Article Text

Original research
Fronto-striatal circuits for cognitive flexibility in far from onset Huntington’s disease: evidence from the Young Adult Study
  1. Christelle Langley1,
  2. Sarah Gregory2,
  3. Katie Osborne-Crowley2,3,
  4. Claire O'Callaghan1,4,
  5. Paul Zeun2,
  6. Jessica Lowe2,
  7. Eileanoir B Johnson2,
  8. Marina Papoutsi2,
  9. Rachael I Scahill2,
  10. Geraint Rees5,
  11. Sarah J Tabrizi2,
  12. Trevor W Robbins6,
  13. Barbara Jacquelyn Sahakian1
  1. 1 Department of Psychiatry, University of Cambridge, Cambridge, UK
  2. 2 Huntington’s Disease Centre, Department of Neurodegenerative disease, Institute of Neurology, University College London, London, UK
  3. 3 Division of Equity, Diversity and Inclusion, University of New South Wales, Sydney, New South Wales, Australia
  4. 4 Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  5. 5 University College London Institute of Cognitive Neuroscience, UCL, London, UK
  6. 6 Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Christelle Langley, Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK; cl798{at}medschl.cam.ac.uk

Abstract

Objectives Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington’s disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.

Methods In the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage.

Results Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants.

Conclusion We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

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Footnotes

  • Twitter @DrCLangley, @rachiscahill, @BJSahakian

  • Contributors JL, PZ, SG, EBJ and RS were involved in participant recruitment. Eligibility and clinical examinations were performed by PZ. Imaging assessments were conceived by SG, RS, EBJ and GR and implemented by SG, RS, EBJ and MP. Image processing was by SG and CL. Statistical analysis was performed by CL, TWR and BJS. CL, TWR and BJS led on drafting the manuscript, with the help and review of all co-authors. All authors edited the manuscript. SJT conceived and led the HD YAS study.

  • Funding This study was supported by a Wellcome Trust Collaborative Award 200181/Z/15/Z awarded to Professor Sarah Tabrizi, Professor Geraint Rees, Professor Gillian Bates, Professor Barbara Sahakian, Professor Trevor Robbins and Dr Hui Zhang.

  • Competing interests CL, SG, KOC, CO’C, PZ, JL, EBJ, MP, RS, GR and SJT have no competing interests. TWR and BJS consult for Cambridge Cognition.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Bloomsbury Research Ethics Committee and all participants gave written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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