Psychological Medicine

Original Articles

Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study

E. Paulesua1 c1, E. Sambugaroa1, T. Tortia1, L. Danellia1, F. Ferria1, G. Scialfaa2, M. Sbernaa2, G. M. Ruggieroa3, G. Bottinia4a5 and S. Sassarolia3

a1 Psychology Department, University of Milano Bicocca, Milano, Italy

a2 Neuroradiology Department, Niguarda Cà Granda Hospital, Milano, Italy

a3 ‘Psicoterapia Cognitiva e Ricerca’ and ‘Studi Cognitivi’, Postgraduate Cognitive Psychotherapy Schools and Research Centres, Milano, Italy

a4 Psychology Department, University of Pavia, Pavia, Italy

a5 Cognitive Neuropsychology Department, Niguarda Cà 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 April 02 2008)

(Revised November 27 2008)

(Accepted February 23 2009)

(Online publication May 07 2009)


c1 Address for correspondence: Professor E. Paulesu, Psychology Department, University of Milano Bicocca, Piazza Ateneo Nuovo 1, 20126 Milan, Italy. (Email: