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FULL-LENGTH ORIGINAL RESEARCH

Reduced language connectivity in pediatric epilepsy
*Leigh N. Sepeta, †Louise J. Croft, ‡Lauren A. Zimmaro, §Elizabeth S. Duke, *Virginia K.
Terwilliger, ¶Benjamin E. Yerys, #XiaozhenYou, #Chandan J. Vaidya, *#William D. Gaillard, and
*Madison M. Berl
Epilepsia, 56(2):273–282, 2015
doi: 10.1111/epi.12859

SUMMARY

Dr. Leigh Sepeta,
Ph.D., is a
neuropsychologist
specializing in epilepsy
research at Children’s
National Medical
Center.

Objective: Functional connectivity (FC) among language regions is decreased in adults
with epilepsy compared to controls, but less is known about FC in children with
epilepsy. We sought to determine if language FC is reduced in pediatric epilepsy, and
examined clinical factors that associate with language FC in this population.
Methods: We assessed FC during an age-adjusted language task in children with lefthemisphere focal epilepsy (n = 19) compared to controls (n = 19). Time series data
were extracted for three left regions of interest (ROIS) and their right homologues:
inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and Wernicke’s area (WA)
using SPM8. Associations between FC and factors such as cognitive performance,
language dominance, and epilepsy duration were assessed.
Results: Children with epilepsy showed decreased interhemispheric connectivity
compared to controls, particularly between core left language regions (IFG, WA) and
their right hemisphere homologues, as well as decreased intrahemispheric right frontal FC. Increased intrahemispheric FC between left IFG and left WA was a positive
predictor of language skills overall, and naming ability in particular. FC of language
areas was not affected by language dominance, as the effects remained only when
examining participants with left language dominance. Overall FC did not differ according to duration of epilepsy or age of onset.
Significance: FC during a language task is reduced in children, similar to findings in
adults. In specific, children with left focal epilepsy demonstrated decreased interhemispheric FC in temporal and frontal language connections and decreased intrahemispheric right frontal FC. These differences were present near the onset of epilepsy.
Greater FC between left language centers is related to better language ability. Our
results highlight that connectivity of language areas has a developmental pattern and
is related to cognitive ability.
KEY WORDS: Functional neuroimaging, Seizures, Neuropsychological assessment.

Cognition requires coordinated processing between
distributed brain regions, which can be quantified through
functional connectivity (FC).1 FC is the correlation of signal
Accepted October 1, 2014; Early View publication December 17, 2014.
*Children’s National Medical Center, Washington, District of
Columbia, U.S.A.; †UCL Institute of Child Health, London, United
Kingdom; ‡University of Louisville, Louisville, Kentucky, U.S.A.;
§University of Maryland, Baltimore, Maryland, U.S.A.; ¶Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.;
and #Georgetown University, Washington, District of Columbia, U.S.A.
Address correspondence to Leigh Sepeta, Comprehensive Pediatric
Epilepsy Program, Children’s National Medical Center, 111 Michigan Ave
NW, Washington, DC 20010, U.S.A. E-mail: lsepeta@childrensnational.org
Wiley Periodicals, Inc.
© 2014 International League Against Epilepsy

changes between brain regions across time during resting
state or active task scans. Adults with epilepsy demonstrate
reduced FC within the language network despite equivalent
hemodynamic response patterns during functional magnetic
resonance imaging (fMRI) language tasks.2–4 Decreased FC
in adults is also associated with worse language performance,1,2 indicating a relationship between cognitive ability
and FC. Less is known about FC of language areas in pediatric epilepsy populations. Numerous pediatric epilepsy studies of FC have been conducted during resting state,5,6 but
only one study has focused on FC during a cognitive task.7
In a study of working memory, children with frontal lobe
epilepsy demonstrated decreases in connectivity compared

