Neurobiological Correlates of Personality Traits: A Study on Harm Avoidance and Neuroticism

Harm Avoidance and Neuroticism are traits that predispose to mental illnesses. Studying them provides a unique way to study predisposition of mental illnesses. Understanding the biological mechanisms that mediate vulnerability could lead to improvement in treatment and ultimately to pre-emptive psychiatry. These personality traits describe a tendency to feel negative emotions such as fear, shyness and worry. Previous studies suggest these traits are regulated by serotonin and opiate pathways. The aim of this thesis was to test the following hypotheses using personality trait measures and positron emission tomography (PET): 1) Brain serotonin transporter density in vivo is associated with Harm Avoidance and Neuroticism traits. 2) μ-opioid receptor binding is associated with Harm Avoidance. In addition, we developed a methodology for studying neurotransmitter interactions in the brain using the opiate and serotonin pathways. 32 healthy subjects who were consistently in either the highest or lowest quartile of the Harm Avoidance trait were recruited from a population-based cohort. Each subject underwent two PET scans, serotonin transporter binding was measured with [11C] MADAM and μ-opioid receptor binding with [11C]carfentanil. We found that the serotonin transporter is not associated with anxious personality traits. However, Harm Avoidance positively correlated with μ-opioid receptor availability. Particularly the tendency to feel shy and the inability to cope with stress were associated μ-opioid receptor availability. We also demonstrated that serotonin transporter binding correlates with μ-opioid receptor binding, suggesting interplay between the two systems. These findings shed light on the neurobiological correlates of personality and have an impact on etiological considerations of affective disorders.

Neurobiological Correlates of Apathy in Alzheimer's Disease and Mild Cognitive Impairment: A Critical Review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

L'hystérie : une entité historique, un trouble psychiatrique ou une maladie neurologique? [Hysteria : an historical entity, a psychiatric condition or a neurological disease?]

Il a été suggéré que l'hystérie avait disparu et n'était qu'un concept ancien, stigmatisant et péjoratif, voire erroné, reflétant l'incapacité de la communauté médicale à établir parfois un diagnostic. Actuellement ces troubles, appelés troubles dissociatifs ou de conversion, restent pourtant une réalité clinique fréquente et invalidante pour les patients. Plusieurs études et revues ont tenté de mieux décrire la présentation clinique, mais également de mieux comprendre les mécanismes neurobiologiques impliqués dans ces troubles grâce au développement de certaines techniques d'imagerie cérébrale. Si les corrélats neurobiologiques sont mieux compris, des traitements efficaces manquent encore et seule une prise en charge multidisciplinaire (généralistes, neurologues et psychiatres) et individualisée peut apporter un bénéfice au patient. It has been suggested that hysteria had waned and was an old-fashioned, stigmatizing and false concept, reflecting the incapacity of the medical community to establish a diagnosis in certain situations. Nowadays, however, those disturbances, now referred to as conversion or dissociative disorders, still remain a frequent and incapacitating condition that every clinician faces. These past decades, several studies have tried to better describe their clinical presentation and their neurobiological mechanisms, with the help of the development of new neuroimaging techniques. If the neurobiological correlates are now better understood, efficient treatments are still lacking and only a multidisciplinary (general practitioners, neurologists and psychiatrists) and individually-tailored therapy might be beneficial to the patients.

Neurobiology of suicide: do biomarkers exist?

Clinical risk factors have a low predictive value on suicide. This may explain the increasing interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. This review aims to present the current neurobiological findings that have been shown to be implicated in suicide completers and to discuss how postmortem studies may be useful in characterizing these individuals. Data on the role of the main neurobiological systems in suicidality, such as the neurotransmitter families, hypothalamic-pituitary-adrenal axis, neurotrophic factors, and polyamines, are exposed at the different biochemical, genetic, and epigenetic levels. Some neuroanatomic and neuropathological aspects as well as their in vivo morphological and functional neuroimaging correlates are also described. Except for the serotoninergic system, particularly with respect to the polymorphism of the gene coding for the serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor, data did not converge to produce a univocal consensus. The possible limitations of currently published studies are discussed, as well as the scope for long-term prospective studies.

Genetic Factors in the Regulation of Striatal and Extrastriatal Dopamine D2 Receptor Expression

Positron emission tomography (PET) studies on healthy individuals have revealed a marked interindividual variability in striatal dopamine D2 receptor density that can be partly accounted for by genetic factors. The examination of the extrastriatal lowdensity D2 receptor populations has been impeded by the lack of suitable tracers. However, the quantification of these D2 receptor populations is now feasible with recently developed PET radioligands. The objective of this thesis was to study brain neurobiological correlates of common functional genetic variants residing in candidate genes relevant for D2 receptor functioning. For this purpose, healthy subjects were studied with PET imaging using [₁₁C]raclopride and [₁₁C]FLB457 as radioligands. The candidate genes examined in this work were the human D2 receptor gene (DRD2) and the catechol-Omethyltransferase gene (COMT). The region-specific genotypic influences were explored by comparing D2 receptor binding properties in the striatum, the cortex and the thalamus. As an additional study objective, the relationship between cortical D2 receptor density and a cognitive phenotype i.e. verbal memory and learning was assessed. The main finding of this study was that DRD2 C957T genotype altered markedly D2 receptor density in the cortex and the thalamus whereas in the striatum the C957T genotype affected D2 receptor affinity, but not density. Furthermore, the A1 allele of the DRD2-related TaqIA polymorphism showed increased cortical and thalamic D2 receptor density, but had the opposite effect on striatal D2 receptor density. The DRD2 –141C Ins/Del or the COMT Val158Met genotypes did not change D2 receptor binding properties. Finally, unlike previously reported, cortical D2 receptor density did not show any significant correlation with verbal memory function. The results of this study suggest that the C957T and the TaqIA genotypes have region-specific neurobiological correlates in brain dopamine D2 receptor availability in vivo. The biological mechanisms underlying these findings are unclear, but they may be related to the region-specific regulation of dopamine neurotranssion, gene/receptor expression and epigenesis. These findings contribute to the understanding of the genetic regulation of dopamine and D2 receptor-related brain functions in vivo in man. In addition, the results provide potentially useful endophenotypes for genetic research on psychiatric and neurological disorders.

Learning and memory

Memory is one of the most fundamental mental processes. Neuroscientists study this process by using extremely diverse strategies. Two different approaches aimed at understanding learning and memory were introduced in this symposium. The first focuses on the roles played by synaptic plasticity, especially in long-term depression in the cerebellum in motor learning, and its regulatory mechanism. The second approach uses an elegant chick-quail transplantation system on defined brain regions to study how neural populations interact in development to form behaviorally important neural circuits and to elucidate neurobiological correlates of perceptual and motor predispositions.

Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia. (c) 2005 Elsevier B.V. All rights reserved.

The functional neuroimaging correlates of psychogenic versus organic dystonia.

The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical-subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.

Deontological and altruistic guilt: evidence for distinct neurobiological substrates.

The feeling of guilt is a complex mental state underlying several human behaviors in both private and social life. From a psychological and evolutionary viewpoint, guilt is an emotional and cognitive function, characterized by prosocial sentiments, entailing specific moral believes, which can be predominantly driven by inner values (deontological guilt) or by more interpersonal situations (altruistic guilt). The aim of this study was to investigate whether there is a distinct neurobiological substrate for these two expressions of guilt in healthy individuals. We first run two behavioral studies, recruiting a sample of 72 healthy volunteers, to validate a set of stimuli selectively evoking deontological and altruistic guilt, or basic control emotions (i.e., anger and sadness). Similar stimuli were reproduced in a event-related functional magnetic resonance imaging (fMRI) paradigm, to investigate the neural correlates of the same emotions, in a new sample of 22 healthy volunteers. We show that guilty emotions, compared to anger and sadness, activate specific brain areas (i.e., cingulate gyrus and medial frontal cortex) and that different neuronal networks are involved in each specific kind of guilt, with the insula selectively responding to deontological guilt stimuli. This study provides evidence for the existence of distinct neural circuits involved in different guilty feelings. This complex emotion might account for normal individual attitudes and deviant social behaviors. Moreover, an abnormal processing of specific guilt feelings might account for some psychopathological manifestation, such as obsessive-compulsive disorder and depression.

Neural correlates of free T3 alteration after catecholamine depletion in subjects with remitted major depressive disorder and in controls.

