Personality, Alzheimer's disease and behavioural and cognitive symptoms of dementia: the PACO prospective cohort study protocol.

BACKGROUND: Alzheimer's disease is characterised by a loss of cognitive function and behavioural problems as set out in the term "Behavioural and Psychological Symptoms of Dementia". These behavioural symptoms have heavy consequences for the patients and their families. A greater understanding of behavioural symptoms risk factors would allow better detection of those patients, a better understanding of crisis situations and better management of these patients. Some retrospective studies or simple observations suggested that personality could play a role in the occurrence of behavioural symptoms. Finally, performance in social cognition like facial recognition and perspective taking could be linked to certain personality traits and the subsequent risks of behavioural symptoms. We propose to clarify this through a prospective, multicentre, multidisciplinary study. Main Objective: -To assess the effect of personality and life events on the risk of developing behavioural symptoms. Secondary Objectives: -To evaluate, at the time of inclusion, the connection between personality and performance in social cognition tests; -To evaluate the correlation between performance in social cognition at inclusion and the risks of occurrence of behavioural symptoms; -To evaluate the correlation between regional cerebral atrophy, using brain Magnetic Resonance Imaging at baseline, and the risk of behavioural symptoms. METHODS/DESIGN: Study type and Population: Prospective multicentre cohort study with 252 patients with Alzheimer's disease at prodromal or mild dementia stage. The inclusion period will be of 18 months and the patients will be followed during 18 months. The initial evaluation will include: a clinical and neuropsychological examination, collection of behavioural symptoms data (Neuropsychiatric-Inventory scale) and their risk factors, a personality study using both a dimensional (personality traits) and categorical approach, an inventory of life events, social cognition tests and an Magnetic Resonance Imaging. Patients will be followed every 6 months (clinical examination and collection of behavioural symptoms data and risk factors) during 18 months. DISCUSSION: This study aims at better identifying the patients with Alzheimer's disease at high risk of developing behavioural symptoms, to anticipate, detect and quickly treat these disorders and so, prevent serious consequences for the patient and his caregivers. TRIAL REGISTRATION: ClincalTrials.gov: NCT01297140.

Disentangling sensory precision and prior expectation of change in autism during tactile discrimination.

Predictive coding theories suggest that core symptoms in autism spectrum disorders (ASD) may stem from atypical mechanisms of perceptual inference (i.e., inferring the hidden causes of sensations). Specifically, there would be an imbalance in the precision or weight ascribed to sensory inputs relative to prior expectations. Using three tactile behavioral tasks and computational modeling, we specifically targeted the implicit dynamics of sensory adaptation and perceptual learning in ASD. Participants were neurotypical and autistic adults without intellectual disability. In Experiment I, tactile detection thresholds and adaptation effects were measured to assess sensory precision. Experiments II and III relied on two-alternative forced choice tasks designed to elicit a time-order effect, where prior knowledge biases perceptual decisions. Our results suggest a subtler explanation than a simple imbalance in the prior/sensory weights, having to do with the dynamic nature of perception, that is the adjustment of precision weights to context. Compared to neurotypicals, autistic adults showed no difference in average performance and sensory sensitivity. Both groups managed to implicitly learn and adjust a prior that biased their perception. However, depending on the context, autistic participants showed no, normal or slower adaptation, a phenomenon that computational modeling of trial-to-trial responses helped us to associate with a higher expectation for sameness in ASD, and to dissociate from another observed robust difference in terms of response bias. These results point to atypical perceptual learning rather than altered perceptual inference per se, calling for further empirical and computational studies to refine the current predictive coding theories of ASD.

Transient suppression of broadband gamma power in the default-mode network is correlated with task complexity and subject performance.

Task performance is associated with increased brain metabolism but also with prominent deactivation in specific brain structures known as the default-mode network (DMN). The role of DMN deactivation remains enigmatic in part because its electrophysiological correlates, temporal dynamics, and link to behavior are poorly understood. Using extensive depth electrode recordings in humans, we provide first electrophysiological evidence for a direct correlation between the dynamics of power decreases in the DMN and individual subject behavior. We found that all DMN areas displayed transient suppressions of broadband gamma (60-140 Hz) power during performance of a visual search task and, critically, we show for the first time that the millisecond range duration and extent of the transient gamma suppressions are correlated with task complexity and subject performance. In addition, trial-by-trial correlations revealed that spatially distributed gamma power increases and decreases formed distinct anticorrelated large-scale networks. Beyond unraveling the electrophysiological basis of DMN dynamics, our results suggest that, rather than indicating a mere switch to a global exteroceptive mode, DMN deactivation encodes the extent and efficiency of our engagement with the external world. Furthermore, our findings reveal a pivotal role for broadband gamma modulations in the interplay between task-positive and task-negative networks mediating efficient goal-directed behavior and facilitate our understanding of the relationship between electrophysiology and neuroimaging studies of intrinsic brain networks.