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N. Atypical language patterns are known to occur in epilepsy. Sepeta et al. Intellectual functioning was assessed by the Wechsler Abbreviated Scale of Intelligence (WASI). multiplied by 100). Nineteen were patients with left-hemisphere focal epilepsy (13 male. intellectual functioning was used to match the subjects.g. we hypothesized that group differences in FC would diminish when examining only left-language dominant individuals because FC differences may be biased by epilepsy patients with atypical language dominance. (3) questionable task accuracy. Task performance was evaluated by the overall accuracy for the task (true positives divided by the sum of the number of correct answers possible and the number of commissions.09 years. Epilepsy patients also had IQ>70 and no significant developmental.7 FC during language tasks. MRI Details of acquisition methods and experimental paradigm were previously described.11. (4) technical problem with raw imaging data. or additional neurologic history (beyond epilepsy) with the exception of learning disorders or attention disorders (e. Data were unavailable for one patient (see Table 1). mean age = 10. one patient had mesial temporal sclerosis (MTS). Precise seizure focus localization was determined for 15 of 19 patients using ictal EEG Epilepsia. and/or (5) movement. Four additional patients had seizures lateralized to the left hemisphere. and number of antiepileptic medications (AEDs). Five additional patients had learning difficulties without a formal diagnosis. particularly language skills. duration of epilepsy. and assent was provided by all children prior to any study procedure. Handedness was measured by child-friendly items from the Edinburgh Handedness Inventory (EHI). Three patients were diagnosed with ADHD and one was diagnosed with a learning disorder and ADHD. would have lower FC. SD = 1.24 years. 56(2):273–282. with undetermined location of seizure focus (interictal EEG: n = 2.10 Thus.18 Dependent variables included the CELF-IV Core Language (CL) score. or z motion exceeding >3 mm (see below for further detail).. All TD controls had normal neurologic examinations and normal structural T1 3T MRI.1111/epi. y. age of onset. All patients had a left hemispheric seizure focus based on interictal or ictal electroencephalography (EEG. has not been investigated in children with focal epilepsy. we hypothesized that patients with indicators of more severe epilepsy (i. we predicted that children with epilepsy would show reduced FC overall compared to controls.13 1. All participants were recruited from the community through flyers. earlier age of onset.e. The study was approved by Children’s National Medical Center Institutional Review Board. Nihon Kohden.15 Controls had no history of developmental. and the EOWPVT total score. interictal EEG (n = 8).. TD controls were drawn from a larger sample14 and selected to match the epilepsy sample based on age (11 months).12 Methods Participants Thirty-eight native English-speaking right-handed children between the ages of 6 and 12 participated in this study. six female. despite the presence of language difficulties in this age group.05 years) and 19 were typically developing (TD) controls some combination of the following factors: (10 male and nine female. however.16 Language functioning was assessed with the Clinical Evaluation of Language Fundamentals. Following epilepsy imaging guidelines. TD controls with atypical language patterns were excluded from the analyses. with informed consent provided by the parents. clinical seizure characteristics alone: n = 2). and a prerecorded “on-hold” message for the hospital. and decreased FC within the frontal lobe of patients was associated with cognitive impairment. or psychiatric disorders and intelligence quotient (IQ)>70. standard deviation [SD] = 2. with seven patients on more than one medication. We also hypothesized that increased language FC would correlate with better neuropsychological performance. Based on adult studies. such as language dominance. Japan) and clinical characteristics (see Table 1).73 years). higher seizure frequency. more AEDs). and clinical seizure characteristics alone (n = 1).274 L. The patients were on various AEDs.5 T structural MRI high-resolution epilepsy protocol was normal in 18 patients. When several TD controls had similar ages to a patient. which measures naming vocabulary. Finally. Regarding movement. Fourth Edition (CELF-IV)17 and the Expressive One-Word Picture Vocabulary Test (EOWPVT). longer duration. One adult study controlled for language dominance by including only controls and patients with left language dominance. Tokyo. to controls. Another 33 patients were excluded due to some combination of the following factors: (1) epileptogenic focus other than the left hemisphere. mean age = 10. attention-deficit/hyperactivity disorder [ADHD]). neurological. a widely distributed hospital newsletter. (2) left-handedness. and did not find reduced left hemisphere functional connectivity in individuals with epilepsy. 2015 doi: 10. psychiatric. (2) FC is associated with cognitive skills.12859 (n = 6). Seizure frequency varied from no seizures in the past year to daily seizures. we excluded subjects with mean or max x. as indicated by special education services or grade retention. and (3) FC is associated with clinical factors.14 but are summarized .8 We address a gap in the understanding of language FC in pediatric focal epilepsy by determining if (1) language FC is reduced in children with epilepsy. which measures expressive and receptive language.9 and reduced FC may be influenced by atypical language dominance. seizure frequency. learning. Neuropsychological testing and task performance Neuropsychological evaluation of intellectual and language functioning was performed in a separate session.

