Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.

Women exhibit greater habituation to painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, pain habituation has been associated with pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), implicating a connection between the sgACC and the descending pain antinociceptive system. Therefore, the thesis hypothesis was that women have stronger connectivity than men between the sgACC and the descending antinociceptive system. Healthy subjects provided informed consent. 3T MRI images included anatomical diffusion-weighted imaging for structural connectivity analyses (SC) with probabilistic tractography and resting-state functional images for functional connectivity (FC) analyses. Women had stronger sgACC FC with nodes of the descending pain modulation system (raphe, PAG) and the medial thalamus. In contrast, men had stronger sgACC FC with nodes of the salience/attention network (anterior insula, TPJ) and stronger sgACC SC with the hypothalamus. These findings implicate a mechanism for pain habituation and its associated sex differences.

Women exhibit greater habituation to painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, pain habituation has been associated with pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), implicating a connection between the sgACC and the descending pain antinociceptive system. Therefore, the thesis hypothesis was that women have stronger connectivity than men between the sgACC and the descending antinociceptive system. Healthy subjects provided informed consent. 3T MRI images included anatomical diffusion-weighted imaging for structural connectivity analyses (SC) with probabilistic tractography and resting-state functional images for functional connectivity (FC) analyses. Women had stronger sgACC FC with nodes of the descending pain modulation system (raphe, PAG) and the medial thalamus. In contrast, men had stronger sgACC FC with nodes of the salience/attention network (anterior insula, TPJ) and stronger sgACC SC with the hypothalamus. These findings implicate a mechanism for pain habituation and its associated sex differences.

Background: Patients with Panic Disorder (PD) direct their attention towards potential threat, followed by panic attacks, and increased sweat production. Onés own anxiety sweat odor influences the attentional focus, and discrimination of threat or non-threat. Since olfactory projection areas overlap with neuronal areas of a panic-specific fear network, the present study investigated the neuronal processing of odors in general and of stress-related sweat odors in particular in patients with PD. Methods: A sample of 13 patients with PD with/ without agoraphobia and 13 age- and gender-matched healthy controls underwent an fMRI investigation during olfactory stimulation with their stress-related sweat odors (TSST, ergometry) as well as artificial odors (peach, artificial sweat) as non-fearful non-body odors. Principal Findings: The two groups did not differ with respect to their olfactory identification ability. Independent of the kind of odor, the patients with PD showed activations in fronto-cortical areas in contrast to the healthy controls who showed activations in olfaction-related areas such as the amygdalae and the hippocampus. For artificial odors, the patients with PD showed a decreased neuronal activation of the thalamus, the posterior cingulate cortex and the anterior cingulate cortex. Under the presentation of sweat odor caused by ergometric exercise, the patients with PD showed an increased activation in the superior temporal gyrus, the supramarginal gyrus, and the cingulate cortex which was positively correlated with the severity of the psychopathology. For the sweat odor from the anxiety condition, the patients with PD showed an increased activation in the gyrus frontalis inferior, which was positively correlated with the severity of the psychopathology. Conclusions: The results suggest altered neuronal processing of olfactory stimuli in PD. Both artificial odors and stress-related body odors activate specific parts of a fear-network which is associated with an increased severity of the psychopathology.

Why is it that only some people who use drugs actually become addicted? In fact, addiction depends on a complicated process involving a confluence of risk factors related to biology, cognition, behaviour, and personality. Notably, all addictive drugs act on a neural system for reinforcement learning called the midbrain dopamine system, which projects to and regulates the brain's system for cognitive control, called frontal cortex and basal ganglia. Further, the development and expression of the dopamine system is determined in part by genetic factors that vary across individuals such that dopamine related genes are partly responsible for addiction-proneness. Taken together, these observations suggest that the cognitive and behavioral impairments associated with substance abuse result from the impact of disrupted dopamine signals on frontal brain areas involved in cognitive control: By acting on the abnormal reinforcement learning system of the genetically vulnerable, addictive drugs hijack the control system to reinforce maladaptive drug-taking behaviors. The goal of this research was to investigate this hypothesis by conducting a series of experiments that assayed the integrity of the dopamine system and its neural targets involved in cognitive control and decision making in young adults using a combination of electrophysiological, behavioral, and genetic assays together with surveys of substance use and personality. First, this research demonstrated that substance dependent individuals produce an abnormal Reward-positivity, an electrophysiological measure of a cortical mechanism for dopamine-dependent reward processing and cognitive control, and behaved abnormally on a decision making task that is diagnostic of dopamine dysfunction. Second, several dopamine-related neural pathways underlying individual differences in substance dependence were identified and modeled, providing a theoretical framework for bridging the gap between genes and behavior in drug addiction. Third, the neural mechanisms that underlie individual differences in decision making function and dysfunction were identified, revealing possible risk factors in the decision making system. In sum, these results illustrate how future interventions might be individually tailored for specific genetic, cognitive and personality profiles. / Graduate

