ContexteAu cours de la maladie de Parkinson, les agonistes dopaminergiques sont associés à la survenue de troubles du contrôle des impulsions (TCI). Leur physiopathologie est supposée liée à une dérégulation du circuit dopaminergique méso-limbique, impliqué dans l’intégration des conséquences d’une action afin d’adapter les comportements ultérieurs. Les agonistes dopaminergiques, par la stimulation tonique qu’ils entrainent, conduiraient à une surestimation des conséquences positives des actions antérieures et la poursuite de comportements aux conséquences néfastes.Nous avons exploré (i) la connectivité fonctionnelle striato-corticale en IRM fonctionnelle de repos, (ii) des marqueurs électro-encéphalographiques (EEG) d’intégration du feedback au cours d’une tache de pari : feedback-related negativity (FRN), feedback-related positivity (FRP) et oscillations dans la bande de fréquence thêta (4-7 Hz) chez 20 patients parkinsoniens avec TCI actif, 19 patients parkinsoniens sans TCI et 19 contrôles sains.IRM fonctionnelle : Le striatum ventral, le noyau caudé dorsal, le putamen antérieur et postérieur étaient segmentés semi-automatiquement. Pour chaque région d’intérêt, une analyse de connectivité fonctionnelle était réalisée sur les données d’IRM fonctionnelle projetées sur la surface corticale.Approche neurophysiologique : les sujets réalisaient une tâche composée de paris répétés, couplée à un enregistrement EEG. Le signal EEG était moyenné pour chaque condition et pour chaque sujet. L’amplitude de la FRP était mesurée en Cz et l’amplitude de la FRN en Fz sur la courbe de différence entre les potentiels évoqués par les pertes et les potentiels évoqués par les gains. Les spectres de puissance ont été calculés en utilisant une transformation en ondelettes sinusoïdales de Morlet et moyennés par condition. La puissance maximale du signal, dans la bande de fréquence thêta, entre 200 et 500 millisecondes après l’affichage du feedback était mesurée.Analyse de la connectivité striato-corticale : Chez les patients parkinsoniens, l’existence d’un TCI était associée à une déconnexion fonctionnelle entre le putamen antérieur gauche et les gyrus cingulaire antérieur et temporal inférieur gauche. Il existait chez ces patients une tendance à une déconnexion fonctionnelle entre (i) le putamen antérieur gauche et le gyrus frontal inférieur, (ii) le putamen postérieur et les gyrus temporal inférieur, frontal supérieur, cingulaire postérieur et frontal médial à gauche, ainsi que les gyrus frontal médial, cingulaire et frontal moyen à droite, (iii), le noyau caudé dorsal et le gyrus rectus, le gyrus frontal moyen et le gyrus temporal inférieur à gauche.Potentiels évoqués : Chez les patients parkinsoniens sans TCI et chez les contrôles, mais pas chez les patients parkinsoniens avec TCI, la FRP était plus ample après les gains qu’après les pertes suite à un choix peu risqué.Analyse temps-fréquence : En Cz, les gains étaient associés à une augmentation plus importante de la puissance thêta que les pertes chez les patients parkinsoniens sans TCI et chez les contrôles, mais pas chez les patients parkinsoniens avec TCI. Il existait une augmentation de la puissance thêta après un résultat ample inattendu (boost), en Fz chez les contrôles et en FCz chez les parkinsoniens avec TCI, mais pas chez les patients parkinsoniens sans TCI.Il existe chez les patients parkinsoniens ayant un TCI une altération de marqueurs EEG d’intégration de la récompense compatible avec une moins bonne discrimination des gains et des pertes et une plus grande sensibilité aux résultats amples, inattendus (boost), supposés entrainer une activation importante des voies dopaminergiques méso-limbiques. Il semble donc bien exister, chez les patients ayant un TCI une dysfonction des mécanismes d’intégration du feedback. Cette dysfonction s’associe, au repos, à une altération de la connectivité striato-corticale qui va au-delà du seul système limbique. / BackgroundIn Parkinson’s disease, dopamine agonists are associated with an increased risk of impulse control disorders (ICD). Their occurrence is supposed to be related with a deregulation of the dopaminergic meso-limbic pathway, involved in the processing of the consequences of previous action to adapt future behaviors. Dopamine agonists, through a tonic stimulation of the dopamine receptors would lead to an overestimation of the positive consequences of actions, and therefore, continuation of a harmful behavior.Method:We investigated (i) the resting-state striato-cortical functional connectivity using functional MRI, and (ii) electro-encephalographic (EEG) markers of feedback processing during a gambling task : the