Functional heterogeneity of medial posterior parietal cortex of macaque monkey

The posterior parietal cortex (PPC) of primates represents a remarkable platform that has evolved over time to solve some of the computational challenges that we face in the everyday life, such as sensorimotor integration, spatial attention, and motor planning. With the aim of further investigating the multifaceted functional characteristics of medial PPC, we conducted three studies to explore the visuomotor, somatic, visual, and attention-related properties of two PPC areas: V6A, a visuomotor area part of the dorsomedial visual stream, and PE, an area strongly dominated by somatomotor input, residing mainly on the exposed surface of the superior parietal lobule. In the first study, we tested the impact of visual feedback on V6A grasp-related activity during arm movements towards objects of different shapes. Our results demonstrate that V6A is modulated by both grip type and visual information during grasping preparation and execution, with a predominance of cells influenced by grip type. In the second study, we explored the influence of depth and direction information on reach-related activity of neurons in the so far largely neglected medial part of area PE. We observed a remarkable trend in medial PPC, going from the joint coding of depth and direction signals caudally, in area V6A, to a largely segregated processing of the two signals rostrally, in area PE. In the third study, we used a combined fMRI-electrophysiology experiment to investigate the neuronal mechanisms underlying covert shift of attention processes in area V6A. Our preliminary results reveal that half of the cells showed shift-selective activity when the monkey covertly shifted its attention towards the receptive field. All together these findings highlight the role of the medial PPC in integrating information coming from different sources (vision, somatosensory and motor) and emphasize the involvement of action-related regions of the dorsomedial visual stream in higher level cognitive functions.

The Psychedelic State Induced By Ayahuasca Modulates The Activity And Connectivity Of The Default Mode Network.

The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.

Distinct Effects of Delta 9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing

Context: Cannabis use can both increase and reduce anxiety in humans. The neurophysiological substrates of these effects are unknown. Objective: To investigate the effects of 2 main psycho-active constituents of Cannabis sativa (Delta 9-tetrahydrocannabinol [Delta 9-THC] and cannabidiol [CBD]) on regional brain function during emotional processing. Design: Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety. Each scanning session was preceded by the ingestion of either 10 mg of Delta 9-THC, 600 mg of CBD, or a placebo in a double-blind, randomized, placebo-controlled design. Participants: Fifteen healthy, English-native, right-handed men who had used cannabis 15 times or less in their life. Main Outcome Measures: Regional brain activation (blood oxygenation level-dependent response), electrodermal activity (skin conductance response [SCR]), and objective and subjective ratings of anxiety. Results: Delta 9-Tetrahydrocannabinol increased anxiety, as well as levels of intoxication, sedation, and psychotic symptoms, whereas there was a trend for a reduction in anxiety following administration of CBD. The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta 9-THC but decreased following administration of CBD. Cannabidiol attenuated the blood oxygenation level dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces, and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations. Delta 9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas. Conclusions: Delta 9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural, electrodermal, and symptomatic response to fearful faces. The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety, whereas the anxiogenic effects of Delta 9-THC may be related to effects in other brain regions.

Emotionally negative stimuli can overcome attentional deficits in patients with visuo-spatial hemineglect.

Left unilateral spatial neglect resulting from right brain damage is characterized by loss of awareness for stimuli in the contralesional side of space, despite intact visual pathways. We examined using fMRI whether patients with neglect are more likely to consciously detect in the neglected hemifield, emotionally negative complex scenes rather than visually similar neutral pictures and if so, what neural mechanisms mediate this effect. Photographs of emotional and neutral scenes taken from the IAPS were presented in a divided visual field paradigm. As expected, the detection rate for emotional stimuli presented in the neglected field was higher than for neutral ones. Successful detection of emotional scenes as opposed to neutral stimuli in the left visual field (LVF) produced activations in the parahippocampal and anterior cingulate areas in the right hemisphere. Detection of emotional stimuli presented in the intact right visual field (RVF) activated a distributed network of structures in the left hemisphere, including anterior and posterior cingulate cortex, insula, as well as visual striate and extrastriate areas. LVF-RVF contrasts for emotional stimuli revealed activations in right and left attention related prefrontal areas whereas RVF-LVF comparison showed activations in the posterior cingulate and extrastriate visual cortex in the left hemisphere. An additional analysis contrasting detected vs. undetected emotional LVF stimuli showed involvement of left anterior cingulate, right frontal and extrastriate areas. We hypothesize that beneficial role of emotion in overcoming neglect is achieved by activation of frontal and limbic lobe networks, which provide a privileged access of emotional stimuli to attention by top-down modulation of processing in the higher-order extrastriate visual areas. Our results point to the importance of top-down regulatory role of the frontal attentional systems, which might enhance visual activations and lead to greater salience of emotional stimuli for perceptual awareness.

