Abstract
While there is mounting evidence of abnormal reactivity of several brain regions in social anxiety disorder, and disrupted functional connectivity between these regions at rest, relatively little is known regarding resting regional neural activity in these structures, or how such activity is affected by pharmacotherapy. Using 2-deoxy-2-(F-18)fluoro-D-glucose positron emission tomography, we compared resting regional brain metabolism between SAD and healthy control groups; and in SAD participants before and after moclobemide therapy. Voxel-based analyses were confined to a predefined search volume. A second, exploratory whole-brain analysis was conducted using a more liberal statistical threshold. Fifteen SAD participants and fifteen matched controls were included in the group comparison. A subgroup of SAD participants (n = 11) was included in the therapy effect comparison. No significant clusters were identified in the primary analysis. In the exploratory analysis, the SAD group exhibited increased metabolism in left fusiform gyrus and right temporal pole. After therapy, SAD participants exhibited reductions in regional metabolism in a medial dorsal prefrontal region and increases in right caudate, right insula and left postcentral gyrus. This study adds to the limited existing work on resting regional brain activity in SAD and the effects of therapy. The negative results of our primary analysis suggest that resting regional activity differences in the disorder, and moclobemide effects on regional metabolism, if present, are small. While the outcomes of our secondary analysis should be interpreted with caution, they may contribute to formulating future hypotheses or in pooled analyses.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American Psychiatric Association, DSM-5 Task Force (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association, Arlington
Arnold-Anteraper S, Triantafyllou C, Sawyer AT et al (2014) Hyper-connectivity of subcortical resting-state networks in social anxiety disorder. Brain Connect. https://doi.org/10.1089/brain.2013.0180
Beck AT, Steer RA, Brown GK, Beck depression inventory—II M (1996) Manual for beck depression inventory-II
Bennett CM, Wolford GL, Miller MB (2009) The principled control of false positives in neuroimaging. Soc Cogn Affect Neurosci 4:417–422. https://doi.org/10.1093/scan/nsp053
Billewicz WZ (1964) Matched samples in medical investigations. Br J Prev Soc Med 18:167–173
Bonnet U (2003) Moclobemide: therapeutic use and clinical studies. CNS Drug Rev 9:97–140. https://doi.org/10.1111/j.1527-3458.2003.tb00245.x
Brühl AB, Delsignore A, Komossa K, Weidt S (2014a) Neuroimaging in social anxiety disorder—a meta-analytic review resulting in a new neurofunctional model. Neurosci Biobehav Rev 47:260–280. https://doi.org/10.1016/j.neubiorev.2014.08.003
Brühl AB, Hänggi J, Baur V et al (2014b) Increased cortical thickness in a frontoparietal network in social anxiety disorder. Hum Brain Mapp 35:2966–2977. https://doi.org/10.1002/hbm.22378
Button KS, Ioannidis JPA, Mokrysz C et al (2013) Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 14:365–376. https://doi.org/10.1038/nrn3475
Bzdok D, Schilbach L, Vogeley K et al (2012) Parsing the neural correlates of moral cognition: ALE meta-analysis on morality, theory of mind, and empathy. Brain Struct Funct 217:783–796. https://doi.org/10.1007/s00429-012-0380-y
Caulfield MD, Servatius RJ (2013) Focusing on the possible role of the cerebellum in anxiety disorders. New Insights into Anxiety Disorders. https://doi.org/10.5772/52954.