Blunted emotion judgments of body movements in Parkinson's disease.

Some of the behavioral disorders observed in Parkinson's disease (PD) may be related to an altered processing of social messages, including emotional expressions. Emotions conveyed by whole body movements may be difficult to generate and be detected by PD patients. The aim of the present study was to compare valence judgments of emotional whole body expressions in individuals with PD and in healthy controls matched for age, gender and education. Twenty-eight participants (13 PD patients and 15 healthy matched control participants) were asked to rate the emotional valence of short movies depicting emotional interactions between two human characters presented with the "Point Light Displays" technique. To ensure understanding of the perceived scene, participants were asked to briefly describe each of the evaluated movies. Patients' emotional valence evaluations were less intense than those of controls for both positive (p < 0.001) and negative (p < 0.001) emotional expressions, even though patients were able to correctly describe the depicted scene. Our results extend the previously observed impaired processing of emotional facial expressions to impaired processing of emotions expressed by body language. This study may support the hypothesis that PD affects the embodied simulation of emotional expression and the potentially involved mirror neuron system.

Impaired social cognition in mild Alzheimer disease.

Abnormal decoding of social information has been associated with the conversion from prodromal Alzheimer's disease (AD) to dementia. Since the distributed neural networks involved in face processing are differentially affected in prodromal and dementia states of AD and in Fronto-Temporal Dementia (FTD), we hypothesized a differential impairment in face processing in these populations. Facial expression, gender and gaze direction decoding abilities were examined in patients with probable amnesic Mild Cognitive Impairment (aMCI, N=10) fulfilling criteria for prodromal AD, in patients with mild and moderate AD (N=10) as well as in FTD patients (N=10) and in a group of age- and sex-matched healthy comparison subjects (N=10). Gender recognition was preserved in all groups. Compared to controls, patients with mild or moderate AD were impaired in expression recognition and FTD patients were impaired in expression and gaze direction determination, whereas MCI patients were not impaired at all.

Early amygdala reaction to fear spreading in occipital, temporal, and frontal cortex: a depth electrode ERP study in human.

The amygdala involvement in fear processing has been reported in behavioral, electrophysiological, and functional imaging studies. However, the literature does not provide precise data on the temporal course of facial emotional processing. Intracranial event-related potentials to facial expressions were recorded in epileptic patients implanted with depth electrodes during a presurgical evaluation. Specific potentials to fear beginning 200 ms poststimulus were observed in amygdala, both individually in two patients and in a ten patient population study. These potentials occurred 100 ms earlier than potentials to disgust recorded in insula in a previous study. Potentials to fear were confined in amygdala during a first transient period and then, during a second period of sustained activity, spread to occipito-temporal, anterior temporal, and orbitofrontal cortex in two patients. This study clarifies the temporal course of the involvement of these structures known to be part of a neural network recruited to process emotional information.

Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The learning-style theory of Autism Spectrum Disorders (ASD) (Qian, Lipkin, Frontiers in Human Neuroscience 5:77, 2011) states that ASD individuals differ from neurotypics in the way they learn and store information about the environment and its structure. ASD would rather adopt a lookup-table strategy (LUT: memorizing each experience), while neurotypics would favor an interpolation style (INT: extracting regularities to generalize). In a series of visual behavioral tasks, we tested this hypothesis in 20 neurotypical and 20 ASD adults. ASD participants had difficulties using the INT style when instructions were hidden but not when instructions were revealed. Rather than an inability to use rules, ASD would be characterized by a disinclination to generalize and infer such rules.

Correction to: Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The original version of this article unfortunately contained a mistake in the article title.

Deciphering human motion to discriminate social interactions: a developmental neuroimaging study.

Non-verbal communication plays a major role in social interaction understanding. Using functional magnetic resonance imaging, we explored the development of the neural networks involved in social interaction recognition based on human motion in children (8-11), adolescents (13-17), and adults (20-41). Participants watched point-light videos depicting two actors interacting or moving independently and were asked whether these agents were interacting or not. All groups successfully performed the discrimination task, but children had a lower performance and longer response times than the older groups. In all three groups, the posterior parts of the superior temporal sulci and middle temporal gyri, the inferior frontal gyri and the anterior temporal lobes showed greater activation when observing social interactions. In addition, adolescents and adults recruited the caudate nucleus and some frontal regions that are part of the mirror system. Adults showed greater activations in parietal and frontal regions (part of them belonging to the social brain) than adolescents.An increased number of regions that are part of the mirror system network or the social brain, as well as the caudate nucleus, were recruited with age. In conclusion, a shared set of brain regions enabling the discrimination of social interactions from neutral movements through human motion is already present in 8-year-old children. Developmental processes such as refinements in the social brain and mirror system would help grasping subtle cues in non-verbal aspects of social interactions.