Ce travail de thèse explore l'organisation fonctionnelle du cortex frontal chez l'homme lors de l'apprentissage et l'utilisation de règles conditionnelles associées à des stimuli contextuels et demandant la réalisation d'actions manuelles, vocales et orofaciales. Ma première étude a démontré chez l'homme que 1) le cortex frontal latéral postérieur (pLFC) est organisé selon un gradient dorso-ventral, où le cortex prémoteur dorsal (PMd) et le cortex préfrontal dorsal (BA 44) sont impliqués respectivement dans les associations conditionnelles manuelles et vocal-orofaciales, et 2) que l'aire motrice cingulaire antérieure (RCZa) au sein du cortex cingulaire moyen (MCC), contribue à l'évaluation des feedback auditifs durant l'apprentissage par essai-erreur de ces associations. Ma seconde étude a révélé qu'au sein du MCC, les trois CMAs sont fonctionnellement couplées avec le cortex préfrontal latéral le long du gradient rostro- caudal où les régions les plus rostrales sont impliqués dans un contrôle comportemental de plus haut niveau. Ces résultats apportent de nouveaux éclaircissements aux théories actuelles concernant l'organisation cortico-frontal du contrôle comportemental. En réalisant une revue de la littérature, j'ai montré qu'au sein du réseau pLFD-MCC les aires BA 44 et RCZa font partie d'un réseau cérébral homologue qui pourrait jouer un rôle similaire dans le contrôle cognitif vocal/orofacial chez les primates - le contrôle adaptatif des actions vocales/orofaciales basés sur l'évaluation des feedback auditifs. Cette hypothèse a été validé chez l'homme dans ma première étude. Cette thèse a mis en évidence un important réseau neural aidant à comprendre comment le contrôle du langage a évolué au cours de l'évolution des primates. Pour finir, j'ai présenté des résultats préliminaires qui montre que la correspondance des profils de connectivité en état de repos est une approche prometteuse pour comparer l'organisation fonctionnelle cérébrale inter-espèces / This thesis primarily investigated how the human frontal cortex is organised to learn and use conditional rules linking contextual stimuli with manual, vocal and orofacial actions. My first study demonstrated that in humans: 1) the posterior lateral frontal cortex (pLFC) is organized along a dorso-ventral gradient, where the dorsal premotor cortex and ventral area 44 are involved in manual and vocal-orofacial conditional associations respectively, and 2) the anterior-most cingulate motor area (RCZa) within the mid-cingulate cortex (MCC), contributes to the evaluation of auditory feedback during the trial-and-error learning of the conditional associations. My second study showed that within the MCC, the three CMAs are functionally coupled with the lateral frontal cortex along a rostral-caudal gradient where more rostral regions are implicated in more abstracted levels of behavioral control. These findings provided important contributions to current theories about frontal cortical organization for behavioural control. Lastly, through an extensive review, I revealed that, within the pLFC-MCC network, area 44 and RCZa are part of a homologous brain network that might play a similar role in cognitive vocal/orofacial control across primates. My hypothesized role of this network in the adaptive control of vocal/orofacial actions based on auditory feedback monitoring had been validated, in humans, from my first study. Thus, my thesis had also revealed an important starting point - the area 44-RCZa, for future investigations into the potential neural changes that occurred across primate evolution to support the emergence of human speech abilities

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Agradecemos a compreensão. on 2016-04-27T16:55:50Z (GMT) / Submitted by ALINE MARQUES DA SILVA BRAGA null (aline.sms@gmail.com) on 2016-05-16T12:39:41Z No. of bitstreams: 1 Tese Aline.pdf: 9957836 bytes, checksum: 6bc924ddc7c437583c8bda4fb0a99ab3 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-05-16T14:36:42Z (GMT) No. of bitstreams: 1 braga_ams_dr_bot.pdf: 9957836 bytes, checksum: 6bc924ddc7c437583c8bda4fb0a99ab3 (MD5) / Made available in DSpace on 2016-05-16T14:36:42Z (GMT). No. of bitstreams: 1 braga_ams_dr_bot.pdf: 9957836 bytes, checksum: 6bc924ddc7c437583c8bda4fb0a99ab3 (MD5) Previous issue date: 2016-02-18 / Fundação de Amparo à Pesquisa do Estado de Mato Grosso (FAPEMAT) / Fundamento: Evidências experimentais de modelos animais de crises de ausência sugerem focalidades no início das descargas generalizadas. Estudos clínicos indicam que pacientes com o diagnóstico de epilepsia generalizada idiopática (EGI) exibem anormalidades focais que envolvem o circuito tálamo-cortical no eletroencefalograma (EEG) e na neuroimagem. Objetivos: Investigar a presença de características focais nas descargas generalizadas interictais usando análise quantitativa do EEG (EEGq) e avaliar o córtex do giro do cíngulo usando múltiplas abordagens quantitativas de neuroimagem. Métodos: 75 EEGs de 64 pacientes foram analisados. A primeira espícula generalizada inequívoca foi marcada para cada descarga. Três métodos de análise de fonte geradora da atividade observada foram aplicados: transformação do dipolo em imagem (dipole source imaging-DSI), abordagem LORETA aplicada iterativamente (CLARA), e análise de dipolo equivalente de componentes independentes com análise de agrupamentos. Após processamento do EEG, 32 pacientes (18 mulheres, 32 ± 11) fizeram ressonância magnética. Foram utilizados três métodos para comparar o giro do cíngulo de pacientes e controles: morfometria baseada em voxel (VBM), análise cortical e análise de formato. Resultados: 753 descargas generalizadas foram analisadas. Usando as três técnicas, o lobo frontal foi a principal fonte das descargas (70%), seguido pelos lobos parietal e occipital (14%) e, por fim, os núcleos da base (12%). As principais fontes anatômicas das descargas generalizadas foram o córtex da porção anterior do giro do cíngulo (36%) e giro frontal medial (23%). A VBM mostrou atrofia de substância cinzenta na porção anterior do giro do cíngulo (972 mm3) e no istmo (168 mm3). Análises individuais do córtex do giro do cíngulo mostraram resultados semelhantes. Comparações de superfície mostraram anormalidades principalmente na porção posterior do giro do cíngulo (718.12 mm2). A análise de formato demonstrou uma predominância de anormalidades nas porções anterior e posterior do giro do cíngulo. Discussão: A análise de fonte não mostrou uma fonte única comum a todas as descargas generalizadas mas indicou predominância do giro do cíngulo e lobo frontal. Além disso, o estudo sugere a existência de anormalidades estruturais sutis no giro do cíngulo, principalmente nas porções anterior e posterior. / Background: Experimental evidence from animal models of absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic and subtle structural abnormalities, which involve the thalamo-cortical circuitry. Aims: The objectives of the current investigation were to investigate whether interictal generalized discharges exhibit focal characteristics using qEEG analysis and to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. Methods: 75 EEG recordings from 64 patients were analyzed. The first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. After EEG analysis, 32 patients (18 women, 30± 10 years) and 36 controls (18 women, 32 ±11 years) were imaged by 3 Tesla magnetic resonance (MRI). We used three models to compare cingulate gyrus of patients and the control group: voxel-based morphometry (VBM), cortical analyses and shape analyses. Results: A total of 753 GSW discharges were spatiotemporally analyzed. Source analysis using all three techniques revealed that the frontal lobe was the principal source of GSW discharges (70%), followed by the parietal and occipital lobes (14%), and the basal ganglia (12%). The main anatomical sources of the generalized discharges were the anterior cingulate cortex (36%) and the medial frontal gyrus (23%). VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm3) and the isthmus (168 mm3). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface- based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm2). Shape analyses demonstrated a predominance of abnormalities in the anterior and posterior portions of cingulate gyrus abnormalities. Discussion: Source analysis did not reveal a common focal source of generalized discharges. However, there was a predominance of GSW discharges originating from the cingulate gyrus and the frontal lobe. Furthermore, this study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients. / FAPEMAT: 11/16452-2

