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An fMRI Study Examining Effects of Acute D-Cycloserine During Symptom Provocation in Spider Phobia

Published online by Cambridge University Press:  07 November 2014

Robin L. Aupperle ,
Lisa R. Hale ,
Rebecca J. Chambers ,
Sharon E. Cain ,
Frank X. Barth ,
Susan C. Sharp ,
Douglas R. Denney  and
Cary R. Savage
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Abstract

Background: Exposure-based therapy for anxiety disorders is believed to operate on the basis of fear extinction. Studies have shown acute administration of D-cycloserine (DCS) enhances fear extinction in animals and facilitates exposure therapy in humans, but the neural mechanisms are not completely understood. To date, no study has examined neural effects of acute DCS in anxiety-disordered populations.

Methods: Two hours prior to functional magnetic resonance imaging scanning, 23 spider-phobic and 23 non-phobic participants were randomized to receive DCS 100 mg or placebo. During scanning, participants viewed spider, butterfly, and Gaussian-blurred baseline images in a block-design paradigm. Diagnostic and treatment groups were compared regarding differential activations to spider versus butterfly stimuli.

Results: In the phobic group, DCS enhanced prefrontal (PFC), dorsal anterior cingulate (ACC), and insula activations. For controls, DCS enhanced ventral ACC and caudate activations. There was a positive correlation between lateral PFC and amygdala activation for the placebo-phobic group. Reported distress during symptom provocation was correlated with amygdala activation in the placebo-phobic group and orbitofrontal cortex activation in the DCS-phobic group.

Conclusions: Results suggest that during initial phobic symptom provocation DCS enhances activation in regions involved in cognitive control and interoceptive integration, including the PFC, ACC, and insular cortices for phobic participants.

Type
Original Research
Information
CNS Spectrums , Volume 14 , Issue 10 , October 2009 , pp. 556 - 571
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