Neuroanatomical Correlates of Recognizing Face Expressions in Mild Stages of Alzheimer's Disease.

Early Alzheimer's disease can involve social disinvestment, possibly as a consequence of impairment of nonverbal communication skills. This study explores whether patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage have impaired recognition of emotions in facial expressions, and describes neuroanatomical correlates of emotion processing impairment. As part of the ongoing PACO study (personality, Alzheimer's disease and behaviour), 39 patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage and 39 matched controls completed tests involving discrimination of four basic emotions-happiness, fear, anger, and disgust-on photographs of faces. In patients, automatic volumetry of 83 brain regions was performed on structural magnetic resonance images using MAPER (multi-atlas propagation with enhanced registration). From the literature, we identified for each of the four basic emotions one brain region thought to be primarily associated with the function of recognizing that emotion. We hypothesized that the volume of each of these regions would be correlated with subjects' performance in recognizing the associated emotion. Patients showed deficits of basic emotion recognition, and these impairments were correlated with the volumes of the expected regions of interest. Unexpectedly, most of these correlations were negative: better emotional facial recognition was associated with lower brain volume. In particular, recognition of fear was negatively correlated with the volume of amygdala, disgust with pallidum, and happiness with fusiform gyrus. Recognition impairment in mild stages of Alzheimer's disease for a given emotion was thus associated with less visible atrophy of functionally responsible brain structures within the patient group. Possible explanations for this counterintuitive result include neuroinflammation, regional ß-amyloid deposition, or transient overcompensation during early stages of Alzheimer's disease.

Seeing without the occipito-parietal cortex: Simultagnosia as a shrinkage of the attentional visual field.

Following bi-parietal lesions patient AT showed a severe inability to relocate her attention within a visual field which perimetry proved to be near-normal. An experimental approach with tasks testing visuo-spatial attention demonstrated a shrinkage of A.T.'s attentional visual field. With her visual attention narrowed to a kind of functional tunnel vision, the patient exhibited simultanagnosia (Wolpert, 1924), a symptom previously described in 1909 by Balint under the label of Psychic paralysis of "Gaze". In striking contrast AT showed an efficient and effortless perception of complex natural scenes, which, according to recent work in normal subjects, necessitate few if any attentional resources.

Face the hierarchy: ERP and oscillatory brain responses in social rank processing.

Recognition of social hierarchy is a key feature that helps us navigate through our complex social environment. Neuroimaging studies have identified brain structures involved in the processing of hierarchical stimuli but the precise temporal dynamics of brain activity associated with such processing remains largely unknown. Here, we used electroencephalography to examine the effect of social hierarchy on neural responses elicited by faces. In contrast to previous studies, the key manipulation was that a hierarchical context was constructed, not by varying facial expressions, but by presenting neutral-expression faces in a game setting. Once the performance-based hierarchy was established, participants were presented with high-rank, middle-rank and low-rank player faces and had to evaluate the rank of each face with respect to their own position. Both event-related potentials and task-related oscillatory activity were investigated. Three main findings emerge from the study. First, the experimental manipulation had no effect on the early N170 component, which may suggest that hierarchy did not modulate the structural encoding of neutral-expression faces. Second, hierarchy significantly modulated the amplitude of the late positive potential (LPP) within a 400-700 ms time-window, with more a prominent LPP occurring when the participants processed the face of the highest-rank player. Third, high-rank faces were associated with the highest reduction of alpha power. Taken together these findings provide novel electrophysiological evidence for enhanced allocation of attentional resource in the presence of high-rank faces. At a broader level, this study brings new insights into the neural processing underlying social categorization.

Influence of emotional content and context on memory in mild Alzheimer's disease.

