Neuroscience and Biobehavioral Reviews 59 (2015) 92–99 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal h om epa ge: www.elsevier.com/locate/neubiorev Review Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review Tamar M. van Veenendaal a,b , Dominique M. IJff b,c , Albert P. Aldenkamp b,c,d,e,f , Paul A.M. Hofman a,b,c , Marielle C.G. Vlooswijk b,c,d , Rob P.W. Rouhl b,c,d , Anton J. de Louw c,d,f , Walter H. Backes a,b , Jacobus F.A. Jansen a,b,∗ a Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands b School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands c Epilepsy Center Kempenhaeghe, PO Box 61, 5590 AB Heeze, The Netherlands d Department of Neurology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands e Department of Neurology, Gent University Hospital, De Pintelaan 185, 9000 Gent, Belgium f Faculty of Electrical Engineering, University of Technology Eindhoven, PO Box 513, 5600 MB Eindhoven, The Netherlands a r t i c l e i n f o Article history: Received 4 March 2015 Received in revised form 7 October 2015 Accepted 12 October 2015 Available online 22 October 2015 Keywords: Cognitive side effects Treatment failure Anticonvulsant MR spectroscopy Functional MRI a b s t r a c t As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be mea- sured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the cur- rent research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects. © 2015 Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 3. Pharmacodynamic and pharmacokinetic mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 4. Magnetic resonance spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 5. Functional MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 6. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 7. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 ∗ Corresponding author at: Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel.: +31 43 387 4908; fax: +31 43 387 6909. E-mail address: jacobus.jansen@mumc.nl (J.F.A. Jansen). 1. Introduction Despite the introduction of several antiepileptic drugs (AEDs) in recent decades, a large number of patients with epilepsy do not respond favorably to AEDs. Ideally, AED usage results in complete seizure freedom, without any unwanted side effects. However, http://dx.doi.org/10.1016/j.neubiorev.2015.10.004 0149-7634/© 2015 Elsevier Ltd. All rights reserved.