Research Article| Volume 10, ISSUE 2, P291-297, March 2017

Medial prefrontal cortex stimulation accelerates therapy response of exposure therapy in acrophobia

Published:November 14, 2016DOI:


      • High-frequency rTMS (10 Hz) can improve the efficacy of virtual reality exposure based therapy (VRET) in acrophobic patients.
      • Higher reduction of phobic anxiety and avoidance after VR exposure therapy in the active stimulation group.
      • R-TMS seems to primarily influence extinction processes and not extinction recall itself.
      • While the general principle of increased fear extinction after rTMS holds up across species, individual effects may differ.



      Animal as well as human research indicated that the ventral medial prefrontal cortex (vmPFC) is highly relevant for fear extinction learning. Recently, we showed that targeting the vmPFC with high-frequency repetitive transcranial magnetic stimulation (rTMS) in a placebo-controlled study with 45 healthy controls induced higher prefrontal activity during extinction of conditioned stimuli (CS+) in the active compared to the sham stimulated group and better extinction learning as indicated by ratings, fear potentiated startles and skin conductance responses.


      In this study, we aimed to proof our concept of accelerating extinction learning using rTMS of the mPFC in a group of anxiety disorder patients.


      To specifically evaluate the impact of rTMS on exposure-based therapy, we applied a sham-controlled protocol over the vmPFC (FPz) succeeded by a virtual reality exposure therapy (VRET) in n = 20 participants with acrophobia and n = 19 controls.


      We found a significantly higher reduction in active compared to sham stimulated group for anxiety (t[37] = 2.33, p < 0.05) as well as avoidance ratings t[37] = 2.34, p < 0.05) from pre to post therapy.


      This study provides first clinical evidence that high-frequency rTMS over the vmPFC improves exposure therapy response of acrophobia symptoms.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Wittchen H.U.
        • Jacobi F.
        • Rehm J.
        • Gustavsson A.
        • Svensson M.
        • Jonsson B.
        • et al.
        The size and burden of mental disorders and other disorders of the brain in Europe 2010. European neuropsychopharmacology.
        J Eur Coll Neuropsychopharmacol. 2011; 21: 655-679
        • Kessler R.C.
        • Angermeyer M.
        • Anthony J.C.
        • Deg R.
        • Demyttenaere K.
        • Gasquet I.
        • et al.
        Lifetime prevalence and age-of-onset distributions of mental disorders in the world health Organization's world mental health survey initiative. World psychiatry.
        official J World Psychiatric Assoc. 2007; 6: 168-176
        • Gustavsson A.
        • Svensson M.
        • Jacobi F.
        • Allgulander C.
        • Alonso J.
        • Beghi E.
        • et al.
        Cost of disorders of the brain in Europe 2010. European neuropsychopharmacology.
        J Eur Coll Neuropsychopharmacol. 2011; 21: 718-779
        • Bandelow B.
        • Lichte T.
        • Rudolf S.
        • Wiltink J.
        • Beutel M.
        S3-Leitlinie angststörungen.
        Springer: Heidelberg, 2015
        • Gloster A.T.
        • Wittchen H.U.
        • Einsle F.
        • Lang T.
        • Helbig-Lang S.
        • Fydrich T.
        • et al.
        Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in CBT.
        J Consult Clin Psychol. 2011; 79: 406-420
        • Bajbouj M.
        • Padberg F.
        A perfect match: noninvasive brain stimulation and psychotherapy.
        Eur Archives Psychiatry Clin Neurosci. 2014; 264: 27-33
        • Vennewald N.
        • Diemer J.
        • Zwanzger P.
        Repetitive transkranielle magnetstimulation (rTMS) bei angsterkrankungen—eine mögliche therapieoption? Eine systematische übersicht. = Repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders—a possible therapeutic option? A systematic review.
        Fortschritte Neurol Psychiatr. 2013; 81: 550-560
        • Deppermann S.
        • Vennewald N.
        • Diemer J.
        • Sickinger S.
        • Haeussinger F.B.
        • Notzon S.
        • et al.
        Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS.
        BioMed Res Int. 2014; 2014: 542526
        • Balconi M.
        • Ferrari C.
        Left DLPFC rTMS stimulation reduced the anxiety bias effect or how to restore the positive memory processing in high-anxiety subjects.
        Psychiatry Res. 2013; 209: 554-559
        • Berlim M.T.
        • Van Den Eynde F.
        Repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for treating posttraumatic stress disorder: an exploratory meta-analysis of randomized, double-blind and sham-controlled trials.
        Can J psychiatry Revue Can de psychiatrie. 2014; 59: 487-496
        • Li H.
        • Wang J.
        • Li C.
        • Xiao Z.
        Repetitive transcranial magnetic stimulation (rTMS) for panic disorder in adults.
        Cochrane database Syst Rev. 2014; 9 (CD009083)
        • Marin M.F.
        • Camprodon J.A.
        • Dougherty D.D.
        • Milad M.R.
        Device-based brain stimulation to augment fear extinction: implications for PTSD treatment and beyond.
        Depress anxiety. 2014; 31: 269-278
        • Vervliet B.
        • Craske M.G.
        • Hermans D.
        Fear extinction and relapse: state of the art.
        Annu Rev Clin Psychol. 2013; 9: 215-248
        • Baek K.
        • Chae J.H.
        • Jeong J.
        The effect of repetitive transcranial magnetic stimulation on fear extinction in rats.
        Neuroscience. 2012; 200: 159-165
        • Quirk G.J.
        • Mueller D.
        Neural mechanisms of extinction learning and retrieval.
        Neuropsychopharmacol official Publ Am Coll Neuropsychopharmacol. 2008; 33: 56-72
        • Phelps E.A.
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        Extinction learning in humans: role of the amygdala and vmPFC.
        Neuron. 2004; 43: 897-905
        • Kalisch R.
        • Korenfeld E.
        • Stephan K.E.
        • Weiskopf N.
        • Seymour B.
        • Dolan R.J.
        Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network.
        J Neurosci official J Soc Neurosci. 2006; 26: 9503-9511
        • Guhn A.
        • Dresler T.
        • Hahn T.
        • Muhlberger A.
        • Strohle A.
        • Deckert J.
        • et al.
        Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy.
        Neuropsychobiology. 2012; 65: 173-182
        • Guhn A.
        • Dresler T.
        • Andreatta M.
        • Müller L.D.
        • Hahn T.
        • Tupak S.V.
        • et al.
        Medial prefrontal cortex stimulation modulates the processing of conditioned fear.
        Front Behav Neurosci. 2014; : 8
        • Deppermann S.
        • Notzon S.
        • Kroczek A.
        • Rosenbaum D.
        • Haeussinger F.B.
        • Diemer J.
        • et al.
        Functional co-activation within the prefrontal cortex supports the maintenance of behavioural performance in fear-relevant situations before an iTBS modulated virtual reality challenge in participants with spider phobia.
        Behav brain Res. 2016; 307: 208-217
        • Muhlberger A.
        • Herrmann M.J.
        • Wiedemann G.C.
        • Ellgring H.
        • Pauli P.
        Repeated exposure of flight phobics to flights in virtual reality.
        Behav Res Ther. 2001; 39: 1033-1050
        • Shiban Y.
        • Schelhorn I.
        • Pauli P.
        • Muhlberger A.
        Effect of combined multiple contexts and multiple stimuli exposure in spider phobia: a randomized clinical trial in virtual reality.
        Behav Res Ther. 2015; 71: 45-53
        • Ressler K.J.
        • Rothbaum B.O.
        • Tannenbaum L.
        • Anderson P.
        • Graap K.
        • Zimand E.
        • et al.
        Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinctionof fear.
        Archives general psychiatry. 2004; 61: 1136-1144
        • Rothbaum B.O.
        • Hodges L.F.
        • Kooper R.
        • Opdyke D.
        • Williford J.S.
        • North M.
        Effectiveness of computer-generated (virtual reality) graded exposure in the treatment of acrophobia.
        Am J psychiatry. 1995; 152: 626-628
        • World Medical A
        World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.
        Jama. 2013; 310: 2191-2194
        • Cohen D.C.
        Comparison of self-report and overt-behavioral procedures for assessing acrophobia.
        Behav Ther. 1977; 8: 17-23
        • Abelson J.L.
        • Curtis G.C.
        Cardiac and neuroendocrine responses to exposure therapy in height phobics: desynchrony within the 'physiological response system.
        Behav Res Ther. 1989; 27: 561-567
        • Spielberger C.D.
        • Sydeman S.J.
        State-Trait Anxiety Inventory and State-Trait Anger Expression Inventory. The use of psychological testing for treatment planning and outcome assessment.
        Lawrence Erlbaum Associates, Inc, Hillsdale, NJ, England1994: 292-321 (pp)
        • Taylor S.
        • Zvolensky M.J.
        • Cox B.J.
        • Deacon B.
        • Heimberg R.G.
        • Ledley D.R.
        • et al.
        Robust dimensions of anxiety sensitivity: development and initial validation of the Anxiety Sensitivity Index-3.
        Psychol Assess. 2007; 19: 176-188
        • Krohne H.W.
        • Egloff B.
        • Kohlmann C.-W.
        • Tausch A.
        Untersuchungen mit einer deutschen Version der” Positive and Negative Affect Schedule”(PANAS).
        Diagnostica. 1996; 42: 139-156
      1. Hautzinger M, Bailer M, Hofmeister D, Keller F. Allgemeine depressionsskala (ADS). Psychiatr Prax 39(06): 302–304.

        • Mühlberger A.
        • Kinateder M.
        • Brütting J.
        • Eder S.
        • Müller M.
        • Gromer D.
        • et al.
        Influence of information and instructions on human behavior in tunnel accidents: a virtual reality study.
        J Virtual Real Broadcast. 2015; 12: 1-13
        • Morina N.
        • Ijntema H.
        • Meyerbroker K.
        • Emmelkamp P.M.
        Can virtual reality exposure therapy gains be generalized to real-life? A meta-analysis of studies applying behavioral assessments.
        Behav Res Ther. 2015; 74: 18-24
        • Madeira O.
        Höhenangst in virtueller Realität.
        University of Würzburg, Würzburg2015 (Master thesis)
        • Gromer D.
        • Madeira O.
        • Gast P.
        • Nehfischer M.
        • Jost M.
        • Müller M.
        • et al.
        Height simulation in a virtual reality CAVE system: effects of presence on fear responses.
        in: 57th conference of experimental psychologists (TeaP): hildesheim, Germany. 2015
        • Jasper H.H.
        The ten twenty electrode system of the international federation.
        Electroencephalogr Clin neurophysiology. 1958; 10: 371-375
        • Kim S.C.
        • Jo Y.S.
        • Kim I.H.
        • Kim H.
        • Choi J.S.
        Lack of medial prefrontal cortex activation underlies the immediate extinction deficit.
        J Neurosci official J Soc Neurosci. 2010; 30: 832-837
        • Milad M.R.
        • Quirk G.J.
        Neurons in medial prefrontal cortex signal memory for fear extinction.
        Nature. 2002; 420: 70-74
        • Milad M.R.
        • Vidal-Gonzalez I.
        • Quirk G.J.
        Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner.
        Behav Neurosci. 2004; 118: 389-394
        • Notzon S.
        • Deppermann S.
        • Fallgatter A.
        • Diemer J.
        • Kroczek A.
        • Domschke K.
        • et al.
        Psychophysiological effects of an iTBS modulated virtual reality challenge including participants with spider phobia.
        Biol Psychol. 2015; 112: 66-76
        • Quirk G.J.
        • Likhtik E.
        • Pelletier J.G.
        • Paré D.
        Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons.
        J Neurosci. 2003; 23: 8800-8807
        • Glotzbach-Schoon E.
        • Andreatta M.
        • Reif A.
        • Ewald H.
        • Troger C.
        • Baumann C.
        • et al.
        Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle.
        Front Behav Neurosci. 2013; 7: 31
        • Diemer J.
        • Alpers G.W.
        • Peperkorn H.M.
        • Shiban Y.
        • Muhlberger A.
        The impact of perception and presence on emotional reactions: a review of research in virtual reality.
        Front Psychol. 2015; 6: 26
        • Baumgartner T.
        • Speck D.
        • Wettstein D.
        • Masnari O.
        • Beeli G.
        • Jancke L.
        Feeling present in arousing virtual reality worlds: prefrontal brain regions differentially orchestrate presence experience in adults and children.
        Front Hum Neurosci. 2008; 2: 8
        • Asthana M.
        • Nueckel K.
        • Muhlberger A.
        • Neueder D.
        • Polak T.
        • Domschke K.
        • et al.
        Effects of transcranial direct current stimulation on consolidation of fear memory.
        Front psychiatry. 2013; 4: 107
        • Wietschorke K.
        • Lippold J.
        • Jacob C.
        • Polak T.
        • Herrmann M.J.
        Transcranial direct current stimulation of the prefrontal cortex reduces cue-reactivity in alcohol dependent patients.
        J Neural Transm. 2016; 123: 1173-1178
        • Vierheilig N.
        • Mühlberger A.
        • Polak T.
        • Herrmann M.J.
        Transcranial direct current stimulation of the prefrontal cortex increases attention to visual target stimuli.
        J Neural Transm. 2016; 123: 1195-1203
        • van 't Wout M.
        • Mariano T.Y.
        • Garnaat S.L.
        • Reddy M.K.
        • Rasmussen S.A.
        • Greenberg B.D.
        Can transcranial direct current stimulation augment extinction of conditioned fear?.
        Brain Stimul. 2016; 9: 529-536