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Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

FULL-LENGTH ORIGINAL RESEARCH

Widespread cortical morphologic changes in juvenile myoclonic epilepsy: Evidence from structural MRI *y1Lisa Ronan, *z1Saud Alhusaini, *Cathy Scanlon, xColin P. Doherty, z{Norman Delanty, and *Mary Fitzsimons *Brain Morphometry Laboratory, Neurophysics Department, Beaumont Hospital, Dublin, Ireland; yBrain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; zDepartment of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; xDepartment of Neurology, St. James’s Hospital, Dublin, Ireland; and {Department of Neurology, Beaumont Hospital, Dublin, Ireland

SUMMARY Purpose: Atypical morphology of the surface of the cerebral cortex may be related to abnormal cortical folding (gyrification) and therefore may indicate underlying malformations of cortical development (MCDs). Using magnetic resonance imaging (MRI)–based analysis, we examined cortical morphology in patients with juvenile myoclonic epilepsy (JME). Methods: MRI data was collected for 24 patients with JME and 40 demographically matched healthy controls. FreeSurfer, an automated cortical surface reconstruction method, was applied to compare cortical morphology between patients and controls. Areas of anomalous cortical morphology were defined as regions of interest (ROIs) to contrast regional cortical parameters, such as surface area, average thickness, and mean curvature between patients and controls.

Juvenile myoclonic epilepsy (JME), one of the common idiopathic generalized epilepsies (IGEs), has a prevalence of 8–10% among adults and adolescents with epilepsy (Panayiotopoulos et al., 1994). JME is characterized by myoclonic jerks, occasional generalized tonic–clonic seizures, and sometimes typical absence seizures (Panayiotopoulos et al., 1994; Renganathan & Delanty, 2003). The epileptiform activity in JME is typically generalized 4–6 Hz spike-wave (SW) activity (Pedersen & Petersen, 1998). However, one third of patients with JME may have subtle focal electroencephalography (EEG) abnormalities, sometimes associated with focal semiologic features (Usui et al., 2005; Jayalakshmi et al., 2010). Accepted January 8, 2012; Early View publication February 23, 2012. Address correspondence to Mary Fitzsimons, Brain Morphometry Laboratory, Neurophysics Department, Beaumont Hospital, Dublin 9, Ireland. E-mail: [email protected] 1 These authors contributed equally to this work. Wiley Periodicals, Inc. ª 2012 International League Against Epilepsy

Key Findings: In patients with JME, changes to cortical morphology were detected in several regions. In the left hemisphere, these were in insular and cingulate cortices, occipital pole, and middle temporal and fusiform gyri. In the right hemisphere, changes were detected in insular cortex, inferior temporal gyrus, and precuneus. Further analysis of ROIs revealed that these changes are related to differences in surface area rather than average cortical thickness. In addition, mean curvature abnormalities were detected in the insula bilaterally, the left cingulate cortex, and right inferior temporal gyrus. Significance: The morphologic findings in this study suggest that structural abnormalities in JME extend beyond mesial frontal lobe regions of the brain. These may be indicative of areas of subtle cortical folding abnormality related to early disruption of cortical development. KEY WORDS: Juvenile myoclonic epilepsy, Cortical morphology, Cortical folding.

Although the underlying pathologic mechanism remains unknown, genetic contributions to JME have long been established. Autosomal dominant (Cossette et al., 2002), autosomal recessive (Panayiotopoulos & Obeid, 1989), two loci (Greenberg et al., 1988), and multifactorial models of inheritance have been proposed (Gardiner, 2005). Important mutations have been identified in genes that encode the voltage-gated calcium channel b4 subunit and a1 subunit of the c-aminobutyric acid (GABA)A receptor (Escayg et al., 2000; Cossette et al., 2002). In addition, mutations in the EF-hand domain (C-terminal) containing 1 (EFHC1) gene have been described in 6 of 44 families with JME (Suzuki et al., 2004). This gene maps to 6p12-p11 and encodes a protein that may have a role in apoptosis and regulation of cell division. Mutations of the EFHC1 gene have been shown to inhibit apoptosis (Suzuki et al., 2004) and to interfere with multiple steps in embryonic cortical development (de Nijs et al., 2009). These findings have suggested subtle alterations in cortical architecture, such as malformations of cortical development (MCDs), as a possible neurobiologic