feedback related negativity (FRN), the feedback related positivity, (FRP), and the theta band oscillations (4-7 Hz) in 20 Parkinson’s disease patients with an active ICD, 19 Parkinson’s disease patients without ICD, and 19 healthy subjects.Functional MRI: The ventral striatum, dorsal caudate, and anterior and posterior putamen were semi-automatically segmented. For each region of interest, a seed-based connectivity analysis was performed on preprocessed fMRI data mapped on the ipsilateral cortical surface.Neurophysiological approach: The subjects underwent an EEG while performing a gambling task. The EEG was averaged for each condition and each subject. The FRP amplitude was measured in Cz, and the FRN amplitude was measured in Fz on the difference wave between the potential evoked by losses and by gains. The power spectra were computed by using a sinusoidal Morlet wavelet transform and averaged by condition. The maximum power in the theta frequency band was computed for each participant and each condition.Results:Cortico-striatal connectivity analysis: The presence of an ICD in patients with PD was associated with functional disconnection between the left anterior putamen and both the left inferior temporal and anterior cingulate gyrus. ICD patients also displayed a trend toward a functional disconnection between (i) the left anterior putamen and the inferior frontal gyrus, (ii) the posterior putamen and the inferior temporal gyrus, superior frontal gyrus, posterior cingulate, and medial frontal gyrus on the left, as well as the medial frontal gyrus, middle frontal gyrus, and cingulate gyrus on the right, (iii) the dorsal caudate and the gyrus rectus and orbitofrontal cortex, and the middle frontal and inferior temporal gyrus on the left.Evoked potentials: In Parkinson’s disease patients without ICD and healthy controls, the FRP was greater after gains that after losses following a non-risky choice. There was no difference in FRP amplitude after losses and gains in Parkinson’s disease patients with ICD.Time-frequency analysis: At Cz, positive outcomes (gains) were associated with greater theta power than negative outcomes (losses) in Parkinson’s disease patients without ICD and in healthy controls, but not in Parkinson’s disease patients with ICD. There was an increase in theta power after unexpectedly high outcomes, at Fz in healthy controls and in FCz in Parkinson’s disease patients with ICD, whereas theta power was not modulated by the magnitude of the outcome in PD patients without ICDs.Conclusions:Parkinson’s disease patients with ICD have an alteration in EEG markers of reward in line with an altered discrimination of gains and losses and a greater sensitivity to unexpectedly high outcomes, supposed to lead to a significant activation in the dopaminergic meso-limbic pathways. These findings are in line with a dysfunction in reward processing in ICD in Parkinson’s disease. This dysfunction is associated, at rest, with an alteration in striato-cortical connectivity that goes beyond a pure dopaminergic meso-limbic dysfunction.

Tricotilomania (TTM) é um transtorno prevalente e incapacitante caracterizado pelo repetitivo arrancar de cabelo, sendo, atualmente, classificada no grupo dos transtornos relacionados ao transtorno obsessivo-compulsivo (APA, 2013). Diversos estudos foram apresentados na literatura clínica, sugerindo que a TTM é mais comum do que se acreditava e várias propostas de tratamento foram apresentadas. As pesquisas do comportamento em pacientes com TTM têm focalizado seus fatores mantenedores. Entretanto, devemos considerar o potencial papel das cognições que podem operar junto com variáveis de comportamento, na etiologia e manutenção da TTM. Exceto por três estudos controlados para Terapia de Reversão de Hábito, até o momento, não foram publicados estudos controlados sobre o uso de Terapia Cognitivo-comportamental (TCC) em TTM; apenas relatos e séries de casos. O presente estudo teve como objetivo testar um programa manualizado de TCC em Grupo (TCC-G) para portadores de TTM, diagnosticados de acordo com o Manual Diagnóstico e Estatístico de Doenças Mentais - 4ª Edição (DSM-IV). Os pacientes com TTM foram alocados aleatoriamente em um dos dois grupos, sendo que um grupo experimental (n=22) participou de TCC-G e o outro grupo controle (n=22) participou de Terapia de Apoio em Grupo (TA-G). Durante o estudo, os participantes do grupo experimental participaram de vinte e duas sessões de um programa de TCC-G manualizado. A principal variável de desfecho foi a Massachusetts General Hospital Hair Pulling Scale (MGH-HPS), as demais variáveis secundárias de desfecho foram: Inventário de Depressão de Beck (Beck Depression Inventory - BDI), Inventário de Ansiedade de Beck (Beck Anxiety Inventory - BAI), Escala Adequação Social (EAS) e Escala de Impressão Clínica Global (CGI). Os grupos experimental e controle foram comparados em três momentos: na triagem, no início e no final das intervenções, utilizando-se análise de variância (ANOVA) para medidas repetidas. Ambos os grupos apresentaram melhora significativa dos sintomas de TTM e depressão ao longo do tratamento (p < 0,001). Sintomas ansiosos e ajustamento social não apresentaram variação significativa. O grupo experimental mostrou uma redução significativamente maior dos sintomas de TTM em comparação com o grupo controle (p=0,038) ao fim do tratamento. Conclui-se que a TCC-G é um método válido para o tratamento da TTM. Revisões futuras e ampliações deste modelo devem ser realizadas para que esse possa abarcar de forma mais eficaz a sintomatologia concorrente, em especial, ansiedade, e o ajustamento social / Trichotillomania (TTM) is a prevalent, disabling disorder, characterized by repetitive hair pulling, which is now included in the obsessive-compulsive and related disorders chapter of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition, DSM-V). There is now evidence that TTM is more common than previously believed, and various treatments have been proposed. Behavioral studies in TTM patients have focused on their maintaining factors. However, it is possible that variables related to cognition, as well as those related to behavior, play a role in etiology and maintenance of TTM. With the exception of three studies of habit reversal therapy, there have been no controlled studies of cognitive-behavioral therapy (CBT) in TTM. The present study aimed to investigate the effectiveness of manual-based group CBT (GCBT), in comparison with that of supportive group therapy (SGT), in 44 patients diagnosed with TTM according to DSM-IV criteria. Patients were randomly allocated to receive 22 sessions of manual-based GCBT (n=22) or SGT (n=22). The main outcome variable was the Massachusetts General Hospital - Hairpulling Scale score. Secondary outcome variables were the Beck Depression and Anxiety Inventory scores, as well as the Social Adjustment Scale-Self-Report score and the Clinical Global Impression score. Using analysis of variance for repeated measures, we compared the two groups at three time points: at the initial screening; at treatment initiation; and at the end of treatment. After treatment, both groups showed significant improvement in symptoms of TTM and depression (p < 0.001), although there were no significant differences in terms of social adjustment or symptoms of anxiety. The improvement in TTM symptoms was more pronounced in the GCBT group than in the SGT group (p=0.038). We conclude that GCBT is a valid method for the treatment of TTM. However, the GCBT treatment model should be revised and expanded in order to treat TTM comorbidities, especially anxiety and social dysfunction, more effectively

INTRODUÇÃO: A despeito das graves consequências comportamentais de indivíduos que sofrem de impulso sexual excessivo (ISE), estudos neuropsicológicos são incipientes e trazem resultados controversos. OBJETIVOS: Por meio de um estudo experimental com sujeitos impulsivos sexuais (pacientes) e não impulsivos sexuais (controles) objetivou-se comparar: a tomada de decisão e a flexibilidade cognitiva no estado basal de vigília (tempo \"0\"); a tomada de decisão e flexibilidade cognitiva no tempo \"0\" e pós-estímulo sexual visual (tempo \"1\") em cada grupo (pacientes e controles) e entre os grupos. MÉTODO: O estudo foi desenvolvido no Ambulatório de ISE do Instituto de Psiquiatria (IPq) do HC-FMUSP. A amostra foi constituída por 30 pacientes e 30 controles recrutados através de divulgação na mídia. Homens, brasileiros, com 18 anos ou mais, que preencheram os critérios diagnósticos para ISE (CID-10 - F 52.7) e os critérios de Goodman para dependência de sexo foram incluídos como pacientes; enquanto participantes assintomáticos e que não preencheram os critérios acima foram incluídos como controles. A investigação neuropsicológica da flexibilidade cognitiva se deu por meio da aplicação Wisconsin Card Sort Test (WCST), enquanto a avaliação da tomada de decisão se deu pela aplicação do Iowa Gambling Task (IGT) no tempo \"0\" e tempo \"1\" (após visualização de vídeo erótico por 20 minutos), respeitando um intervalo mínimo de seis meses entre os tempos. Em ambos os tempos foi aplicada a Escala de Compulsividade Sexual, e no tempo \"1\" foi aplicado o Inventário do Desejo e da Excitação Sexual. RESULTADOS: No estado basal, os pacientes apresentaram maior