17  0.0 years) Daily: n = 5. The control condition consists of reverse speech with tone identification where the participant pushes a button when the tone follows reverse speech (70% have tones. clonazepam: n = 1. weekly: n = 2. mean y = 0.12  0.0–11. spatially smoothed using an 8 mm full width at half maximum Gaussian kernel.9 years (2.038  0. levetiracetam: n = 3. phenobarbital: n = 1.4 years) 6..19  0. TD controls) (p’s > 0.92  0. each cycle consisted of an experimental condition that alternated with a control condition and each hemicycle lasted 30 s. and fMRI task performance Seizure characteristics Localization (left focus) Seizure duration (mean) Age of onset Seizure frequencya AEDsa Group Patients 6 Temporal. MA. Movement parameters were not different between groups (epilepsy vs.68  0.21. valproate: n = 3.21 participants were excluded for excessive movement resulting in >3 mm for both mean or max movement (controls: mean x = 0.14 Image preprocessing and FC preprocessing Preprocessing and group analyses were performed using Statistical Parametric Mapping (SPM8. lamotrigine: n = 3. Germany) equipped with a standard circularly polarized (CP) head coil.59. MathWorks. Task performance was assessed by accuracy data.34. Images were collected parallel to the anterior commissure–posterior commissure plane.67). Whole-brain functional MRI was collected on a 3. 2 temporoparietal. phenytoin: n = 1. “A long yellow fruit is a banana. the participant hears an auditory clue (five to six word sentences) that describes and names an object (e.23. Visual stimuli were presented through a rear projection screen. patients: mean x = 0.275 Pediatric Epilepsy Language Connectivity Table 1. For the group analyses.068  0.040. United Kingdom) using MATLAB (Version 8. max x = 0. none in past 6 months: n = 2.083  0. Seventy percent of items are correct targets and 30% are foils. Tasks were presented via E-Prime software version 1. Given the potential sensitivity of FC analyses to motion.34  0.0 Tesla Siemens Magnetom Trio (Erlangen.69.085. Experimental paradigm Auditory description decision task For the experimental condition.14. diazepam: n = 2. max z = 0. 30% are foils).12859 .30  0. max x = 0. mean z = 0.4 years (3.). mean y = 0. Individual stimuli were presented every 3 s for a total of 10 per block. auditory stimuli were digitized and presented via pneumatic earphones. range = 0.32  0. Pittsburgh. The task is designed to provide in-scanner monitoring of performance by requiring a semantic decision identified by button press response.S.047  0.1 (Psychology Software Tools. WASI.3–10. topiramate: n = 1. Each subject’s anatomic scan was coregistered to the SPM8 white matter template and then segmented. U. 4 frontal.A..20 The auditory description decision task is known to activate frontal and temporal language areas.g.043. max z = 0.18. neuropsychological assessment. a Seizure frequency and AED information was not available for one patient.S.2. lacosamide: n = 1. 1 occipital 3. Responses were performed via fiberoptic push button response recorded by computer in EPrime. oxcarbazepine: n = 9. Sherborn. The three left regions of interest (ROIs) were Epilepsia. here. 2015 doi: 10. 56(2):273–282.). 1 parietal. The mean echo-planar imaging (EPI) image was then coregistered to the segmented gray matter and the transformation was applied to all of the EPI images. max y = 0. PA. max y = 0. CELF-IV-CL. and EOWPVT scores for patients and TD controls.057. U. range = 1.”) and pushes a button when the correct object is described. Functional images were spatially normalized to the Montreal Neurological Institute (MNI) standard anatomic space.19 We used a block design composed of five epoch cycles. Inc. Inc. lorazepam: n = 1. London. and temporally filtered (high-pass filter: 128s).. The task was adjusted by age-level with different versions of the tasks developed based on word frequency normative data derived from children’s reading materials. Wellcome Department of Cognitive Neurology.1.6. Seizure characteristics. individual t-maps were generated with movement parameters as covariates of no interest. none in past year: n = 4 Carbamazepine: n = 3. monthly: n = 5.1111/epi. 1 frontotemporal. Total scan time was 5 min.A. zonisamide: n = 2 Measure Intellectual assessment FSIQ VIQ PIQ Language measures CELF-IV-CL EOWPVT fMRI task performance Overall accuracy Patients Controls 106(19) (n = 18) 107(19) (n = 18) 103(16) (n = 18) 110(11) 111(14) 106(11) 103(14) (n = 17) 107(16) (n = 18) 108(11) 112(16) 71%(25%) (n = 17) 80%(16) (n = 18) Mean and standard deviations of fMRI task performance.05). mean z = 0.

