Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Huntington's Disease | Research

The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals

Authors: Filipa Júlio, Gina Caetano, Cristina Januário, Miguel Castelo-Branco

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

Login to get access

Abstract

Background

This study aims to test response inhibition in premanifest Huntington’s disease individuals (Pre-HD), in the context of a saccadic paradigm with working memory demands and fronto-executive load as a way to measure inhibitory control deficits and impulsive behavior in Huntington’s disease (HD).

Methods

The oculomotor function of 15 Pre-HD and 22 Control individuals was assessed using an experimental paradigm comprising four horizontal saccadic tasks: prosaccade (PS), antisaccade (AS), 1- or 2-back memory prosaccade (MPS), and 1- or 2-back memory antisaccade (MAS). Success rate, latency, directional and timing errors were calculated for each task. A comprehensive battery of neuropsychological tests was also used to assess the overall cognitive functioning of study participants. Statistical correlations between oculomotor, clinical and cognitive measures were computed for the Pre-HD group.

Results

Pre-HD participants showed reduced success rate in the AS task, increased direction errors in the AS and MAS tasks and decreased latency in the MAS task when compared to Controls, despite presenting similar executive and memory scores in the conventional neuropsychological tests applied. Significant associations were identified between specific AS and MAS parameters and disease-related measures, cognitive skills and other oculomotor results of Pre-HD participants.

Conclusions

Our results show that oculomotor performance in premanifest Huntington’s disease deteriorates once inhibitory control, working memory and/or fronto-executive load are added to the task. A more automatic pattern of performance, including a faster response time and directionally erroneous eye movements were detected in the oculomotor behavior of the Pre-HD group—these alterations were significantly correlated with disease stage and cognitive status. Our saccadic paradigm was able to capture impulsivity and inhibitory control deficits in a group of Pre-HD individuals on average far from symptom onset, thus holding the potential to identify the earliest disease-related changes.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Dumas EM, van den Bogaard SJ, Middelkoop HA, Roos RA. A review of cognition in Huntington’s disease. Front Biosci (Schol Ed). 2013;5:1–18.CrossRef
5.
O’Keeffe GC, Michell AW, Barker RA. Biomarkers in Huntington’s and Parkinson’s disease. Ann N Y Acad Sci. 2009;1180:97–110.CrossRefPubMed
6.
Weir DW, Sturrock A, Leavitt BR. Development of biomarkers for Huntington's disease. Lancet Neurol. 2011;10(6):573–90.CrossRefPubMed
7.
Diamond R, White RF, Myers RH, Mastromauro C, Koroshetz WJ, Butters N, et al. Evidence of presymptomatic cognitive decline in Huntington’s disease. J Clin Exp Neuropsychol. 1992;14(6):961–75.CrossRefPubMed
8.
Harrington DL, Smith MM, Zhang Y, Carlozzi NE, Paulsen JS. Group tP-HIotHS. Cognitive domains that predict time to diagnosis in prodromal Huntington disease. J Neurol Neurosurg Psychiatry. 2012;83(6):612–9.CrossRefPubMed
9.
Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014;10(4):204–16.CrossRefPubMed
10.
Stout JC, Paulsen JS, Queller S, Solomon AC, Whitlock KB, Campbell JC, et al. Neurocognitive signs in prodromal Huntington disease. Neuropsychology. 2011;25(1):1–14.CrossRefPubMedPubMedCentral
11.
Solomon AC, Stout JC, Weaver M, Queller S, Tomusk A, Whitlock KB, et al. Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease. Mov Disord. 2008;23(13):1830–6.CrossRefPubMedPubMedCentral
12.
Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol. 2011;98:297–323.CrossRefPubMed
13.
van Asselen M, Almeida I, Júlio F, Januário C, Campos EB, Simões M, et al. Implicit contextual learning in prodromal and early stage Huntington’s disease patients. J Int Neuropsychol Soc. 2012;18(4):689–96.CrossRefPubMed
14.
van Asselen M, Júlio F, Januário C, Bobrowicz Campos E, Almeida I, Cavaco S, et al. Scanning patterns of faces do not explain impaired emotion recognition in Huntington disease: evidence for a high level mechanism. Front Psychol. 2012;3:31.
15.
Hart EP, Dumas EM, Schoonderbeek A, Wolthuis SC, van Zwet EW, Roos RA. Motor dysfunction influence on executive functioning in manifest and premanifest Huntington’s disease. Mov Disord. 2014;29(3):320–6.CrossRefPubMed
16.
Papoutsi M, Labuschagne I, Tabrizi SJ, Stout JC. The cognitive burden in Huntington’s disease: pathology, phenotype, and mechanisms of compensation. Mov Disord. 2014;29(5):673–83.CrossRefPubMed
17.
Papp KV, Kaplan RF, Snyder PJ. Biological markers of cognition in prodromal Huntington’s disease: a review. Brain Cognit. 2011;77(2):280–91.CrossRef
18.
19.
Paulsen JS. Early detection of Huntington disease. Future Neurol. 2010;5(1):85–104.CrossRef
20.
Rupp J, Blekher T, Jackson J, Beristain X, Marshall J, Hui S, et al. Progression in prediagnostic Huntington disease. J Neurol Neurosurg Psychiatry. 2010;81(4):379–84.CrossRefPubMed
21.
Stout JC, Queller S, Baker KN, Cowlishaw S, Sampaio C, Fitzer-Attas C, et al. HD-CAB: a cognitive assessment battery for clinical trials in Huntington’s disease1,2,3. Mov Disord. 2014;29(10):1281–8.CrossRefPubMed
22.
Tabrizi SJ, Scahill RI, Owen G, Durr A, Leavitt BR, Roos RA, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 2013;12(7):637–49.CrossRefPubMed
23.
Nasr S, Rosas H. Impact of Huntington’s disease on mental rotation performance in motor pre-symptomatic individuals. J Huntington’s Dis. 2019;8(3):339–56.CrossRef
24.
Carvalho JO, Long JD, Westervelt HJ, Smith MM, Bruce JM, Kim J-I, et al. The impact of oculomotor functioning on neuropsychological performance in Huntington disease. J Clin Exp Neuropsyc. 2016;38(2):217–26.CrossRef
