development [traditionally regarded as around 5 to 6 years of age (32,34,35)] may result in interhemispheric shift in language dominance, whereas later injury is more likely to cause reorganization of language within the hemisphere (32,34–37). The only patient in our series with an early-acquired lesion involving the inferior left frontal lobe (patient 13) showed right-lateralized language consistent with this premise. Developmental lesions, even those causing intractable epilepsy, do not necessarily result in transfer of language function; rather language often develops in proximity to the lesion in the dominant hemisphere (4,34,38), perhaps due to the functional integrity of some dysplastic cortex (39). Only one patient in the previously reported pediatric fMRI series is reported to have had a developmental lesion (cortical dysplasia) specifically in the inferior left frontal lobe (9), language being left lateralized. In five of the six children in our series with developmental lesions involving the left inferior or middle frontal cortex, fMRI showed left or bilateral language activation overlying or abutting the lesion, consistent with the previous observations (4,34). Patient 24, with an extensive left perisylvian dysplasia and right lateralized language, suggests that developmental lesions may also lead to interhemispheric language reorganization when involvement of the left hemisphere is so widespread that it precludes intrahemispheric reorganization.
Right dominance is rare in dextrals (33) and is seen in only 10% of normal left-handers when assessed with fMRI (29). Innate right-hemisphere language may account for three cases of right-lateralized activation seen in our series. It is the most likely explanation in the left-handed child with a late acquired left-hemisphere stroke that did not disturb language (patient 17). It may also be the explanation in the two left-handed children with small, discrete developmental tumors in the left temporal lobe in whom associated seizures did not produce aphasia (patients 16, 23). As discussed earlier, right-hemisphere language may result from a focal lesion in the left frontal language cortex if the lesion is acquired early in development (patient 13), or from a large developmental lesion in the left hemisphere (patient 24). Patient 29 is also a likely example of interhemispheric transfer of language, given that her language recovered over the 6 months after her left hemisphere stroke at age 13 years, and was associated with right or bilateral language activation. Cases of language reorganization beyond the age of 6 years are reported with progressive cerebral pathology (17,40,41) and challenge the traditional limit of the critical period for language development. A further case of aberrant language lateralization was that of patient 8, who also had an extensive left-hemisphere acquired lesion and whose fMRI was bilateral and consistent with the failure of left frontal cortical stimulation to elicit aphasia (although right dominance cannot be excluded on the basis of the cortical stimulation evidence alone). This may reflect reorganization of language function but again, the underlying mechanism is uncertain. It is interesting to speculate that the trend to higher receptive language and intellectual scores in the nine patients with language in the right hemisphere, contralateral to their lesions, was a function of effective language development in a normal hemisphere, either innately or as a result of “transfer.”
The three cases of potential discordance between language lateralization on fMRI highlight the need for caution in interpretation of fMRI findings in pediatric patients. It is noteworthy that the two patients who remained discordant despite careful clinical consideration were the only children in the sample with epileptogenic lesions in the inferior frontal gyrus. These suggest that the interpretation of fMRI activation in children with epileptogenic lesions in inferior frontal language cortex is not straightforward, and might produce false lateralization or the impression of bilaterality in some patients. Lesions in the inferior frontal gyrus may distort activation and lead to misinterpretation of visual images or incorrect asymmetry indices, particularly when automated quantitation is used. The effect of seizures in the case of epileptogenic lesions and the meaning of activation contralateral to expected language are not well understood (16–18).
An appreciation of the impact of neurologic conditions on the organization of language is essential in planning for neurosurgery in the dominant hemisphere. Determination of language lateralization by clinical prediction (e.g., from handedness, lesion location, or nature of lesion in terms of developmental versus acquired and age at lesion) is problematic and should certainly not be the sole basis of surgical planning. fMRI is a useful, noninvasive tool for lateralization of language function in children with cerebral lesions, particularly as data are increasingly available in normal children (5,6,10–12,42) and indicate that word-generation paradigms produce a reliable pattern of mostly lateralized frontal activation. fMRI language lateralization can be performed at 1.5 T in a clinical setting, is well tolerated by neurologically afflicted children, and generally leads to robust activation in a consistent pattern that can be readily interpreted without the need for quantitative analysis, Bonferroni correction of data, or coregistration with anatomic images. The neurobiologic basis or explanation of specific fMRI findings in individual patients often requires consideration of a number of factors, including handedness, lesion location and type, innate factors, and the presence of seizures. Consequently, individual interpretation is often required. The issues of plasticity and transfer are hypothetical to all practical intents and purposes. At a clinical level, corroboration from other modalities, and the favorable language outcome after surgery in our series, suggest that fMRI of language is likely to replace modalities such as ICA for language lateralization in pediatric patients. Now many groups internationally report fMRI language lateralization in children, and many more use this technology clinically. A need exists for consensus in acceptable paradigms, image-acquisition parameters, and analytic approaches to allow application of reported data to clinical practice. Currently we believe the greatest challenge in pediatric fMRI is the understanding of activation and absence of activation in terms of “plasticity” and its clinical implications.