Chen JJ, Jann K, Wang DJJ (2015) Characterizing resting-state brain function using arterial spin labeling. Brain Connect 5:527–542. https://doi.org/10.1089/brain.2015.0344
Chua P, Krams M, Toni I et al (1999) A functional anatomy of anticipatory anxiety. NeuroImage 9:563–571
Cremers HR, Roelofs K (2016) Social anxiety disorder: a critical overview of neurocognitive research. Wiley Interdiscip Rev Cogn Sci 7:218–232. https://doi.org/10.1002/wcs.1390
Crippa JAS, Derenusson GN, Ferrari TB et al (2011) Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol Oxf Engl 25:121–130. https://doi.org/10.1177/0269881110379283
Devlin JT, Russell RP, Davis MH et al (2000) Susceptibility-induced loss of signal: comparing PET and fMRI on a semantic task. NeuroImage 11:589–600
Ding J, Chen H, Qiu C et al (2011) Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study. Magn Reson Imaging 29:701–711. https://doi.org/10.1016/j.mri.2011.02.013
Doruyter A, Groenewold NA, Dupont P, Stein DJ, Warwick JM (2017) Resting-state FMRI and social cognition: an opportunity to connect. Hum Psychopharmacol Clin Exp e2627. https://doi.org/10.1002/hup.2627
Etkin A, Egner T, Kalisch R (2011) Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 15:85–93. https://doi.org/10.1016/j.tics.2010.11.004
Evans KC, Simon NM, Dougherty DD et al (2009) A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 34:390–398. https://doi.org/10.1038/npp.2008.69
First MB, Spitzer RL, Gibbon M, Williams JBW (1996) Structured clinical interview for DSM-IV Axis I disorders — clinician edition. Biometrics Research Department, New York State Research Institute, New York
Freitas-Ferrari MC, Hallak EC, Trzesniak C et al (2010) Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog Neuro-Psychopharmacol Biol Psychiatry 34:565–580. https://doi.org/10.1016/j.pnpbp.2010.02.028
Frith CD (2007) The social brain? Philos Trans R Soc B Biol Sci 362:671–678. https://doi.org/10.1098/rstb.2006.2003
Frith C, Frith U (2006) The neural basis of Mentalizing. Neuron 50:531–534. https://doi.org/10.1016/j.neuron.2006.05.001
Guideline For Good Clinical Practice: ICH Harmonised Tripartite Guideline. European Medicines Agency (2002) www.edctp.org/fileadmin/documents/EMEA_ICH-GCP_Guidelines_July_2002.pdf Accessed 9 Oct 2017
Guy W (1976) Clinical global impression (CGI). ECDEU assessment manual for psychopharmacology, revised. US Department of Health, Education, and Welfare, Rockville
Hertz L, Dienel GA (2002) Energy metabolism in the brain. Int Rev Neurobiol 51:1
Kessler RC, Berglund P, Demler O et al (2005) Lifetime prevalence and age-of-onset distributions of dsm-iv disorders in the national comorbidity survey replication. Arch Gen Psychiatry 62:593–602. https://doi.org/10.1001/archpsyc.62.6.593
Kestemont J, Ma N, Baetens K et al (2015) Neural correlates of attributing causes to the self, another person and the situation. Soc Cogn Affect Neurosci 10:114–121. https://doi.org/10.1093/scan/nsu030
Langer JK, Rodebaugh TL (2014) Comorbidity of social anxiety disorder and depression. https://doi.org/10.1093/oxfordhb/9780199797004.013.030
Lecrubier Y, Wittchen H-U, Faravelli C et al (2000) A European perspective on social anxiety disorder. Eur Psychiatry 15:5–16
Liebowitz MR (1987) Social phobia. Mod Probl Pharmacopsychiatry 22:141–173
Liu F, Zhu C, Wang Y et al (2015) Disrupted cortical hubs in functional brain networks in social anxiety disorder. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 126:1711–1716. https://doi.org/10.1016/j.clinph.2014.11.014
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19:1233–1239
Maldjian JA, Laurienti PJ, Burdette JH (2004) Precentral gyrus discrepancy in electronic versions of the Talairach atlas. NeuroImage 21:450–455
Manning J, Reynolds G, Saygin ZM et al (2015) Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder. PLoS One 10:e0125286. https://doi.org/10.1371/journal.pone.0125286
