Original Research The Impact of Accelerated HF-rTMS on the Subgenual Anterior Cingulate Cortex in Refractory Unipolar Major Depression: Insights From 18 FDG PET Brain Imaging Chris Baeken a, b, c, * , Daniele Marinazzo d , Hendrik Everaert e , Guo-Rong Wu d, f , Christian Van Hove g , Kurt Audenaert a , Ingeborg Goethals h , Filip De Vos i , Kathelijne Peremans j , Rudi De Raedt k a Ghent University, Department of Psychiatry and Medical Psychology, Ghent, Belgium b Department of Psychiatry, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101,1090 Brussels, Belgium c Ghent University, Ghent Experimental Psychiatry (GHEP) Lab, Ghent, Belgium d Ghent University, Department of Data Analysis, Ghent, Belgium e Department of Nuclear Medicine, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101,1090 Brussels, Belgium f Key Laboratory of Cognition and Personality, Faculty of Psychology, Southwest University, Chongqing, China g iMinds Medical IT-IBiTech e MEDISIP, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium h Ghent University, Department of Nuclear Medicine, Ghent, Belgium i Ghent University, Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent, Belgium j Ghent University, Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Merelbeke, Belgium k Ghent University, Department of Experimental Clinical and Health Psychology, Ghent, Belgium article info Article history: Received 18 October 2014 Received in revised form 17 January 2015 Accepted 31 January 2015 Available online xxx Keywords: Treatment-resistance Unipolar major depression HF-rTMS 18 FDG PET sgACC CMRglc abstract Background: Although one of the most frequent diagnosed mental illnesses worldwide, it appears to be challenging to successfully treat major depressive disorder (MDD). Although the phenomenon of treat- ment-resistant depression (TRD) still remains unclear, the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible neurobiological marker to evaluate clinical effects of a variety of antide- pressant treatments, including repetitive transcranial magnetic stimulation (rTMS). Accelerated high-fre- quency (HF)-rTMS may have the potential to rapidly result in beneficial clinical outcomes in TRD. No studies yet examined the clinical effects of such accelerated stimulation treatment paradigms on sgACC regional glucose metabolism (CMRglc), nor the predictive value of the latter for clinical outcome. Objective: First, we investigated the predictive value of baseline sgACC metabolic activity for clinical outcome. Second, we hypothesized that in clinical responders only accelerated HF-rTMS treatment would result in significant metabolic decreases. Methods: We recruited right-handed antidepressant-free unipolar melancholic TRD patients to participate in a two-week randomized sham-controlled crossover HF-rTMS treatment study. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). Fifteen patients underwent 18FDG PET (CMRglc) at baseline (T0), after the first week (T1) of accelerated HF-rTMS and at the end of the treatment after the second week (T2). Results: Higher baseline sgACC metabolic activity may indicate beneficial clinical outcome to this kind of accelerated HF-rTMS treatment. Moreover, clinical response resulted in a significant decrease in sgACC CMRglc. Non-response did not affect sgACC CMRglc. Conclusions: Our results add to the sgACC as a specific neurobiological marker for anti-depressive response in accelerated HF-rTMS treatment paradigms. Such protocols may not only have the ability to result in fast clinical responses but they may also have potential to acutely modulate a dysfunctional sgACC. Ó 2015 Elsevier Inc. All rights reserved. Introduction Major depressive disorder (MDD) is not only a worldwide major mental health problem, not all patients respond to the available pharmacological treatment algorithms [1e3]. Further, when chal- lenged by refractory MDD, treatment options are limited [4,5]. Electroconvulsive therapy (ECT) is a well-known and widely used This research was supported by a grant from the Scientific Fund W. Gepts and by the Ghent University Multidisciplinary Research Partnership “The integrative neuroscience of behavioral control”. Financial disclosures: None to report. * Corresponding author. Department of Psychiatry and Medical Psychology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Tel.: þ32 (0)9 332 5543; fax: þ32 (0)9 332 4989. E-mail address: chris.baeken@UGent.be (C. Baeken). Contents lists available at ScienceDirect Brain Stimulation journal homepage: www.brainstimjrnl.com http://dx.doi.org/10.1016/j.brs.2015.01.415 1935-861X/Ó 2015 Elsevier Inc. All rights reserved. Brain Stimulation xxx (2015) 1e8