Pure amnesia after unilateral left polar thalamic infarct: topographic and sequential neuropsychological and metabolic (PET) correlations.

A 54-year-old patient who had an isolated small polar thalamic infarct and acute global amnesia with slight frontal type dysfunction but without other neurological dysfunction was studied. Memory improved partially within 8 months. At all stages the impairment was more severe for verbal than non-verbal memory. Autobiographic recollections and newly acquired information tended to be disorganised with respect to temporal order. Procedural memory was unaffected. Both emotional involvement and pleasure in reading were lost. On MRI, the infarct was limited to the left anterior thalamic nuclei and the adjacent mamillothalamic tract. The regional cerebral metabolic rate of glucose (measured with PET) was decreased on the left in the thalamus, amygdala, and posterior cingulate cortex 2 weeks after the infarct, and in the thalamus and posterior cingulate cortex 9 months later. These findings stress the specific role of the left anterior thalamic region in memory and confirm that longlasting amnesia from a thalamic lesion can occur without significant structural damage to the dorsomedial nucleus. Furthermore, they suggest that the anterior thalamic nuclei and possibly their connections with the posterior cingulate cortex play a role in emotional involvement linked to ipsilateral hemispheric functions.

Effect of mindfulness meditation on the neural substrates of emotion processing and resting state in experienced and beginner meditators

La méditation par le ‘mindfulness’ favorise la stabilité émotionelle, mais les mécanismes neuroneux qui sous-tendent ces effets sont peu connus. Ce projet investiga l’effet du ‘mindfulness’ sur les réponses cérébrales et subjectives à des images négatives, positives et neutres chez des méditants expérimentés et des débutants au moyen de l’imagerie par résonance magnétique fonctionnelle (IRMf). Le ‘mindfulness’ atténua l’intensité émotionelle via différents mécanismes cérébraux pour chaque groupe. Comparés aux méditants, les débutants manifestèrent une déactivation de l’amygdale en réponse aux stimuli émotifs durant le ‘mindfulness’. Comparés aux débutants, les méditants exhibèrent une déactivation de régions du réseau du mode par défaut (RMD) pendant le ‘mindfulness’ pour tous stimuli (cortex médian préfrontal [CMP], cortex cingulaire postérieur [CCP]). Le RMD est constitué de régions fonctionnellement connectées, activées au repos et déactivées lors de tâches explicites. Cependant, nous ne connaissons pas les impacts de l’entraînement par la méditation sur la connectivité entre régions du RMD et si ces effets persistent au-delà d’un état méditatif. La connectivité fonctionnelle entre régions du RMD chez les méditants et débutants au repos fut investiguée au moyen de l’IRMf. Comparés aux débutants, les méditants montrèrent une connectivité affaiblie entre subdivisions du CMP, et une connectivité accrue entre le lobule pariétal inférieur et trois regions du RMD. Ces résultats reflètent que les bienfaits immédiats du ‘mindfulness’ sur la psychopathologie pourraient être dûs à une déactivation de régions limbiques impliquées dans la réactivité émotionelle. De plus, les bienfaits à long-terme de la méditation sur la stabilité émotionelle pourrait être dûs à une déactivation de régions corticales et cingulaires impliquées dans l’évaluation de la signification émotive et une connectivité altérée entre régions du RMD à l’état de repos.

L’impulsivité en toxicomanie : un regard sur les mécanismes neuronaux de la rechute à la nicotine

Contexte : Jusqu’à 90% des fumeurs qui tentent d’arrêter de fumer vont rechuter dans l’année suivant la date d’arrêt. L’impulsivité, au même titre que le « craving », a démontré être un bon facteur de prédiction de la rechute tabagique. Ainsi, la présente étude visait à évaluer, à l’aide de la neuroimagerie fonctionnelle, l’influence de l’impulsivité sur les mécanismes neuronaux du « craving » de la cigarette. Parmi les régions cérébrales impliquées dans le « craving » de la nicotine, les cortex préfrontal dorsolatéral, orbitofrontal et cingulaire sont d’importantes structures dans les processus de contrôle de soi. Méthodes : 31 fumeurs chroniques ont passé une session de neuroimagerie durant laquelle ils devaient regarder des images appétitives de cigarettes et des images neutres. Ils ont ensuite dû inscrire le « craving » ressenti à la vue des images et répondre à un questionnaire portant sur les traits de personnalité de l’impulsivité (BIS-11). Résultats : Tel qu’attendu, le score d’impulsivité était positivement corrélé au « craving » rapporté par les participants à la vue d’images de cigarettes. Au niveau cérébral, plus les fumeurs présentaient de forts traits d’impulsivité, moins grande était l’activité du cortex cingulaire postérieur (CCP) durant le « craving ». Enfin, l’activité du CCP présentait une connectivité fonctionnelle négative avec l’insula, le cortex préfrontal dorsolatéral et le cortex cingulaire antérieur. Conclusions : Comme le CCP est le siège des processus de mentalisation et de référence à soi, nous suggérons que plus les fumeurs étaient impulsifs, moins ils prenaient conscience de leur état et moins ils en exerçaient un contrôle, donc plus ils ressentaient de forts « cravings ». En poussant plus loin, nos résultats mettent l’accent sur l’aspect identitaire (le soi, les mémoires autobiographiques) et l’aspect d’introspection en toxicomanie : deux avenues à explorer.