25.
Coppen EM, van der Grond J, Hart EP, Lakke EAJF, Roos RAC. The visual cortex and visual cognition in Huntington’s disease: an overview of current literature. Behav Brain Res. 2018;351:63–74.CrossRefPubMed
26.
27.
Balci F, Day M, Rooney A, Brunner D. Disrupted temporal control in the R6/2 mouse model of Huntington's disease. Behav Neurosci. 2009;123(6):1353–8.CrossRefPubMed
28.
Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol. 2013;108:44–79.CrossRefPubMed
29.
Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69(4):680–94.CrossRefPubMed
30.
Rosas HD, Hevelone ND, Zaleta AK, Greve DN, Salat DH, Fischl B. Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology. 2005;65(5):745–7.CrossRefPubMed
31.
Rao JA, Harrington DL, Durgerian S, Reece C, Mourany L, Koenig K, et al. Disruption of response inhibition circuits in prodromal Huntington disease. Cortex. 2014;58:72–85.CrossRefPubMedPubMedCentral
32.
Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC. Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry. 2007;62(12):1341–6.CrossRefPubMed
33.
Gorges M, Pinkhardt EH, Kassubek J. Alterations of eye movement control in neurodegenerative movement disorders. J Ophthalmol. 2014;2014:11.
34.
Henderson T, Georgiou-Karistianis N, White O, Millist L, Williams DR, Churchyard A, et al. Inhibitory control during smooth pursuit in Parkinson’s disease and Huntington's disease. Mov Disord. 2011;26(10):1893–9.CrossRefPubMed
35.
Manfré G, Doyere V, Bossi S, Riess O, Nguyen HP, El Massioui N. Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. Behav Brain Res. 2016;299:6–10.CrossRefPubMed
36.
Zhang J, Nombela C, Wolpe N, Barker RA, Rowe JB. Time on timing: dissociating premature responding from interval sensitivity in Parkinson's disease. Mov Disord. 2016;31(8):1163–72.CrossRefPubMedPubMedCentral
37.
Zhang J, Rittman T, Nombela C, Fois A, Coyle-Gilchrist I, Barker RA, et al. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease. Brain. 2016;139(1):161–73.CrossRefPubMed
38.
Bayard S, Joly E, Ghisletta P, Rossignol A, Herades Y, Geny C, et al. A multidimensional approach to impulsivity in Parkinson’s disease: measurement and structural invariance of the UPPS impulsive behaviour scale. Psychol Med. 2016;46(14):2931–41.CrossRefPubMed
39.
Vela L, Martínez Castrillo JC, García Ruiz P, Gasca-Salas C, Macías Macías Y, Pérez Fernández E, et al. The high prevalence of impulse control behaviors in patients with early-onset Parkinson's disease: a cross-sectional multicenter study. J Neurol Sci. 2016;368:150–4.CrossRefPubMed
40.
Anderson TJ, MacAskill MR. Eye movements in patients with neurodegenerative disorders. Nat Rev Neurol. 2013;9(2):74–85.CrossRefPubMed
41.
Blekher T, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, et al. Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease. Vis Res. 2004;44(23):2729–36.CrossRefPubMed
42.
Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C. Identification of an oculomotor biomarker of preclinical Huntington disease. Neurology. 2006;67(3):485–7.CrossRefPubMed
43.
Patel SS, Jankovic J, Hood AJ, Jeter CB, Sereno AB. Reflexive and volitional saccades: biomarkers of Huntington disease severity and progression. J Neurol Sci. 2012;313(1–2):35–41.CrossRefPubMed
44.
Peltsch A, Hoffman A, Armstrong I, Pari G, Munoz DP. Saccadic impairments in Huntington’s disease. Exp Brain Res. 2008;186(3):457–69.CrossRefPubMed
45.
Tabrizi SJ, Reilmann R, Roos RAC, Durr A, Leavitt B, Owen G, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012;11(1):42–53.CrossRefPubMed
46.
Turner TH, Goldstein J, Hamilton JM, Jacobson M, Pirogovsky E, Peavy G, et al. Behavioral measures of saccade latency and inhibition in manifest and premanifest Huntington’s disease. J Mot Behav. 2011;43(4):295–302.CrossRefPubMed
47.
Vaca-Palomares I, Brien DC, Coe BC, Ochoa-Morales A, Martínez-Ruano L, Munoz DP, et al. Implicit learning impairment identified via predictive saccades in Huntington's disease correlates with extended cortico-striatal atrophy. Cortex. 2019;121:89–103.CrossRefPubMed
48.
Antoniades CA, Xu Z, Mason SL, Carpenter RH, Barker RA. Huntington’s disease: changes in saccades and hand-tapping over 3 years. J Neurol. 2010;257(11):1890–8.CrossRefPubMed
