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Brain Advance Access published online on May 20, 2008
Brain, doi:10.1093/brain/awn082
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease

M. Hoefer1,2, S. C. Allison1,2, G. F. Schauer1,2, J. M. Neuhaus3, J. Hall1,2, J. N. Dang4, M. W. Weiner1,5,6, B. L. Miller1,2 and H. J. Rosen1,2

1University of California at San Francisco Department of Neurology, 2USCF Memory and Aging Center, 3UCSF Department of Epidemiology and Biostatistics, 4UCSF School of Pharmacy, 5San Francisco Veterans Affairs Hospital Magnetic Resonance Imaging Unit and 6UCSF Department of Radiology, San Francisco, CA, USA

Correspondence to: Howard J. Rosen, UCSF Department of Neurology, Memory and Aging Center, 350 Parnassus Ave., Box 1207, Suite 706, San Francisco, CA 94143-1207, USA E-mail: hrosen{at}memory.ucsf.edu

Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological–anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.

Key Words: frontotemporal lobar degeneration; Alzheimer's disease; emotion; fear conditioning

Abbreviations: ACC, anterior cingulate cortex; CS, conditioned stimulus; FC, fear conditioning; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; GDS, Geriatric Depression Scale; OFC, orbitofrontal cortex; ROI, regions of interest; SCL, skin conductance level; SCR, skin conductance response; SD, semantic dementia; US, unconditioned stimulus; VBM, voxel-based morphometry

Received September 22, 2007. Revised March 4, 2008. Accepted April 11, 2008.


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