Thus. Regarding seizure frequency.14 We entered the center coordinates for each of the three left ROIs into an fMRI database (http:// beta. Language-dominance patterns and overall FC by language pattern Rates Language dominance Typical Left Atypical Right Crossed Bilateral Total Patients (n = 19) Controls (n = 19) 15 19 2 2 0 4 0 0 0 0 Patterns of language dominance: typical (left) and atypical (right. epilepsy) as a between-group factor and connection as a within-subject factor for only the left dominant language participants. left IFG. followed by the two interhemispheric connections (left and right IFG. MFG. none in past year: n = 4]). for both models the main intrahemispheric language connection (left IFG and left WA) implicated in adult FC studies was entered into the model first. Right homologues were defined as mirror images of left ROIs. seizure duration. epilepsy) as a between-group factor and connection as a within-subject factor (inter.14 Table 2. number of AEDs). all p-values were adjusted for multiple comparisons using the Bonferroni procedure (p = 0. epilepsy) at a threshold of p = 0.neurosynth. Regarding predictor variables.org) to confirm that >18 studies of language also found activation within approximately 6 mm of our center coordinates for each ROI. epilepsy duration. less frequent or 0–1 AED vs.20. inferior frontal gyrus (IFG. but participants with bilateral activation in one region and unilateral activation in the other were considered dominant on the side of unilateral region activation. we ran the mixed model ANOVA with group (TD controls vs. N.276 L. Activation time series data were extracted for each subject from each ROI with MarsBar. therefore. Determination of language dominance To determine language dominance. and middle frontal gyrus (MFG). Broca’s area). or crossed patterns were considered to be atypical (see Table 2).05) for a larger group map of pediatric TD controls within the anatomic boundaries of Wernicke’s Area (WA).and intrahemispheric connections of IFG. Group differences (epilepsy and TD controls) in neuropsychological performance were assessed by one-way ANOVA. we used a mixed model ANOVA with group (more vs. Sepeta et al. MFG. we calculated a lateralization index (LI) for each subject’s IFG and WA ROIs and categorized language based on a commonly used cut-off value of 0. 2015 doi: 10. epilepsy characteristics (age of onset. regressor of volume index that exceeds 0. We performed additional analyses to examine the effects of neuropsychological performance.19 The participants categorized as left language dominant were considered to have typical language dominance.24 Using the LI Toolbox bootstrap method (LI-Toolbox for SPM8).5 mm FD.g. see Fig. and language dominance on language connectivity. bilateral. we divided the epilepsy group into a group taking one AED or less (n = 11) and those taking more than one AED (n = 7). bilateral if LI <|0. we also compared activation between the two groups (TD controls vs.25 ROIs were individually categorized as left-lateralized if LI ≥ 0. Crossed dominance patterns occurred when participants had discrepant LIs between the two ROIs (e. or right if LI ≤ 0.20. >1 AED) as a between-group factor and connection as a within-subject factor (inter. We examined a cumulative total of four tests of clinical variables (age of onset.and intrahemispheric connections of IFG. MFG and WA).. none in past 6 months: n = 2. FWE. The relationship between (1) seizure duration and (2) age of onset and FC for ROI pairs was examined using Pearson r correlation.05. bilateral. hierarchical multiple linear regression models were used to predict naming vocabulary (EOWPVT scores) and overall language ability (CELF-IV-CL scores) from FC for IFG and WA connections. similar to masks used in a previous study.20.013 for these analyses). we divided the pediatric epilepsy group into a group with more frequent seizures (total: n = 7 [daily: n = 5. Epilepsia. . seizure frequency.22 Individual linear correlation coefficients were computed between pairs of time course signals extracted from the ROIs. For AEDs. and those with right. six ROIs were used. For the seizure frequency and AED analyses. left and right WA).23 and signal from ventricle and white matter regions of interest. and number of AEDs). weekly: n = 2]) and those with fewer seizures (total: n = 11 [monthlyn = 5. 1A for all paired ROI combinations).1111/epi. and WA. seizure frequency. To investigate the effect of language dominance. 56(2):273–282. defined by significant clusters of functional activation from whole brain activation (thresholded at family-wise error (FWE). crossed) for patients and TD controls.12859 Data analyses The primary analysis examined FC differences between patients and controls (across inter. To ensure that connectivity results were not a matter of activation differences. right WA). This demonstrated that our ROIs were not unduly influenced by our sample and confirmed that these are common areas for language activation.20. and WA).and intrahemispheric connections of IFG. Time course correlation coefficients were transformed to Fisher’s z-scores and submitted into a mixed model analysis of variance (ANOVA) with group (TD controls vs. To examine the relationship between language FC and neuropsychological performance. p = 0. partialling out the following parameters to control for motion and physiologic noise: framewise displacement (FD).

