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Irritability in pre-clinical Huntington's disease

Klöppel, Stefan and Stonnington, Cynthia M. and Petrovic, Predrag and Mobbs, Dean and Tüscher, Oliver and Craufurd, David and Tabrizi, Sarah J. and Frackowiak, Richard S. J. (2010) Irritability in pre-clinical Huntington's disease. Neuropsychologia, 48 (2). pp. 549-557. ISSN 0028-3932. PMCID PMC2809920. doi:10.1016/j.neuropsychologia.2009.10.016.

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Irritability, together with depression and anxiety, form three salient clinical features of pre-symptomatic Huntington's disease (HD). To date, the understanding of irritability in HD suffers from a paucity of experimental data and is largely based on questionnaires or clinical anecdotes. Factor analysis suggests that irritability is related to impulsivity and aggression and is likely to engage the same neuronal circuits as these behaviours, including areas such as medial orbitofrontal cortex (OFC) and amygdala. 16 pre-symptomatic gene carriers (PSCs) and 15 of their companions were asked to indicate the larger of two squares consecutively shown on a screen while undergoing functional magnetic resonance imaging (fMRI). Despite correct identification of the larger square, participants were often told that they or their partner had given the wrong answer. Size differences were subtle to make negative feedback credible but detectable. Although task performance, baseline irritability, and reported task-induced irritation were the same for both groups, fMRI revealed distinct neuronal processing in those who will later develop HD. In controls but not PSCs, task-induced irritation correlated positively with amygdala activation and negatively with OFC activation. Repetitive negative feedback induced greater amygdala activations in controls than PSCs. In addition, the inverse functional coupling between amygdala and OFC was significantly weaker in PSCs compared to controls. Our results argue that normal emotion processing circuits are disrupted in PSCs via attenuated modulation of emotional status by external or internal indicators. At later stages, this dysfunction may increase the risk for developing recognised, HD-associated, psychiatric symptoms such as irritability.

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Mobbs, Dean0000-0003-1175-3772
Additional Information:© 2009 Elsevier Ltd. Open access under CC BY license. Open Access funded by Wellcome Trust. Received 7 March 2009, Revised 9 August 2009, Accepted 20 October 2009, Available online 28 October 2009. Competing interests: None. This work was supported by the Wellcome Trust (grant 075696 2/04/2 to R.S.J.F., and S.J.T.) and the Bundesministerium für Forschung und Gesundheit (BMBF grant 01GW0730 to O.T.). While writing the manuscript S.K. was funded by the Medizinische Fakultät of the University of Freiburg. P.P. is supported by a grant from Vetenskaps rådet and Hjärnfonden, Sweden. Acknowledgements: We would like to thank Susie Henley as well as Maggie Burrows, Rachel Taylor, Tom Warner and Edward Wild for their help with the recruitment. We also thank Natasja van Harskamp for the scoring of the NART. Furthermore, we would like to thank Chris Frith and Christoph Kaller for helpful suggestions for the preparation of this manuscript.
Funding AgencyGrant Number
Wellcome Trust075696 2/04/2
Bundesministerium für Bildung und Forschung (BMBF)01GW0730
University of FreiburgUNSPECIFIED
Vetenskaps rådet and HjärnfondenUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC2809920
Record Number:CaltechAUTHORS:20180306-141346246
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Official Citation:Stefan Klöppel, Cynthia M. Stonnington, Predrag Petrovic, Dean Mobbs, Oliver Tüscher, David Craufurd, Sarah J. Tabrizi, Richard S.J. Frackowiak, Irritability in pre-clinical Huntington's disease, Neuropsychologia, Volume 48, Issue 2, 2010, Pages 549-557, ISSN 0028-3932, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85144
Deposited By: Tony Diaz
Deposited On:06 Mar 2018 22:38
Last Modified:15 Nov 2021 20:26

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