Healthy subjects remember emotional stimuli better than neutral, as well as stimuli embedded in an emotional context. This better memory of emotional messages is linked to an amygdalo-hippocampal cooperation taking place in a larger fronto-temporal network particularly sensitive to pathological aging. Amygdala is mainly involved in gist memory of emotional messages. Whether emotional content or context enhances memory in mild Alzheimer's disease (AD) patients is still debated. The aim of the present study is to examine the influence of emotional content and emotional context on the memory in mild AD, and whether this influence is linked to amygdala volume. Fifteen patients affected by mild AD and 15 age-matched controls were submitted to series of negative, positive, and neutral pictures. Each series was embedded in an emotional or neutral sound context. At the end of each series, participants had to freely recall pictures, and answer questions about each picture. Amygdala volumes were measured on patient 3D-MRI scans. In the present study, emotional content significantly favored memory of gist but not of details in healthy elderly and in AD patients. Patients' amygdala volume was positively correlated to emotional content memory effect, implying a reduced memory benefit from emotional content when amygdala was atrophied. A positive context enhanced memory of pictures in healthy elderly, but not in AD, corroborating early fronto-temporal dysfunction and early working memory limitation in this disease.

A comparison of facial emotion processing in neurological and psychiatric conditions.

Patients suffering from various neurological and psychiatric disorders show different levels of facial emotion recognition (FER) impairment, sometimes from the early phases of the disease. Investigating the relative severity of deficits in FER across different clinical and high-risk populations has potential implications for the diagnosis and treatment of these diseases, and could also allow us to understand the neurobiological mechanisms of emotion perception itself. To investigate the role of the dopaminergic system and of the frontotemporal network in FER, we reanalyzed and compared data from four of our previous studies investigating FER performance in patients with frontotemporal dysfunctions and/or dopaminergic system abnormalities at different stages. The performance of patients was compared to the performance obtained by a specific group of matched healthy controls using Cohen's d effect size. We thus compared emotion and gender recognition in patients with frontotemporal dementia (FTD), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD) at the mild dementia stage, major depressive disorder, Parkinson's disease treated by l-DOPA (PD-ON) or not (PD-OFF), remitted schizophrenia (SCZ-rem), first-episode schizophrenia treated by antipsychotic medication (SCZ-ON), and drug-naïve first-episode schizophrenia (SCZ-OFF), as well as in unaffected siblings of patients with schizophrenia (SIB). The analyses revealed a pattern of differential impairment of emotion (but not gender) recognition across pathological conditions. On the one hand, dopaminergic medication seems not to modify the moderate deficits observed in SCZ and PD groups (ON vs. OFF), suggesting that the deficit is independent from the dopaminergic system. On the other hand, the observed increase in effect size of the deficit among the aMCI, AD, and FTD groups (and also among the SIB and SCZ-rem groups) suggests that the deficit is dependent on neurodegeneration of the frontotemporal neural networks. Our transnosographic approach combining clinical and high-risk populations with the impact of medication provides new information on the trajectory of impaired emotion perception in neuropsychiatric conditions, and on the role of the dopaminergic system and the frontotemporal network in emotion perception.

Emotional facial expression detection in the peripheral visual field.

BACKGROUND: In everyday life, signals of danger, such as aversive facial expressions, usually appear in the peripheral visual field. Although facial expression processing in central vision has been extensively studied, this processing in peripheral vision has been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Using behavioral measures, we explored the human ability to detect fear and disgust vs. neutral expressions and compared it to the ability to discriminate between genders at eccentricities up to 40°. Responses were faster for the detection of emotion compared to gender. Emotion was detected from fearful faces up to 40° of eccentricity. CONCLUSIONS: Our results demonstrate the human ability to detect facial expressions presented in the far periphery up to 40° of eccentricity. The increasing advantage of emotion compared to gender processing with increasing eccentricity might reflect a major implication of the magnocellular visual pathway in facial expression processing. This advantage may suggest that emotion detection, relative to gender identification, is less impacted by visual acuity and within-face crowding in the periphery. These results are consistent with specific and automatic processing of danger-related information, which may drive attention to those messages and allow for a fast behavioral reaction.

Intracerebral γ modulations reveal interaction between emotional processing and action outcome evaluation in the human orbitofrontal cortex.

The orbitofrontal cortex (OFC) plays a key role not only in processing emotions but also in monitoring performance outcome. Although the neuroanatomical substrates underlying each of the two processes have been extensively investigated, they have predominantly been probed separately and therefore a precise knowledge of the functional overlap within the multiple OFC sub-portions involved is still lacking. Here, we explore the neural dynamics mediating performance monitoring and emotional processing using direct intracranial EEG (iEEG) recordings from multiple OFC sites of an epileptic patient. Neural activity was recorded during two experiments. The first task required processing of emotional faces and the second investigated action outcome evaluation based on a visual feedback on the subject's performance. Task-related neural dynamics were assessed using modulations of high frequency responses in the gamma-band (50-150Hz). Our results reveal that processing negative facial emotions as well as receiving negative feedback both elicited gamma-band responses in the lateral OFC. By contrast, the mid-OFC was selectively activated for positive feedback. Furthermore, we also found significant gamma-band deactivation in the gyrus rectus during processing of negative feedback. Our findings provide novel evidence for an intricate valence-selective interaction between the networks mediating emotion processing and performance monitoring in human OFC and support the hypothesis of a tight relationship between gamma-band activity and behavior.