40*Indicates language connections with a significant difference between groups. inferior frontal. When the two interhemispheric connections (left and right IFG. the model approached significance. F3. The brain networks were visualized with BrainNet Viewer (http://nitrc. Hierarchical linear regression analyses revealed that the left intrahemispheric connection (left WA and left IFG) was a significant positive predictor of naming vocabulary (EOWPVT scores).03 (Table 3. Epilepsia. and left and right MFG (p = 0.05.07. 3A). Functional connectivity: Group differences in paired ROI time course correlations A main effect of group (F1.03). p = 0. Task performance (overall accuracy) was not different between groups (see Table 1). (B) Visual depiction of the ROIs and the significantly different connections between patients and TD controls. Fig. PIQ) and language skills (CELF-IV. 2015 doi: 10.97. 56(2):273–282. 1). There was no two-way (group 9 connection) interaction.1111/epi. right IFG and MFG: p = 0. accounting for 12% of the variance. FC between paired language regions for each group (patients vs. FWE. F1. Patients also had a lower left and right intrahemispheric connection than controls for IFG and MFG (left IFG and MFG: p = 0. VIQ. k ≥ 20 voxels).36 = 6.001) demonstrated that FC strength differed between language regions. Epilepsia ILAE B Results fMRI activation during the language task The activation maps during the auditory description decision task revealed activation of a frontotemporal network (p = 0. TD controls). We did not find any significant differences between patients and controls used in this study. p < 0. (A) Graph of the FC values for each paired language region for each group.47) demonstrated that FC was stronger in TD controls than in patients (Fig. Relationship between FC and neuropsychological performance The mean score for all neuropsychological measures was within the average to high average range for all participants (see Table 1). and accounted for an additional 6% of the variance. left and right IFG (p = 0. suggesting that both groups show a similar FC profile among core language regions.36 = 10. Exploratory analyses revealed that patients had lower interhemispheric connections of core homologous temporal. p = 0. p = 0.31.04. Intellectual functioning (FSIQ. A main effect of ROI (F8.12859 . Cohen’s d = 0. All models presented passed tests for multicollinearity. and middle frontal language regions compared to controls: left and right WA (p = 0.01. EOWPVT) were not different between groups likely due to matching and inclusion criteria.org/ projects/bnv/).02).04).35 = 4. with the strongest connection between left and right WA (See Fig.53. 1A). left and right WA) were added (step 2).33 = 2.277 Pediatric Epilepsy Language Connectivity A Figure 1.80.02) (Figs 1B and 2).

However. Figure 2.12 13.77 7. p = 0. Hierarchical regression analyses predicting language ability EOWPVT Predictor Step 1 IFG L-WA L Step 2 IFG L-WA L IFG L-IFG R WA L-WA R b SE B b t DF DR2 21. *p < 0. Color-coded matrices representing FC for the nine main language connections.60 10.24 0.57 0. less frequent) or numbers of AEDs (0–1 AED vs. >1 AEDs).28 0.07 1. Effect of language dominance on FC of language regions The majority of study participants had typical language dominance (left).10). as expected. 56(2):273–282. Table 3. Using mixed model ANOVA.12859 . p = 0. left WA) (see Table 2).51 0. Cohen’s d = 0.51 6. Sepeta et al. similar to the results from the overall analysis (with atypical and typical language patterns included). *Indicates language connections with a significant difference between groups. Matrices for TD controls are displayed on the left panel.51 8. TD controls demonstrated stronger connectivity than patients (F1. but this did not survive Bonferroni correction.11 1.09 10.76 0. Neither age of onset nor seizure duration was correlated with FC of the language regions. The colors range from dark red (z = 0.32 = 5.06 DF DR2 CELF-IV-CL Predictor Step 1 IFG L-WA L Step 2 IFG L-WA L IFG L-IFG R WA L-WA R b SE B b 16.85 0. One connection. including right-lateralized (right WA.17 0.0–0.17. but four (21%) patients with epilepsy demonstrated atypical language dominance.30) to yellow (z = 0.12 15. right WA or right IFG.43 1. Connections that were not examined in the current study are identified by a gray color in the matrices. Effect of epilepsy characteristics on FC of language regions We also examined the relationship between language FC and (1) age of onset.02 t Results of the hierarchical multiple linear regression models used to predict naming vocabulary (EOWPVT scores) and overall language ability (CELF-IV-CL scores) from FC for IFG and WA connections (IFG L-WA L.47.79 8.1111/epi. For the left language dominant participants.05).57 0. WA L-WA R).60 0.45 1. 3B). (3) seizure frequency. (2) seizure duration. we also did not find language FC differences based on seizure frequency (more vs.49 7.41 0.03.46). demonstrated a negative correlation with age of onset (r = 0.20* 4.49 0. Fig.29 0.97* 0.23 0. N. right MFG to right WA.36 5.35 2.25 0.54 9. IFG L-IFG R.05. the model was not significant when the two interhemispheric connections (left and right IFG. 2015 doi: 10. and patients with epilepsy on the right.55 4. right IFG) and crossed patterns (left IFG.83.23* 4.04 (Table 3. p = 0.83* 0.35 2. and (4) number of AEDs.90–1.34 = 4. F1. Epilepsia ILAE The left intrahemispheric connection (left WA and left IFG) was also a significant positive predictor of overall language ability (CELF-IV-CL) and accounted for 12% of the variance.278 L.76 4.76 9. Epilepsia. left and right WA) were added (step 2) suggesting that left intrahemispheric connection alone was a strong predictor.