49.
Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology. 2006;67(3):394–9.CrossRefPubMed
50.
Rupp J, Dzemidzic M, Blekher T, West J, Hui S, Wojcieszek J, et al. Comparison of vertical and horizontal saccade measures and their relation to gray matter changes in premanifest and manifest Huntington disease. J Neurol. 2012;259(2):267–76.CrossRefPubMed
51.
Antoniades CA, Altham PM, Mason SL, Barker RA, Carpenter R. Saccadometry: a new tool for evaluating presymptomatic Huntington patients. Neuroreport. 2007;18(11):1133–6.CrossRefPubMed
52.
Mitchell JP, Macrae CN, Gilchrist ID. Working memory and the suppression of reflexive saccades. J Cognitive Neurosci. 2002;14(1):95–103.CrossRef
53.
Robert MPA, Nachev PC, Hicks SL, Golding CVP, Tabrizi SJ, Kennard C. Saccadometry of conditional rules in presymptomatic Huntington’s disease. Ann N Y Acad Sci. 2009;1164(1):444–50.CrossRefPubMed
54.
Van der Stigchel S. The search for oculomotor inhibition: interactions with working memory. Exp Psychol. 2010;57(6):429–35.CrossRefPubMed
55.
Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9.CrossRefPubMed
56.
Simões MR, Freitas S, Santana I, Firmino H, Martins C, Nasreddine Z, et al. MoCA. Versão final portuguesa [MoCA 7.1. Portuguese final version]. 2008.
57.
Freitas S, Simões MR, Alves L, Santana I. Montreal cognitive assessment (MoCA): normative study for the Portuguese population. J Clin Exp Neuropsyc. 2011;33(9):989–96.CrossRef
58.
Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, International Huntington’s Disease Collaborative G. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet. 2004;65(4):267–77.CrossRefPubMed
59.
Huntington-Study-Group. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord. 1996;11(2):136–42.CrossRef
60.
Orth M, Handley OJ, Schwenke C, Dunnett SB, Craufurd D, Ho AK, et al. Observing Huntington’s disease: the European Huntington’s disease network’s REGISTRY. PLoS Curr Huntington Dis. 2010;2:RRN1184.CrossRefPubMedCentral
61.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643–62.CrossRef
62.
Trenerry MR, Crosson B, DeBoe J, Lebel WR. Stroop Neuropsychological Screening Test (SNTC). USA: Psychological Assessment Resources; 1989.
63.
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9(1):97–113.CrossRefPubMed
64.
Wechsler D. WAIS-III administration and scoring manual. 3rd ed. San Antonio: The Psychological Corporation; 1997.
65.
Wechsler D. WAIS-III: Escala de Inteligência de Wechsler para adultos - Manual. 3rd ed. Portuguese Version [Wechsler Adult Intelligence Scale - WAIS-III]. Lisbon: Cegoc; 2008.
66.
Cavaco S, Pinto C, Gonçalves A, Gomes F, Pereira A, Malaquias C. Auditory verbal learning test: dados normativos dos 21 aos 65 anos. Psychologica. 2008;49:208–21.
67.
Rey A. Rey verbal learning test. L’examen clinique en psychologie. 2nd ed. Paris: Presses universitaires de France; 1964.
68.
Raven J, Raven JC, Court JH. Manual for Raven’s progressive matrices and vocabulary scales. Sections 1–7. 1993 ed. Oxford: Oxford Psychologists Press; 1993.
69.
Berch DB, Krikorian R, Huha EM. The Corsi block-tapping task: methodological and theoretical considerations. Brain Cognit. 1998;38(3):317–38.CrossRef
70.
Kessels RP, van Zandvoort MJ, Postma A, Kappelle LJ, de Haan EH. The Corsi block-tapping task: standardization and normative data. Appl Neuropsychol. 2000;7(4):252–8.CrossRefPubMed
71.
Benton AL. The revised visual retention test : clinical and experimental applications. 4th ed. New York: Psychological Corporation; 1974.
72.
Benton AL, Hamsher KD, Varney NR, Spreen O. Contributions to neuropsychological assessment: a clinical manual. 1st ed. New York: Oxford University Press; 1983.
73.
Lezak MD. Neuropsychological assessment. 3rd ed. New York: Oxford University Press; 1995.
74.
Ardila A, Ostrosky-Solís F, Bernal B. Cognitive testing toward the future: the example of Semantic Verbal Fluency (ANIMALS). Int J Psychol. 2006;41(5):324–32.CrossRef
75.
Snaith RP, Constantopoulos AA, Jardine MY, McGuffin P. A clinical scale for the self-assessment of irritability. Br J Psychiatry. 1978;132(2):164–71.CrossRefPubMed
76.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–70.CrossRefPubMed
77.
