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The Primacy Effect in Amnestic Mild Cognitive Impairment: Associations with Hippocampal Functional Connectivity

Brueggen, K and Kasper, E and Dyrba, M and Bruno, D and Pomara, N and Ewers, M and Duering, M and Buerger, K and Teipel, S (2016) The Primacy Effect in Amnestic Mild Cognitive Impairment: Associations with Hippocampal Functional Connectivity. Frontiers in Aging Neuroscience. ISSN 1663-4365

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Background: The “primacy effect,” i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI.

Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall.

Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI.


Impaired consolidation of verbal information into long-term episodic memory is the dominant symptom in Alzheimer's disease (AD) (Carlesimo and Oscar-Berman, 1992; Pena-Casanova et al., 2012; Weintraub et al., 2012). The primacy effect relies on effective memory consolidation and refers to the phenomenon that the first items of a series are remembered better than subsequent items (Murdock, 1962). In amnestic mild cognitive impairment (aMCI), which is associated with increased risk of AD dementia (Petersen et al., 1999; Albert et al., 2011), memory consolidation is impaired and the primacy effect is reduced (Howieson et al., 2011; Cunha et al., 2012; Moser et al., 2014). A reduced recall of primacy words has been shown to predict conversion from MCI to AD (Egli et al., 2014), and to distinguish MCI patients who converted to AD from nonconverters (Cunha et al., 2012).

Primacy recall performance relies on the functionality of the hippocampal system and neocortical regions, as shown for young healthy subjects in functional magnetic resonance imaging (fMRI) studies using memory tasks (Strange et al., 2002; Talmi et al., 2005; Axmacher et al., 2009) and for elderly healthy subjects in volumetric MRI studies (Bruno et al., 2015). Especially activation of the anterior part of the hippocampal body (Strange et al., 2002) and the hippocampus in the left hemisphere (Talmi et al., 2005) were associated with the retrieval of primacy words. With regard to neocortical regions, fMRI studies in healthy subjects showed that higher activation in the (para)hippocampus and posterior fusiform gyrus was associated with higher primacy recall in a verbal memory task (Strange et al., 2002), and that higher activation in the inferior parietal lobe (including angular gyrus and supramarginal gyrus) and in the superior occipital gyrus, fusiform gyrus and cuneus were associated with higher primacy recall in a visual memory task (Sommer et al., 2006).

In aMCI, the association between primacy recall and functional brain changes has not been investigated yet. However, a volumetric MRI study in aMCI showed that the primacy effect was associated with volume of the parieto-temporal lobe, including the supramarginal gyrus in inferior parietal regions, as well as the middle and inferior temporal gyrus (Kasper et al., 2016). Given previous findings on the central role of hippocampus activation in primacy recall in healthy adults and the fact that the hippocampus is impaired in aMCI (e.g., Apostolova et al., 2010), we aimed to test whether functional connectivity of the hippocampus to other cortical areas typically involved in memory is associated with residual primacy recall in aMCI. Functionally connected regions that have been associated with episodic memory include regions of the default mode network (DMN; i.e., ventral parietal, posterior cingulate, medial prefrontal, and hippocampal regions; Huijbers et al., 2011), as well as basal ganglia, cerebellum, temporal lobe regions (Bai et al., 2009), and parietal cortical regions (Kim, 2011).

Thus, in the present study, we aimed at investigating the association of hippocampal functional connectivity (FC) at resting state with delayed recall of primacy words in patients with aMCI. We hypothesized that higher resting state hippocampal FC (especially FC of the anterior and left hippocampus) with frontal, temporal and parietal cortical regions of the brain, particularly areas belonging to the DMN, would be associated with higher delayed primacy recall. To address this issue, we used linear regression analyses and a partial least squares (PLS) analysis, which allowed the simultaneous assessment of functional connectivity of these regions in a multivariate framework (Krishnan et al., 2011).

Item Type: Article
Additional Information: This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Natural Sciences and Psychology
Publisher: Frontiers Media
Date Deposited: 21 Oct 2016 13:46
Last Modified: 21 Oct 2016 13:46
URI: http://researchonline.ljmu.ac.uk/id/eprint/4677

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