Different stages of language development for children compared to adults may account for these discrepant findings.2 In contrast to adult epilepsy studies. Reduced synchrony between frontal language regions (left and right IFG) has also been identified in studies of adults with epilepsy.4 however. Gross pathology. Correlations between FC and neuropsychological variables.12859 . and predominantly normal MRIs. 2015 doi: 10. such that increased connectivity between left language areas (IFG and WA) correlated with better performance on language measures. Correlation between FC for IFG L ↔ WA L and naming vocabulary (EOWPVT) and overall language ability (CELF-IV-CL). demonstrated reduced FC of language areas compared to TD controls. children with left focal epilepsy. movement. removing these characteristics as potential contributing factors. we did not find differences in left intrahemispheric FC. left and right IFG) in children with epilepsy. Contrary to our hypothesis. Epilepsia ILAE Discussion In the present study. and there is a shift from strong interhemispheric connectivity during infancy/ childhood to strong intrahemispheric connectivity in Epilepsia. The FC of language areas was related to language ability. The pediatric epilepsy group showed a decrease specifically in the homologues of IFG and WA and the right intrahemispheric IFG-MFG connection.279 Pediatric Epilepsy Language Connectivity A B Figure 3.3. and IQ did not differ between groups. 56(2):273–282.1111/epi. We found reduced interhemispheric frontal and temporal connectivity (left and right WA. Evidence suggests that maturation of language connectivity is protracted. FC did not differ according to the epilepsy characteristics we examined.

