Epilepsy surgery outcome and functional network alterations in longitudinal MEG: A minimum spanning tree analysis Edwin van Dellen a,b, ⁎, Linda Douw a,d,e , Arjan Hillebrand b , Philip C. de Witt Hamer c , Johannes C. Baayen c , Jan J. Heimans a , Jaap C. Reijneveld a , Cornelis J. Stam b a Department of Neurology, Cancer Center Amsterdam, VU University Medical Center, De Boelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands b Department of Clinical Neurophysiology and MEG Center, Neuroscience Campus Amsterdam, VU University Medical Center, De Boelelaan 1118, P.O. Box 7057, Amsterdam, The Netherlands c Neurosurgical Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands d Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 Thirteenth Street, Suite 2301, Charlestown, MA, USA e Harvard Medical School, Boston, MA, USA abstract article info Article history: Accepted 4 October 2013 Available online 12 October 2013 Keywords: Lesional epilepsy Glioma Resective surgery Magnetoencephalography Minimum spanning tree Network analysis Functional connectivity Seizure freedom after resective epilepsy surgery is not obtained in a substantial number of patients with medically intractable epilepsy. Functional neural network analysis is a promising technique for more accurate identification of the target areas for epilepsy surgery, but a better understanding of the correlations between changes in functional network organization due to surgery and postoperative seizure status is required. We explored these correlations in longitudinal magnetoencephalography (MEG) recordings of 20 lesional epilepsy patients. Resting-state MEG recordings were obtained at baseline (preoperatively; T0) and at 3–7 (T1) and 9–15 months after resection (T2). We assessed frequency-specific functional connectivity and performed a minimum spanning tree (MST) network analysis. The MST captures the most important connections in the network. We found a significant positive correlation between functional connectivity in the lower alpha band and seizure frequency at T0, especially in regions where lesions were located. MST leaf fraction, a measure of integration of information in the network, was significantly increased between T0 and T2, only for the seizure- free patients. This is in line with previous work, which showed that lower functional network integration in lesional epilepsy patients is related to higher epilepsy burden. Finally, eccentricity and betweenness centrality, which are measures of hub-status, decreased between T0 and T2 in seizure free patients, also in regions that were anatomically close to resection cavities. Our results increase insight into functional network changes in successful epilepsy surgery and might eventually be utilized for optimization of neurosurgical approaches. © 2013 Elsevier Inc. All rights reserved. Introduction Epilepsy is common in patients with circumscribed brain abnormalities, such as primary brain tumors and mesiotemporal sclerosis. In a substantial number of patients, anti-epileptic drug treat- ment is ineffective (Berg, 2008; Duffau et al., 2002; Hildebrand et al., 2005; Picot et al., 2008). Many patients with medically intractable non- tumoral lesional epilepsy are referred to epilepsy surgery programs. The aim of these programs is to identify patients in whom it is possible to localize and remove the epileptogenic zone (EZ), i.e. the brain regions that need to be resected to achieve seizure freedom. This strategy succeeds in only 27–67% of these patients, depending on the specific histopathology of the lesion (Tellez-Zenteno et al., 2005). Although the primary aim of surgery in patients with brain tumors is the removal of the tumor, seizure reduction often is an important secondary aim (Chang et al., 2008). For both patient groups, seizure freedom is extremely relevant, as epilepsy is an important limiting factor for quality of life and cognitive functioning (Klein et al., 2003; Markand et al., 2000; Tellez-Zenteno et al., 2007). The high prevalence of persistent seizures after epilepsy surgery demonstrates that the EZ is insufficiently identified and removed in these patients. The EZ is increasingly seen as an epileptogenic network instead of a localized cortical area, and removal of key regions in this network may increase success rates of epilepsy surgery (Kramer and Cash, 2012; Stam and van Straaten, 2012). Apart from the EZ, the functional organization of the brain network as a whole is disturbed in lesional epilepsy (Kramer and Cash, 2012). Overall, functional connectivity is increased particularly in the delta and theta frequency ranges (0.5–8 Hz) in MEG and EEG recordings, which is a hallmark of (tumor-related) epilepsy (Bettus et al., 2008; Douw et al., 2010a; Horstmann et al., 2010; van Dellen et al., 2012). However, network disturbances are not limited to this pathological increase in slow wave synchrony. The spatial organization or topology of functional neural NeuroImage 86 (2014) 354–363 Abbreviations: EZ, epileptogenic zone; MEG, magnetoencephalography; MST, minimum spanning tree; PLI, phase lag index; SF, seizure free; POS, post-operative seizures. ⁎ Corresponding author at: Department of Neurology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Fax: +31 20 4442800. E-mail address: E.vanDellen@vumc.nl (E. van Dellen). 1053-8119/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neuroimage.2013.10.010 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg