Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study E. Paulesu 1 *, E. Sambugaro 1 , T. Torti 1 , L. Danelli 1 , F. Ferri 1 , G. Scialfa 2 , M. Sberna 2 , G. M. Ruggiero 3 , G. Bottini 4,5 and S. Sassaroli 3 1 Psychology Department, University of Milano Bicocca, Milano, Italy 2 Neuroradiology Department, Niguarda Ca ` Granda Hospital, Milano, Italy 3 ‘ Psicoterapia Cognitiva e Ricerca ’ and ‘ Studi Cognitivi ’, Postgraduate Cognitive Psychotherapy Schools and Research Centres, Milano, Italy 4 Psychology Department, University of Pavia, Pavia, Italy 5 Cognitive Neuropsychology Department, Niguarda Ca ` Granda Hospital, Milano, Italy Background. Worry is considered a key feature of generalized anxiety disorder (GAD), whose neural correlates are poorly understood. It is not known whether the brain regions involved in pathological worry are similar to those involved in worry-like mental activity in normal subjects or whether brain areas associated with worry are the same for different triggers such as verbal stimuli or faces. This study was designed to clarify these issues. Method. Eight subjects with GAD and 12 normal controls underwent functional magnetic resonance imaging (fMRI) mood induction paradigms based on spoken sentences or faces. Sentences were either neutral or designed to induce worry. Faces conveyed a sad or a neutral mood and subjects were instructed to empathize with those moods. Results. We found that the anterior cingulate and dorsal medial prefrontal cortex [Brodmann area (BA) 32/23 and BA 10/11] were associated with worry triggered by sentences in both subjects with GAD and normal controls. However, GAD subjects showed a persistent activation of these areas even during resting state scans that followed the worrying phase, activation that correlated with scores on the Penn State Worry Questionnaire (PSWQ). This region was activated during the empathy experiment for sad faces. Conclusions. The results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying. Received 2 April 2008 ; Revised 27 November 2008 ; Accepted 23 February 2009 ; First published online 7 May 2009 Key words : Activation, anterior cingulate cortex, empathy, fMRI, generalized anxiety disorder (GAD), introspection, medial prefrontal cortex, mood induction, Penn State Worry Questionnaire, theory of mind, worry. Introduction Worry is a mental process that is widely considered a key component of anxiety (Borkovec et al. 1998) and it is the central feature of generalized anxiety disorder (GAD) as defined by the DSM-IV (APA, 1994 ; Brown et al. 2001 ; Fresco et al. 2003). Worry is also frequently associated with depressive rumination (Borkovec, 1994 ; Segerstrom et al. 2000 ; Fresco et al. 2002, 2003 ; Watkins et al. 2005), which is characterized by the predominance of chronic, excessive and uncontrol- lable negative thoughts (Borkovec, 1994). People tend to use worry as a strategy for gaining emotional self-control. However, excessive worry is a fallacious strategy to solve objective and subjective difficulties. In fact, worrying people do not plan com- plex responses to overwhelming events, rather they tend to repeat to themselves that things will get worse. In figuring out strategies to overcome negative events, worriers use both verbal thinking and visual imagery (Scho ¨ npflug, 1989). Worry is a prolonged phenomenon, not easy to stop because worrying individuals have tightly organized clusters of worry-related information stored in long- term memory (Pratt et al. 1997). This is an interesting * Address for correspondence : Professor E. Paulesu, Psychology Department, University of Milano Bicocca, Piazza Ateneo Nuovo 1, 20126 Milan, Italy. (Email : eraldo.paulesu@unimib.it) Psychological Medicine (2010), 40, 117–124. f Cambridge University Press 2009 doi:10.1017/S0033291709005649 ORIGINAL ARTICLE