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652 L. Ronan et al. basis underpinning the disorder (Wong, 2010). MCDs at the macroscopic through to the histological level are a common cause of chronic epilepsy, usually diagnosed by magnetic resonance imaging (MRI), and include many disorders that differ in their genetic basis, structural effects, and associated pathology (Sisodiya, 2004). In the clinical setting, qualitative assessment of MRI data in JME is generally negative (Koepp, 2005). However, several quantitative neuroimaging studies have revealed multiple subtle structural and metabolic brain abnormalities. For example, bilateral thalamic volume loss and increased mesial frontal and frontobasal gray matter concentration have been revealed (Woermann et al., 1999; Betting et al., 2006; Kim et al., 2007; Lin et al., 2009b) as well as altered thalamic and prefrontal metabolic function (Savic et al., 2000; Mory et al., 2003; Lin et al., 2009a). Furthermore, abnormal thalamofrontal lobe connectivity has also been demonstrated (Deppe et al., 2008; Vulliemoz et al., 2011). Such quantitative MRI studies support findings from EEGbased studies (Tucker et al., 2007; Holmes et al., 2010), and suggest that JME is a frontally predominant disorder of thalamocortical networks, rather than a generalized epilepsy syndrome (Koepp, 2005). Despite the predominant evidence of thalamic and frontal lobe dysfunction, findings in other brain regions should not be ignored (Anderson & Hamandi, 2011). Structural abnormalities and functional dysfunction reported in the hippocampus, the cerebellum, and nonfrontal cortical regions, such as the insular, occipital, and posterior cingulate cortices (Tae et al., 2006; Lin et al., 2009a,b; O’Muircheartaigh et al., 2011) suggest that brain dysfunction in JME extends beyond thalamofrontal regions. Further, evidence of localized epileptiform discharges frequently propagating through restricted cortical networks that involved frontal as well as temporal regions has recently been highlighted (Holmes et al., 2010). Analyses of cortical surface morphology have proven useful in identifying anatomic features characteristic of abnormal gyral folding that are not usually captured by cortical thickness and volume measurements. In this study, we applied FreeSurfer, an automated cortical surface–based reconstruction method, to compare global and regional cerebral cortical morphology in patients with JME and demographically matched healthy controls. We hypothesized that local changes in cortical morphology may reflect underlying cortical folding abnormalities associated with subtle MCDs in patients with JME.

Methods Study population Forty control subjects (20 male, 20 female) with no neurologic deficits were chosen at random from a bank of MRI data at Beaumont Hospital, Dublin. Age range was 22–43 years (mean and standard deviation: 28 € 5 years) Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