Le rôle de la méthylation de l’ADN dans les fonctions cérébrales fronto-limbiques et la réactivité au stress quotidien

La sérotonine (5-HT) joue un rôle crucial dans l'étiologie des troubles mentaux comme la dépression majeure, les troubles de comportement et les troubles anxieux. Des études ont montré que des altérations précoces du système 5-HT peuvent potentiellement influencer le développement du cerveau et le fonctionnement du système fronto-limbique, engendrant des conséquences pour la régulation émotionnelle. Il existe aussi des évidences que le stress précoce peut affecter la méthylation de l'ADN résultant d'une altération de l'expression génique. Toutefois, le lien entre la méthylation de l'ADN et la réactivité comportementale à des facteurs de stress de la vie quotidienne est inconnu. La méthylation du gène transporteur 5-HT (SLC6A4) est d'un intérêt particulier, étant donné le rôle de SLC6A4 dans le développement du cerveau, les troubles mentaux et la régulation du stress. L'objectif de cette thèse est d'étudier l'association entre (1) les niveaux périphériques de méthylation de l'ADN dans le gène SLC6A4 et les réponses neurales aux stimuli émotionnels dans les circuits fronto-limbiques du cerveau, ainsi qu’entre (2) la méthylation périphérique de SLC6A4 et la réactivité comportementale au stress de la vie quotidienne. Nous explorons également l'association entre les réponses neuronales fronto-limbique à des stimuli émotionnels et la réactivité comportementale au stress de la vie quotidienne (3). À cette fin, vingt-deux personnes (11 femmes) d’âge moyen de 34,0 ans (SD : 1,5) avec différents niveaux de méthylation au gène SLC6A4 ont été recrutés à partir de deux études longitudinales. Les participants ont subi une analyse IRMf qui comprenait une tâche de traitement émotionnel. Un questionnaire en ligne sur la réactivité au stress quotidien de la vie a été réalisé pendant 5 jours consécutifs. Des analyses corrélationnelles et de régression ont été effectuées pour examiner les associations entre les variables primaires. Les résultats préliminaires de cette étude ont montré que la méthylation de l'ADN est associée à la désactivation significative du gyrus précentral et gyrus fusiforme respectivement face à des stimuli de peur et de tristesse. Aucune association significative n'a été observée entre les niveaux de méthylation et l'activation de l'amygdale. En outre, les scores obtenus aux variables de stress de la vie quotidienne tels que la détresse chronique ont été associées à la désactivation du précuneus et du cortex cingulaire postérieur face à la tristesse. Ces résultats suggèrent l'implication potentielle des processus épigénétiques dans l'activation cérébrale spécifique et la sensibilité au stress de la vie courante.

Alterações da default mode network provocadas pela ingestão de Ayahuasca investigadas por Ressonância Magnética Funcional

Ayahuasca is psychotropic beverage that has been used for ages by indigenous populations in South America, notably in the Amazon region, for religious and medicinal purposes. The tea is obtained by the decoction of leaves from the Psychotria viridis with the bark and stalk of a shrub, the Banisteriopsis caapi. The first is rich in N-N-dimethyltryptamine (DMT), which has an important and well-known hallucinogenic effect due to its agonistic action in serotonin receptors, specifically 5-HT2A. On the other hand, β-carbolines present in B. caapi, particularly harmine and harmaline, are potent monoamine oxidase inhibitors (MAOi). In addition, the tetrahydroharmine (THH), also present in B. caapi, acts as mild selective serotonin reuptake inhibitor and a weak MAOi. This unique composition induces a number of affective, sensitive, perceptual and cognitive changes in individuals under the effect of Ayahuasca. On the other hand, there is growing interest in the Default Mode Network (DMN), which has been consistently observed in functional neuroimaging studies. The key components of this network include structures in the brain midline, as the anterior medial frontal cortex, ventral medial frontal cortex, posterior cingulate cortex, precuneus, and some regions within the inferior parietal lobe and middle temporal gyrus. It has been argued that DMN participate in tasks involving self-judgments, autobiographical memory retrieval, mental simulations, thinking in perspective, meditative states, and others. In general, these tasks require an internal focus of attention, hence the conclusion that the DMN is associated with introspective mental activity. Therefore, this study aimed to evaluate by functional magnetic resonance imaging (fMRI) changes in DMN caused via the ingestion of Ayahuasca by 10 healthy subjects while submitted to two fMRI protocols: a verbal fluency task and a resting state acquisition. In general, it was observed that Ayahuasca causes a reduction in the fMRI signal in central nodes of DMN, such as the anterior cingulate cortex, the medial prefrontal cortex, the posterior cingulate cortex, precuneus and inferior parietal lobe. Furthermore, changes in connectivity patterns of the DMN were observed, especially a decrease in the functional connectivity of the precuneus. Together, these findings indicate an association between the altered state of consciousness experienced by individuals under the effect of Ayahuasca, and changes in the stream of spontaneous thoughts leading to an increased introspective mental activity

