Erin P. Hussey

Pattern separation and pattern completion in Alzheimer's disease: Evidence of rapid forgetting in amnestic mild cognitive impairment

Over the past four decades, the characterization of memory loss associated with Alzheimers disease (AD) has been extensively debated. Recent iterations have focused on disordered encoding versus rapid forgetting. To address this issue, we used a behavioral pattern separation task to assess the ability of the hippocampus to create and maintain distinct and orthogonalized visual memory representations in patients with amnestic mild cognitive impairment (aMCI) and mild AD. We specifically used a lag‐based continuous recognition paradigm to determine whether patients with aMCI and mild AD fail to encode visual memory representations or whether these patients properly encode representations that are rapidly forgotten. Consistent with the rapid forgetting hypothesis of AD, we found that patients with aMCI demonstrated decreasing pattern separation rates as the lag of interfering objects increased. In contrast, patients with AD demonstrated consistently poor pattern separation rates across three increasingly longer lags. We propose a continuum that reflects underlying hippocampal neuropathology whereby patients with aMCI are able to properly encode information into memory but rapidly lose these memory representations, and patients with AD, who have extensive hippocampal and parahippocampal damage, cannot properly encode information in distinct, orthogonal representations. Our results also revealed that whereas patients with aMCI demonstrated similar behavioral pattern completion rates to healthy older adults, patients with AD showed lower pattern completion rates when we corrected for response bias. Finally, these behavioral pattern separation and pattern completion results are discussed in terms of the dual process model of recognition memory.

Using mental imagery to improve memory in patients with Alzheimer disease: trouble generating or remembering the mind's eye?

This study was conducted to understand whether patients with mild Alzheimer disease (AD) could use general or self-referential mental imagery to improve their recognition of visually presented words. Experiment 1 showed that, unlike healthy controls, patients generally did not benefit from either type of imagery. To help determine whether the patients’ inability to benefit from mental imagery at encoding was due to poor memory or due to an impairment in mental imagery, participants performed 4 imagery tasks with varying imagery and cognitive demands. Experiment 2 showed that patients successfully performed basic visual imagery, but degraded semantic memory, coupled with visuospatial and executive functioning deficits, impaired their ability to perform more complex types of imagery. Given that patients with AD can perform basic mental imagery, our results suggest that episodic memory deficits likely prevent AD patients from storing or retrieving general mental images generated during encoding. Overall, the results of both experiments suggest that neurocognitive deficits do not allow patients with AD to perform complex mental imagery, which may be most beneficial to improving memory. However, our data also suggest that intact basic mental imagery and rehearsal could possibly be helpful if used in a rehabilitation multisession intervention approach.

A case of hyperthymesia: rethinking the role of the amygdala in autobiographical memory

Much controversy has been focused on the extent to which the amygdala belongs to the autobiographical memory (AM) core network. Early evidence suggested the amygdala played a vital role in emotional processing, likely helping to encode emotionally charged stimuli. However, recent work has highlighted the amygdalas role in social and self-referential processing, leading to speculation that the amygdala likely supports the encoding and retrieval of AM. Here, cognitive as well as structural and functional magnetic resonance imaging data was collected from an extremely rare individual with near-perfect AM, or hyperthymesia. Right amygdala hypertrophy (approximately 20%) and enhanced amygdala-to-hippocampus connectivity (>10 SDs) was observed in this volunteer relative to controls. Based on these findings and previous literature, we speculate that the amygdala likely charges AMs with emotional, social, and self-relevance. In heightened memory, this system may be hyperactive, allowing for many types of autobiographical information, including emotionally benign, to be more efficiently processed as self-relevant for encoding and storage.

Gist-based conceptual processing of pictures remains intact in patients with amnestic mild cognitive impairment.