for female subjects, and 21–40 years (mean and standard deviation: 28 € 4 years) for male subjects. A sample of 24 patients with JME (11 male, 13 female) who attended the epilepsy service at Beaumont Hospital, Dublin, was recruited for this study. The age range was 21–33 years (mean and standard deviation: 28 € 4 years) for female patients and 22–51 years (mean and standard deviation: 30 € 9 years) for male patients. See Table 1 for a detailed clinical description of the participating patients with JME. The medical research ethics committee at Beaumont Hospital Dublin approved the study and written informed consent was obtained from all participants. MR image acquisition Patients and control subjects were imaged using a 1.5-T GE MRI system (Signa, GE, Milwaukee, WI, U.S.A.) with a standard head coil. A three-dimensional (3-D) spoiled gradient (SPGR) sequence was acquired from a sagittal localizer in the coronal plane. The following imaging parameters were used: 10.1, 4.2, 450 msec (TR/TE/TI); one excitation; flip angle of 20.0 degrees; field of view (FOV) 24 · 24 cm; matrix, 256 · 256, resulting in 124 · 1.5- mm-thick image slices. MR image processing MR images were transferred in DICOM format to a dedicated Linux workstation (Ubuntu version 7.04; Canonical Ltd., London, United Kingdom). FreeSurfer (version 4.1.0, http://surfer.nmr.mgh.harvard.edu) was used for cortical surface reconstruction of the MR images and cortical morphology assessment for each individual. The FreeSurfer process has been described in detail previously (Dale et al., 1999; Fischl et al., 1999a,b, 2001, 2002, 2004) and has undergone extensive investigations to assess its accuracy, validity, and applicability (Rosas et al., 2002; Han et al., 2006; Lee et al., 2006; Dickerson et al., 2008; Morey et al., 2010). In summary, for each subject, DICOM format images were converted to FreeSurfer format, followed by removal of nonbrain tissue (Segonne et al., 2004), transformation to Talairach space, segmentation of the subcortical white matter and deep gray matter structures (e.g., hippocampus) (Fischl et al., 2002), and intensity normalization (Sled et al., 1998). Gray matter and white matter boundary was tessellated and topologic defects were automatically corrected (Fischl et al., 2001; Segonne et al., 2007). Transition of gray/white and gray/cerebrospinal fluid borders was indicated by detecting the greatest shift in intensity through surface deformation (Dale et al., 1999). After creation of cortical representations, the cerebral cortex was parcellated into subject-specific anatomic regions. FreeSurfer provides an estimate of total intracranial volume (ICV) on the basis of the transformation of the full brain mask into Talairach space (Buckner et al., 2004). Regular visual inspections for quality assurance were performed at several stages of FreeSurfer’s processing stream.

653 Cortical Morphology in JME Table 1. Characteristics of patients with JME: age and age at onset of seizures are reported in years Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Age at scanning

Gender

Age at onset of seizures

Family history

Early insult

GTCS

Myoclonic seizures

Absence seizures

AEDs

23 28 27 32 33 34 26 28 32 22 30 24 30 29 42 29 51 31 23 26 30 23 23 31

Female Female Female Female Female Female Female Female Female Female Female Female Female Male Male Male Male Male Male Male Male Male Male Male

12 11 4 17 18 19 12 16 1 10 12 20 16 7 17 15 16 16 19 8 8 16 4 18

No Yes Yes No Yes No Yes Yes Yes No Yes No No No Yes No No Yes No No No Yes No Yes

None None None None None None None None FS None None None None None None None None None None FS None None None None

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes No Yes Yes No Yes Yes Yes Yes

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

No No No No No No No No Yes Yes Yes Yes Yes Yes No No No Yes No Yes No No Yes Yes

TPM LMT, LEV TPM, ZNS LMT, TPM LMT LMT VPA LMT VPA, LEV TPM, ZNS LEV VPA, LEV LEV, LMT VPA VPA, LMT VPA LMT VPA VPA VPA VPA VPA LMT, LEV LEV, TPM

GTCS, generalized tonic–clonic seizure; AEDs, antiepileptic drugs; FS, febrile seizure; TPM, topiramate; LMT, lamotrigine; LEV, levetiracetam; ZNS, zonisamide; VPA, valproate.