Análise quantitativa das descargas epileptiformes generalizadas e da neuroimagem de pacientes com epilepsia generalizada idiopática

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

Electroencephalographic topography measures of experienced utility

Economic theory distinguishes two concepts of utility: decision utility, objectively quantifiable by choices, and experienced utility, referring to the satisfaction by an obtainment. To date, experienced utility is typically measured with subjective ratings. This study intended to quantify experienced utility by global levels of neuronal activity. Neuronal activity was measured by means of electroencephalographic (EEG) responses to gain and omission of graded monetary rewards at the level of the EEG topography in human subjects. A novel analysis approach allowed approximating psychophysiological value functions for the experienced utility of monetary rewards. In addition, we identified the time windows of the event-related potentials (ERP) and the respective intracortical sources, in which variations in neuronal activity were significantly related to the value or valence of outcomes. Results indicate that value functions of experienced utility and regret disproportionally increase with monetary value, and thus contradict the compressing value functions of decision utility. The temporal pattern of outcome evaluation suggests an initial (∼250 ms) coarse evaluation regarding the valence, concurrent with a finer-grained evaluation of the value of gained rewards, whereas the evaluation of the value of omitted rewards emerges later. We hypothesize that this temporal double dissociation is explained by reward prediction errors. Finally, a late, yet unreported, reward-sensitive ERP topography (∼500 ms) was identified. The sources of these topographical covariations are estimated in the ventromedial prefrontal cortex, the medial frontal gyrus, the anterior and posterior cingulate cortex and the hippocampus/amygdala. The results provide important new evidence regarding “how,” “when,” and “where” the brain evaluates outcomes with different hedonic impact.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

The effects of catecholamine depletion on the neural response to fearful faces in remitted depression

Recent evidence suggests that increased psychophysiological response to negatively valenced emotional stimuli found in major depressive disorder (MDD) may be associated with reduced catecholaminergic neurotransmission. Fourteen unmedicated, remitted subjects with MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral α-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover trial. Subjects were exposed to fearful (FF) and neutral faces (NF) during a scan with [15O]H2O positron emission tomography to assess the brain-catecholamine interaction in brain regions previously associated with emotional face processing. Treatment with AMPT resulted in significantly increased, normalized cerebral blood flow (CBF) in the left inferior temporal gyrus (ITG) and significantly decreased CBF in the right cerebellum across conditions and groups. In RMDD, flow in the left posterior cingulate cortex (PCC) increased significantly in the FF compared to the NF condition after AMPT, but remained unchanged after placebo, whereas healthy controls showed a significant increase under placebo and a significant decrease under AMPT in this brain region. In the left dorsolateral prefrontal cortex (DLPFC), flow decreased significantly in the FF compared to the NF condition under AMPT, and increased significantly under placebo in RMDD, whereas healthy controls showed no significant differences. Differences between AMPT and placebo of within-session changes in worry-symptoms were positively correlated with the corresponding changes in CBF in the right subgenual prefrontal cortex in RMDD. In conclusion, this study provided evidence for a catecholamine-related modulation of the neural responses to FF expressions in the left PCC and the left DLPFC in subjects with RMDD that might constitute a persistent, trait-like abnormality in MDD.

Comparative Behavioral and Neural Effects of Tryptophan and Catecholamine Depletion in Remitted Depression

Background: Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catechominergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber’s selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Methods: Using identical neuroimaging procedures with [18F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared to healthy controls in a double-blind, randomized, crossover design. Results: While TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex (PCC). While we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. Conclusions: In conclusion, this study showed that serotonin and catecholamines play common and differential roles in the pathophysiology of depression.