Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Cognitive anatomy of the temporal lobe: Effect of personality in population with mild cognitive impairment & Functional specialization for memory systems in healthy individuals.

Résumé: L'impact de la maladie d'Alzheimer (MA) est dévastateur pour la vie quotidienne de la personne affectée, avec perte progressive de la mémoire et d'autres facultés cognitives jusqu'à la démence. Il n'existe toujours pas de traitement contre cette maladie et il y a aussi une grande incertitude sur le diagnostic des premiers stades de la MA. La signature anatomique de la MA, en particulier l'atrophie du lobe temporal moyen (LTM) mesurée avec la neuroimagerie, peut être utilisée comme un biomarqueur précoce, in vivo, des premiers stades de la MA. Toutefois, malgré le rôle évident du LMT dans les processus de la mémoire, nous savons que les modèles anatomiques prédictifs de la MA basés seulement sur des mesures d'atrophie du LTM n'expliquent pas tous les cas cliniques. Au cours de ma thèse, j'ai conduit trois projets pour comprendre l'anatomie et le fonctionnement du LMT dans (1) les processus de la maladie et dans (2) les processus de mémoire ainsi que (3) ceux de l'apprentissage. Je me suis intéressée à une population avec déficit cognitif léger (« Mild Cognitive Impairment », MCI), à risque pour la MA. Le but du premier projet était de tester l'hypothèse que des facteurs, autres que ceux cognitifs, tels que les traits de personnalité peuvent expliquer les différences interindividuelles dans le LTM. De plus, la diversité phénotypique des manifestations précliniques de la MA provient aussi d'une connaissance limitée des processus de mémoire et d'apprentissage dans le cerveau sain. L'objectif du deuxième projet porte sur l'investigation des sous-régions du LTM, et plus particulièrement de leur contribution dans différentes composantes de la mémoire de reconnaissance chez le sujet sain. Pour étudier cela, j'ai utilisé une nouvelle méthode multivariée ainsi que l'IRM à haute résolution pour tester la contribution de ces sous-régions dans les processus de familiarité (« ou Know ») et de remémoration (ou « Recollection »). Finalement, l'objectif du troisième projet était de tester la contribution du LTM en tant que système de mémoire dans l'apprentissage et l'interaction dynamique entre différents systèmes de mémoire durant l'apprentissage. Les résultats du premier projet montrent que, en plus du déficit cognitif observé dans une population avec MCI, les traits de personnalité peuvent expliquer les différences interindividuelles du LTM ; notamment avec une plus grande contribution du neuroticisme liée à une vulnérabilité au stress et à la dépression. Mon étude a permis d'identifier un pattern d'anormalité anatomique dans le LTM associé à la personnalité avec des mesures de volume et de diffusion moyenne du tissu. Ce pattern est caractérisé par une asymétrie droite-gauche du LTM et un gradient antéro-postérieur dans le LTM. J'ai interprété ce résultat par des propriétés tissulaires et neurochimiques différemment sensibles au stress. Les résultats de mon deuxième projet ont contribué au débat actuel sur la contribution des sous-régions du LTM dans les processus de familiarité et de remémoration. Utilisant une nouvelle méthode multivariée, les résultats supportent premièrement une dissociation des sous-régions associées aux différentes composantes de la mémoire. L'hippocampe est le plus associé à la mémoire de type remémoration et le cortex parahippocampique, à la mémoire de type familiarité. Deuxièmement, l'activation correspondant à la trace mnésique pour chaque type de mémoire est caractérisée par une distribution spatiale distincte. La représentation neuronale spécifique, « sparse-distributed», associée à la mémoire de remémoration dans l'hippocampe serait la meilleure manière d'encoder rapidement des souvenirs détaillés sans interférer les souvenirs précédemment stockés. Dans mon troisième projet, j'ai mis en place une tâche d'apprentissage en IRM fonctionnelle pour étudier les processus d'apprentissage d'associations probabilistes basé sur le feedback/récompense. Cette étude m'a permis de mettre en évidence le rôle du LTM dans l'apprentissage et l'interaction entre différents systèmes de mémoire comme la mémoire procédurale, perceptuelle ou d'amorçage et la mémoire de travail. Nous avons trouvé des activations dans le LTM correspondant à un processus de mémoire épisodique; les ganglions de la base (GB), à la mémoire procédurale et la récompense; le cortex occipito-temporal (OT), à la mémoire de représentation perceptive ou l'amorçage et le cortex préfrontal, à la mémoire de travail. Nous avons également observé que ces régions peuvent interagir; le type de relation entre le LTM et les GB a été interprété comme une compétition, ce qui a déjà été reporté dans des études récentes. De plus, avec un modèle dynamique causal, j'ai démontré l'existence d'une connectivité effective entre des régions. Elle se caractérise par une influence causale de type « top-down » venant de régions corticales associées avec des processus de plus haut niveau venant du cortex préfrontal sur des régions corticales plus primaires comme le OT cortex. Cette influence diminue au cours du de l'apprentissage; cela pourrait correspondre à un mécanisme de diminution de l'erreur de prédiction. Mon interprétation est que cela est à l'origine de la connaissance sémantique. J'ai également montré que les choix du sujet et l'activation cérébrale associée sont influencés par les traits de personnalité et des états affectifs négatifs. Les résultats de cette thèse m'ont amenée à proposer (1) un modèle expliquant les mécanismes possibles liés à l'influence de la personnalité sur le LTM dans une population avec MCI, (2) une dissociation des sous-régions du LTM dans différents types de mémoire et une représentation neuronale spécifique à ces régions. Cela pourrait être une piste pour résoudre les débats actuels