All cortical surfaces and subcortical segmentations were visually checked prior to group analysis. No manual edits were necessary. Analysis of cerebral volume, cortical surface area, and average cortical thickness Following cortical reconstruction, we derived individual cerebral volume, cortical surface area, and average cortical thickness for each hemisphere using the automated analysis tools implemented in FreeSurfer to investigate differences between patients and controls in each parameter. These parameters were examined to detect any evidence of global brain atrophy, surface area contraction, or cortical thinning in the patient group compared to the healthy controls. Analyses of cortical morphology To assess cerebral morphology, convoluted reconstructions of the cortex were inflated using FreeSurfer to produce a smooth surface for each subject. This allowed both the sulcal and gyral folds to be viewed. Subsequently, each vertex on the inflated surface was registered to a sphere (Fischl et al., 1999a). Each subject’s surface spherical representation was then mapped to an average surface template (Fischl et al., 1999b) in a way that minimizes metric distortion. The Jacobian matrix, a measure executed in FreeSurfer, quantifies the amount of metric distortion per

vertex required to register a subject’s cortical surface to the template. As this measure is driven largely by cortical folding and morphology (Fischl et al., 1999b), we measured the Jacobian for each subject within each group to determine regions of morphologic differences between the groups. Quantification of cortical geometric parameters in regions of abnormal cortical morphology Using Query Design Estimate Contrast (QDEC) interface of FreeSurfer, clusters of cortical morphology changes (metric distortion) from the group-wise cortical morphology analysis were defined as anatomic labels (i.e., regions of interest [ROIs]). Labels were then mapped to each subject, and different surface-based cortical geometric measurements including surface area, average thickness, and mean curvature were then calculated for each label using the automated analysis tools implemented in FreeSurfer. Correlation of cortical parameters in regions of abnormal morphology and clinical variables To determine if cortical morphology changes are related to clinical variables we correlated surface area, average thickness, and mean curvature measurements for each region of abnormal cortical morphology with duration of epilepsy and age at onset of seizures in the patients’ group. Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

654 L. Ronan et al. Statistical analysis Analysis of covariance (ANCOVA) was applied to compare hemispheric cerebral volume, cortical surface area, and average cortical thickness between patients with JME and controls. Estimated intracranial volume (ICV) was included as a covariate in the analysis of cerebral volume and cortical surface area. Using QDEC interface of FreeSurfer, group differences in metric distortion (Jacobian) between controls and patients with JME were examined by computing a general linear model of the effect of group on the measure at each vertex of the surface. The data were smoothed with a 20-mm full width half maximum (FWHM) Gaussian kernel. False discovery rate (FDR) of p < 0.05 was applied to clusters that displayed group differences in metric distortion to correct for multiple comparisons. Within each cluster that survived FDR correction, we compared surface area, average thickness, and mean curvature between patients and controls using ANCOVA with total brain volume included as covariate. Partial correlations, controlling for the effect of age, were performed to assess the correlation between cortical parameters in regions of abnormal cortical morphology and duration of epilepsy and age at onset of seizures. ANCOVA and partial correlation analyses were performed using SPSS statistical software (PASW statistics version 18.0; IBM, Armonk, NY, U.S.A.). Corrections for multiple comparisons were made by applying Holm–Bonferroni method at level p = 0.05 (Holm, 1979).

Results Total cerebral volume, cortical surface area, and average cortical thickness Results of total cortical volume, surface area, and average thickness in each hemisphere are reported in Table 2. No statistically significant difference in total cerebral volume, cortical surface area, or average cortical thickness was detected between patients and controls. Cortical morphology changes Statistically significant morphology (Jacobian matrix) differences were detected in patients with JME in several cortical regions when compared to healthy controls (Fig. 1).