Snowden JS, Craufurd D, Thompson J, Neary D. Psychomotor, executive, and memory function in preclinical Huntington’s disease. J Clin Exp Neuropsyc. 2002;24(2):133–45.CrossRef
78.
Butler KM, Zacks RT, Henderson JM. Suppression of reflexive saccades in younger and older adults: age comparisons on an antisaccade task. Mem Cogn. 1999;27(4):584–91.CrossRef
79.
80.
Robert MPA, Nachev PC, Hicks SL, Golding CVP, Tabrizi SJ, Kennard C. Saccadometry of conditional rules in presymptomatic Huntington’s disease. Basic Clin Aspects Vertigo Dizziness. 2009;1164:444–50.
81.
82.
Ali FR, Michell AW, Barker RA, Carpenter RHS. The use of quantitative oculometry in the assessment of Huntington’s disease. Exp Brain Res. 2006;169(2):237–45.CrossRefPubMed
83.
Farrow M, Chua P, Churchyard A, Bradshaw JL, Chiu E, Georgiou-Karistianis N. Proximity to clinical onset influences motor and cognitive performance in presymptomatic Huntington disease gene carriers. Cogn Behav Neurol. 2006;19(4):208–16.CrossRefPubMed
84.
85.
Vaportzis E, Georgiou-Karistianis N, Churchyard A, Stout JC. Dual task performance in Huntington’s disease: a comparison of choice reaction time tasks. Neuropsychology. 2015;29(5):703–12.CrossRefPubMed
86.
Kagan J, Pearson L, Welch L. Conceptual impulsivity and inductive reasoning. Child Dev. 1966;37(3):583–94.PubMed
87.
Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, et al. Detection of Huntington’s disease decades before diagnosis: the predict-HD study. J Neurol Neurosurg Psychiatry. 2008;79(8):874–80.CrossRefPubMed
88.
Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord. 2006;21(9):1317–25.CrossRefPubMed
89.
Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, et al. Quantitative neuropathological changes in presymptomatic Huntington’s disease. Ann Neurol. 2001;49(1):29–34.CrossRefPubMed
90.
Miranda Â, Lavrador R, Júlio F, Januário C, Castelo-Branco M, Caetano G. Classification of Huntington’s disease stage with support vector machines: a study on oculomotor performance. Behav Res Methods. 2016;48(4):1667–77.CrossRefPubMed
91.
Wiecki TV, Antoniades CA, Stevenson A, Kennard C, Borowsky B, Owen G, et al. A computational cognitive biomarker for early-stage Huntington’s disease. PLoS One. 2016;11(2):e0148409.CrossRefPubMedPubMedCentral
92.
Witjes-Ané M-NW, Vegter-van der Vlis M, van Vugt JPP, Lanser JBK, Hermans J, Zwinderman AH, et al. Cognitive and motor functioning in gene carriers for Huntington’s disease: a baseline study. J Neuropsychiatry Clin Neurosci. 2003;15(1):7–16.CrossRefPubMed
93.
Biglan KM, Zhang Y, Long JD, Geschwind M, Kang GA, Killoran A, et al. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci. 2013;5:12.CrossRefPubMedPubMedCentral
94.
Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RAC, Durr A, Craufurd D, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9):791–801.CrossRefPubMedPubMedCentral
95.
Júlio F, Ribeiro MJ, Patrício M, Malhão A, Pedrosa F, Gonçalves H, et al. A novel ecological approach reveals early executive function impairments in Huntington’s disease. Front Psychol. 2019;10:585.CrossRefPubMedPubMedCentral
96.
Stout JC, Glikmann-Johnston Y, Andrews SC. Cognitive assessment strategies in Huntington’s disease research. J Neurosci Methods. 2016;265:19–24.CrossRefPubMed
Metadata
Title
The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals
Authors
Filipa Júlio
Gina Caetano
Cristina Januário
Miguel Castelo-Branco
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1218-y

Other articles of this Issue 1/2019

Orphanet Journal of Rare Diseases 1/2019 Go to the issue

Research

Primary pulmonary lymphoma in children

Letter to the Editor

Incomplete description of the current body of evidence of the health economics of Duchenne muscular dystrophy

Research

Development of national consensus statements on food labelling interpretation and protein allocation in a low phenylalanine diet for PKU

Letter to the Editor

Of the importance of the clinical phenotypes in the interpretation of the studies dealing with Fabry disease

Research

Thyroid involvement in Chanarin-Dorfman syndrome in adults in the largest series of patients carrying the same founder mutation in ABHD5 gene

Research

Comparing access to orphan medicinal products in Europe