quantidade de respostas corretas, em relação aos controles, no teste que investiga flexibilidade cognitiva (p = 0,01). Quando comparamos o desempenho de ambos os grupos com eles mesmos entre os tempos, observamos que os controles apresentaram melhor desempenho inicial (Bloco 1) na tomada de decisão (p = 0,01), bem como apresentaram mais acertos no teste que avalia flexibilidade cognitiva (p = 0,01) no tempo \"1\". O mesmo não foi observado em relação aos pacientes. Quando comparamos as médias da diferença (tempo \"1\" - tempo \"0\"), entre os grupos, observamos também melhor desempenho dos controles em relação à quantidade de acertos (p = 0,02). CONCLUSÕES: Desde onde sabemos, este é o primeiro estudo avaliando funções executivas em impulsivos sexuais, após exposição a estímulo visual sexual. Quanto à avaliação no estado basal, os pacientes apresentaram melhores resultados na flexibilidade cognitiva, contrariando a hipótese inicial. Controles apresentaram melhores desempenhos na flexibilidade cognitiva e tomada de decisão inicial após exposição ao estímulo visual sexual, quando comparados com os resultados no estado basal. Na análise da diferença de desempenho pós-estímulo visual sexual comparado com o estado basal, entre os grupos, os controles novamente apresentaram melhor desempenho cognitivo. Tais resultados indicam escolhas iniciais menos impulsivas, e melhor flexibilidade cognitiva, após exposição ao estímulo erótico, pelos controles, sugerindo dificuldades de modulação inicial do comportamento, bem como de funções cognitivas, pelos pacientes, diante do estímulo sexual, apoiando nossas hipóteses / INTRODUCTION: Despite the serious behavioral consequences of individuals suffering from excessive sexual drive (ESD), neuropsychological studies are incipient and bring controversial results. OBJECTIVES: Through an experimental study of sexually impulsive subjects (patients) and non-sexually impulsive (control group) our aim was to compare: decision making and cognitive flexibility during basal wakefulness (Time \"0\"); decision making and cognitive flexibility at time \"0\" and after visual sexual stimulation (time \"1\") in each group (patients and control group) and among groups. METHOD: The study was developed at the ESD Clinic of the Psychiatry Institute (IPq), HC-FMUSP. The sample consisted of 30 patients and 30 people in the control group recruited through media coverage. Brazilian men, 18 years and older who met the diagnostic criteria for ISE (ICD - 10 - 52.7 F) and the Goodman criteria for addiction to sex were included as patients; while asymptomatic participants and that did not meet the above criteria were included in the control group. The neuropsychological research of the cognitive flexibility was made by applying the Wisconsin Card Sort Test (WCST), while the evaluation of the decision-making was made through the application of the Iowa Gambling Task (IGT) at time \"0\" and time \"1\" (after viewing an erotic video for 20 minutes), subject to a minimum interval of six months between times. In both times, the Sexual Compulsivity Scale was applied and to time \"1\", we applied the Sexual Arousal and Desire Inventory. RESULTS: During basal wakefulness patients presented a higher number of correct responses compared to the control group, in the test that investigates cognitive flexibility (p = 0.01). When comparing the performance of both groups to each other in between times, we found that the control group had a better initial performance (Block 1) in decision making (p = 0.01) as well as provided more correct answers in the test that evaluates cognitive flexibility (p = 0.01) at time \"1\". The same was not observed in the patients group. When comparing the average of the difference (time \"1\" - time \"0\") between the groups, we noted a better performance in the control group in what concerns the amount of correct responses (p = 0.02). CONCLUSION: As far as we know, this is the first study assessing executive functions in sexual impulsive, after exposure to sexual visual stimuli. As for the evaluation at basal wakefulness, patients presented better results regarding cognitive flexibility, opposite to the initial hypothesis. The control group presented a better performance concerning cognitive flexibility and initial decision making after exposure to sexual visual stimuli, when compared with results during basal wakefulness. When analyzing the performance difference after visual sexual stimulation compared with basal wakefulness in the two groups, the control group, once again, showed better cognitive performance. Such results indicate less impulsive initial choices and better cognitive flexibility after exposure to erotic stimulation in the control group, suggesting difficulties in the initial modulation of behavior, as well ass of cognitive functions, by patients before sexual stimulation, supporting our hypothesis

