Brain Structure and Function

, Volume 220, Issue 1, pp 501–512 | Cite as

Functional changes during working memory in Huntington’s disease: 30-month longitudinal data from the IMAGE-HD study

  • Govinda R. Poudel
  • Julie C. Stout
  • Juan F. Domínguez D
  • Marcus A. Gray
  • Louisa Salmon
  • Andrew Churchyard
  • Phyllis Chua
  • Beth Borowsky
  • Gary F. Egan
  • Nellie Georgiou-Karistianis
Original Article


We characterized 30-month longitudinal change in functional activation and connectivity during working memory in premanifest (pre-HD) and symptomatic (symp-HD) Huntington’s disease (HD). In a case–control longitudinal study (baseline, 18 months, and 30 months), we compared change in fMRI activity over time during working memory in 22 pre-HD, 11 symp-HD, and 20 control participants. Outcome measures were BOLD (blood-oxygen-level-dependent) activity during 1-BACK and 2-BACK working memory and functional connectivity between dorsolateral prefrontal cortex (DLPFC) and caudate. Compared with controls, the pre-HD group showed significantly increased activation longitudinally during 1-BACK in the left DLPFC and medial frontal cortex, and further increased activation during 2-BACK in the bilateral caudate, putamen, and temporal cortex. Longitudinal change in symp-HD was not significantly different from controls. Longitudinal changes in pre-HD were associated with disease burden and years to onset. The pre-HD group showed longitudinal decreased functional connectivity between left DLPFC and caudate during both 1-BACK and 2-BACK performance. We provide an evidence for longitudinal changes in BOLD activity during working memory prior to clinical manifestations of HD. The ability to increase activation in the prefrontal cortex over time may represent an early compensatory response during the premanifest stage, which may reflect an early marker for clinically relevant functional changes in HD.


Functional connectivity fMRI Huntington’s disease Longitudinal Working memory 



We would like to acknowledge the contribution of all the participants who took part in this study. We are also grateful to the CHDI Foundation Inc. New York (USA) (Grant Number A: 3433) and to the National Health and Medical Research Council (NHMRC) (Grant Number: 606650), for their support in funding this research. This research was supported by the VLSCI’s Life Sciences Computation Centre; a collaboration between Melbourne, Monash and La Trobe Universities and an initiative of the Victorian Government, Australia. We also thank the Royal Children’s Hospital for the use of their 3T MR scanner. GFE is a Principal NHMRC Research Fellow.

Conflict of interest

All authors reported no biomedical financial interests or potential conflicts of interest.

Supplementary material

429_2013_670_MOESM1_ESM.docx (33 kb)
Supplementary material 1 (DOCX 32 kb)
429_2013_670_MOESM2_ESM.docx (48 kb)
Supplementary material 2 (DOCX 48 kb)
429_2013_670_MOESM3_ESM.docx (18 kb)
Supplementary material 3 (DOCX 17 kb)
429_2013_670_MOESM4_ESM.docx (21 kb)
Supplementary material 4 (DOCX 20 kb)
429_2013_670_MOESM5_ESM.docx (30 kb)
Supplementary material 5 (DOCX 29 kb)