OBJECTIVE The picture superiority effect, better memory for pictures compared to words, has been found in young adults, healthy older adults, and, most recently, in patients with Alzheimers disease and mild cognitive impairment. Although the picture superiority effect is widely found, there is still debate over what drives this effect. One main question is whether it is enhanced perceptual or conceptual information that leads to the advantage for pictures over words. In this experiment, we examined the picture superiority effect in healthy older adults and patients with amnestic mild cognitive impairment (MCI) to better understand the role of gist-based conceptual processing. METHOD We had participants study three exemplars of categories as either words or pictures. In the test phase, participants were again shown pictures or words and were asked to determine whether the item was in the same category as something they had studied earlier or whether it was from a new category. RESULTS We found that all participants demonstrated a robust picture superiority effect, better performance for pictures than for words. CONCLUSIONS These results suggest that the gist-based conceptual processing of pictures is preserved in patients with MCI. While in healthy older adults preserved recollection for pictures could lead to the picture superiority effect, in patients with MCI it is most likely that the picture superiority effect is a result of spared conceptually based familiarity for pictures, perhaps combined with their intact ability to extract and use gist information.

Vessel-Encoded Arterial Spin Labeling (VE-ASL) Reveals Elevated Flow Territory Asymmetry in Older Adults With Substandard Verbal Memory Performance

To evaluate how flow territory asymmetry and/or the distribution of blood through collateral pathways may adversely affect the brains ability to respond to age‐related changes in brain function. These patterns have been investigated in cerebrovascular disease; however, here we evaluated how flow‐territory asymmetry related to memory generally in older adults.

Understanding age-related reductions in visual working memory capacity: Examining the stages of change detection

Visual working memory (VWM) capacity is reduced in older adults. Research has shown age-related impairments to VWM encoding, but aging is likely to affect multiple stages of VWM. In the present study, we recorded the event-related potentials (ERPs) of younger and older adults during VWM maintenance and retrieval. We measured encoding-stage processing with the P1 component, maintenance-stage processing with the contralateral delay activity (CDA), and retrieval-stage processing by comparing the activity for old and new items (old–new effect). Older adults showed lower behavioral capacity estimates (K) than did younger adults, but surprisingly, their P1 components and CDAs were comparable to those of younger adults. This remarkable dissociation between neural activity and behavior in the older adults indicated that the P1 and CDA did not accurately assess their VWM capacity. However, the neural activity evoked during VWM retrieval yielded results that helped clarify the age-related differences. During retrieval, younger adults showed early old–new effects in frontal and occipital areas and a late central–parietal old–new effect, whereas older adults showed a late right-lateralized parietal old–new effect. The younger adults’ early old–new effects strongly resembled an index of perceptual fluency, suggesting that perceptual implicit memory was activated. The activation of implicit memory could have facilitated the younger adults’ behavior, and the lack of these early effects in older adults may suggest that they have much lower-resolution memory than do younger adults. From these data, we speculated that younger and older adults store the same number of items in VWM, but that younger adults store a higher-resolution representation than do older adults.

Inverse correspondence between hippocampal perfusion and verbal memory performance in older adults

Understanding physiological changes that precede irreversible tissue damage in age‐related pathology is central to optimizing treatments that may prevent, or delay, cognitive decline. Cerebral perfusion is a tightly regulated physiological property, coupled to tissue metabolism and function, and abnormal (both elevated and reduced) hippocampal perfusion has been reported in a range of cognitive disorders. However, the size and location of the hippocampus complicates perfusion quantification, as many perfusion techniques acquire data with spatial resolution on the order of or beyond the size of the hippocampus, and are thus suboptimal in this region (especially in the presence of hippocampal atrophy and reduced flow scenarios). Here, the relationship between hippocampal perfusion and atrophy as a function of memory performance was examined in cognitively normal healthy older adults (n = 20; age=67 ± 7 yr) with varying genetic risk for dementia using a custom arterial spin labeling acquisition and analysis procedure. When controlling for hippocampal volume, it was found that hippocampal perfusion correlated inversely (P = 0.04) with memory performance despite absent hippocampal tissue atrophy or white matter disease. The hippocampal flow asymmetry (left hippocampus perfusion–right hippocampus perfusion) was significantly (P = 0.04) increased in APOE‐ϵ4 carriers relative to noncarriers. These findings demonstrate that perfusion correlates more strongly than tissue volume with memory performance in cognitively normal older adults, and furthermore that an inverse trend between these two parameters suggests that elevation of neuronal activity, possibly mediated by neuroinflammation and/or excitation/inhibition imbalance, may be closely associated with minor changes in memory performance.