Au-delà des symptômes moteurs, la maladie de Parkinson (MP) est également caractérisée par une myriade de symptômes neuropsychiatriques allant de l’apathie et la dépression aux troubles du contrôle des impulsions (TCI). Les TCI représentent un groupe d’addictions comportementales incluant le jeu pathologique, l’hypersexualité et les achats faits de manière compulsive. Observés chez 10 à 14 % des patients parkinsoniens sous traitement dopaminergique, ils affectent fortement leur qualité de vie. L’impulsivité cognitive reflétant notamment l’incapacité à tolérer les délais de renforcements, est au cœur des TCI. En effet, différentes études suggèrent que cette impulsivité serait exacerbée dans la MP et sous traitements dopaminergiques. Cependant, les mécanismes sous-tendant les TCI dans la MP demeurent méconnus, et la contribution respective de la lésion, du traitement dopaminergique, et de certains facteurs de vulnérabilité reste à déterminer. De plus, l’impulsivité d’attente, une autre forme de déficit d’inhibition qui peut conduire au développement de comportements compulsifs, a été peu étudiée dans le cadre des TCI.L’objectif de ce projet de thèse a été d’évaluer l’influence d’une dénervation dopaminergique de la voie nigrostriée, avec ou sans adjonction d’agoniste dopaminergique, sur le développement d’impulsivité. Pour cela, nous avons utilisé un modèle lésionnel des troubles non-moteurs de la MP. Ces rats ont reçu une injection bilatérale de neurotoxine 6-OHDA dans la SNc, afin d’induire une dénervation sélective, bilatérale et partielle du striatum dorsal. Ils ont ensuite été traités avec du pramipexole, un agoniste des récepteurs D2/3, connu pour favoriser le développement de TCI chez les patients parkinsoniens. Les tâches d’intolérance au délai et de réaction en série à 5 choix (5-CSRTT) ont été utilisées pour évaluer respectivement l’impulsivité cognitive et l’impulsivité d’attente. Dans le premier paradigme, les rats doivent appuyer sur un levier pour choisir entre une petite récompense immédiate, ou une plus grosse récompense, avec un un délai. Dans le second paradigme, ils doivent inhiber l’émission d’une réponse motrice jusqu’à l’apparition d’un stimulus lumineux. Le traitement chronique au pramipexole augmente considérablement les choix impulsifs effectués dans la tâche d’intolérance au délai, mais seulement chez les rats non lésés. En effet, la lésion dopaminergique seule ou avec le traitement ne favorise pas les comportements impulsifs. Dans la tâche de 5-CSRTT, le pramipexole semble également promouvoir l’émission de réponses prématurées (effet pro-impulsif), lorsque l’intervalle inter-essais est constant. Cependant, lorsque cet intervalle augmente, le pramipexole provoque à l’inverse une diminution des réponses prématurées (effet anti-impulsif). Cette modulation d’impulsivité étant seulement observée chez les rats hautement impulsifs, ceci suggère qu’un endophénotype impulsif puisse être un facteur de vulnérabilité à l’effet iatrogène du pramipexole.A l’échelle neuronale, ce traitement favorise la surexpression des ARNm codants pour les récepteurs dopaminergiques D2 dans le striatum et y modifie la connectivité glutamatergique telle qu’observée en microscopie électronique. De plus, nous avons observé une suractivation de la voie mTORC1 dans le noyau accumbens, comme déjà constaté dans les processus addictifs. Afin d’apporter un lien causal à cette étude, nous avons bloqué l’activité de la voie mTORC1 par un inhibiteur spécifique, la rapamycine, chez des rats traités au pramipexole. Etonnamment, cette combinaison accentue fortement l’intolérance au délai, alors que la rapamycine seule ne provoque aucun effet notable. Ceci pourrait s’expliquer par une cinétique d’activation et d’inhibition complexe de cette voie. L’ensemble de ces résultats suggère que l’impulsivité observée dans la MP serait causée par une action iatrogène du pramipexole via une activation anormale de la voie mTORC1 dans le noyau accumbens. / Beyond motor symptoms, Parkinson’s disease (PD) is also characterized by a plethora of neuropsychiatric deficits, ranging from apathy and depression to Impulse control disorders (ICDs). ICDs represent a complex group of behavioral addictions including gambling disorders, hypersexuality and compulsive shopping, displayed by 10 to 14% of PD patients under dopamine replacement therapies, whose quality of life is greatly diminished. Importantly, cognitive impulsivity