These differences reflected either an increase or decrease in the metric distortion required to register JME cortical surfaces to a template compared to that required for controls. In the left hemisphere, localized clusters of cortical morphology changes were identified in the insular and cingulate cortices, middle temporal and fusiform gyri, and occipital pole. Metric distortion was greater in patients with JME relative to controls in the clusters within the insula, middle temporal gyrus, and anterior cingulate cortex. On the other hand, metric distortion was greater in the controls relative to patients with JME in the clusters within the fusiform gyrus and occipital pole. In the right hemisphere, localized clusters of cortical morphology changes were detected in the insula, inferior temporal gyrus, and precuneus. Metric distortion was greater in the patients with JME relative to controls in the clusters within the insula and inferior temporal gyrus, whereas metric distortion was greater in controls relative to patients with JME in the cluster within the precuneus (see Fig. 1 and Table 3). Quantification of cortical geometric parameters in regions of abnormal cortical morphology Results of surface area, average thickness, and mean curvatures for each cluster of cortical morphology change are reported in Table 3. All clusters showed no change in cortical thickness. Clusters showing greater metric distortion in patients had reduced surface area in the patient group compared to controls, with the exception of the cluster within the left insula where statistical significance was not reached. In addition, mean curvature was also reduced in the same clusters, except the middle temporal gyrus cluster. In contrast, clusters with lesser metric distortion in patients with JME showed increased surface area in the patient group compared to controls but no mean curvature changes. The majority of these significant differences survived correction for multiple comparisons. The few that did not survive the correction were surface area changes in right insula and right inferior temporal gyrus; and mean curvature changes in right inferior temporal gyrus and left anterior cingulate cortex (see Table 3).

Table 2. Group mean and SD of total brain volume, cortical volume, cortical surface area, and average cortical thickness in both hemispheres Left hemisphere Group Controls JME patients

Total hemispheric volumea 551,477 (55,030) 506,967 (50,452)

Cortical volumea

Surface areaa

Right hemisphere Thickness

244,001 (22,801) 80,141 (8,125) 2.678 (0.084) 229,989 (22,809) 76,065 (7,770) 2.691 (0.0762)

a

Estimated intracranial volume (ICV) was included as covariate. Volume values are reported in mm3, surface area in mm2, and thickness in mm.

Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

Total hemispheric volumea 554,051 (51,956) 509,340 (53,392)

Cortical volumea

Surface areaa

Thickness

242,897 (22,365) 80,318 (8,210) 2.65 (0.078) 230,648 (22,777) 76,116 (8,184) 2.69 (0.072)

655 Cortical Morphology in JME

Figure 1. Clusters of cortical morphology differences between patients with JME and healthy controls in the left and right hemispheres. Lateral and medial views of left and right hemispheres with clusters of altered cortical morphology and their locations are shown. All labeled clusters survived False Discovery Rate (FDR) correction at p < 0.05. Epilepsia ILAE

Table 3. Location of clusters of significant cortical morphology changes, the direction of metric distortion in patients with JME relative to controls, and the morphologic parameters (surface area, average thickness, and mean curvature) of each cluster Location Left hemisphere Cluster 1 Controls JME Cluster 2 Controls JME Cluster 3 Controls JME Cluster 4 Controls JME Cluster 5 Controls JME Right hemisphere Cluster 6 Controls JME Cluster 7 Controls JME Cluster 8 Controls JME

Direction of distortion

Surface area

1,665 (173) 1,527 (172)

Thickness

Mean curvature

3.034 (0.14) 3.04 (0.16)

0.128 (0.01) 0.119 (0.01)**a

Insula

JME > controls

Middle temporal gyrus

JME > controls

877 (175) 692 (145)***a

3.02 (0.19) 2.92 (0.28)

0.163 (0.01) 0.160 (0.01)

Occipital pole

Controls > JME

263 (63) 310 (63)**a

2.33 (0.24) 2.41 (0.42)

0.176 (0.02) 0.183 (0.02)

Caudal anterior cingulate

JME > controls

799 (110) 668 (103)***a

2.67 (0.26) 2.55 (0.23)

0.151 (0.01) 0.158 (0.01)*

Fusiform

Controls > JME

269 (57) 291 (54)**a

2.11 (0.39) 2.16 (0.43)

0.140 (0.03) 0.141 (0.03)

Insula

JME > controls

361 (36) 322 (48)*

3.54 (0.69) 3.71 (0.30)

0.167 (0.03) 0.135 (0.02)***a

Inferior temporal gyrus

JME > controls

690 (160) 569 (103)*

2.81 (0.35) 2.72 (0.27)

0.182 (0.01) 0.171 (0.02)**

Precuneus

Controls > JME

795 (141) 906 (158)***a

2.66 (0.22) 2.61 (0.25)

0.158 (0.01) 0.153 (0.01)

*p < 0.05; **p < 0.01; ***p < 0.001. a Survived correction for multiple comparisons (Holm–Bonferroni method was applied). Morphology parameters (covaried for brain volume) are reported: surface area values are reported in mm2, average thickness values are reported in mm, and mean curvature values are reported in per mm.

Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

656 L. Ronan et al. Correlation of cortical geometric parameters in regions of abnormal morphology and clinical variables No evidence of correlation was noted between cortical geometric parameters (surface area, mean curvature, and average thickness) within regions of altered cortical morphology and age at seizure onset or duration of epilepsy prior to or after partialling out age at scanning.

Discussion In this study, we present evidence of widespread changes to cortical morphology in a group of patients with JME. To our knowledge, this is the first study to use an entire cortex approach to examine on a vertex-wise basis mean metric distortion (Jacobian matrix), a sensitive measure for cortical folding and morphology in patients with JME. We report lateralized cortical morphology changes involving various localized cortical regions outside the frontal lobe. Changes in local cortical morphology identified in this study may point to areas of subtle cortical folding abnormalities. Alternatively, they may be related to cortical deafferentation secondary to epilepsy chronicity and seizure-induced injury. The underlying pathophysiologic mechanisms in JME have traditionally been linked to abnormal frontally predominant corticothalamic networks. By definition, the electrophysiologic activity in JME recorded using standard EEG recordings shows simultaneous and bilateral involvement of cerebral hemispheres at the onset of seizure activity (Nordli, 2005). Bilateral frontothalamic structural and metabolic alteration has also been identified (Woermann et al., 1999; Betting et al., 2006). In some patients with JME, however, subtle focal EEG abnormalities, sometimes associated with focal semiologic features may exist (Usui et al., 2005; Jayalakshmi et al., 2010). Studying 10 JME patients, Holmes et al. (2010) found all patients to show localized epileptiform discharges at the onset of seizure activity, with these frequently propagating through restricted cortical networks that involve frontal and temporal regions. These observations indicate that the epileptiform discharges in JME can be localized and not necessarily generalized; in addition, they may involve cortical regions outside the frontal lobe. Our findings of lateralized atypical cortical morphology involving various localized cortical regions suggest that structural changes of the cerebral cortex also exist outside the frontal lobe. Particularly, our findings are consistent with recent reports from voxel-based morphometry (VBM) studies that found gray matter volume (GMV) reduction in insular, occipital, and cingulate cortices (Lin et al., 2009b; O’Muircheartaigh et al., 2011). VBM-based findings, however, are limited and cannot be attributed to a single biologically meaningful process. GMV generally combines a mixture of geometric parameters including thickness, surface area, and folding; each reflects on distinct neurobiologic and Epilepsia, 53(4):651–658, 2012 doi: 10.1111/j.1528-1167.2012.03413.x