RATIONALE: Thyroid hormones and their interactions with catecholamines play a potentially important role in alterations of mood and cognition. OBJECTIVES: This study aimed to examine the neurobiological effects of catecholamine depletion on thyroid hormones by measuring endocrine and cerebral metabolic function in unmedicated subjects with remitted major depressive disorder (RMDD) and in healthy controls. METHODS: This was a randomized, placebo-controlled, and double-blind crossover trial that included 15 unmedicated RMDD subjects and 13 healthy control subjects. The participants underwent two 3-day-long sessions at 1-week intervals; each participant was randomly administered oral α-methyl-para-tyrosine in one session (catecholamine depletion) and an identical capsule containing hydrous lactose (sham depletion) in the other session prior to a [(18)F]-fluorodeoxyglucose positron emission tomography scan. RESULTS: Serum concentrations of free T3 (FT3), free T4 (FT4), and TSH were obtained and assessed with respect to their relationship to regional cerebral glucose metabolism. Both serum FT3 (P = 0.002) and FT4 (P = 0.0009) levels were less suppressed after catecholamine depletion compared with placebo treatment in the entire study sample. There was a positive association between both FT3 (P = 0.0005) and FT4 (P = 0.002) and depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale. The relative elevation in FT3 level was correlated with a decrease in regional glucose metabolism in the right dorsolateral prefrontal cortex (rDLPFC; P < 0.05, corrected). CONCLUSIONS: This study provided evidence of an association between a thyroid-catecholamine interaction and mood regulation in the rDLPFC.

Neural correlates of 'pessimistic' attitude in depression

BACKGROUND Preparing for potentially threatening events in the future is essential for survival. Anticipating the future to be unpleasant is also a cognitive key feature of depression. We hypothesized that 'pessimism'-related emotion processing would characterize brain activity in major depression.MethodDuring functional magnetic resonance imaging, depressed patients and a healthy control group were cued to expect and then perceive pictures of known emotional valences--pleasant, unpleasant and neutral--and stimuli of unknown valence that could have been either pleasant or unpleasant. Brain activation associated with the 'unknown' expectation was compared with the 'known' expectation conditions. RESULTS While anticipating pictures of unknown valence, activation patterns in depressed patients within the medial and dorsolateral prefrontal areas, inferior frontal gyrus, insula and medial thalamus were similar to activations associated with expecting unpleasant pictures, but not with expecting positive pictures. The activity within a majority of these areas correlated with the depression scores. Differences between healthy and depressed persons were found particularly for medial and dorsolateral prefrontal and insular activations. CONCLUSIONS Brain activation in depression during expecting events of unknown emotional valence was comparable with activation while expecting certainly negative, but not positive events. This neurobiological finding is consistent with cognitive models supposing that depressed patients develop a 'pessimistic' attitude towards events with an unknown emotional meaning. Thereby, particularly the role of brain areas associated with the processing of cognitive and executive control and of the internal state is emphasized in contributing to major depression.

Rivalry of homeostatic and sensory-evoked emotions: dehydration attenuates olfactory disgust and its neural correlates

Neural correlates have been described for emotions evoked by states of homeostatic imbalance (e.g. thirst, hunger, and breathlessness) and for emotions induced by external sensory stimulation (such as fear and disgust). However, the neurobiological mechanisms of their interaction, when they are experienced simultaneously, are still unknown. We investigated the interaction on the neurobiological and the perceptional level using subjective ratings, serum parameters, and functional magnetic resonance imaging (fMRI) in a situation of emotional rivalry, when both a homeostatic and a sensory-evoked emotion were experienced at the same time. Twenty highly dehydrated male subjects rated a disgusting odor as significantly less repulsive when they were thirsty. On the neurobiological level, we found that this reduction in subjective disgust during thirst was accompanied by a significantly reduced neural activity in the insular cortex, a brain area known to be considerably involved in processing of disgust. Furthermore, during the experience of disgust in the satiated condition, we observed a significant functional connectivity between brain areas responding to the disgusting odor, which was absent during the stimulation in the thirsty condition. These results suggest interference of conflicting emotions: An acute homeostatic imbalance can attenuate the experience of another emotion evoked by the sensory perception of a potentially harmful external agent. This finding offers novel insights with regard to the behavioral relevance of biologically different types of emotions, indicating that some types of emotions are more imperative for behavior than others. As a general principle, this modulatory effect during the conflict of homeostatic and sensory-evoked emotions may function to safeguard survival.

