Altered frontostriatal coupling in pre-manifest Huntington's disease: effects of increasing cognitive load

Eur J Neurol. 2008 Nov;15(11):1180-90. doi: 10.1111/j.1468-1331.2008.02253.x. Epub 2008 Aug 27.


Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre-symptomatic individuals with the Huntington's disease (HD) gene mutation (pre-HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre-HD individuals.

Methods: Sixteen healthy controls and sixteen pre-HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load-dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions.

Results: In pre-HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre-HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre-HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset.

Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre-HD individuals are modulated by cognitive demand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Brain Mapping
  • Cognition / physiology
  • Cognition Disorders / diagnosis*
  • Cognition Disorders / etiology*
  • Cognition Disorders / physiopathology
  • Corpus Striatum / physiopathology*
  • DNA Mutational Analysis
  • Disability Evaluation
  • Disease Progression
  • Early Diagnosis
  • Female
  • Gyrus Cinguli / physiopathology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / complications*
  • Huntington Disease / genetics
  • Huntington Disease / psychology
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Neural Pathways / physiopathology
  • Neuropsychological Tests
  • Nuclear Proteins / genetics
  • Prefrontal Cortex / physiopathology*
  • Putamen / physiopathology


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins