Mécanismes cérébraux de la régulation de la douleur : perception de la douleur et hypoalgésie induite psychologiquement

Objectif : Cette thèse a pour but de préciser les mécanismes neuropsychologiques de la douleur, de la régulation endogène de la douleur et de l'hypoalgésie induite psychologiquement (HIP) par la synthèse de près de trente ans de recherche imagerie cérébrale fonctionnelle. Méthodologie : Étant donné l'abondance des études sur le sujet et le manque d'intégration de leurs résultats, la technique de métaanalyse quantitative basée sur les coordonnées d'activation cérébrale fut privilégiée dans cette thèse, telle qu’implémentée dans l'algorithme ALE (Activation Likelyhood Estimate). Une force supplémentaire de cette thèse repose sur la rigueur du processus de sélection des articles. En effet, les études incluses dans les métaanalyses devaient satisfaire des critères stricts d'inclusion, ceci dans le but de favoriser la précision et la validité des conclusions subséquentes. Étude 1 : Le premier article visait à identifier les aires cérébrales impliquées dans la réduction de la douleur par des méthodes psychologiques d'interventions. Les articles retenus portent sur une variété de méthodes d'intervention, telles que le placebo, l'hypnose, la méditation, la perception de contrôle sur la stimulation douloureuse et l'induction d'émotions. Les résultats indiquent que l'HIP implique un vaste réseau d'activation qui comprend le cortex cingulaire antérieur, l'insula antérieure, les zones orbitofrontale et préfrontale latérale, ainsi que les régions pariétale, temporale et souscorticales. Ces activations reflèteraient l'implication des mécanismes neuropsychologiques cognitifs et émotionnels sous-tendent les interventions psychologiques ciblées par ces études, incluant la conscience de soi et la motivation. De plus, les divergences de patron d'activation entre les approches ont été explorées, notamment pour le placebo et la distraction. Étude 2 : Le deuxième article a identifié des patrons d'activations préférentiellement associés à la perception de la douleur, à l'HIP, ainsi que des activations communément associées à la douleur et l'HIP. Les résultats indiquent que 1) la perception de la douleur est associée à l'activation d'aires somatosensorielles et motrices, ce qui pourrait être le reflet de la préparation d'une action adaptative, 2) l'HIP est liée à l'engagement de régions préfrontales antéromédianes et orbitales, possiblement en lien avec des processus motivationnels et émotionnels, et 3) la douleur et l'HIP sont associés à l'activation d'aires préfrontales dorsolatérales, de l'insula antérieure et du cortex cingulaire moyen, ce qui pourrait refléter l'engagement spontané pendant la douleur de mécanismes endogènes de régulation descendante. Conclusion : Par ces études, cette thèse fait le point sur les mécanismes cérébraux impliqués différentiellement dans la perception de la douleur, dans sa régulation endogène et dans l'hypoalgésie induite psychologiquement.

Análisis del gen adra2a receptor alfa 2a adrenergico en pacientes con trastorno de hiperactividad y déficit de atención

El trastorno de hiperactividad y déficit de atención (THDA), es definido clínicamente como una alteración en el comportamiento, caracterizada por inatención, hiperactividad e impulsividad. Estos aspectos son clasificados en tres subtipos, que son: Inatento, hiperactivo impulsivo y mixto. Clínicamente se describe un espectro amplio que incluye desordenes académicos, trastornos de aprendizaje, déficit cognitivo, trastornos de conducta, personalidad antisocial, pobres relaciones interpersonales y aumento de la ansiedad, que pueden continuar hasta la adultez. A nivel global se ha estimado una prevalencia entre el 1% y el 22%, con amplias variaciones, dadas por la edad, procedencia y características sociales. En Colombia, se han realizado estudios en Bogotá y Antioquia, que han permitido establecer una prevalencia del 5% y 15%, respectivamente. La causa específica no ha sido totalmente esclarecida, sin embargo se ha calculado una heredabilidad cercana al 80% en algunas poblaciones, demostrando el papel fundamental de la genética en la etiología de la enfermedad. Los factores genéticos involucrados se relacionan con cambios neuroquímicos de los sistemas dopaminérgicos, serotoninérgicos y noradrenérgicos, particularmente en los sistemas frontales subcorticales, corteza cerebral prefrontal, en las regiones ventral, medial, dorsolateral y la porción anterior del cíngulo. Basados en los datos de estudios previos que sugieren una herencia poligénica multifactorial, se han realizado esfuerzos continuos en la búsqueda de genes candidatos, a través de diferentes estrategias. Particularmente los receptores Alfa 2 adrenérgicos, se encuentran en la corteza cerebral, cumpliendo funciones de asociación, memoria y es el sitio de acción de fármacos utilizados comúnmente en el tratamiento de este trastorno, siendo esta la principal evidencia de la asociación de este receptor con el desarrollo del THDA. Hasta la fecha se han descrito más de 80 polimorfismos en el gen (ADRA2A), algunos de los cuales se han asociado con la entidad. Sin embargo, los resultados son controversiales y varían según la metodología diagnóstica empleada y la población estudiada, antecedentes y comorbilidades. Este trabajo pretende establecer si las variaciones en la secuencia codificante del gen ADRA2A, podrían relacionarse con el fenotipo del Trastorno de Hiperactividad y el Déficit de Atención.

Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression

Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.

Prolonged neglect following unilateral disruption of a prefrontal cortical-dorsal striatal system.

We investigated the potential function of the system formed by connections between the medial prefrontal cortex and the dorsomedial striatum in aspects of attentional function in the rat. It has been reported previously that disconnection of the same corticostriatal circuit produced marked deficits in performance of a serial, choice reaction-time task while sparing the acquisition of an appetitive Pavlovian approach behaviour in an autoshaping task (Christakou et al., 2001). Here, we hypothesized that unilateral disruption of the same circuit would lead to hemispatial inattention, contrasting with the global attention deficit following complete disconnection of the system. Combined unilateral lesions of the medial prefrontal cortex (mPFC) and the medial caudate-putamen (mCPu) within the same hemisphere produced a severe and long-lasting contralesional neglect syndrome while sparing the acquisition of autoshaping. These results provide further evidence for the involvement of the medial prefrontal-dorsomedial striatal circuit in aspects of attentional function, as well as insight into the nature of neglect deficits following lesions at different levels within corticostriatal circuitry.

Prefrontal cortical-ventral striatal interactions involved in affective modulation of attentional performance: implications for corticostriatal circuit function

Anatomically segregated systems linking the frontal cortex and the striatum are involved in various aspects of cognitive, affective, and motor processing. In this study, we examined the effects of combined unilateral lesions of the medial prefrontal cortex (mPFC) and the core subregion of the nucleus accumbens (AcbC) in opposite hemispheres (disconnection) on a continuous performance, visual attention test [five-choice serial reaction-time task (5CSRTT)]. The disconnection lesion produced a set of specific changes in performance of the 5CSRTT, resembling changes that followed bilateral AcbC lesions while, in addition, comprising a subset of the behavioral changes after bilateral mPFC lesions previously reported using the same task. Specifically, both mPFC/AcbC disconnection and bilateral AcbC lesions markedly affected aspects of response control related to affective feedback, as indexed by perseverative responding in the 5CSRTT. These effects were comparable, although not identical, to those in animals with either bilateral AcbC or mPFC/AcbC disconnection lesions. The mPFC/AcbC disconnection resulted in a behavioral profile largely distinct from that produced by disconnection of a similar circuit described previously, between the mPFC and the dorsomedial striatum, which were shown to form a functional network underlying aspects of visual attention and attention to action. This distinction provides an insight into the functional specialization of corticostriatal circuits in similar behavioral contexts.

Functional disconnection of a prefrontal cortical-dorsal striatal system disrupts choice reaction time performance: implications for attentional function

This series of experiments investigated the role of a prefrontal cortical-dorsal striatal circuit in attention, using a continuous performance task of sustained and spatially divided visual attention. A unilateral excitotoxic lesion of the medial prefrontal cortex and a contralateral lesion of the medial caudate-putamen were used to "disconnect" the circuit. Control groups of rats with unilateral lesions of either structure were tested in the same task. Behavioral controls included testing the effects of the disconnection lesion on Pavlovian discriminated approach behavior. The disconnection lesion produced a significant reduction in the accuracy of performance in the attentional task but did not impair Pavlovian approach behavior or affect locomotor or motivational variables, providing evidence for the involvement of this medial prefrontal corticostriatal system in aspects of visual attentional function.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.

Amygdala-prefrontal coupling underlies individual differences in emotion regulation

Despite growing evidence on the neural bases of emotion regulation, little is known about the mechanisms underlying individual differences in cognitive regulation of negative emotion, and few studies have used objective measures to quantify regulatory success. Using a trait-like psychophysiological measure of emotion regulation, corrugator electromyography, we obtained an objective index of the ability to cognitively reappraise negative emotion in 56 healthy men (session 1), who returned 1.3 years later to perform the same regulation task using fMRI (session 2). Results indicated that the corrugator measure of regulatory skill predicted amygdala-prefrontal functional connectivity. Individuals with greater ability to down-regulate negative emotion as indexed by corrugator at session 1 showed not only greater amygdala attenuation but also greater inverse connectivity between the amygdala and several sectors of the prefrontal cortex while down-regulating negative emotion at session 2. Our results demonstrate that individual differences in emotion regulation are stable over time and underscore the important role of amygdala-prefrontal coupling for successful regulation of negative emotion.

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets.