  1. Anderson KE, Perera GM, Hilton J, Zubin N, Dela Paz R, Stern Y (2002) Functional magnetic resonance imaging study of word recognition in normal elders. Prog Neuropsychopharmacol Biol Psychiatry 26:647–650PubMedCrossRefGoogle Scholar
  2. Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. NeuroImage 11:805–821PubMedCrossRefGoogle Scholar
  3. Berryhill ME, Olson IR (2008) Is the posterior parietal lobe involved in working memory retrieval? Evidence from patients with bilateral parietal lobe damage. Neuropsychologia 46:1775–1786PubMedCentralPubMedCrossRefGoogle Scholar
  4. Cabeza R, Ciaramelli E, Olson IR, Moscovitch M (2008) The parietal cortex and episodic memory: an attentional account. Nat Rev Neurosci 9:613–625PubMedCentralPubMedCrossRefGoogle Scholar
  5. Callicott JH, Egan MF, Mattay VS, Bertolino A, Bone AD, Verchinksi B, Weinberger DR (2003) Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am J Psychiatry 160:709–719PubMedCrossRefGoogle Scholar
  6. Coull JT, Nobre AC (1998) Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI. J Neurosci 18:7426–7435PubMedGoogle Scholar
  7. Georgiou-Karistianis N, Gray MA, Domínguez D JF, Dymowski AR, Bohanna I, Johnston LA, Churchyard A, Chua P, Stout JC et al (2013) Automated differentiation of pre-diagnosis Huntington’s disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: the IMAGE-HD study. Neurobiol Dis 51:82–92PubMedCrossRefGoogle Scholar
  8. Gray MA, Egan GF, Ando A, Churchyard A, Chua P, Stout JC, Georgiou-Karistianis N (2013) Prefrontal activity in Huntington’s disease reflects cognitive and neuropsychiatric disturbances: the IMAGE-HD study. Exp Neurol 239:218–228PubMedCrossRefGoogle Scholar
  9. Gusnard DA, Akbudak E, Shulman GL, Raichle ME (2001) Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci USA 98:4259–4264PubMedCentralPubMedCrossRefGoogle Scholar
  10. Hacker C, Perlmutter J, Criswell S, Ances B, Snyder A (2012) Resting state functional connectivity of the striatum in Parkinson’s disease. BrainGoogle Scholar
  11. Han SD, Bangen KJ, Bondi MW (2009) Functional magnetic resonance imaging of compensatory neural recruitment in aging and risk for Alzheimer’s disease: review and recommendations. Dement Geriatr Cogn Disord 27:1–10PubMedCentralPubMedCrossRefGoogle Scholar
  12. Jolles DD, Grol MJ, Van Buchem MA, Rombouts SA, Crone EA (2010) Practice effects in the brain: changes in cerebral activation after working memory practice depend on task demands. NeuroImage 52:658–668PubMedCrossRefGoogle Scholar
  13. Kloppel S, Draganski B, Golding CV, Chu C, Nagy Z, Cook PA, Hicks SL, Kennard C, Alexander DC et al (2008) White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington’s disease. Brain 131:196–204PubMedCrossRefGoogle Scholar
  14. Kloppel S, Draganski B, Siebner HR, Tabrizi SJ, Weiller C, Frackowiak RS (2009) Functional compensation of motor function in pre-symptomatic Huntington’s disease. Brain 132:1624–1632PubMedCentralPubMedCrossRefGoogle Scholar
  15. Laatsch LK, Thulborn KR, Krisky CM, Shobat DM, Sweeney JA (2004) Investigating the neurobiological basis of cognitive rehabilitation therapy with fMRI. Brain Inj 18:957–974PubMedCrossRefGoogle Scholar
  16. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR (2004) A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 65:267–277PubMedCrossRefGoogle Scholar
  17. Miller BR, Bezprozvanny I (2010) Corticostriatal circuit dysfunction in Huntington’s disease: intersection of glutamate, dopamine and calcium. Future Neurol 5:735–756PubMedCentralPubMedCrossRefGoogle Scholar
  18. Nelson HE, Willison J, Owen AM (1992) National adult reading test, 2nd edition. Int J Geriatr Psychiatry 7:533Google Scholar
  19. Oldfield RC (1971) The assessment and analysis of handedness: the edinburgh inventory. Neuropsychologia 9:97–113PubMedCrossRefGoogle Scholar
  20. Paulsen JS (2009) Functional imaging in Huntington’s disease. Exp Neurol 216:272–277PubMedCrossRefGoogle Scholar
  21. Paulsen JS, Zimbelman JL, Hinton SC, Langbehn DR, Leveroni CL, Benjamin ML, Reynolds NC, Rao SM (2004) fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s Disease. Am J Neuroradiol 25:1715–1721PubMedGoogle Scholar
  22. Penney JB Jr, Vonsattel JP, MacDonald ME, Gusella JF, Myers RH (1997) CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann Neurol 41:689–692PubMedCrossRefGoogle Scholar
