title: The role of the amygdala during emotional processing in Huntington's disease: from pre-manifest to late stage disease.
abstract: BACKGROUND
  Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis.
  
  
  METHODS
  We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: "the Reading the Mind in the Eyes Test" which has been previously been shown to be amygdala dependent.
  
  
  RESULTS
  Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the "Reading the Mind in the Eyes Test" correlated negatively with proximity to disease onset and became progressively worse with each stage of disease.
  
  
  CONCLUSIONS
  Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the "Reading the Mind in the Eyes Test" is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD.
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, UK. Electronic address: slm64@cam.ac.uk.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mason
authors.affiliation: MRC Cognition and Brian Sciences Unit, University of Cambridge, UK.
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, UK.
authors.forename: Faye
authors.initials: F
authors.lastname: Begeti
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, UK.
authors.forename: Natalie Valle
authors.initials: NV
authors.lastname: Guzman
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, UK.
authors.forename: Alpar S
authors.initials: AS
authors.lastname: Lazar
authors.affiliation: Department of Clinical Neuroscience, University of Cambridge, UK; MRC Cognition and Brian Sciences Unit, University of Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
authors.affiliation: Department of Clinical Neuroscience, University of Cambridge, UK; MRC Cognition and Brian Sciences Unit, University of Cambridge, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Division of Brain Sciences, Imperial College London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Hampshire
mesh_terms: D000328:Adult; D017668:Age of Onset; D000679:Amygdala / Q000098:blood supply / Q000503:physiopathology*; D058070:Asymptomatic Diseases; D001931:Brain Mapping; D003071:Cognition; D004644:Emotions / Q000502:physiology*; D005149:Facial Expression; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D007091:Image Processing, Computer-Assisted; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009434:Neural Pathways / Q000098:blood supply; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010775:Photic Stimulation; D011930:Reaction Time; D056345:Theory of Mind
chemical_list: D010100:Oxygen
keywords: Amygdala; Effective connectivity; Reading the mind in the eyes; Theory of mind; fMRI