Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 48
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Beaudreau, Sherry A. MacKay-Brandt, Anna and Reynolds, Jeremy 2013. Application of a cognitive neuroscience perspective of cognitive control to late-life anxiety. Journal of Anxiety Disorders, Vol. 27, Issue. 6, p. 559.

    Price, R B Eldreth, D A and Mohlman, J 2011. Deficient prefrontal attentional control in late-life generalized anxiety disorder: an fMRI investigation. Translational Psychiatry, Vol. 1, Issue. 10, p. e46.

    Flaten, Magne Arve Aslaksen, Per M. and Lyby, Peter S. 2013. Placebo and Pain.

    Stevens, Francis L. 2016. The anterior cingulate cortex in psychopathology and psychotherapy: effects on awareness and repression of affect. Neuropsychoanalysis, Vol. 18, Issue. 1, p. 53.

    Larson, Michael J. Clawson, Ann Clayson, Peter E. and Baldwin, Scott A. 2013. Cognitive conflict adaptation in generalized anxiety disorder. Biological Psychology, Vol. 94, Issue. 2, p. 408.

    Vander Haegen, Marie Etienne, Anne-Marie and Duregger, Cornelia 2016. Cognitive processes across anxiety disorders related to intolerance of uncertainty: Clinical review. Cogent Psychology, Vol. 3, Issue. 1,

    Servaas, Michelle Nadine Riese, Harriëtte Ormel, Johan and Aleman, André 2014. The neural correlates of worry in association with individual differences in neuroticism. Human Brain Mapping, Vol. 35, Issue. 9, p. 4303.

    John Mann, J. and Yin, Honglei 2015. Brain Mapping.

    Moul, Douglas E. 2010. Science of Awakening.

    Demerdzieva, Aneta and Pop-Jordanova, Nada 2015. Relation Between Frontal Alpha Asymmetry and Anxiety in Young Patients with Generalized Anxiety Disorder. PRILOZI, Vol. 36, Issue. 2,

    Verplanken, Bas and Fisher, Naomi 2014. Habitual Worrying and Benefits of Mindfulness. Mindfulness, Vol. 5, Issue. 5, p. 566.

    Bandelow, Borwin Baldwin, David Abelli, Marianna Altamura, Carlo Dell’Osso, Bernardo Domschke, Katharina Fineberg, Naomi A. Grünblatt, Edna Jarema, Marek Maron, Eduard Nutt, David Pini, Stefano Vaghi, Matilde M. Wichniak, Adam Zai, Gwyneth and Riederer, Peter 2016. Biological markers for anxiety disorders, OCD and PTSD – a consensus statement. Part I: Neuroimaging and genetics. The World Journal of Biological Psychiatry, Vol. 17, Issue. 5, p. 321.

    Fonzo, Gregory A. Ramsawh, Holly J. Flagan, Taru M. Sullivan, Sarah G. Simmons, Alan N. Paulus, Martin P. and Stein, Murray B. 2014. Cognitive-behavioral therapy for generalized anxiety disorder is associated with attenuation of limbic activation to threat-related facial emotions. Journal of Affective Disorders, Vol. 169, p. 76.

    Wang, Yiming Chai, Fangxian Zhang, Hongming Liu, Xingde Xie, Pingxia Zheng, Lei Yang, Lixia Li, Lingjiang and Fang, Deyu 2016. Cortical functional activity in patients with generalized anxiety disorder. BMC Psychiatry, Vol. 16, Issue. 1,

    Makovac, Elena Meeten, Frances Watson, David R. Herman, Aleksandra Garfinkel, Sarah N. D. Critchley, Hugo and Ottaviani, Cristina 2015. Alterations in Amygdala-Prefrontal Functional Connectivity Account for Excessive Worry and Autonomic Dysregulation in Generalized Anxiety Disorder. Biological Psychiatry,

    Fonzo, G. A. Ramsawh, H. J. Flagan, T. M. Sullivan, S. G. Letamendi, A. Simmons, A. N. Paulus, M. P. and Stein, M. B. 2015. Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders. The British Journal of Psychiatry, Vol. 206, Issue. 3, p. 206.

    Roy, Amy K. Fudge, Julie L. Kelly, Clare Perry, Justin S.A. Daniele, Teresa Carlisi, Christina Benson, Brenda Xavier Castellanos, F. Milham, Michael P. Pine, Daniel S. and Ernst, Monique 2013. Intrinsic Functional Connectivity of Amygdala-Based Networks in Adolescent Generalized Anxiety Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, Vol. 52, Issue. 3, p. 290.

    Coakeley, Sarah Martens, Kaylena Ehgoetz and Almeida, Quincy J 2014. Management of anxiety and motor symptoms in Parkinson’s disease. Expert Review of Neurotherapeutics, Vol. 14, Issue. 8, p. 937.

    Diefenbach, Gretchen J. Assaf, Michal Goethe, John W. Gueorguieva, Ralitza and Tolin, David F. 2016. Improvements in emotion regulation following repetitive transcranial magnetic stimulation for generalized anxiety disorder. Journal of Anxiety Disorders, Vol. 43, p. 1.

    Newman, Michelle G. Llera, Sandra J. Erickson, Thane M. Przeworski, Amy and Castonguay, Louis G. 2013. Worry and Generalized Anxiety Disorder: A Review and Theoretical Synthesis of Evidence on Nature, Etiology, Mechanisms, and Treatment. Annual Review of Clinical Psychology, Vol. 9, Issue. 1, p. 275.


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

  • E. Paulesu (a1), E. Sambugaro (a1), T. Torti (a1), L. Danelli (a1), F. Ferri (a1), G. Scialfa (a2), M. Sberna (a2), G. M. Ruggiero (a3), G. Bottini (a4) (a5) and S. Sassaroli (a3)
  • DOI:
  • Published online: 07 May 2009

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.


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.


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.


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.

Corresponding author
*Address for correspondence: Professor E. Paulesu, Psychology Department, University of Milano Bicocca, Piazza Ateneo Nuovo 1, 20126 Milan, Italy. (Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

KD Alex , EA Pehek (2007). Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacology and Therapeutics 113, 296320.

E Behar , O Alcaine , AR Zuellig , TD Borkovec (2003). Screening for generalized anxiety disorder using the Penn State Worry Questionnaire: a receiver operating characteristic analysis. Journal of Behavior Therapy and Experimental Psychiatry 34, 2543.

TD Borkovec , J Inz (1990). The nature of worry in generalized anxiety disorder: a predominance of thought activity. Behaviour Research and Therapy 28, 153158.

TD Borkovec , WJ Ray , J Stober (1998). Worry: a cognitive phenomenon intimately linked to affective, physiological, and interpersonal behavioral processes. Cognitive Therapy and Research 22, 561576.

I Dinstein , C Thomas , M Behrmann , DJ Heeger (2008). A mirror up to nature. Current Biology 18, R13R18.

WG Frankle , M Laruelle , SN Haber (2006). Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. Neuropsychopharmacology 31, 16271636.

DM Fresco , AN Frankel , DS Mennin , CL Turk , RG Heimberg (2002). Distinct and overlapping features of rumination and worry: the relationship of cognitive production to negative affective states. Cognitive Therapy and Research 26, 179188.

DM Fresco , DS Mennin , RG Heimberg , CL Turk (2003). Using the Penn State Worry Questionnaire to identify individuals with generalized anxiety disorder: a receiver operating characteristic analysis. Journal of Behavior Therapy and Experimental Psychiatry 34, 283291.

L Frison , SJ Pocock (1992). Repeated measures in clinical trials: analysis using mean summary statistics and its implications for design. Statistics in Medicine 11, 16851704.

KJ Friston , CD Frith , R Turner , RS Frackowiak (1995). Characterizing evoked hemodynamics with fMRI. Neuroimage 2, 157165.

KJ Friston , AP Holmes , KJ Worsley (1999). How many subjects constitute a study? Neuroimage 10, 15.

CD Frith , U Frith (1999). Interacting minds: a biological basis. Science 286, 16921695.

CD Frith , U Frith (2006). The neural basis of mentalizing. Neuron 50, 531534.

V Gallese , L Fadiga , L Fogassi , G Rizzolatti (1996). Action recognition in the premotor cortex. Brain 119, 593609.

R Hoehn-Saric , MW Schlund , SH Wong (2004). Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder. Psychiatry Research 131, 1121.

M Iacoboni , RP Woods , M Brass , H Bekkering , JC Mazziotta , G Rizzolatti (1999). Cortical mechanisms of human imitation. Science 286, 25262528.

TJ Meyer , ML Miller , RL Metzger , TD Borkovec (1990). Development and validation of the Penn State Worry Questionnaire. Behaviour Research and Therapy 28, 487495.

MG Newman , AR Zuellig , KE Kachin , MJ Constantino , A Przeworski , T Erickson , L Cashman-McGrath (2002). Preliminary reliability and validity of the Generalized Anxiety Disorder Questionnaire-IV: a revised self-report diagnostic measure of generalized anxiety disorder. Behavior Therapy 33, 215233.

MH Pollack , R Zaninelli , A Goddard , JP McCafferty , KM Bellew , DB Burnham , MK Iyengar (2001). Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial. Journal of Clinical Psychiatry 62, 350357.

P Pratt , F Tallis , M Eysenck (1997). Information-processing, storage characteristics and worry. Behaviour Research and Therapy 35, 10151023.

N Ramnani , AM Owen (2004). Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nature Reviews Neuroscience 5, 184194.

SC Segerstrom , JCI Tsao , LE Alden , MG Craske (2000). Worry and rumination: repetitive thought as a concomitant and predictor of negative mood. Cognitive Therapy and Research 24, 671688.

E Watkins , M Moulds , B Mackintosh (2005). Comparisons between rumination and worry in a non-clinical population. Behaviour Research and Therapy 43, 15771585.

SM Williams , PS Goldman-Rakic (1998). Widespread origin of the primate mesofrontal dopamine system. Cerebral Cortex 8, 321345.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *