The Timing of Gaze Direction Perception: ERP Decoding and Task Modulation.

Distinguishing the direction of another person's eye gaze is extremely important in everyday social interaction, as it provides critical information about people's attention and, therefore, intentions. The temporal dynamics of gaze processing have been investigated using event-related potentials (ERPs) recorded with electroencephalography (EEG). However, the moment at which our brain distinguishes the gaze direction (GD), irrespectively of other facial cues, remains unclear. To solve this question, the present study aimed to investigate the time course of gaze direction processing, using an ERP decoding approach, based on the combination of a support vector machine and error-correcting output codes. We recorded EEG in young healthy subjects, 32 of them performing GD detection and 34 conducting face orientation tasks. Both tasks presented 3D realistic faces with five different head and gaze orientations each: 30°, 15° to the left or right, and 0°. While the classical ERP analyses did not show clear GD effects, ERP decoding analyses revealed that discrimination of GD, irrespective of head orientation, started at 140 ms in the GD task and at 120 ms in the face orientation task. GD decoding accuracy was higher in the GD task than in the face orientation task and was the highest for the direct gaze in both tasks. These findings suggest that the decoding of brain patterns is modified by task relevance, which changes the latency and the accuracy of GD decoding.

Effect of perceived eye gaze on the N170 component - A systematic review.

Direction of another person's eye gaze provides crucial information about their attention and intentions, which is essential for an effective social interaction. Event-related potential (ERP) measures offer precise temporal tracking of neural processes related to gaze perception. While the sensitivity of the ERP component N170 to face processing is principally agreed, the research on gaze direction effect on this component is thus far inconsistent. Here, we systematically reviewed literature on the sensitivity of N170 to gaze direction. We analysed if four factors, known to affect the face N170 (i.e., emotion, face orientation, task demand, and stimuli motion), were modulated by gaze direction. N170 sensitivity to gaze was reported the most in the studies that involved deviated faces, dynamic stimuli, and that used explicit tasks directly related to gaze or face processing. The present review provides a much-needed summary of the literature to date, highlighting the complexity of the effect of gaze direction on the N170 component, and the need of systematic studies investigating the combination of these factors.

Deficient Novelty Detection and Encoding in Early Alzheimer's Disease: An ERP Study.

Patients with early Alzheimer's disease (AD) have difficulty in learning new information and in detecting novel stimuli. The underlying physiological mechanisms are not well known. We investigated the electrophysiological correlates of the early (< 400 ms), automatic phase of novelty detection and encoding in AD. We used high-density EEG Queryin patients with early AD and healthy age-matched controls who performed a continuous recognition task (CRT) involving new stimuli (New), thought to provoke novelty detection and encoding, which were then repeated up to 4 consecutive times to produce over-familiarity with the stimuli. Stimuli then reappeared after 9-15 intervening items (N-back) to be re-encoded. AD patients had substantial difficulty in detecting novel stimuli and recognizing repeated ones. Main evoked potential differences between repeated and new stimuli emerged at 180-260 ms: neural source estimations in controls revealed more extended MTL activation for N-back stimuli and anterior temporal lobe activations for New stimuli compared to highly familiar repetitions. In contrast, AD patients exhibited no activation differences between the three stimulus types. In direct comparison, healthy subjects had significantly stronger MTL activation in response to New and N-back stimuli than AD patients. These results point to abnormally weak early MTL activity as a correlate of deficient novelty detection and encoding in early AD.

Rapid Sequential Implication of the Human Medial Temporal Lobe in Memory Encoding and Recognition.

The medial temporal lobe (MTL) is crucial for memory encoding and recognition. The time course of these processes is unknown. The present study juxtaposed encoding and recognition in a single paradigm. Twenty healthy subjects performed a continuous recognition task as brain activity was monitored with a high-density electroencephalography. The task presented New pictures thought to evoke encoding. The stimuli were then repeated up to 4 consecutive times to produce over-familiarity. These repeated stimuli served as "baseline" for comparison with the other stimuli. Stimuli later reappeared after 9-15 intervening items, presumably associated with new encoding and recognition. Encoding-related differences in evoked response potential amplitudes and in spatiotemporal analysis were observed at 145-300 ms, whereby source estimation indicated MTL and orbitofrontal activity from 145 to 205 ms. Recognition-related activity evoked by late repetitions occurred at 405-470 ms, implicating the MTL and neocortical structures. These findings indicate that encoding of information is initiated before it is recognized. The result helps to explain modifications of memories over time, including false memories, confabulation, and consolidation.