1.Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–627.Google Scholar
2.Black, DW. Efficacy of combined pharmacotherapy and psychotherapy versus monotherapy in the treatment of anxiety disorders. CNS Spectr. 2006;11(Suppl 12):29–33.Google Scholar
3.Hofmann, SG, Smits, JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. J Clin Psychiatry. 2008;69:621–632.Google Scholar
4.Foa, EB, Franklin, ME, Moser, J. Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination? Biol Psychiatry. 2002;52:987–997.Google Scholar
5.Walker, DL, Ressler, KJ, Lu, K, Davis, M. Facilitation of conditioned fear extinction by systematic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:2343–2351.Google Scholar
6.Ledgerwood, L, Richardson, R, Cranney, J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci. 2003;11:341–349.Google Scholar
7.Ledgerwood, L, Richardson, R, Cranney, J. D-cycloserine facilitates extinction of learned fear: Effects on reacquisition and generalized extinction. Biol Psychiatry. 2005;57:841–847.Google Scholar
8.Ledgerwood, L, Richardson, R, Cranney, J. D-cycloserine and the facilitation of conditioned fear: Consequences of reinstatement. Behav Neurosci. 2004;118:505–513.Google Scholar
9.Watson, GB, Bolanowski, MA, Baganoff, MP, Deppeler, CL, Lanthorn, TH. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res. 1990;510:158–160.Google Scholar
10.Bliss, TV, Collingridge, GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31–39.CrossRefGoogle ScholarPubMed
11.Malenka, RC, Nicoll, RA. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 1993;16:521–527.Google Scholar
12.Sakurai, S, Yu, L, Tan, SE. Roles of hippocampal N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II in amphetamine-produced conditioned place preference in rats. Behav Pharmacol. 2007;18:497–506.Google Scholar
13.Rouaud, E, Billard, JM. D-cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices. Br J Pharmacol. 2003;140:1051–1056.Google Scholar
14.Wu, SL, Hsu, LS, Tu, WT, et al.Effects of D-cycloserine on the behavior and ERK activity in the amygdala: role of individual anxiety levels. Behav Brain Res. 2008;187:246–253.Google Scholar
15.Fujihira, T, Kanematsu, S, Umino, A, Yamamoto, N, Nishikawa, T. Selective increase in the extracellular D-serine contents by D-cycloserine in the rat medial frontal cortex. Neurochem Int. 2007;51:233–236.Google Scholar
16.Ressler, KJ, Rothbaum, BO, Tannenbaum, L, et al.Cognitive enhancers as adjuncts to psychotherapy. Arch Gen Psychiatry. 2004;61:1136–1144.Google Scholar
17.Hofmann, SG, Meuret, AE, Smits, JA, et al.Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry. 2006;63:298–304.Google Scholar
18.Guastella, AJ, Richardson, R, Lovibond, PF, et al.A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry. 2008;63:544–549.CrossRefGoogle ScholarPubMed
19.Kushner, MG, Kim, SW, Donahue, C, et al.. D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol Psychiatry. 2007;62:835–838.Google Scholar
20.Wilhelm, S, Buhlmann, U, Tolin, DF, et al.Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder. Am J Psychiatry. 2008;65:335–341.Google Scholar
21.Storch, EA, Merlo, LJ, Bengtson, M, et al.D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2007;22:230–237.Google Scholar
22.Rothbaum, BO. Critical parameters for D-cycloserine enhancement of cognitive-behaviorial therapy for obsessive-compulsive disorder. Am J Psychiatry. 2008;165:293–296.Google Scholar
23.Britton, JC, Gold, AL, Feczko, EJ, Rauch, SL, Williams, D, Wright, CI. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr. 2007;12:600–605.Google Scholar
24.Kalisch, R, Holt, B, Petrovic, P, et al.The NMDA Agonist D-Cycloserine Facilitates Fear Memory Consolidation in Humans. Cereb Cortex. 2009;19:187–196.Google Scholar
25.Maren, S. Building and burying fear memories in the brain. Neuroscientist. 2005;11:89–99.CrossRefGoogle ScholarPubMed
26.Norberg, MM, Krystal, JH, Tolin, DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry. 2008;63:1118–1126.Google Scholar
27.Brown, TA, DiNardo, P, Barlow, DH. Anxiety Disorders Interview Schedule for DSM IV (ADIS-IV). New York, NY: Oxford University Press; 1994.Google Scholar
28.Klorman, R, Hastings, JE, Weerts, TC, Melamed, BG, Lang, PJ. Psychometric Description of Some Specific-Fear Questionnaires. Behav Therapy. 1974;5:401–409.Google Scholar
29.Beck, AT, Steer, RA, Brown, GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation; 1996.Google Scholar
30.Wechsler, D. Wechsler adult intelligence scale, third edition (WAIS-III) administration and scoring manual. San Antonio, TX: Psychological Corporation; 1997.Google Scholar
31.Merckelbach, H, Jong, P, Arntz, A. Case history and shorter communication: Imagery ability and exposure in vivo in spider phobia. Behav Res Ther. 1991;29:203–205.Google Scholar
32.D'Souza, DC, Gil, R, Cassello, K, et al.IV Glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans. Biol Psychiatry. 2000;47:450–462.Google Scholar
33.Baron, H, Epstein, IG, Mulinos, MG, Nair, KG. Absorption, distribution, and excretion of cycloserine in man. Antiobiot Annu. 1956;3:136–140.Google Scholar
34.Straube, T, Glauer, M, Dilger, S, Mentzel, H, Miltner, W. Effects of cognitive-behavioral therapy on brain activation in specific phobia. NeuroImage. 2006;29:125–135.Google Scholar
35.Lang, PJ, Bradley, M, Cuthbert, B. The International Affective Picture System: Technical Manual and Affective Ratings. Gainesville, FL: The Center for Research in Psychophysiology, University of Florida; 1999.Google Scholar
36.Pissiota, A, Frans, O, Michelgård, A, et al.Amygdala and anterior cingulate cortex activation during affective startle modulation: a PET study of fear. Eur J Neurosci. 2003;18:1325–1331.Google Scholar
37.Goebel, R, Jansma, H. Brain voyager, OX, version 2.0. Brain Innovation BV; 2004.Google Scholar
38.Talairach, J., Tournoux, P. Co-planar Steriotaxic Atlas of the Human Brain. New York, NY: Thieme Medical Publishers; 1988.Google Scholar