Marquand AF, Rezek I, Buitelaar J, Beckmann CF (2016) Understanding heterogeneity in clinical cohorts using normative models: beyond case-control studies. Biol Psychiatry 80:552–561. https://doi.org/10.1016/j.biopsych.2015.12.023
Murray RJ, Schaer M, Debbané M (2012) Degrees of separation: a quantitative neuroimaging meta-analysis investigating self-specificity and shared neural activation between self- and other-reflection. Neurosci Biobehav Rev 36:1043–1059. https://doi.org/10.1016/j.neubiorev.2011.12.013
National Collaborating Centre for Mental Health (UK) (2013) Social anxiety disorder: recognition, Assessment and treatment. British Psychological Society, Leicester (UK)
Ohayon MM, Schatzberg AF (2010) Social phobia and depression: prevalence and comorbidity. J Psychosom Res 68:235–243. https://doi.org/10.1016/j.jpsychores.2009.07.018
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113
Olson IR, Plotzker A, Ezzyat Y (2007) The enigmatic temporal pole: a review of findings on social and emotional processing. Brain 130:1718–1731. https://doi.org/10.1093/brain/awm052
Phillips J, Hewedi DH, Eissa A, Moustafa AA (2015) The cerebellum and psychiatric disorders. Name. Front Public Health 3:66
Poldrack RA (2007) Region of interest analysis for fMRI. Soc Cogn Affect Neurosci 2:67–70. https://doi.org/10.1093/scan/nsm006
Qiu C, Liao W, Ding J et al (2011) Regional homogeneity changes in social anxiety disorder: a resting-state fMRI study. Psychiatry Res 194:47–53. https://doi.org/10.1016/j.pscychresns.2011.01.010
Schulte-Rüther M, Markowitsch HJ, Fink GR, Piefke M (2007) Mirror neuron and theory of mind mechanisms involved in face-to-face interactions: a functional magnetic resonance imaging approach to empathy. J Cogn Neurosci 19:1354–1372
Schultz RT, Grelotti DJ, Klin A et al (2003) The role of the fusiform face area in social cognition: implications for the pathobiology of autism. Philos Trans R Soc B Biol Sci 358:415–427
Spielberger CD, Gorsuch RL (1983) Manual for the state-trait anxiety inventory (Form Y) (Self-evaluation questionnaire). Consulting Psychologists Press, Palo Alto
Spreng RN, Mar RA, Kim AS (2009) The common neural basis of autobiographical memory, prospection, navigation, theory of mind, and the default mode: a quantitative meta-analysis. J Cogn Neurosci 21:489–510
Stein MB, Leslie WD (1996) A brain single photon-emission computed tomography (SPECT) study of generalized social phobia. Biol Psychiatry 39:825–828. https://doi.org/10.1016/0006-3223(95)00570-6
Stein DJ, Cameron A, Amrein R, Montgomery SA (2002) Moclobemide is effective and well tolerated in the long-term pharmacotherapy of social anxiety disorder with or without comorbid anxiety disorder. Int Clin Psychopharmacol 17:161–170
Stein DJ, Ruscio AM, Lee S et al (2010) Subtyping social anxiety disorder in developed and developing countries. Depress Anxiety 1091-4269(27):390–403. https://doi.org/10.1002/da.20639
Stein DJ, Lim CCW, Roest AM et al (2017) The cross-national epidemiology of social anxiety disorder: data from the world mental health survey initiative. BMC Med 15:143. https://doi.org/10.1186/s12916-017-0889-2
Takeuchi H, Taki Y, Sassa Y et al (2014) Regional gray matter volume is associated with empathizing and systemizing in young adults. PLoS One 9:1–16. https://doi.org/10.1371/journal.pone.0084782
Tillfors M, Furmark T, Marteinsdottir I, Fredrikson M (2002) Cerebral blood flow during anticipation of public speaking in social phobia: a PET study. Biol Psychiatry 52:1113–1119
Tong J, Meyer JH, Furukawa Y et al (2013) Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 33:863–871. https://doi.org/10.1038/jcbfm.2013.19
van der Linden G, van Heerden B, Warwick J et al (2000) Functional brain imaging and pharmacotherapy in social phobia: single photon emission computed tomography before and after treatment with the selective serotonin reuptake inhibitor citalopram. Prog Neuro-Psychopharmacol Biol Psychiatry 24:419–438
van Overwalle F, D’aes T, Mariën P (2015) Social cognition and the cerebellum: a meta-analytic connectivity analysis: social cognition and cerebellum connectivity. Hum Brain Mapp 36:5137–5154. https://doi.org/10.1002/hbm.23002
Warwick JM, Carey P, Van der Linden G et al (2006) A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder. Metab Brain Dis 21:241–252. https://doi.org/10.1007/s11011-006-9009-2
Warwick JM, Carey P, Jordaan GP et al (2008) Resting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects. Prog Neuro-Psychopharmacol Biol Psychiatry 32:1251–1256
Warwick JM, Carey PD, Cassimjee N et al (2012) Dopamine transporter binding in social anxiety disorder: the effect of treatment with escitalopram. Metab Brain Dis 27:151–158. https://doi.org/10.1007/s11011-012-9280-3
Wehrl HF, Hossain M, Lankes K et al (2013) Simultaneous PET-MRI reveals brain function in activated and resting state on metabolic, hemodynamic and multiple temporal scales. Nat Med 19:1184–1189
Weiner KS, Grill-Spector K (2012) The improbable simplicity of the fusiform face area. Trends Cogn Sci 16:251–254. https://doi.org/10.1016/j.tics.2012.03.003
Wittchen HU, Beloch E (1996) The impact of social phobia on quality of life. Int Clin Psychopharmacol 11(Suppl 3):15–23
Wittchen H-U, Fehm L (2003) Epidemiology and natural course of social fears and social phobia. Acta Psychiatr Scand 108:4–18. https://doi.org/10.1034/j.1600-0447.108.s417.1.x
World Medical Association (2013) World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194. https://doi.org/10.1001/jama.2013.281053
Zhu H, Qiu C, Meng Y et al (2017) Altered topological properties of brain networks in social anxiety disorder: a resting-state functional MRI study. Sci Rep 7:43089. https://doi.org/10.1038/srep43089
Zimmer ER, Parent MJ, Souza DG et al (2017) [18F]FDG PET signal is driven by astroglial glutamate transport. Nat Neurosci 20:393–395. https://doi.org/10.1038/nn.4492
Acknowledgements
The PhD from which this study emanated was funded by the South African Medical Research Council under the MRC Clinician Researcher Programme. Study costs were funded by the Nuclear Technologies in Medicine and the Biosciences Initiative (NTeMBI), a national technology platform developed and managed by the South African Nuclear Energy Corporation (Necsa) and funded by the department of Science and Technology; and the Harry Crossley Foundation.
Author information
Authors and Affiliations
Contributions
Data collection: A Doruyter, L Taljaard, C Lochner.
Data processing and analysis: A Doruyter, P Dupont.
Manuscript: A Doruyter.
Manuscript review: All authors.
Supervisors: JM Warwick, C Lochner.
Corresponding author
Ethics declarations
None of the funders played any role in study design; collection, analysis, or interpretation of data; in the writing of this article or in the decision to submit it for publication.
Disclosure of potential conflicts of interest
This study was funded by the South African Medical Research Council under the MRC Clinician Researcher Programme; the Nuclear Technologies in Medicine and the Biosciences Initiative (NTeMBI), a national technology platform developed and managed by the South African Nuclear Energy Corporation (Necsa) and funded by the department of Science and Technology; and the Harry Crossley Foundation.
Profs Stein and Lochner receive funding from the MRC.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Doruyter, A., Dupont, P., Taljaard, L. et al. Resting regional brain metabolism in social anxiety disorder and the effect of moclobemide therapy. Metab Brain Dis 33, 569–581 (2018). https://doi.org/10.1007/s11011-017-0145-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-017-0145-7