Prefrontal afferents to the dorsal raphe nucleus in the rat

The prefrontal cortex (PFC) receives strong inputs from monoaminergic cell groups in the brainstem and also sends projections to these nuclei. Recent evidence suggests that the PFC exerts a powerful top-down control over the dorsal raphe nucleus (DR) and that it may be involved in the actions of pharmaceutical drugs and drugs of abuse. In the light of these findings, the precise origin of prefrontal inputs to DR was presently investigated by using the cholera toxin subunit b (CTb) as retrograde tracer. All the injections placed in DR produced retrograde labeling in the medial, orbital, and lateral divisions of the PFC as well as in the medial part of the frontal polar cortex. The labeling was primarily located in layer V. Remarkably, labeling in the medial PFC was denser in its ventral part (infralimbic and ventral prelimbic cortices) than in its dorsal part (dorsal prelimbic, anterior cingulate and medial precentral cortices). After injections in the rostral or caudal DR, the largest number of labeled neurons was observed in the medial PFC, whereas after injections in the mid-rostrocaudal DR, the labeled neurons were more homogeneously distributed in the three main PFC divisions. A cluster of labeled neurons also was observed around the apex of the rostral pole of the accumbens, especially after rostral and mid-rostrocaudal DR injections. Overall, these results confirm the existence of robust preftontal projections to DR, mainly derived from the ventral part of the medial PFC, and underscore a substantial contribution of the frontal polar cortex. (C) 2008 Elsevier Inc. All rights reserved.

Cardiovascular effects of noradrenaline microinjected into the insular cortex of unanesthetized rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Caracterização de subpopulações de interneurônios imunorreativos para proteínas ligantes de cálcio no córtex pré-frontal do Sagui (Callithrix jacchus): distribuição e morfologia

Cortical interneurons are characterized by their distinct morphological, physiological and biochemical properties, acting as modulators of the excitatory activity by pyramidal neurons, for example. Various studies have revealed differences in both distribution and density of this cell group throughout distinct cortical areas in several species. A particular class of interneuron closely related to cortical modulation is revealed by the immunohistochemistry for calcium binding proteins calbindin (CB), calretinina (CR) and parvalbumin (PV). Despite the growing amount of studies focusing on calcium binding proteins, the prefrontal cortex of primates remains relatively little explored, particularly in what concerns a better understanding of the organization of the inhibitory circuitry across its subdivisions. In the present study we characterized the morphology and distribution of neurons rich in calcium-binding proteins in the medial, orbital and dorsolateral areas of the prefrontal cortex of the marmoset (Callithrix jacchus). Using both morphometric and stereological techniques, we found that CR-reactive neurons (mainly double bouquet and bipolar cells) have a more complex dendritic arborization than CB-reactive (bitufted and basket cells) and PV-reactive neurons (chandelier cells). The neuronal densities of CR- and CB-reactive cells are higher in the supragranular layers (II/III) whilst PV-reactive neurons, conversely, are more concentrated in the infragranular layers (V/VI). CR-reactive neurons were the predominant group in the three regions evaluated, being most prevalent in dorsomedial region. Our findings point out to fundamental differences in the inhibitory circuitry of the different areas of the prefrontal cortex in marmoset

Involvement of the insular cortex in the consolidation and expression of contextual fear conditioning

The insular cortex (IC) has been reported to be involved in the modulation of memory and autonomic and defensive responses. However, there is conflicting evidence about the role of the IC in fear conditioning. To explore the IC involvement in both behavioral and autonomic responses induced by contextual fear conditioning, we evaluated the effects of the reversible inhibition of the IC neurotransmission through bilateral microinjections of the non-selective synapse blocker CoCl2 (1 mm) 10 min before or immediately after the conditioning session or 10 min before re-exposure to the aversive context. In the conditioning session, rats were exposed to a footshock chamber (context) and footshocks were used as the unconditioned stimulus. Forty-eight hours later, the animals were re-exposed to the aversive context for 10 min, but no shock was given. Behavioral (freezing) as well as cardiovascular (arterial pressure and heart rate increases) responses induced by re-exposure to the aversive context were analysed. It was observed that the local IC neurotransmission inhibition attenuated freezing and the mean arterial pressure and heart rate increase of the groups that received the CoCl2 either immediately after conditioning or 10 min before re-exposure to the aversive context, but not when the CoCl2 was injected before the conditioning session. These findings suggest the involvement of the IC in the consolidation and expression of contextual aversive memory. However, the IC does not seem to be essential for the acquisition of memory associated with aversive context. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Iptakalim: A Potential Antipsychotic Drug with Novel Mechanisms?

Iptakalim is a novel putative adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener. In the brain, iptakalim is thought to act on the neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels. Because iptakalim demonstrates an action on the regulation of dopamine and glutamate release in the forebrain regions, we examined its potential antipsychotic efficacy in several preclinical tests. First, we show that iptakalim is effective in reducing amphetamine- and phencyclidine-induced hyperlocomotion as well as selectively disrupting conditioned avoidance responding. Next, we show that combined iptakalim and amphetamine treatment produces a reduction on prepulse inhibition of acoustic startle and this combined drug effect is also found with haloperidol, but not with clozapine. Finally, we show that iptakalim and clozapine preferentially increase c-Fos expression in the medial prefrontal cortex, nucleus accumbens and lateral septal nucleus, whereas haloperidol induces a greater increase in the nucleus accumbens, the dorsolateral striatum and lateral septal nucleus. Collectively, our findings indicate that iptakalim is likely to be a potential antipsychotic drug with distinct mechanisms of action. This study also suggests that neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels may be a novel target that deserves attention for antipsychotic drug development. Future research using other sensitive tests is needed to confirm this property of iptakalim.

Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients

Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.