39.Kim, H, Somerville, LH, Johnstone, T, Alexander, AL, Whalen, PJ. Inverse amygdala and medial prefrontal cortex responses to surprised faces. Neuroreport. 2003;14:2317–2322.Google Scholar
40.McNally, RJ. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin Psychol Rev. 2007;27:750–759.Google Scholar
41.Shin, LM, Orr, SP, Carson, MA, et al.Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry. 2004;61:168–176.Google Scholar
42.Shin, LM, Wright, CI, Cannistraro, PA, et al.A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005;62:273–281.Google Scholar
43.SPSS Inc. SPSS Base 8.0 for Windows User's Guide. Chicago, IL: SPSS Inc.; 1998.Google Scholar
44.Friston, KJ, Holmes, AP, Worsley, K, Poline, JB, Frith, C, Frackowiak, RS. Statistical parametric maps in functional imaging: A general linear approach. Hum Brain Map. 1995;2:189–210.Google Scholar
45.Hajnal, JV, Myers, R, Oatridge, A, Schwieso, JE, Young, IR, Bydder, GM. Artifacts due to stimulus correlated motion in functional imaging of the brain. Magn Reson Med. 1994;31:283–291.Google Scholar
46.Morgan, VL, Dawant, BM, Li, Y, Pickens, DR. Comparison of fMRI statistical software packages and strategies for analysis of images containing random and stimulus-correlated motion. Comput Med Imaging Graph. 2007;31:436–446.CrossRefGoogle ScholarPubMed
47.Paquette, V, Levesque, J, Morson, B, Leroux, JM, Beaudoin, G, Bourgouin, P. Change the mind and you change the brain: Effects of cognitive behavioral therapy on the neural correlates of spider phobia. NeuroImage. 2003;18:401–409.Google Scholar
48.Schienle, A, Schäfer, A, Hermann, A, Rohrmann, S, Vaitl, D. Symptom provocation and reduction in patients suffering from spider phobia: an fMRI study on exposure therapy. Eur Arch Psychiatry Clin Neurosci. 2007;257:486–493.Google Scholar
49.Straube, T, Mentzel, HJ, Miltner, WH. Waiting for spiders: brain activation during anticipatory anxiety in spider phobics. NeuroImage. 2007;37:1427–1436.Google Scholar
50.Millecamps, M, Centeno, MV, Berra, HH, et al.D-cycloserine reduces neuropathic pain behavior through limbic NMDA-mediated circuitry. Pain. 2007;132:108–123.Google Scholar
51.Murai, R, Noda, Y, Matsui, K, et al.Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: implications for abnormalities of glutamate release and NMDA-CaMKII signaling. Behav Brain Res. 2007;180:152–160.Google Scholar
52.Kalisch, R, Korenfeld, E, Stephan, KE, Weiskopf, N, Seymour, B, Dolan, RJ. Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. J Neurosci. 2006;26:9503–9511.Google Scholar
53.Kalisch, R, Wiech, K, Critchley, HD, et al.Anxiety reduction through detachment: subjective, physiological, and neural effects. J Cogn Neurosci. 2005;17:874–883.Google Scholar
54.Milad, MR, Rauch, SL. The role of the orbitofrontal cortex in anxiety disorders. Ann N Y Acad Sci. 2007;1121:546–561.Google Scholar
55.Critchley, HD. Neural mechanisms of autonomic, affective, and cognitive integration. J Comp Neurol. 2005;493:154–166.Google Scholar
56.Phillips, ML, Drevets, WC, Rauch, SL, Lane, R. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry. 2003;54:504–514.Google Scholar
57.Paulus, MP, Stein, MB. An insular view of anxiety. Biol Psychiatry. 2006;60:383–387.Google Scholar
58.Simmons, A, Matthews, SC, Paulus, MP, Stein, MB. Intolerance of uncertainty correlates with insula activation during affective ambiguity. Neurosci Lett. 2008;430:92–97.Google Scholar
59.Stein, MB, Simmons, AN, Feinstein, JS, Paulus, MP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry. 2007;164:318–27.Google Scholar
60.Dilger, S, Straube, T, Mentzel, HJ, et al.Brain activation to phobia-related pictures in spider phobic humans: an event-related fMRI study. Neurosci Lett. 2003;348:29–32.Google Scholar
61.Goossens, L, Sunaert, S, Peeters, R, Griez, EJ, Schruers, KR. Amygdala hyperfunction in phobic fear normalizes after exposure. Biol Psychiatry. 2007;62:1119–1125.Google Scholar
62.Cechetto, DF. Identification of a cortical site for stress-induced cardiovascular dysfunction. Integr Physiol Behav Sci. 1994;29:362–373.Google Scholar
63.Craig, AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3:655–666.Google Scholar
64.Foa, EB, Kozak, MJ. Emotional processing of fear: Exposure to corrective information. Psychol Bull. 1986;99:20–35.Google Scholar
65.Lang, PJ. Imagery in therapy: An information processing analysis of fear. Behav Ther. 1977;8:862–886.Google Scholar
66.Lang, PJ. A bio-informational theory of emotional imagery. Psychophysiology. 1979;16:495–512.Google Scholar
67.Rodebaugh, TL, Chambless, DL. Cognitive therapy for performance anxiety. J Clin Psychol. 2004;60:809–820.Google Scholar
68.Davis, M, Myers, KM, Chhatwal, J, Ressler, KJ. Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx. 2006;3:82–96.Google Scholar
69.Bush, G, Luu, P, Posner, MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4:215–222.CrossRefGoogle ScholarPubMed
70.Yaka, R, Biegon, A, Grigoriadis, N, et al.D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J. 2007;21:2033–2041.Google Scholar
71.Yang, YL, Lu, KT. Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala. Neuroscience. 2005;134:247–260.Google Scholar
72.Yamamoto, S, Morinobu, S, Fuchikami, M, Kurata, A, Kozuru, T, Yamawaki, S. Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD. Neuropsychopharmacology. 2008;33:2108–2116.Google Scholar
73.Kim, H, Somerville, LH, Johnstone, T, Polis, S, Alexander, AL, Shin, LM, Whalen, PJ. Contextual modulation of amygdala responsivity to surprised faces. J Cogn Neurosci. 2004;16:1730–45.Google Scholar
74.Tsukada, H, Kakiuchi, T, Shizuno, H, Nishiyama, S. Interactions of cholinergic and glutamatergic neuronal systems in the functional activation of cerebral blood flow response: a PET study in unanesthetized monkeys. Brain Res. 1998;796:82–90.CrossRefGoogle ScholarPubMed