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The Fast Periodic Visual Stimulation: a sensitive and objective approach to identify early cognitive markers of AD

Periodic Reporting for period 1 - ElectroMAD (The Fast Periodic Visual Stimulation: a sensitive and objective approach to identify early cognitive markers of AD)

Reporting period: 2016-04-01 to 2018-03-31

Demographic analyses predict that one third of the European population in 2050 will be above 60 years of age. Since aging is the major risk factor for dementia, this increase in the proportion of seniors is closely linked to the increased prevalence of dementia, of which Alzheimer's disease (AD) represents 70%. AD is characterized by an alteration of episodic memory, with additional deficits in at least one other cognitive domain, these deficits interfering with normal social functioning and activities of daily living. Prospective studies have shown that cerebral degeneration is already present years prior to the diagnosis of AD. These observations have led to define a clinical condition between normal aging and AD, ‘Mild Cognitive Impairment’ (MCI). MCI is conceptualized as a cognitive impairment in memory or in another cognitive domain, without consequences on daily functioning. These patients have a higher risk to evolve into AD than healthy elderly individuals.
In this context, it is interesting that although verbal episodic memory is commonly assessed for the diagnosis of AD, other cognitive functions might be more affected by this pathology. It has been shown that patients with mild AD are impaired in the recognition of newly learned faces. With the advent of promising symptomatic treatment, it is critical to diagnose AD at its earliest stages. However, the diagnosis of AD raises an important issue: performance at neuropsychological tests shows a large amount of variance in the normal population, especially in the older population. This variance is only partly due to genuine inter-individual differences in the targeted neuropsychological function (e.g. memory). Indeed, attentional, comprehension, decisional or motivational processes are likely to affect behavioral performance in neuropsychological tests. These factors question the sensitivity of tests used for the diagnosis of AD.
The objective of this project was to develop implicit measures of memory encoding for the early diagnostic of AD. Although implicit memory was traditionally considered as preserved in AD, subtle deficits have been shown in very early-impaired patients. If indeed some aspects of the implicit processing of information in incipient AD were impaired, this would open the way to develop new diagnostic tools of memory impairment. Therefore, in the purpose of large-scale population screening, this projects aims to develop sensitive measures of visual memory that can be rapidly obtained and objectively defined.
To develop sensitive measures of visual memory for the diagnosis of AD, we used electroencephalography (EEG) with entirely novel paradigms, relying on the exact synchronization of the human brain to a visual stimulus repeated at a periodic, fixed rate. This approach – the Fast Periodic Visual Stimulation (FPVS) – provides an objective measure of a process by sampling this process periodically, without requiring an explicit task for the participant, and with an extremely high sensitivity compared to conventional approaches.
We applied the FPVS approach to identify early deficits in face identity discrimination and memory for faces in aged individuals and MCI and AD patients.
Face stimuli were displayed at a constant rate of 6 Hz (F) through sinusoidal contrast modulation from 0% to 100% (Figure 1A). In a first sequence assessing face identity discrimination, one face identity (A) was presented continuously during a 60 s sequence. Every fifth stimulus (i.e F/5 = 1.2 Hz), different oddball face identities were presented, resulting in a sequence of AAAABAAAAC... (Figure 1B). If participants discriminated face A from face B or C, a significant response should appear at 1.2 Hz and multiple integer of this frequency (i.e. harmonics). The following sequence assessed face encoding/consolidation processes by testing face recognition. The facial identity (A) presented during the previous sequence was alternated with the presentation of a novel face identity (i.e. resulting in a sequence of AZAZA) (Figure 1C). The repetition frequency for one face identity was therefore 3 Hz (i.e. F/2). If participants recognized face A, a significant response is expected at 3Hz.
The validation of these experiments in young adults showed that FPVS is suitable to assess face discrimination and face recognition processes. These results were published in an international peer-reviewed journal (Lithfous & Rossion, 2018) and were presented during the Annual Meeting of the International Neuropsychology Society in 2017.
Investigation of face identity discrimination processes in healthy elderly showed that, although significant responses were observed at frequencies of interest, amplitude of the response was significantly reduced compared to young adults. These results suggest slight age-related effects on neural processes involved in face discrimination processes. These results were presented at the Annual Meeting of the Society for Neuroscience in 2016. Face recognition was found to be preserved during normal aging.
Face identity discrimination processes were preserved in AD and MCI, whereas face recognition was impaired. More particularly, the 3Hz response was observed only in 15% of the patients, compared to 80% of the healthy elderly (Figure 2). These results support deficits in implicit memory in AD pathology. Moreover, deficits in implicit memory were observed in mild stage of AD and in MCI, which can be considered as the prodromal stage of the disease, suggesting that deficits in implicit memory appear early in the course of the disease.
The objective of studying face identity discrimination and implicit memory for faces in FPVS-EEG was to develop sensitive diagnostic tools for AD. FPVS offers several advantages compared to conventional approaches : i) it allows exempting from the influence of motivational and decisional processes on the participant’s performance. In the context of the diagnosis of AD, this might be a considerable advantage, since these processes may be disrupted due to the pathological lesions of AD. ii) FPVS does not require an explicit response from the participant, which prevents from comprehension or attentional deficits often observed in patients with AD. iii) FPVS may be easily applicable in hospitals for the early diagnostic of AD and does not require expensive equipment. iv) Few minutes of stimulation are enough to induce a cerebral response at the exact frequency of stimulation. This approach may thus provide a rapid evaluation of memory encoding processes, and may be extended to other cognitive processes in the future.
In the context of global aging, it is critical to diagnose AD at the earliest stage that is, before behavioral consequences of cognitive deficits. This project of developing sensitive diagnostic tools relying on implicit visual categorization and memory encoding/consolidation processes took place in this context. The results of this project are likely to be of interest to neurologists or physicians in their clinical practice.
Figure 1. Experimental procedure
Figure 2. Face recognition in healthy elderly and Alzheimer's patient