www.elsevier.com/locate/brainres Available online at www.sciencedirect.com Research Report Functional dissociation within insular cortex: The effect of pre-stimulus anxiety on pain Chia-Shu Lin a , Jen-Chuen Hsieh a,b,c , Tzu-Chen Yeh a,b,c , Shyh-Yuan Lee d , David M. Niddam a,b,c,Ã a Integrated Brain Research Unit, Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan b Brain Research Center, National Yang-Ming University, Taipei, Taiwan c Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan d School of Dentistry, National Yang-Ming University, Taipei, Taiwan article info Article history: Accepted 19 November 2012 Available online 29 November 2012 Keywords: Anticipatory anxiety fMRI Insula Pain Emotional distress abstract Brain activity resulting from changes in pain intensity may not only reflect changes in stimulus intensity but also in emotional distress. The anterior and mid-posterior insula have been associated with anticipatory anxiety and sensory-discrimination, respectively. We hypothesized that the two sub-divisions would exhibit different post-stimulus responses to increased pain intensity after removing the confounding effect of anticipatory anxiety. Using functional magnetic resonance imaging, activity was found in the anterior and mid-posterior insula in response to both low- and high-intensity painful stimuli delivered at the same level of anticipatory anxiety. Anterior insula activity covaried with anxiety ratings. When the pain intensity increased and the level of anticipatory anxiety was matched, increased activity was found in the mid-posterior insula but not in the anterior insula. The increase in activity covaried with increased pain intensity. These findings support the notion that encoding in the anterior insula primarily depends on the pre-stimulus context, i.e., anticipatory anxiety rather than the perceived pain intensity, and encoding in the mid-posterior insula is related to pain intensity changes. & 2012 Elsevier B.V. All rights reserved. 1. Introduction Pain is an interoceptive sensation with a high threat value (Craig, 2003; Paulus and Stein, 2006). Receiving pain or merely anticipating it can induce anxiety (Asmundson and Katz, 2009; Ploghaus et al., 2003) and result in maladaptive beha- vior, such as fear-avoidance of pain (Vlaeyen and Linton, 2000). This is particularly important in clinical context, such as dental treatment or needle insertion, where patients often anticipate strong pain and perceive increased pain due to anticipatory anxiety (Armfield et al., 2007). Cumulating evi- dence has shown that the pain experience is associated with the activation of a network of brain regions, including the insular cortex, the anterior cingulate cortex (ACC), the pri- mary (SI) and secondary (SII) somatosensory cortices, and the thalamus (Apkarian et al., 2005; Tracey and Mantyh, 2007). The findings are often obtained by contrasting brain activity in response to high- and low- intensity stimuli. However, 0006-8993/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.brainres.2012.11.035 Ã Correspondence to: Brain Research Center and Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Taipei 112, Taiwan. Fax: þ886 2 28273123. E-mail addresses: niddam@vghtpe.gov.tw, niddam@ym.edu.tw (D.M. Niddam). brain research 1493 (2013) 40–47