reflecting in particular, an inability to tolerate delays to reinforcements, appears as a core symptom of ICDs. Indeed, recent evidence suggested that this kind of impulsivity would be exacerbated in PD and under treatment by dopaminergic D2/3 receptor agonists. However, the mechanisms underlying ICDs in PD remain unknown and the respective contribution of dopamine lesion and treatment, combined with factors of vulnerability, remain to be determined. Moreover, waiting impulsivity, another form of behavioral inhibition which may lead to compulsive behaviors, has been poorly investigated in the framework of ICDs.In this thesis project, using a lesional rodent model of non-motor symptoms of PD, we addressed the question of whether denervation of the dopaminergic nigrostriatal system would promote the development of impulsivity when combined with dopamine agonist treatments. Rats were bilaterally injected in the SNc with the neurotoxin 6-OHDA to induce selective and partial denervation of the dorsal striatum. We then treated them with the dopamine D2/3 receptor agonist, pramipexole, a medication known to favor the development of ICDs in PD patients. Two different tasks were used to measure cognitive and motor impulsivity: the delay discounting task (DDT) and the 5-choice serial reaction time task (5-CSRTT) respectively. In the former, rats have to press a lever and choose between a smaller, but immediate reward and a larger, but delayed reward. For the latter, they have to wait for a stimulus light to come on. In the DDT, chronic administration of pramipexole treatment only increased impulsive choices in non-lesioned rats. Indeed, the dopaminergic lesion by itself, or in adjunction with the treatment, did not increase impulsivity. In the 5-CSRTT, pramipexole progressively increased premature responses, reflecting a pro-impulsive effect when the inter-trial interval is constant. However, when the interval was increased, pramipexole reduced the premature responses, exhibiting an anti-impulsive effect. Interestingly, this modulation of motor impulsivity was only observed in rats with a high level of impulsivity, suggesting that an impulsive endophenotype might be an important factor of vulnerability to the iatrogenic effects of pramipexole.The effect of this treatment was then investigated at a cellular level. It promotes overexpression of the dopamine D2 receptor mRNA within the striatum, and seems to alter glutamatergic synaptic connectivity suggested by electron microscopy. Moreover, we showed that the mammalian target of rapamycin complex 1 (mTORC1) pathway is lastingly over-activated in the nucleus accumbens, as already observed in drug addictions. In an attempt to make a causal link between this pathway and the behavioral changes, we treated rats with pramipexole and rapamycine, a specific inhibitor of this pathway. Surprisingly, this combination accentuated impulsivity even more, whereas rapamycine by itself did not promote impulsivity. This effect may be explained by the complexity of the kinetics of activation and inhibition of mTORC1 pathway.Taken together, these results suggest that impulsivity in PD may be triggered by an iatrogenic effect of the dopaminergic pramipexole treatment through an abnormal activation of the mTORC1 pathway within the nucleus accumbens.

Indiana University-Purdue University Indianapolis (IUPUI) / Harmful alcohol use is a global concern, which has made research in this area a prime public health interest. Previous research has identified alcohol-related attentional biases (Cox et al., 2002, 2007; Marissen et al., 2006; Streeter et al., 2008) and impulsivity (see Acton, 2003; Dick et al., 2010; Mulder, 2002) as two important predictors that affect alcohol use, seeking, and relapse (Cox et al., 2002; Robbins & Ehrman, 2004). Recent review of the literature has also revealed that there is a significant relationship between these two constructs (Coskunpinar & Cyders, 2013). The current study used college undergraduate social drinkers (at least 3 drinks per week) (n = 42, mean age = 23.27 (SD = 5.21), female: 69.2%) to examine the relationship between specific trait impulsivity facets and alcohol-related attentional biases and to examine how this relationship is affected by measurement type (eye movement, reaction time measures), attentional bias constructs (initial orientation, delayed disengagement), and environmental cues (specifically mood and alcohol olfactory cues). Participants had alcohol-related attentional bias as measured by reaction time (areas of interest: p < .05) and eye-movement data (areas of interest: p < .05), which was not affected by mood, odor, or urgency.

