title: A Computational Cognitive Biomarker for Early-Stage Huntington's Disease.
abstract: Huntington's disease (HD) is genetically determined but with variability in symptom onset, leading to uncertainty as to when pharmacological intervention should be initiated. Here we take a computational approach based on neurocognitive phenotyping, computational modeling, and classification, in an effort to provide quantitative predictors of HD before symptom onset. A large sample of subjects-consisting of both pre-manifest individuals carrying the HD mutation (pre-HD), and early symptomatic-as well as healthy controls performed the antisaccade conflict task, which requires executive control and response inhibition. While symptomatic HD subjects differed substantially from controls in behavioral measures [reaction time (RT) and error rates], there was no such clear behavioral differences in pre-HD. RT distributions and error rates were fit with an accumulator-based model which summarizes the computational processes involved and which are related to identified mechanisms in more detailed neural models of prefrontal cortex and basal ganglia. Classification based on fitted model parameters revealed a key parameter related to executive control differentiated pre-HD from controls, whereas the response inhibition parameter declined only after symptom onset. These findings demonstrate the utility of computational approaches for classification and prediction of brain disorders, and provide clues as to the underlying neural mechanisms.
authors.affiliation: Cognitive, Linguistic & Psychological Sciences, Brown, Providence, United States of America.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Wiecki
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Level 6 West Wing, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom.
authors.forename: Chrystalina A
authors.initials: CA
authors.lastname: Antoniades
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Level 6 West Wing, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stevenson
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Level 6 West Wing, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kennard
authors.affiliation: CHDI Management Inc/CHDI Foundation, 155 Village Boulevard, Suite 200, Princeton, NJ 08540, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Borowsky
authors.affiliation: Huntington's Disease Research Centre, UCL Institute of Neurology, 2nd Floor Russell Square House, 10-12 Russell Square, London, WC1B 5EH, United Kingdom.
authors.forename: Gail
authors.initials: G
authors.lastname: Owen
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Blair
authors.initials: B
authors.lastname: Leavitt
authors.affiliation: Department of Neurology, Leiden University Medical Centre, 2300RC Leiden, The Netherlands.
authors.forename: Raymund
authors.initials: R
authors.lastname: Roos
authors.affiliation: Department of Genetics and Cytogenetics, and INSERM UMR S679, APHP Hôpital de la Salpêtrière, 75013 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Huntington's Disease Research Centre, UCL Institute of Neurology, 2nd Floor Russell Square House, 10-12 Russell Square, London, WC1B 5EH, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.affiliation: Cognitive, Linguistic & Psychological Sciences, Brown, Providence, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Frank
mesh_terms: D000328:Adult; D001479:Basal Ganglia / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology*; D003198:Computer Simulation; D018450:Disease Progression; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008875:Middle Aged; D008960:Models, Psychological; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology; D011379:Prognosis; D011581:Psychological Tests; D011930:Reaction Time; D012438:Saccades / Q000502:physiology
chemical_list: D015415:Biomarkers