Exploring the emotional brain: Neural correlates of homeostatic and sensory-evoked emotions and their interaction in emotional rivalry

Human emotions are essential for survival. They are vital for the satisfaction of basic needs, the regulation of personal life and successful integration into social structures. Depending on which aspect of an emotion is used in its definition, many different theories offer possible answers to the questions of what emotions are and how they can be distinguished. The systematic investigation of emotions in cognitive neuroscience is relatively new, and neuroimaging studies specifically focussing on the neural correlates of different categories of emotions are still lacking. Therefore, the current thesis aimed at investigating the behavioural and neurophysiological correlates of different human emotional levels and their interaction in healthy subjects. We differentiated between emotions according to their cerebral entry site and neural processing pathways: homeostatic emotions, which are elicited by metabolic changes and processed by the interoceptive system (such as thirst, hunger, and need for air), and sensory-evoked emotions, which are evoked by external inputs via the eyes, ears or nose, or their corresponding mental representations and processed in the brain as sensory perception (e.g. fear, disgust, or pride). Using functional magnetic resonance imaging (fMRI) and behavioural parameters, we examined both the specific neural underpinnings of a homeostatic emotion (thirst) and a sensory-evoked emotion (disgust), and their interaction in a situation of emotional rivalry when both emotions were perceived simultaneously. This thesis comprises three research articles reporting the results of this research. The first paper presents disgust-related brain imaging data in a thirsty and a satiated condition. We found that disgust mainly activated the anterior insular cortex. In the thirsty condition, however, we observed an interaction effect between disgust and thirst: when thirsty, the subjects rated the disgusting stimulus as less repulsive. On the neurobiological level, this reduction of subjective disgust was accompanied by significantly reduced neural activity in the insular cortex. These results provide new neurophysiological evidence for a hierarchical organization among homeostatic and sensory-evoked emotions, revealing that in a situation of emotional conflict, homeostatic emotions are prioritized over sensory-evoked emotions. In the second paper, findings on brain perfusion over four different thirst stages are reported, with a special focus on the parametric progression of thirst. Cerebral perfusion differences over all thirst stages were found in the posterior insular cortex. Taking this result together with the findings of the first paper, the insular cortex seems to be a key player in human emotional processing, since it comprises specific representations of homeostatic and sensory-evoked emotions and also represents the site of cortical interaction between the two levels of emotions. Finally, although this thesis focussed on the homeostatic modulation of disgust, we were also interested in whether dehydration modulates taste perception. The results of this behavioural experiment are described in the third paper, where we show that dehydration alters the perception of neutral taste stimuli.

Spinal Cord Atrophy Correlates With Disease Duration And Severity In Amyotrophic Lateral Sclerosis.

Our objective was to investigate spinal cord (SC) atrophy in amyotrophic lateral sclerosis (ALS) patients, and to determine whether it correlates with clinical parameters. Forty-three patients with ALS (25 males) and 43 age- and gender-matched healthy controls underwent MRI on a 3T scanner. We used T1-weighted 3D images covering the whole brain and the cervical SC to estimate cervical SC area and eccentricity at C2/C3 level using validated software (SpineSeg). Disease severity was quantified with the ALSFRS-R and ALS Severity scores. SC areas of patients and controls were compared with a Mann-Whitney test. We used linear regression to investigate association between SC area and clinical parameters. Results showed that mean age of patients and disease duration were 53.1 ± 12.2 years and 34.0 ± 29.8 months, respectively. The two groups were significantly different regarding SC areas (67.8 ± 6.8 mm² vs. 59.5 ± 8.4 mm², p < 0.001). Eccentricity values were similar in both groups (p = 0.394). SC areas correlated with disease duration (r = - 0.585, p < 0.001), ALSFRS-R score (r = 0.309, p = 0.044) and ALS Severity scale (r = 0.347, p = 0.022). In conclusion, patients with ALS have SC atrophy, but no flattening. In addition, SC areas correlated with disease duration and functional status. These data suggest that quantitative MRI of the SC may be a useful biomarker in the disease.

Serum Bdnf Levels Are Not Reliable Correlates Of Neurodegeneration In Ms Patients.

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