ERP, fMRI and functional connectivity studies of brain response to odor in normal aging and Alzheimer's disease

More than 14 million Americans over 50 suffer from smell impairment (Murphy et al., 2002). In a series of studies we have sought the underlying cortical substrates of olfactory loss with aging. We used psychophysical, neuropsychological, event related potentials (ERPs) and functional magnetic resonance imaging (fMRI) techniques to address the problem. Psychophysical investigations have revealed significant losses in olfactory threshold sensitivity, odor identification and odor memory. These impairments are significantly worse in patients with neurodegenerative diseases such as Alzheimer’s disease (AD) (Murphy, 2002). The earliest lesions of AD are in the mesial temporal regions of the brain critical to olfactory processing, thus the potential exists for reflection of incipient disease in olfactory tasks. The investigation of olfactory function in aging and AD is of basic science interest and may contribute to the development of more sensitive diagnostic batteries for AD (Murphy, 2002). ERPs provide real-time temporal information about the brain’s response to odor stimulation. We have used this technique to investigate brain response over the lifespan in the normally aging brain (Murphy et al., 2000) and in patients with neurodegenerative diseases such as Alzheimer’s disease (Morgan and Murphy, 2002). The results suggest that the odor evoked response of the brain is significantly reduced in amplitude and delayed in its latency in normally aging persons and dramatically more delayed in Alzheimer’s patients. These results confirm the importance of considering a central origin for the olfactory loss associated with aging and AD. fMRI is a powerful tool for investigation of brain structure and of functional activation in specific regions of interest (ROIs). We have used fMRI to investigate the cortical substrate of olfactory impairment in the elderly. The fMRI data were analyzed with individual, group and ROI analyses. Results are described in Cerf-Ducastel and Murphy (2003), Ferdon and Murphy (2003) and Wiser et al. (2000). Older adults showed less activation in important olfactory ROIs: entorhinal cortex, amygdala, insula and piriform cortex. Cerebellar activation was lower in areas Crus I and II. A number of approaches have been taken to achieve an understanding of integrated brain activity. Functional connectivity involves correlation between fMRI activity in two brain regions during performance of a task. The technique permits testing the hypothesis that interacting brain regions, rather than isolated regions of interest, are the cortical substrate for performance. We have approached functional connectivity with more than one analysis strategy. Calhoun-Haney et al. (2004) used the seed voxel method to examine correlations between individual voxels in hippocampus and in ROIs for olfactory processing during an olfactory task. A number of investigators have conducted connectivity analysis on regional brain activation using correlational methods (Horwitz, 1989). Here we aimed to identify significant correlations in fMRI activation among ROIs for olfactory tasks and to test the hypothesis that the pattern of correlations among these regions is significantly impacted by aging. Activity was correlated separately for young adults, older adults and AD patients.