Orientador: Luiz Eduardo Gomes Garcia Betting / Resumo: Fundamento: Evidências experimentais de modelos animais de crises de ausência sugerem focalidades no início das descargas generalizadas. Estudos clínicos indicam que pacientes com o diagnóstico de epilepsia generalizada idiopática (EGI) exibem anormalidades focais que envolvem o circuito tálamo-cortical no eletroencefalograma (EEG) e na neuroimagem. Objetivos: Investigar a presença de características focais nas descargas generalizadas interictais usando análise quantitativa do EEG (EEGq) e avaliar o córtex do giro do cíngulo usando múltiplas abordagens quantitativas de neuroimagem. Métodos: 75 EEGs de 64 pacientes foram analisados. A primeira espícula generalizada inequívoca foi marcada para cada descarga. Três métodos de análise de fonte geradora da atividade observada foram aplicados: transformação do dipolo em imagem (dipole source imaging-DSI), abordagem LORETA aplicada iterativamente (CLARA), e análise de dipolo equivalente de componentes independentes com análise de agrupamentos. Após processamento do EEG, 32 pacientes (18 mulheres, 32 ± 11) fizeram ressonância magnética. Foram utilizados três métodos para comparar o giro do cíngulo de pacientes e controles: morfometria baseada em voxel (VBM), análise cortical e análise de formato. Resultados: 753 descargas generalizadas foram analisadas. Usando as três técnicas, o lobo frontal foi a principal fonte das descargas (70%), seguido pelos lobos parietal e occipital (14%) e, por fim, os núcleos da base (12%... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Experimental evidence from animal models of absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic and subtle structural abnormalities, which involve the thalamo-cortical circuitry. Aims: The objectives of the current investigation were to investigate whether interictal generalized discharges exhibit focal characteristics using qEEG analysis and to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. Methods: 75 EEG recordings from 64 patients were analyzed. The first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. After EEG analysis, 32 patients (18 women, 30± 10 years) and 36 controls (18 women, 32 ±11 years) were imaged by 3 Tesla magnetic resonance (MRI). We used three models to compare cingulate gyrus of patients and the control group: voxel-based morphometry (VBM), cortical analyses and shape analyses. Results: A total of 753 GSW discharges were spatiotemporally analyzed. Source analysis using all three techniques revealed that the frontal lobe was the principal ... (Complete abstract click electronic access below) / Doutor

Background: Patients with Panic Disorder (PD) direct their attention towards potential threat, followed by panic attacks, and increased sweat production. Onés own anxiety sweat odor influences the attentional focus, and discrimination of threat or non-threat. Since olfactory projection areas overlap with neuronal areas of a panic-specific fear network, the present study investigated the neuronal processing of odors in general and of stress-related sweat odors in particular in patients with PD. Methods: A sample of 13 patients with PD with/ without agoraphobia and 13 age- and gender-matched healthy controls underwent an fMRI investigation during olfactory stimulation with their stress-related sweat odors (TSST, ergometry) as well as artificial odors (peach, artificial sweat) as non-fearful non-body odors. Principal Findings: The two groups did not differ with respect to their olfactory identification ability. Independent of the kind of odor, the patients with PD showed activations in fronto-cortical areas in contrast to the healthy controls who showed activations in olfaction-related areas such as the amygdalae and the hippocampus. For artificial odors, the patients with PD showed a decreased neuronal activation of the thalamus, the posterior cingulate cortex and the anterior cingulate cortex. Under the presentation of sweat odor caused by ergometric exercise, the patients with PD showed an increased activation in the superior temporal gyrus, the supramarginal gyrus, and the cingulate cortex which was positively correlated with the severity of the psychopathology. For the sweat odor from the anxiety condition, the patients with PD showed an increased activation in the gyrus frontalis inferior, which was positively correlated with the severity of the psychopathology. Conclusions: The results suggest altered neuronal processing of olfactory stimuli in PD. Both artificial odors and stress-related body odors activate specific parts of a fear-network which is associated with an increased severity of the psychopathology.

Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.