Absence of an early hippocampal encoding signal after medial temporal lesions: No consequence for the spacing effect.

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200-300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)-the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL-mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200-300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's.

Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer's Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology. OBJECTIVE: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. METHODS: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aß1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. RESULTS: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aß1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aß1-42 and tau levels. CONCLUSION: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond.

BACKGROUND: Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. METHODS: Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/ß-Amyloid 1-42 peptide chain [Aß1-42] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ε4 carrier status. RESULTS: The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aß1-42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE ε4 carriers. CONCLUSIONS: We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ε4 carriers.

Interaction between personality traits and cerebrospinal fluid biomarkers of Alzheimer's disease pathology modulates cognitive performance.

BACKGROUND: During adulthood, personality characteristics may contribute to the individual capacity to compensate the impact of developing cerebral Alzheimer's disease (AD) pathology on cognitive impairment in later life. In this study we aimed to investigate whether and how premorbid personality traits interact with cerebrospinal fluid (CSF) markers of AD pathology to predict cognitive performance in subjects with mild cognitive impairment or mild AD dementia and in participants with normal cognition. METHODS: One hundred and ten subjects, of whom 66 were patients with mild cognitive impairment or mild AD dementia and 44 were healthy controls, had a comprehensive medical and neuropsychological examination as well as lumbar puncture to measure CSF biomarkers of AD pathology (amyloid beta1-42, phosphorylated tau and total-tau). Participants' proxies completed the Revised NEO Personality Inventory, Form R to retrospectively assess subjects' premorbid personality. RESULTS: In hierarchical multivariate regression analyses, including age, gender, education, APOEε4 status and cognitive level, premorbid neuroticism, conscientiousness and agreeableness modulated the effect of CSF biomarkers on cognitive performance. Low premorbid openness independently predicted lower levels of cognitive functioning after controlling for biomarker concentrations. CONCLUSION: Our findings suggest that specific premorbid personality traits are associated with cerebral AD pathology and modulate its impact on cognitive performance. Considering personality characteristics may help to appraise a person's cognitive reserve and the risk of cognitive decline in later life.

Markers of neuroinflammation associated with Alzheimer's disease pathology in older adults.

BACKGROUND: In vitro and animal studies have linked neuroinflammation to Alzheimer's disease (AD) pathology. Studies on markers of inflammation in subjects with mild cognitive impairment or AD dementia provided inconsistent results. We hypothesized that distinct blood and cerebrospinal fluid (CSF) inflammatory markers are associated with biomarkers of amyloid and tau pathology in older adults without cognitive impairment or with beginning cognitive decline. OBJECTIVE: To identify blood-based and CSF neuroinflammation marker signatures associated with AD pathology (i.e. an AD CSF biomarker profile) and to investigate associations of inflammation markers with CSF biomarkers of amyloid, tau pathology, and neuronal injury. DESIGN/METHODS: Cross-sectional analysis was performed on data from 120 older community-dwelling adults with normal cognition (n=48) or with cognitive impairment (n=72). CSF Aß1-42, tau and p-tau181, and a panel of 37 neuroinflammatory markers in both CSF and serum were quantified. Least absolute shrinkage and selection operator (LASSO) regression was applied to determine a reference model that best predicts an AD CSF biomarker profile defined a priori as p-tau181/Aß1-42 ratio >0.0779. It was then compared to a second model that included the inflammatory markers from either serum or CSF. In addition, the correlations between inflammatory markers and CSF Aß1-42, tau and p-tau181 levels were assessed. RESULTS: Forty-two subjects met criteria for having an AD CSF biomarker profile. The best predictive models included 8 serum or 3 CSF neuroinflammatory markers related to cytokine mediated inflammation, vascular injury, and angiogenesis. Both models improved the accuracy to predict an AD biomarker profile when compared to the reference model. In analyses separately performed in the subgroup of participants with cognitive impairment, adding the serum or the CSF neuroinflammation markers also improved the accuracy of the diagnosis of AD pathology. None of the inflammatory markers correlated with the CSF Aß1-42 levels. Six CSF markers (IL-15, MCP-1, VEGFR-1, sICAM1, sVCAM-1, and VEGF-D) correlated with the CSF tau and p-tau181 levels, and these associations remained significant after controlling for age, sex, cognitive impairment, and APOEε4 status. CONCLUSIONS: The identified serum and CSF neuroinflammation biomarker signatures improve the accuracy of classification for AD pathology in older adults. Our results suggest that inflammation, vascular injury, and angiogenesis as reflected by CSF markers are closely related to cerebral tau pathology.