A passive and objective measure of recognition memory in Alzheimer's disease using Fastball memory assessment

Abstract

Earlier diagnosis of Alzheimer's disease requires biomarkers sensitive to associated structural and functional changes. While considerable progress has been made in the development of structural biomarkers, functional biomarkers of early cognitive change, unconfounded by effort, practice and level of education, are still needed. We present Fastball, a new EEG method for the passive and objective measurement of recognition memory, that requires no behavioural memory response or comprehension of the task . Younger adults, older adults and Alzheimer's disease patients (n = 20 per group) completed the Fastball task, lasting just under 3 min. Participants passively viewed rapidly presented images and EEG assessed their automatic ability to differentiate between images based on previous exposure, i.e. old/new. Participants were not instructed to attend to previously seen images and provided no behavioural response. Following the Fastball task, participants completed a two-alternative forced choice (2AFC) task to measure their explicit behavioural recognition of previously seen stimuli. Fastball EEG detected significantly impaired recognition memory in Alzheimer's disease compared to healthy older adults (P < 0.001, Cohen's d = 1.52), whereas behavioural recognition was not significantly different between Alzheimer's disease and healthy older adults. Alzheimer's disease patients could be discriminated with high accuracy from healthy older adult controls using the Fastball measure of recognition memory (AUC = 0.86, P < 0.001), whereas discrimination performance was poor using behavioural 2AFC accuracy (AUC = 0.63, P = 0.148). There were no significant effects of healthy ageing, with older and younger adult controls performing equivalently in both the Fastball task and behavioural 2AFC task. Early diagnosis of Alzheimer's disease offers potential for early treatment when quality of life and independence can be retained through disease modification and cognitive enhancement. Fastball provides an alternative way of testing recognition responses that holds promise as a functional marker of disease pathology in stages where behavioural performance deficits are not yet evident. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball provides a new powerful method for the assessment of cognition in dementia and opens a new door in the development of early diagnosis tools.

Keywords: EEG; fast periodic visual stimulation; fastball; objective; recognition memory.

Figure 1

Schematic illustration of the FPVS frequency tagging design. Letters in red indicate a stream of visual presented standard and oddball stimuli. Black and blue lines represent the hypothesized neural response to the stimuli. The frequency plot illustrates the narrowband responses to stimulation frequencies.

Figure 2

Task designs across the recognition, repetition and control conditions. Pre-Fastball Encoding: In the recognition condition only subjects named the image out loud, then identified the image in a 2AFC discrimination task paired with previously unseen image (foil). Fastball: For all three conditions a base frequency F is elicited in response to the presentation of every image at 3 Hz. Black and blue lines indicate the hypothesized neural response to standard and oddball images. For the recognition condition an oddball response f is elicited due to the previous viewing of the images during the encoding task and the repeated presentation (13 times each, pseudo-random order) of the oddball images during the Fastball task. For the repetition condition an oddball response f is elicited only due to the repeated presentation (13 times each, pseudo-random order) of the oddball images during the Fastball task. Subjects attended to the fixation cross and pressed a key when the cross turned red in 10% of randomly selected standard images. Post-Fastball 2AFC: Subjects identified previously seen oddballs and a randomly selected subset of standard images in a 2AFC task. Previously seen images were presented alongside novel, previously unseen images (foils).

Figure 3

Neural recognition performance. (A) Violin plots showing oddball recognition responses (quantified as the signal to noise ratio of f+) for the three conditions and three groups, averaged across all electrodes (n = 63). Tukey box plots reflect the median and interquartile ranges, width of the violin plots reflects kernel density estimated using MATLAB’s ksdensity function. Brackets indicate statistical significance of post hoc comparisons of young versus old and old versus Alzheimer’s disease (AD). **P < 0.01, *P < 0.05, ns = P > 0.05. Topographic plots illustrate the SNR of f+ in the three conditions, for the three groups. Topographic plots illustrating the baseline corrected amplitude of f+ are provided in the Supplementary material. Key results are summarized below and in full in the text. Recognition: Alzheimer’s disease patients showed significantly impaired recognition memory compared to older adults, indexed by the reduced oddball response to previously seen images. There was no significant difference between younger and older adult controls. Repetition: Alzheimer’s disease patients showed reduced repetition detection compared to older adults, indexed by the reduced oddball response to repeated images. There was no significant difference between younger and older adult controls. (B) Violin plots illustrating SNR of F, the 3 Hz steady state response to image presentation for the three groups, averaged across all electrodes (n = 63). Tukey box plots reflect the median and interquartile ranges, width of the violin plots reflects kernel density estimated using MATLAB’s ksdensity function. (C) Topographic plots illustrate the electrodes identified by cluster permutation analysis as showing significant differences between older adults and Alzheimer’s disease patients in the SNR of f+ in the recognition and repetition conditions.

Figure 4

Behavioural recognition performance. Violin plots illustrating % accuracy for the 2AFC tasks. Scores reflect the correct recognition of either an oddball or standard stimulus compared to a foil in a 2AFC. Tukey box plots reflect the median and interquartile ranges, width of the violin plots reflects kernel density estimated using MATLAB’s ksdensity function. Oddball stimuli recall: Performance was significantly different between groups, driven by the difference between younger adults and patients with Alzheimer’s disease (AD). Post hoc comparisons of young versus old and old versus Alzheimer’s disease comparisons showed no significant differences. Standard stimuli recall: There were no significant differences between the groups in the recognition of standard stimuli, with performance around chance level (50%).

Figure 5

Alzheimer’s versus healthy older adult classification. Receiver operator characteristics (ROC) plots indicating the classification accuracies of Alzheimer’s disease versus healthy older adult controls using neural (f+) and behavioural measures (% accuracy) of recognition memory. Control: There were no significant differences between the groups in the control condition.