genetic processes (Panizzon et al., 2009). In our study, we were able to demonstrate that abnormality in cortical surface morphology is related to changes in cortical surface area and mean curvature rather than cortical thinning. Further, the relationship we observed between metric distortion and surface area patterns indicate that these surface morphology changes are related to abnormal cortical folding and most likely independent of global brain atrophy or epilepsy chronicity. During normal neurodevelopment and brain maturation, differential growth of brain cortical layers (Armstrong et al., 1995) and the establishment of interregional axonal connections (Van Essen, 1997) change the smooth fetal brain to a more complex and folded adult human brain. Gyral folding is believed to begin early in life, with all major gyri present by 25 weeks of gestation and cortical folding pattern fully completed close to term (Amunts et al., 1997). Alteration to gyral folding, whether by genetic or early environmental factors, may result in cortical malformations (Armstrong et al., 1995). Indeed, many MCDs are associated with either too many small gyri (polymicrogyri) or too few large gyri (pachygyri) (Barkovich et al., 2005). Previously identified mutations in a nonchannel gene, EFHC1, in families of patients with JME (Suzuki et al., 2004) are believed to inhibit apoptosis and interfere with embryonic cortical development (de Nijs et al., 2009) and thus contribute to MCDs (Wong, 2010). These findings suggest that MCDs can explain the underlying pathogenesis in JME. Although, it is difficult to attribute exact interpretation to the specific sites of cortical morphologic changes observed in this study, our finding indicates abnormal cortical folding and thus suggest the possibility of cortical developmental abnormalities, such as MCDs. Histologic studies, however, are needed to confirm this hypothesis. A change in cortical folding is believed to reflect on aberrant cortical–cortical connectivity (Goldman-Rakic, 1980). Evidence of a relationship between morphologic indexes (e.g., gyrification) and aberrant patterns of cortical connections has been suggested by several studies of different psychiatric and neurodevelopmental disorders such as schizophrenia (White et al., 2003), autism (Hardan et al., 2004), William’s syndrome (Van Essen et al., 2006), and Turner syndrome (Molko et al., 2003). Concordantly, our findings may illustrate aberrant patterns of cortical connectivity involved in seizure generation or propagation in JME. This is supported by the growing evidence of restricted cortical hyperexcitability involving networks distributed throughout the cortex (Lin et al., 2009a; Holmes et al., 2010). This speculation further supports the experimental cortical focus theory for generalized seizures (Meeren et al., 2005), which suggests that the cortex may play a leading role in seizure generation with the thalamus facilitating the spread of seizure activity. Combined EEG/functional MRI (fMRI) studies of SW activity in patients with IGE (including patients with JME)

657 Cortical Morphology in JME have shown that the initial bilateral thalamic and mesial frontal cortical activation during SW is usually accompanied with deactivation of the association cortex, the so-called ‘‘default mode’’ networks (Archer et al., 2003; Aghakhani et al., 2004; Gotman et al., 2005). Cortical hypoactivations were attributed to seizure-induced injury and deafferentation of the cortex during generalized SW seizures, mediated by thalamic hyperexcitability (Gotman et al., 2005). These suggestions may provide an alternative explanation to our findings. However, the increased surface area in some of the clusters of abnormal cortical morphology in addition to the lack of correlation between disease variables and cortical parameters suggest that these findings are likely independent of epilepsy chronicity. Despite the interesting findings, limitations of this study are acknowledged. For example, the patient sample was relatively small; therefore, the findings may be specific to the cohort investigated and replication of the study in a larger sample of patients with JME is recommended. In addition, the heterogeneity of our patients with JME, in relation to seizure semiology, severity of seizures, duration of epilepsy, and antiepileptic medication, could not be eliminated. In terms of the image analysis, a nonspecific measure of cortical morphology, the Jacobian matrix, was employed to capture general shape differences. However, given that this general parameter encompasses all aspects of shape change we believe it is a useful surrogate marker of abnormal cortical folding. Finally, we could not determine if the detected changes in cortical morphology in different regions of the brain were independent from each other or are due to a common process. It is possible that the investigation of the underlying pathogenesis of JME would improve further by combining MRI-based cortical morphology measurements with diffusion tensor imaging (DTI), functional MRI, and/ or EEG.

Conclusion In this study, we present evidence of widespread cortical morphology changes in patients with JME that involved cortical regions beyond the frontal lobe. Cortical morphology changes may point to cortical folding abnormality related to early disruption of cortical development and regions of malformation of cortical developments (MCDs).

Acknowledgments The authors thank all patients and participants who took part in this study. This work was funded by a Health Research Board fellowship (HSR/ 2006/7) awarded to LR.

Disclosure The authors have no conflicts of interest to disclose. 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.

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