Cortical dynamics of a self driven choice: a MEG study during a card sorting task.

OBJECTIVE: The aim of this study was to disclose the dynamics of the frontal processes involved in a task shifting between two attentional states. METHODS: Magnetoencephalographic activities were recorded during a Wisconsin Card Sorting Test where subjects had to match card stimuli according to one of three possible dimensions ("maintained condition"). The matching dimension was intermittently changed and subjects, after feedback presentation, had to identify the new correct dimension ("shifted condition"). RESULTS: Source activations following the feedback to the subject's response in these two attentional conditions did not differ before 350 ms post feedback. After 350 ms, in the shifted condition, a lateral/posterior frontal activation was maintained later, while a medial/anterior frontal activation appeared up to 450 ms. CONCLUSIONS: The dynamics of activities corresponding to the two conditions disclose a spread of activation from posterior lateral frontal in the "maintained condition" to anterior medial frontal in the "shifted condition". SIGNIFICANCE: These results are consistent with fMRI results concerning the major involvement of medial frontal cortex in tasks involving reasoning and choice making.

Unconsciously perceived fear in peripheral vision alerts the limbic system: a MEG study.

BACKGROUND: In ecological situations, threatening stimuli often come out from the peripheral vision. Such aggressive messages must trigger rapid attention to the periphery to allow a fast and adapted motor reaction. Several clues converge to hypothesize that peripheral danger presentation can trigger off a fast arousal network potentially independent of the consciousness spot. METHODOLOGY/PRINCIPAL FINDINGS: In the present MEG study, spatio-temporal dynamics of the neural processing of danger related stimuli were explored as a function of the stimuli position in the visual field. Fearful and neutral faces were briefly presented in the central or peripheral visual field, and were followed by target faces stimuli. An event-related beamformer source analysis model was applied in three time windows following the first face presentations: 80 to 130 ms, 140 to 190 ms, and 210 to 260 ms. The frontal lobe and the right internal temporal lobe part, including the amygdala, reacted as soon as 80 ms of latency to fear occurring in the peripheral vision. For central presentation, fearful faces evoked the classical neuronal activity along the occipito-temporal visual pathway between 140 and 190 ms. CONCLUSIONS: Thus, the high spatio-temporal resolution of MEG allowed disclosing a fast response of a network involving medial temporal and frontal structures in the processing of fear related stimuli occurring unconsciously in the peripheral visual field. Whereas centrally presented stimuli are precisely processed by the ventral occipito-temporal cortex, the related-to-danger stimuli appearing in the peripheral visual field are more efficient to produce a fast automatic alert response possibly conveyed by subcortical structures.

Experiencing and detecting happiness in humans: the role of the supplementary motor area.

Understanding emotions in others may involve neural structures implicated in both perception and action.1 Laughter is a socially important behavior and its neural correlates are poorly understood. Depth electrode electrophysiological techniques offer a rare opportunity to both record and stimulate neural structures involved in emotion processing. (2,3) This kind of direct electrophysiological investigation in humans is particularly determinant because laughter processing cannot be studied in animals.

Attention modulates gamma-band oscillations differently in the human lateral occipital cortex and fusiform gyrus.

We studied the existence, localization and attentional modulation of gamma-band oscillatory activity (30-130 Hz) in the human intracranial region. Two areas known to play a key role in visual object processing: the lateral occipital (LO) cortex and the fusiform gyrus. These areas consistently displayed large gamma oscillations during visual stimulus encoding, while other extrastriate areas remained systematically silent, across 14 patients and 291 recording sites scattered throughout extrastriate visual cortex. The lateral extent of the responsive regions was small, in the range of 5 mm. Induced gamma oscillations and evoked potentials were not systematically co-localized. LO and the fusiform gyrus displayed markedly different patterns of attentional modulation. In the fusiform gyrus, attention enhanced stimulus-driven gamma oscillations. In LO, attention increased the baseline level of gamma oscillations during the expectation period preceding the stimulus. Subsequent gamma oscillations produced by attended stimuli were smaller than those produced by unattended, irrelevant stimuli. Attentional modulations of gamma oscillations in LO and the fusiform gyrus were thus very different, both in their time-course (preparatory period and/or stimulus processing) and direction of modulation (increase or decrease). Our results thus suggest that the functional role of gamma oscillations depends on the area in which they occur.