sur la mémoire de reconnaissance. Finalement, (3) le LTM est aussi un système de mémoire impliqué dans l'apprentissage et qui peut interagir avec les GB par une compétition. Nous avons aussi mis en évidence une interaction dynamique de type « top -down » et « bottom-up » entre le cortex préfrontal et le cortex OT. En conclusion, les résultats peuvent donner des indices afin de mieux comprendre certains dysfonctionnements de la mémoire liés à l'âge et la maladie d'Alzheimer ainsi qu'à améliorer le développement de traitement. Abstract: The impact of Alzheimer's disease is devastating for the daily life of the affected patients, with progressive loss of memory and other cognitive skills until dementia. We still lack disease modifying treatment and there is also a great amount of uncertainty regarding the accuracy of diagnostic classification in the early stages of AD. The anatomical signature of AD, in particular the medial temporal lobe (MTL) atrophy measured with neuroimaging, can be used as an early in vivo biomarker in early stages of AD. However, despite the evident role of MTL in memory, we know that the derived predictive anatomical model based only on measures of brain atrophy in MTL does not explain all clinical cases. Throughout my thesis, I have conducted three projects to understand the anatomy and the functioning of MTL on (1) disease's progression, (2) memory process and (3) learning process. I was interested in a population with mild cognitive impairment (MCI), at risk for AD. The objective of the first project was to test the hypothesis that factors, other than the cognitive ones, such as the personality traits, can explain inter-individual differences in the MTL. Moreover, the phenotypic diversity in the manifestations of preclinical AD arises also from the limited knowledge of memory and learning processes in healthy brain. The objective of the second project concerns the investigation of sub-regions of the MTL, and more particularly their contributions in the different components of recognition memory in healthy subjects. To study that, I have used a new multivariate method as well as MRI at high resolution to test the contribution of those sub-regions in the processes of familiarity and recollection. Finally, the objective of the third project was to test the contribution of the MTL as a memory system in learning and the dynamic interaction between memory systems during learning. The results of the first project show that, beyond cognitive state of impairment observed in the population with MCI, the personality traits can explain the inter-individual differences in the MTL; notably with a higher contribution of neuroticism linked to proneness to stress and depression. My study has allowed identifying a pattern of anatomical abnormality in the MTL related to personality with measures of volume and mean diffusion of the tissue. That pattern is characterized by right-left asymmetry in MTL and an anterior to posterior gradient within MTL. I have interpreted that result by tissue and neurochemical properties differently sensitive to stress. Results of my second project have contributed to the actual debate on the contribution of MTL sub-regions in the processes of familiarity and recollection. Using a new multivariate method, the results support firstly a dissociation of the subregions associated with different memory components. The hippocampus was mostly associated with recollection and the surrounding parahippocampal cortex, with familiarity type of memory. Secondly, the activation corresponding to the mensic trace for each type of memory is characterized by a distinct spatial distribution. The specific neuronal representation, "sparse-distributed", associated with recollection in the hippocampus would be the best way to rapidly encode detailed memories without overwriting previously stored memories. In the third project, I have created a learning task with functional MRI to sudy the processes of learning of probabilistic associations based on feedback/reward. That study allowed me to highlight the role of the MTL in learning and the interaction between different memory systems such as the procedural memory, the perceptual memory or priming and the working memory. We have found activations in the MTL corresponding to a process of episodic memory; the basal ganglia (BG), to a procedural memory and reward; the occipito-temporal (OT) cortex, to a perceptive memory or priming and the prefrontal cortex, to working memory. We have also observed that those regions can interact; the relation type between the MTL and the BG has been interpreted as a competition. In addition, with a dynamic causal model, I have demonstrated a "top-down" influence from cortical regions associated with high level cortical area such as the prefrontal cortex on lower level cortical regions such as the OT cortex. That influence decreases during learning; that could correspond to a mechanism linked to a diminution of prediction error. My interpretation is that this is at the origin of the semantic knowledge. I have also shown that the subject's choice and the associated brain activation are influenced by personality traits and negative affects. Overall results of this thesis have brought me to propose (1) a model explaining the possible mechanism linked to the influence of personality on the MTL in a population with MCI, (2) a dissociation of MTL sub-regions in different memory types and a neuronal representation specific to each region. This could be a cue to resolve the actual debates on recognition memory. Finally, (3) the MTL is also a system involved in learning and that can interact with the BG by a competition. We have also shown a dynamic interaction of « top -down » and « bottom-up » types between the pre-frontal cortex and the OT cortex. In conclusion, the results could give cues to better understand some memory dysfunctions in aging and Alzheimer's disease and to improve development of treatment.

Does working memory training affect decision making ? : a neuroeconomic study

We all make decisions of varying levels of importance every day. Because making a decision implies that there are alternative choices to be considered, almost all decision involves some conflicts or dissatisfaction. Traditional economic models esteem that a person must weight the positive and negative outcomes of each option, and based on all these inferences, determines which option is the best for that particular situation. However, individuals rather act as irrational agents and tend to deviate from these rational choices. They somewhat evaluate the outcomes' subjective value, namely, when they face a risky choice leading to losses, people are inclined to have some preference for risk over certainty, while when facing a risky choice leading to gains, people often avoid to take risks and choose the most certain option. Yet, it is assumed that decision making is balanced between deliberative and emotional components. Distinct neural regions underpin these factors: the deliberative pathway that corresponds to executive functions, implies the activation of the prefrontal cortex, while the emotional pathway tends to activate the limbic system. These circuits appear to be altered in individuals with ADHD, and result, amongst others, in impaired decision making capacities. Their impulsive and inattentive behaviors are likely to be the cause of their irrational attitude towards risk taking. Still, a possible solution is to administrate these individuals a drug treatment, with the knowledge that it might have several side effects. However, an alternative treatment that relies on cognitive rehabilitation might be appropriate. This project was therefore aimed at investigate whether an intensive working memory training could have a spillover effect on decision making in adults with ADHD and in age-matched healthy controls. We designed a decision making task where the participants had to select an amount to gamble with the chance of 1/3 to win four times the chosen amount, while in the other cases they could loose their investment. Their performances were recorded using electroencephalography prior and after a one-month Dual N-Back training and the possible near and far transfer effects were investigated. Overall, we found that the performance during the gambling task was modulated by personality factors and by the importance of the symptoms at the pretest session. At posttest, we found that all individuals demonstrated an improvement on the Dual N-Back and on similar untrained dimensions. In addition, we discovered that not only the adults with ADHD showed a stable decrease of the symptomatology, as evaluated by the CAARS inventory, but this reduction was also detected in the control samples. In addition, Event-Related Potential (ERP) data are in favor of an change within prefrontal and parietal cortices. These results suggest that cognitive remediation can be effective in adults with ADHD, and in healthy controls. An important complement of this work would be the examination of the data in regard to the attentional networks, which could empower the fact that complex programs covering the remediation of several executive functions' dimensions is not required, a unique working memory training can be sufficient. -- Nous prenons tous chaque jour des décisions ayant des niveaux d'importance variables. Toutes les décisions ont une composante conflictuelle et d'insatisfaction, car prendre une décision implique qu'il y ait des choix alternatifs à considérer. Les modèles économiques traditionnels estiment qu'une personne doit peser les conséquences positives et négatives de chaque option et en se basant sur ces inférences, détermine quelle option est la meilleure dans une situation particulière. Cependant, les individus peuvent dévier de ces choix rationnels. Ils évaluent plutôt les valeur subjective des résultats, c'est-à-dire que lorsqu'ils sont face à un choix risqué pouvant les mener à des pertes, les gens ont tendance à avoir des préférences pour le risque à la place de la certitude, tandis que lorsqu'ils sont face à un choix risqué pouvant les conduire à un gain, ils évitent de prendre des risques et choisissent l'option la plus su^re. De nos jours, il est considéré que la prise de décision est balancée entre des composantes délibératives et émotionnelles. Ces facteurs sont sous-tendus par des régions neurales distinctes: le chemin délibératif, correspondant aux fonctions exécutives, implique l'activation du cortex préfrontal, tandis que le chemin émotionnel active le système limbique. Ces circuits semblent être dysfonctionnels chez les individus ayant un TDAH, et résulte, entre autres, en des capacités de prise de décision altérées. Leurs comportements impulsifs et inattentifs sont probablement la cause de ces attitudes irrationnelles face au risque. Cependant, une solution possible est de leur administrer un traitement médicamenteux, en prenant en compte les potentiels effets secondaires. Un traitement alternatif se reposant sur une réhabilitation cognitive pourrait être appropriée. Le but de ce projet est donc de déterminer si un entrainement intensif de la mémoire de travail peut avoir un effet sur la prise de décision chez des adultes ayant un TDAH et chez des contrôles sains du même âge. Nous avons conçu une tâche de prise de décision dans laquelle les participants devaient sélectionner un montant à jouer en ayant une chance sur trois de gagner quatre fois le montant choisi, alors que dans l'autre cas, ils pouvaient perdre leur investissement. Leurs performances ont été enregistrées en utilisant l'électroencéphalographie avant et après un entrainement d'un mois au Dual N-Back, et nous avons étudié les possibles effets de transfert. Dans l'ensemble, nous avons trouvé au pré-test que les performances au cours du jeu d'argent étaient modulées par les facteurs de personnalité, et par le degré des sympt^omes. Au post-test, nous avons non seulement trouvé que les adultes ayant un TDAH montraient une diminutions stable des symptômes, qui étaient évalués par le questionnaire du CAARS, mais que cette réduction était également perçue dans l'échantillon des contrôles. Les rsultats expérimentaux mesurés à l'aide de l'éléctroencéphalographie suggèrent un changement dans les cortex préfrontaux et pariétaux. Ces résultats suggèrent que la remédiation cognitive est efficace chez les adultes ayant un TDAH, mais produit aussi un effet chez les contrôles sains. Un complément important de ce travail pourrait examiner les données sur l'attention, qui pourraient renforcer l'idée qu'il n'est pas nécessaire d'utiliser des programmes complexes englobant la remédiation de plusieurs dimensions des fonctions exécutives, un simple entraiment de la mémoire de travail devrait suffire.

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24 h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [3H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [3H]methyllycaconitine binding was increased a 42.1% with NIC + MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the a7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain a4 and b2 subunits. Western blots with specific a4 and a7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis.

Transcranial Direct Current Stimulation for the Treatment of Chronic Tinnitus: A Randomized Controlled Study.

BACKGROUND: Tinnitus is an often disabling condition for which there is no effective therapy. Current research suggests that tinnitus may develop due to maladaptive plastic changes and altered activity in the auditory and prefrontal cortex. Transcranial direct current stimulation (tDCS) modulates brain activity and has been shown to transiently suppress tinnitus in trials. OBJECTIVE: To investigate the efficacy and safety of tDCS in the treatment of chronic subjective tinnitus. METHODS: In a randomized, parallel, double-blind, sham-controlled study, the efficacy and safety of cathodal tDCS to the auditory cortex with anode over the prefrontal cortex was investigated in five sessions over five consecutive days. Tinnitus was assessed after the last session on day 5, and at follow-up visits 1 and 3 months post stimulation using the Tinnitus Handicap Inventory (THI, primary outcome measure), Subjective Tinnitus Severity Scale, Hospital Anxiety and Depression scale, Visual Analogue Scale, and Clinical Global Impression scale. RESULTS: 42 patients were investigated, 21 received tDCS and 21 sham stimulation. There were no beneficial effects of tDCS on tinnitus as assessed by primary and secondary outcome measures. Effect size assessed with Cohen's d amounted to 0.08 (95% CI: -0.52 to 0.69) at 1 month and 0.18 (95% CI: -0.43 to 0.78) at 3 months for the THI. CONCLUSION: tDCS of the auditory and prefrontal cortices is safe, but does not improve tinnitus. Different tDCS protocols might be beneficial.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