Indiana University-Purdue University Indianapolis (IUPUI) / Prior research indicated a high prevalence of problematic drinking among college students, suggesting a need for more effective screening approaches and treatments. The tendency to act rashly in face of strong emotions (e.g. positive and negative urgency), alcohol cravings, and cue reactivity all have been associated with problematic alcohol use. However, no studies have examined the interactive effects of alcohol cravings, urgency, and cue reactivity. I hypothesized that alcohol cravings will be associated with greater problematic drinking among individuals with higher levels of (1) urgency, (2) cue reactivity, and (3) cue reactivity and urgency. Data were collected from a sample (final n = 240) of college students through a survey, which consisted of measures of urgency, problematic drinking, and alcohol cravings. On the survey, participants were also exposed to alcohol and non-alcohol pictures, after which they assessed their level of cue reactivity. Results were examined using multiple regression and simple slope analyses. Results provided partial support for our hypotheses. Alcohol cravings were associated with greater problematic drinking at lower levels of negative urgency (b = 7.36, p< 0.001). Furthermore, alcohol cravings were most strongly associated with problematic drinking at high levels of cue reactivity and low levels of negative urgency (b = 8.69, p<0.001), and at low levels of cue reactivity and high levels of positive urgency (b = 6.56, p<0.001). These findings emphasize the importance of considering urgency and cue reactivity in understanding how alcohol cravings create risk for problematic drinking.

Indiana University-Purdue University Indianapolis (IUPUI) / Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is found in heavy alcohol users. Negative urgency is a personality trait reflecting the tendency to act rashly in response to negative emotional states, and is associated with problematic alcohol consumption. The current study examined the relationship between negative urgency and HPA axis functioning following (1) negative mood induction and (2) intravenous alcohol administration among heavy social drinkers (proposed n = 40). I hypothesized the following: (1) Negative mood induction would result in an increase of cortisol release as compared to neutral mood induction; (1a) Negative urgency would be related to increased cortisol release in response to negative mood induction; (1b) Negative urgency would partially mediate the relationship between mood induction and cortisol release; (2) Acute IV alcohol administration would result in increased cortisol levels in the neutral mood condition, but decreased cortisol levels in the negative mood condition; and (2a) Negative urgency would be related to the suppression of cortisol release in the negative mood condition in response to acute IV alcohol administration. Repeated measures analyses of variance, the PROCESS macro, and paired samples t-tests were used to examine study hypotheses. Hypotheses were largely unsupported. Writing mood induction procedures reduced salivary cortisol levels in negative mood (t(35)= 2.49, p= 0.02) and there was a trend decrease in neutral mood (t(35)= 1.87, p= 0.07). Alcohol administration also reduced salivary cortisol levels in both negative mood (t(35)= 3.99, p< 0.01) and neutral mood (t(35)= 2.60, p= 0.01). However, salivary cortisol changes were no different than typical circadian patterns in response to mood induction (t(231)= 0.37, p=0.71) or in response to acute alcohol administration (t(231)= 0.44, p= 0.64). Negative urgency had a trend main effect on salivary cortisol level in response to acute IV alcohol administration, such that those higher in negative urgency were more similar to typical circadian patterns (F(19,28)= 1.59, p=0.13). This could serve as preliminary support for a psychological mechanism for the alcohol sensitivity hypothesis. Overall these findings suggest the current study failed to sufficiently manipulate salivary cortisol levels. Future studies should consider methodological techniques when exploring these relationships, including IV compared to oral alcohol administration, mood compared to stress manipulations, and cortisol compared to other HPA axis biomarkers.