  23. Stout JC, Paulsen JS, Queller S, Solomon AC, Whitlock KB, Campbell JC, Carlozzi N, Duff K, Beglinger LJ et al (2011) Neurocognitive signs in prodromal Huntington disease. Neuropsychology 25:1–14PubMedCentralPubMedCrossRefGoogle Scholar
  24. Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, Kennard C, Hicks SL, Fox NC et al (2009) Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 8:791–801PubMedCentralPubMedCrossRefGoogle Scholar
  25. Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H et al (2011) Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 10:31–42PubMedCrossRefGoogle Scholar
  26. Tessitore A, Esposito F, Vitale C, Santangelo G, Amboni M, Russo A, Corbo D, Cirillo G, Barone P et al (2012) Default-mode network connectivity in cognitively unimpaired patients with Parkinson disease. Neurology 79:2226–2232PubMedCrossRefGoogle Scholar
  27. Thiruvady DR, Georgiou-Karistianis N, Egan GF, Ray S, Sritharan A, Farrow M, Churchyard A, Chua P, Bradshaw JL et al (2007) Functional connectivity of the prefrontal cortex in Huntington’s disease. J Neurol Neurosurg Psychiatry 78:127–133PubMedCentralPubMedCrossRefGoogle Scholar
  28. Threlkeld ZD, Jicha GA, Smith CD, Gold BT (2011) Task deactivation reductions and atrophy within parietal default mode regions are overlapping but only weakly correlated in mild cognitive impairment. J Alzheimers Dis 27:415–427PubMedCentralPubMedGoogle Scholar
  29. Wolf RC, Vasic N, Schonfeldt-Lecuona C, Landwehrmeyer GB, Ecker D (2007) Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington’s disease: evidence from event-related fMRI. Brain 130:2845–2857PubMedCrossRefGoogle Scholar
  30. Wolf RC, Sambataro F, Vasic N, Schönfeldt-Lecuona C, Ecker D, Landwehrmeyer B (2008a) Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington’s disease. Exp Neurol 213:137–144PubMedCrossRefGoogle Scholar
  31. Wolf RC, Sambataro F, Vasic N, Schönfeldt-Lecuona C, Ecker D, Landwehrmeyer B (2008b) Altered frontostriatal coupling in pre-manifest Huntington’s disease: effects of increasing cognitive load. Eur J Neurol 15:1180–1190PubMedCrossRefGoogle Scholar
  32. Wolf RC, Vasic N, Carlos S-L, Ecker D, Landwehrmeyer GB (2009) Cortical dysfunction in patients with Huntington’s disease during working memory performance. Hum Brain Mapp 30:327–339PubMedCrossRefGoogle Scholar
  33. Wolf RC, Sambataro F, Vasic N, Wolf ND, Thomann PA, Landwehrmeyer GB, Orth M (2011) Longitudinal functional magnetic resonance imaging of cognition in preclinical Huntington’s disease. Exp Neurol 231:214–222PubMedCrossRefGoogle Scholar
  34. Wolf RC, Grön G, Sambataro F, Vasic N, Wolf ND, Thomann PA, Saft C, Landwehrmeyer GB, Orth M (2012a) Brain activation and functional connectivity in premanifest Huntington’s disease during states of intrinsic and phasic alertness. Hum Brain Mapp 33:2161–2173PubMedCrossRefGoogle Scholar
  35. Wolf RC, Sambataro F, Vasic N, Wolf ND, Thomann PA, Saft C, Landwehrmeyer GB, Orth M (2012b) Default-mode network changes in preclinical Huntington’s disease. Exp Neurol 237:191–198PubMedCrossRefGoogle Scholar
  36. Zimbelman JL, Paulsen JS, Mikos A, Reynolds NC, Hoffmann RG, Rao SM (2007) fMRI detection of early neural dysfunction in preclinical Huntington’s disease. J Int Neuropsychol Soc 13:758–769PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Govinda R. Poudel
    • 1
    • 2
    • 8
  • Julie C. Stout
    • 1
  • Juan F. Domínguez D
    • 1
  • Marcus A. Gray
    • 4
  • Louisa Salmon
    • 1
  • Andrew Churchyard
    • 3
  • Phyllis Chua
    • 1
  • Beth Borowsky
    • 5
  • Gary F. Egan
    • 1
    • 2
    • 6
    • 7
    • 8
  • Nellie Georgiou-Karistianis
    • 1
  1. 1.School of Psychology and PsychiatryMonash UniversityClaytonAustralia
  2. 2.Monash Biomedical Imaging (MBI)Monash UniversityMelbourneAustralia
  3. 3.Department of NeurologyMonash Medical CentreClaytonAustralia
  4. 4.Gehrmann Laboratory, Centre for Advanced ImagingThe University of QueenslandSt LuciaAustralia
  5. 5.CHDI Management/CHDI FoundationNew YorkUSA
  6. 6.Centre for NeuroscienceUniversity of MelbourneParkvilleAustralia
  7. 7.Howard Florey Institute, Florey Neuroscience InstitutesParkvilleAustralia
  8. 8.VLSCI Life Sciences and Computation CentreCarltonAustralia

Personalised recommendations