Noradrenergic stimulation enhances human action monitoring

Noradrenergic neurotransmission has been associated with the modulation of higher cognitive functions mediated by the prefrontal cortex. In the present study, the impact of noradrenergic stimulation on the human action-monitoring system, as indexed by eventrelated brain potentials, was examined. After the administration of a placebo or the selective 2 -adrenoceptor antagonist yohimbine, which stimulates firing in the locus ceruleus and noradrenaline release, electroencephalograpic recordings were obtained from healthy volunteers performing a letter flanker task. Yohimbine led to an increase in the amplitude of the error-related negativity in conjunction with a significant reduction of action errors. Reaction times were unchanged, and the drug did not modify the N2 in congruent versus incongruent trials, a measure of preresponse conflict, or posterror adjustments as measured by posterror slowing of reaction time. The present findings suggest that the locus ceruleusnoradrenaline system exerts a rather specific effect on human action monitoring.

Nucleus accumbens is involved in human action monitoring: evidence from invasive electrophysiological recordings

The Nucleus accumbens (Nacc) has been proposed to act as a limbic-motor interface. Here, using invasive intraoperative recordings in an awake patient suffering from obsessive-compulsive disease (OCD), we demonstrate that its activity is modulated by the quality of performance of the subject in a choice reaction time task designed to tap action monitoring processes. Action monitoring, that is, error detection and correction, is thought to be supported by a system involving the dopaminergic midbrain, the basal ganglia, and the medial prefrontal cortex. In surface electrophysiological recordings, action monitoring is indexed by an error-related negativity (ERN) appearing time-locked to the erroneous responses and emanating from the medial frontal cortex. In preoperative scalp recordings the patient's ERN was found to be signifi cantly increased compared to a large (n = 83) normal sample, suggesting enhanced action monitoring processes. Intraoperatively, error-related modulations were obtained from the Nacc but not from a site 5 mm above. Importantly, crosscorrelation analysis showed that error-related activity in the Nacc preceded surface activity by 40 ms. We propose that the Nacc is involved in action monitoring, possibly by using error signals from the dopaminergic midbrain to adjust the relative impact of limbic and prefrontal inputs on frontal control systems in order to optimize goal-directed behavior.

Neural mechanisms underlying adaptive actions after slips

An increase in cognitive control has been systematically observed in responses produced immediately after the commission of an error. Such responses show a delay in reaction time (post-error slowing) and an increase in accuracy. To characterize the neurophysiological mechanism involved in the adaptation of cognitive control, we examined oscillatory electrical brain activity by electroencephalogram and its corresponding neural network by event-related functional magnetic resonance imaging in three experiments. We identified a new oscillatory thetabeta component related to the degree of post-error slowing in the correct responses following an erroneous trial. Additionally, we found that the activity of the right dorsolateral prefrontal cortex, the right inferior frontal cortex, and the right superior frontal cortex was correlated with the degree of caution shown in the trial following the commission of an error. Given the overlap between this brain network and the regions activated by the need to inhibit motor responses in a stop-signal manipulation, we conclude that the increase in cognitive control observed after the commission of an error is implemented through the participation of an inhibitory mechanism.

An fMRI Study of Emotional engagement in decicion-making

It has been suggested that decisionmaking depends on sensitive feelings associatedwith cognitive processing rather than cognitiveprocessing alone. From human lesions, we knowthe medial anterior inferior-ventral prefrontalcortex processes the sensitivity associated withcognitive processing, it being essentiallyresponsible for decision making.In this fMRI (functional Magnetic ResonanceImage) study 15 subjects were analyzed usingmoral dilemmas as probes to investigate the neuralbasis for painful-emotional sensitivity associatedwith decision making. We found that a networkcomprising the posterior and anterior cingulateand the medial anterior prefrontal cortex wassignificantly and specifically activated by painfulmoral dilemmas, but not by non-painful dilemmas.These findings provide new evidence that thecingulate and medial anterior prefrontal areinvolved in processing painful emotionalsensibility, in particular, when decision makingtakes place. We speculate that decision makinghas a cognitive component processed by cognitivebrain areas and a sensitivity component processedby emotional brain areas. The structures activatedsuggest that decision making depends on painfulemotional feeling processing rather than cognitiveprocessing when painful feeling processinghappens

Brain Dopamine and Serotonin Receptors in the Perception of Pain. Positron Emission Tomography Studies in Healthy Subjects