INTRODUÇÃO: A dependência química engloba alterações comportamentais, cognitivas e fisiológicas. A impulsividade está presente em muitos transtornos psiquiátricos. Sobre a impulsividade na dependência química de cocaína, os estudos existentes são relativamente novos. A Estimulação Magnética Transcraniana de repetição (EMTr) é um método capaz de neuromodular o cérebro. Este estudo avaliou os efeitos da EMTr sobre a impulsividade em dependentes de cocaína. MÉTODOS: Em um estudo randomizado, duplamente encoberto, 25 pacientes diagnosticados pelo DSM-IV-TR foram tratados com EMTr de alta frequência ativa (1250 pulsos/dia) ou EMTr placebo. O tratamento consistiu em 1 mês de aplicação de EMTr seguido de 2 meses em acompanhamento ambulatorial semanal em um grupo de prevenção de recaídas. Os pacientes foram avaliados antes do início do tratamento com EMTr (T0) e após o término das aplicações (T1), através dos instrumentos: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale e The Leeds Dependence Questionnaire. RESULTADOS: 25 pacientes foram tratados e a análise dos dados demonstraram redução nos índices de impulsividade em ambos os grupos ao longo do tempo, porém, quando comparados entre si, os valores de interação não se mostraram significativos. CONCLUSÃO: Os efeitos da EMTr não diferiram em eficácia terapêutica na redução da impulsividade em dependentes de cocaína, com o efeito ativo correspondendo com o placebo / INTRODUCTION: Chemical addiction involves behavioral, cognitive and physiological alterations. Impulsivity is present in many psychiatric disorders. Studies about impulsivity and cocaine chemical addiction are relatively new. Transcranial Magnetic Stimulation (EMTr) is a method capable of neuromodulation the brain. This study evaluated the effects of EMTr over impulsivity in cocaine addicts. METHODS: This is a randomized doubly covert study with 25 patients diagnosed by the DSM-IV-TR who were treated with active high frequency EMTr (1250 pulses/day) or placebo. Treatment was consisted of one month of application of EMTr followed by 2 months of clinical follow-up in a relapse prevention group. Patients were evaluated before the treatment with EMTr (T0) and after the end of the applications (T1), through the instruments: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale and The Leeds Dependence Questionnaire. RESULTS: 25 patients were treated and data analysis showed a reduction in the levels of impulsivity in both groups throughout the time. However, group comparisons did not show statistical differences. CONCLUSION: EMTr\'s effects did not differ in terms of therapeutical efficacy in the reduction of impulsivity in cocaine addicts

INTRODUÇÃO: A dependência química engloba alterações comportamentais, cognitivas e fisiológicas. A impulsividade está presente em muitos transtornos psiquiátricos. Sobre a impulsividade na dependência química de cocaína, os estudos existentes são relativamente novos. A Estimulação Magnética Transcraniana de repetição (EMTr) é um método capaz de neuromodular o cérebro. Este estudo avaliou os efeitos da EMTr sobre a impulsividade em dependentes de cocaína. MÉTODOS: Em um estudo randomizado, duplamente encoberto, 25 pacientes diagnosticados pelo DSM-IV-TR foram tratados com EMTr de alta frequência ativa (1250 pulsos/dia) ou EMTr placebo. O tratamento consistiu em 1 mês de aplicação de EMTr seguido de 2 meses em acompanhamento ambulatorial semanal em um grupo de prevenção de recaídas. Os pacientes foram avaliados antes do início do tratamento com EMTr (T0) e após o término das aplicações (T1), através dos instrumentos: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale e The Leeds Dependence Questionnaire. RESULTADOS: 25 pacientes foram tratados e a análise dos dados demonstraram redução nos índices de impulsividade em ambos os grupos ao longo do tempo, porém, quando comparados entre si, os valores de interação não se mostraram significativos. CONCLUSÃO: Os efeitos da EMTr não diferiram em eficácia terapêutica na redução da impulsividade em dependentes de cocaína, com o efeito ativo correspondendo com o placebo / INTRODUCTION: Chemical addiction involves behavioral, cognitive and physiological alterations. Impulsivity is present in many psychiatric disorders. Studies about impulsivity and cocaine chemical addiction are relatively new. Transcranial Magnetic Stimulation (EMTr) is a method capable of neuromodulation the brain. This study evaluated the effects of EMTr over impulsivity in cocaine addicts. METHODS: This is a randomized doubly covert study with 25 patients diagnosed by the DSM-IV-TR who were treated with active high frequency EMTr (1250 pulses/day) or placebo. Treatment was consisted of one month of application of EMTr followed by 2 months of clinical follow-up in a relapse prevention group. Patients were evaluated before the treatment with EMTr (T0) and after the end of the applications (T1), through the instruments: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale and The Leeds Dependence Questionnaire. RESULTS: 25 patients were treated and data analysis showed a reduction in the levels of impulsivity in both groups throughout the time. However, group comparisons did not show statistical differences. CONCLUSION: EMTr\'s effects did not differ in terms of therapeutical efficacy in the reduction of impulsivity in cocaine addicts

Indiana University-Purdue University Indianapolis (IUPUI) / Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.