This has important implications for timing of interventions because our findings and others7 suggest that decreased FC is associated with lower cognitive skills. several adult epilepsy studies found a group difference (controls > patients) in left intrahemispheric connectivity. which have the advantage of capturing variability in patient language localization. reduced interhemispheric structural connectivity of the temporal lobe predicts language impairment.27–29 when language skills are more advanced.280 L.g.2 These results suggest that the shift from inter. and this plasticity diminishes through childhood. or be a marker of.28. Epilepsy may disrupt and/or delay the ongoing functional specialization of network connections that underlie the development of cognitive skills. the evidence suggests that intrahemispheric.28 TD children (ages 5–7) demonstrate strong functional interhemispheric connectivity. lower cognitive skills are evident at onset of epilepsy. rather than ROI. As noted above. Overall differences in connectivity in children with epilepsy did not depend on duration of epilepsy or age of onset.. such as language.9 The majority of adult studies of language FC in epilepsy include patients with epilepsy that have typical and atypical language representation. in combination with our findings. BA 44. such as larger and/or different ROIs for our FC analysis. Epilepsy—or any source of atypical development.12859 cognitive ability. which then may be a predictor of outcome. such as factors related to preterm birth—may disrupt or alter the FC developmental process for some children.31–33 In atypical development. frontotemporal functional connections are strengthened later in life. of epilepsy on other cognitive networks and their interplay with language systems.37 The differences between our pediatric study and the adult studies may be related to methodologic differences. N. 47) and may have limited our ability to identify relationships between performance and more localized patterns of synchrony. The use of whole-brain.to intrahemispheric connections across development may facilitate. our hypothesis is that reduced interhemispheric connectivity at an early age may represent reduced capacity for the brain to compensate for neural disruption to the language networks. in the current study of children (ages 6–12). definitive conclusions regarding the relationship of language dominance and connectivity are limited because the sample size of patients with atypical language representation in the current study was small (n = 4).27 Two-day-old infants show strong FC between hemispheres during an auditory language task. Based on one adult study of controls and patients with left language dominance.10 we hypothesized that differences in FC between controls and patients would relate to these known differences in language dominance. Whole-brain. identifies interhemispheric connectivity as an important stage in the typical development of language.1111/epi. Limitations In this study we used large ROIs.2–4 and we did not for our pediatric sample. while adults display strong intrahemispheric connectivity (between left frontal and temporal language areas) during a language task. Sepeta et al. homologous language connections were strong in both the TD control and epilepsy groups.11 which may suggest a timeframe for when ongoing epilepsy interferes with FC. or association.11. Our findings did not support the hypothesis that language dominance influences changes in FC between language areas overall.3–10. whereas others studied adults.35 Our study differs from prior results in several important ways.12 However. It is also possible .26. our findings are supported by other studies that show that seizure activity does not necessarily account for differences in cognitive ability. since our pediatric groups (TD controls and epilepsy) had comparable language skills. particularly for the control group. We postulate that greater interhemispheric FC in children may be an index of available plasticity for the establishment of language dominance. increased cognitive efficiency and language ability. such that adults with left focal epilepsy exhibited a positive correlation between verbal IQ and left intrahemispheric FC. particularly in the superior temporal regions. such as preterm children. our patient population had a shorter duration and range of epilepsy (0. 2015 doi: 10. for example. up to 30% compared to 5% in TD populations.30 The protracted development of FC parallels structural studies using diffusion tensor imagingwhere frontotemporal connections mature slower than other language region connections.9. Second. Increased left WA and left IFG FC was a positive predictor of naming vocabulary in particular. 56(2):273–282. voxel-wise analyses may allow for further characterization of FC and the relationship between network synchrony and cognitive performance. The previously mentioned body of research. First. However.28. We expand previous work by finding that children who had stronger left intrahemispheric language FC had better language ability. A possible explanation for these discrepant findings may relate to Epilepsia. The strongest connectivity was between left and right WA. Previous FC and electrocorticographicstudies of both childhood and adult onset epilepsy suggest that a prolonged duration of epilepsy is related to decreased network synchrony in adulthood.36 but the disadvantage of averaging time courses across large numbers of voxels. we studied children. Another disadvantage may be that large ROIs average variability from within smaller functional ROIs (e. adulthood. despite reduced FC in these connections for children with epilepsy compared to controls. Adult studies have also shown that stronger cognitive ability is related to increased intrahemispheric FC. 45.31–33 Similar to these findings.27 Overall. A higher incidence of atypical language patterns is known to occur in patients with epilepsy. the interhemispheric. analyses may provide additional insights by examining the effect.34 Thus.4 years) than the adult series (0–50 years).