The role of dopamine and serotonin in spinal pain regulation is well established. However, little is known concerning the role of brain dopamine and serotonin in the perception of pain in humans. The aim of this study was to assess the potential role of brain dopamine and serotonin in determining experimental pain sensitivity in humans using positron emission tomography (PET) and psychophysical methods. A total of 39 healthy subjects participated in the study, and PET imaging was performed to assess brain dopamine D2/D3 and serotonin 5-HT_1A receptor availability. In a separate session, sensitivity to pain and touch was assessed with traditional psychophysical methods, allowing the evaluation of potential associations between D2/D3 and 5-HT_1A binding and psychophysical responses. The subjects’ responses were also analyzed according to Signal Detection Theory, which enables separate assessment of the subject’s discriminative capacity (sensory factor) and response criterion (non-sensory factor). The study found that the D2/D3 receptor binding in the right putamen was inversely correlated with pain threshold and response criterion. 5-HT_1A binding in cingulate cortex, inferior temporal gyrus and medial prefrontal cortex was inversely correlated with discriminative capacity for touch. Additionally, the response criterion for pain and intensity rating of suprathreshold pain were inversely correlated with 5-HT_1A binding in multiple brain areas. The results suggest that brain D2/D3 receptors and 5-HT_1A receptors modulate sensitivity to pain and that the pain modulatory effects may, at least partly, be attributed to influences on the response criterion. 5-HT_1A receptors are also involved in the regulation of touch by having an effect on discriminative capacity.

PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [¹⁸F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [¹⁸F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.

The brain decade in debate: I. Neurobiology of learning and memory

This article is a transcription of an electronic symposium in which some active researchers were invited by the Brazilian Society for Neuroscience and Behavior (SBNeC) to discuss the last decade's advances in neurobiology of learning and memory. The way different parts of the brain are recruited during the storage of different kinds of memory (e.g., short-term vs long-term memory, declarative vs procedural memory) and even the property of these divisions were discussed. It was pointed out that the brain does not really store memories, but stores traces of information that are later used to create memories, not always expressing a completely veridical picture of the past experienced reality. To perform this process different parts of the brain act as important nodes of the neural network that encode, store and retrieve the information that will be used to create memories. Some of the brain regions are recognizably active during the activation of short-term working memory (e.g., prefrontal cortex), or the storage of information retrieved as long-term explicit memories (e.g., hippocampus and related cortical areas) or the modulation of the storage of memories related to emotional events (e.g., amygdala). This does not mean that there is a separate neural structure completely supporting the storage of each kind of memory but means that these memories critically depend on the functioning of these neural structures. The current view is that there is no sense in talking about hippocampus-based or amygdala-based memory since this implies that there is a one-to-one correspondence. The present question to be solved is how systems interact in memory. The pertinence of attributing a critical role to cellular processes like synaptic tagging and protein kinase A activation to explain the memory storage processes at the cellular level was also discussed.

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean ± SEM, pg/20 µl, was 3.0 ± 0.4 for LDS, 3.8 ± 0.3 for HDS and 6.4 ± 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (±)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500%) as compared with LDS (248%) or RDS (243%) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900% in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line.

Engagement of multifocal neural circuits during recall of autobiographical happy events

Happy emotional states have not been extensively explored in functional magnetic resonance imaging studies using autobiographic recall paradigms. We investigated the brain circuitry engaged during induction of happiness by standardized script-driven autobiographical recall in 11 healthy subjects (6 males), aged 32.4 ± 7.2 years, without physical or psychiatric disorders, selected according to their ability to vividly recall personal experiences. Blood oxygen level-dependent (BOLD) changes were recorded during auditory presentation of personal scripts of happiness, neutral content and negative emotional content (irritability). The same uniform structure was used for the cueing narratives of both emotionally salient and neutral conditions, in order to decrease the variability of findings. In the happiness relative to the neutral condition, there was an increased BOLD signal in the left dorsal prefrontal cortex and anterior insula, thalamus bilaterally, left hypothalamus, left anterior cingulate gyrus, and midportions of the left middle temporal gyrus (P < 0.05, corrected for multiple comparisons). Relative to the irritability condition, the happiness condition showed increased activity in the left insula, thalamus and hypothalamus, and in anterior and midportions of the inferior and middle temporal gyri bilaterally (P < 0.05, corrected), varying in size between 13 and 64 voxels. Findings of happiness-related increased activity in prefrontal and subcortical regions extend the results of previous functional imaging studies of autobiographical recall. The BOLD signal changes identified reflect general aspects of emotional processing, emotional control, and the processing of sensory and bodily signals associated with internally generated feelings of happiness. These results reinforce the notion that happiness induction engages a wide network of brain regions.