γ-Aminobutyric acid (GABA) concentration inversely correlates with basal perfusion in human occipital lobe.

Commonly used neuroimaging approaches in humans exploit hemodynamic or metabolic indicators of brain function. However, fundamental gaps remain in our ability to relate such hemo-metabolic reactivity to neurotransmission, with recent reports providing paradoxical information regarding the relationship among basal perfusion, functional imaging contrast, and neurotransmission in awake humans. Here, sequential magnetic resonance spectroscopy (MRS) measurements of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA+macromolecules normalized by the complex N-acetyl aspartate-N-acetyl aspartyl glutamic acid: [GABA+]/[NAA–NAAG]), and magnetic resonance imaging (MRI) measurements of perfusion, fractional gray-matter volume, and arterial arrival time (AAT) are recorded in human visual cortex from a controlled cohort of young adult male volunteers with neurocognitive battery-confirmed comparable cognitive capacity (3 T; n=16; age=23±3 years). Regression analyses reveal an inverse correlation between [GABA+]/[NAA–NAAG] and perfusion (R=−0.46; P=0.037), yet no relationship between AAT and [GABA+]/[NAA–NAAG] (R=−0.12; P=0.33). Perfusion measurements that do not control for AAT variations reveal reduced correlations between [GABA+]/[NAA–NAAG] and perfusion (R=−0.13; P=0.32). These findings largely reconcile contradictory reports between perfusion and inhibitory tone, and underscore the physiologic origins of the growing literature relating functional imaging signals, hemodynamics, and neurotransmission.

Preserved conceptual implicit memory for pictures in patients with Alzheimer’s disease

The current study examined different aspects of conceptual implicit memory in patients with mild Alzheimers disease (AD). Specifically, we were interested in whether priming of distinctive conceptual features versus general semantic information related to pictures and words would differ for the mild AD patients and healthy older adults. In this study, 14 healthy older adults and 15 patients with mild AD studied both pictures and words followed by an implicit test section, where they were asked about distinctive conceptual or general semantic information related to the items they had previously studied (or novel items). Healthy older adults and patients with mild AD showed both conceptual priming and the picture superiority effect, but the AD patients only showed these effects for the questions focused on the distinctive conceptual information. We found that patients with mild AD showed intact conceptual picture priming in a task that required generating a response (answer) from a cue (question) for cues that focused on distinctive conceptual information. This experiment has helped improve our understanding of both the picture superiority effect and conceptual implicit memory in patients with mild AD in that these findings support the notion that conceptual implicit memory might potentially help to drive familiarity-based recognition in the face of impaired recollection in patients with mild AD.

The effect of echo time and post-processing procedure on blood oxygenation level-dependent (BOLD) functional connectivity analysis.

While spontaneous BOLD fMRI signal is a common tool to map functional connectivity, unexplained inter- and intra-subject variability frequently complicates interpretation. Similar to evoked BOLD fMRI responses, spontaneous BOLD signal is expected to vary with echo time (TE) and corresponding intra/extravascular sensitivity. This may contribute to discrepant conclusions even following identical post-processing pipelines. Here we applied commonly-utilized independent component analysis (ICA) as well as seed-based correlation analysis and investigated default mode network (DMN) and visual network (VN) detection from BOLD data acquired at three TEs (3T; TR=2500ms; TE=15ms, 35ms, and 55ms) and from quantitative R2* maps. Explained variance in ICA analysis was significantly higher (P<0.05) when R2*-derived maps were considered relative to single-TE data with no post-processing. While explained variance in the BOLD data increased with motion correction, R2* derived DMN and VN were minimally affected by motion correction. Explained variance increased in all data when physiological noise confounds were removed using CompCor. Notably, the R2*-derived connectivity patterns were least affected by motion and physiological noise confounds in a seed-based correlation analysis. Intermediate (35ms) and long (55ms) TE data provided similar spatial and temporal characteristics only after reducing motion and physiological noise contamination. Results provide an exemplar for how 3T spontaneous BOLD network detection varies with TE and post-processing procedure over the range of commonly acquired TE values.