1 Dept. of Bioimages and Radiological Sciences Catholic University of ROME – ITALY 2 I.T.A.B. – Dept. of Neurosciences “G. d’Annunzio” University – CHIETI - ITALY Mail to: Functional Connectivity MRI (FC-MRI) of the Language Network in patients with drug-resistant Epilepsy Pravatà E 1, Sestieri C 2, Mantini D 2, Briganti C 2, Colicchio G 1, Colosimo C 1, Tartaro A 2, Romani GL 2, Caulo M 2

1 van Rijckevorsel 2006; 2 Wheless 2002; 3 Davie Bràzdil 2005; 5 Springer 1999 Introduction Epilepsy, Language and Functional Connectivity “Epilepsy is more than seizures” (1) : Subtle linguistic dysfunctions -especially receptive language- in up to a third of adults with chronic Epilepsy (2,3) In epileptic patients, different patterns of language activation and lateralization at f-MRI studies compared to normal subjects (4,5) Functional Connectivity (FC) – MRI investigates cortical connectivity by evaluating correlations of spontaneous low-frequency BOLD signal fluctuations between distant regions (6) 6 Biswal 1995;

Purposes To evaluate hemispheric language lateralization during a conventional verb- generation task experiment in patients with drug-resistant epilepsy and healthy subjects To investigate the pattern of FC across six language-related “seeding” regions in both hemispheres (IFG, T1p, T2ml) already identified in previous works 1 To correlate FC-MRI data to patients’ verbal-Intelligence Quotients (vIQs) scores 1 : Heim S. Neurosci Lett 2002 Seghier ML Hum Brain Mapp 2004 Luke KK. Hum Brain Mapp 2002 Vigneau M. Neuroimage 2006

Subjects and Methods Right-handed* Patients, (Age: 30 ± 10; range 16-51), with Drug-Resistant Epilepsy Right-Epileptogenic focus ( RE ) (N = 11)Left-Epileptogenic focus ( RE ) (N = 11) MTS4 6 Cryptogenetic4DNT2 1Cavernoma1 AVM1Cortical Dysplasia1 Micropoligyrya1 1 *As from the Edinburgh Handedness Inventory test (Italian ver.) Drug-Resistant Epilepsy (and Epileptogenic Focus side) diagnoses based on EEG recordings, MRI examination and clinical assessment. Only Pts with lesions not having a tendency to grow nor to broadly alter the normal anatomy and distant from cortical regions for speech The control group included 12 healthy right-handed*, age- and sex-matched subjects (mean age = 35) 17/22 Patients’ verbal-IQ derived from the Wechsler Adult Intelligence Scale IV- Revised (WAIS-IV- R) test for language Data were acquired on 1.5T systems (Magnetom Vision, Siemens, Erlangen, Germany and Achieva, Philips Medical Systems, Best, the Netherlands)

Subjects and Methods – 2 FC Analysis 1. FC time-course extracted from experiment’s BOLD time-course according to the procedures described in Fox et al. (2005) and Fair et al. (2006): Band-pass filtering between and 0.08 Hz; Regression of: deterministic task-evoked components, white matter and ventricle signals, and motion parameters. 2. Pair-Wise and Voxel-Wise analyses using Pearson’s correlation coefficients (r) to generate: - FC Diagrams and Matrices between LN seeding regions in pairs - FC Maps from individual seeds, covering all the acquisition volume Voxel-Wise Functional Connectivity Maps Random Effect Analysis, P <.05, FDR-corrected ) Pair-Wise Functional Connectivity Plots and Matrices (two-tailed t-test P <.01)

Taken together, all patients (22) showed more complex and bilateral language activations compared to controls: mean LI = 0.23 vs. 0.43; P <.05 Results – 1 “Conventional” Task-Evoked Experiment f-MRI Language Activations … however Only LE patients (11) had significant less lateralized language activations compared to controls: (Mean LI=0.11 vs. 0.43; P <.05) LR (P 10 mm 2 are represented)

Plots (upper row) show significant correlations by segments of variable thickness. These are further represented in the Ccolor-coded matrices (lower row), ranging from white (z = 0) to dark red (z = 0.7). Only correlations significant at P <.01 are shown. Results – 2 FC Pair-Wise analysis Patients’ significantly reduced FC links at P <.01 are shown in black lines between the nodes. - 4 links

Random Effect Analysis; p 5mm 2 are shown. Panel A: Controls Panel B: Patients Results – 3 FC Voxel-Wise Statistical Maps R Seed: Left – T1p Controls demonstrate that the L-T1p region showed correlation almost exclusively with other regions of the LN Patients suffered significant reduction of connectivity between L-T1p and other LN regions L-T1p was functionally connected with the Posterior Cingulate Cortex (PCC) only in the patient group

Results – 4 Separated Patients Groups according to the EF side Connectivity plots show statistically significant correlations by segments of variable thickness according to the Pearson’s coefficients values. Only correlations significant at P <.05 are shown. Patients with L – Epileptogenic Focus Patients with R – Epileptigenic Focus Verbal – IQ scores Left Intra-hemispheric FC (z-scores) r = 0.7; P <.0 5

Conclusions -1 We found that regardless the EF side, FC was strongly reduced in the dominant hemisphere and in particular in the T1p region, demonstrating the central role of Wernicke’s area in the LN In patients with left EF, the combination of reduced language lateralization and FC in the dominant hemisphere, correlated with the reduction of patients’ linguistic performance The connectivity links to the DMN suggest the presence of plasticity changes due to Epilepsy also involving areas not related to language The evaluation of FC underlying task-evoked activations may provide better understanding of the functional modification induced by epilepsy.

Results – 4 Correlation with Post-Operative Language Performance 10 Patients were tested again at least 6 months after surgery, and all of them had no seizures and had no change in medical therapy. Verbal – IQ scores Inter-hemispheric FC (z-scores) r = -0.6; P <.05 From these partial results, it seems that a stronger FC between the hemispheres before surgery might be unfavourable for post-operative performance.

Thank you!