2:239–246. 1R21MH092615. 4. large samples are required to accumulate a sufficient sample for statistical analysis. Stock (held with spouse): Johnson and Johnson. Acknowledgments This work was supported by The National Institutes of Neurological Disorders and Stroke (NINDS).Y. The department conducts industrysupported trials from which no salary support is derived and includes: Ovation Pharmaceuticals. localizing the seizure focus. Centers for Disease Control and Prevention (CDC)1UO1DP003255. as found in the current study. and number of AEDs.D. Epilepsia. Functional connectivity: the principal-component analysis of large (PET) data sets. Jansen JFA. Functional connectivity networks are disrupted in left temporal lobe epilepsy. Frith CD. Childrens Research Institute Avery Award [to M. However.M. there remain limitations to these analyses and other factors could be examined.32:532–540. NIH [M01RR020359]. and these differences are present near the onset of epilepsy. Neurology 2010. et al. Friston KJ. et al. task performance. and naming vocabulary in particular. The remaining authors have no potential conflicts of interest to report. Overvliet GM. the authors would like to acknowledge the patients and typically developing children who participated in the study. interhemispheric FC is decreased in children with left lateralized focal epilepsy compared to controls. Waites AB. AJNR Am J Neuroradiol 2011.. which prevents serial EEG from providing additional confirmation of the focus. and Citizens United for Research in Epilepsy (CURE).N. one would expect that potential medication effects would be global rather than affecting subsets of the distributed language network. We confirm that we have read Epilepsia’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.B. 5K23MH086111 to B. more importantly. Dr. however. Functional connectivity MR imaging of the language network in patients with drug-resistant epilepsy. duration.B. the majority of patients with epilepsy in our sample had normal structural MRIs. Army Medical Research Acquisition Activity (DOD/ USAMRAA) W81XWH-11-2-0198. Editorial board of Epilepsia and Epilepsy Research. NIH grant 5T32HD046388-08). Dr.12859 . such as type of AED. Dr. Federal support provided by NINDS1P30HD40677-01. as well as other cognitive systems.E. Saling MM. Lily.]. 2015 doi: 10. Yerys received funding from the Frederick and Elizabeth Singer Foundation (PI: Gaillard and Kenworthy) and is funded by National Institute of Mental Health (NIMH) grants 5K23MH086111 and 1R21MH092615. Clinical 2013. PRA International/Eisai. 3. Foundation support from Epilepsy Foundation of America. Pravata E. References 1.75:395–402. however. Sestieri C. Majoie HJM. First. Sepeta has received research support from Epilepsy Foundation of America (EFA and The Eunice Kennedy Shriver National Institute of Child Health and Human Development. NIH [5T32HD046388-08 to L.S. Functional connectivity and language impairment in cryptogenic localizationrelated epilepsy. Childrens National Medical Center Clinical and Translational Science Award (CTSA). Language dominance might be expected to affect intrahemispheric connections but not connections between homologous regions. King Pharmaceuticals. Liddle PF. We recognize the migratory nature of epileptiform discharges in some patients who have normal MRI. Dr. particularly within modest sample sizes. National Science Foundation (NSF)095998. Mantini D.]. assessing the impact of AED type is challenging. Greater intrahemispheric FC between left language centers is related to better language ability in general. Because atypical language dominance is a minority pattern. microscopic anatomic abnormalities cannot be excluded. Future investigations should also look at intrinsic connectivity via resting-state study designs. Future studies with larger samples are needed to examine the relationship between these comorbidities and language processing. by matching on IQ when possible. Conclusions The results of the current study contribute to our understanding of the functional connectivity of language regions during development through two important findings. Similarly. particularly in the primary frontal and temporal language connections. National Institutes of Health (NIH) [R01 NS44280 to W. Future studies with larger samples will also be able to examine fully the effect of atypical language dominance on connectivity. Briellmann RS.59:335–343.is well known and is a limitation to this study. J Cereb Blood Flow Metab 1993. Vaidya is funded by NIMH grant MH084961. Furthermore. et al. Second. 2. as well as Institutional Discretionary Funds – The Children’s Hospital of Philadelphia. Reduced functional integration of the sensorimotor and language network in rolandic epilepsy.1111/epi. 5K23NS065121-01A2 to M. age of onset. Glaxo-SmithKline. 5. the Intellectual and Developmental Disabilities Research Center and Children’s National Medical Center Grant [HD040677-07].G. given the heterogeneity of response. and PICORE 527. the National Center for Research Resources. Vlooswijk MCG. et al. The Eunice Kennedy Shriver National Institute of Child Health and Human Development. 56(2):273–282. Berl is funded by NINDS grant 5K23NS065121-01A2. et al. Furthermore. our findings extend the theory that connectivity has a developmental pattern and is related to cognitive ability. Siemens and General Electric. tasks that produce frontal versus those that yield temporal and frontal language area activation.M. Finally. Although we addressed several possible influences on FC including IQ. thus a limitation of this study is the cross-sectional design. our sample reflects general epilepsy populations where 30–50% have comorbid learning problems39 and these patients were not excluded.S. Department of Defense/U. Disclosure or Conflicts of Interest Dr. MRI abnormalities. for example.281 Pediatric Epilepsy Language Connectivity that these discrepancies were due to differences in the experimental tasks.. Ann Neurol 2006. Jansen JFA. our patients did not differ on the neuropsychological measures we used in this study. American Epilepsy Society. Besseling RMH. Infantile Epilepsy Research Foundation (Lundbeck).. Gaillard’s income derives from clinical revenue generated for CNMC clinical care. seizure frequency. the Epilepsy Foundation of America (EFA).38 The laterality and location of the seizure focus was based on available clinical and electrophysiologic data. NeuroImage. 2K12NS052159-06A1NIMHRO1 MH084961. Pfizer.13:5–14. The assurance of clinical features and interictal and ictal EEG in lateralizing and. even when children are taking the same dose of the same AED.

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