A depressão pós-parto (DPP) tem sido associada com alterações no funcionamento do eixo hipotálamo-hipófise-adrenal (HHA), mas pouco se sabe do envolvimento de estruturas cerebrais, ou outros mecanismos subjacentes a estas alterações. Uma hipótese fundamental é que o estresse inerente ao período puerperal, vulnerabilidade individual e, principalmente, as alterações hormonais decorrentes do final da gravidez desempenham um importante papel causal nas alterações do eixo HHA e na incidência da DPP. Estudos sobre o transtorno depressivo maior mostram que alterações funcionais em áreas cerebrais como o giro do cíngulo anterior (GCA) estão relacionadas com humor deprimido, e outros pesquisadores investigaram a relação entre a neuroquímica do GCA e a atividade do eixo HHA. Pesquisas sobre genes de interesse do eixo HHA também têm reportado associações entre polimorfismos nestes genes e alterações nos níveis de cortisol. O presente trabalho testou a hipótese de que mulheres deprimidas no puerpério remoto apresentariam atenuação no funcionamento do eixo HHA, medido pelos níveis de cortisol em 30 minutos após o despertar (CAR) e ao longo da variação diurna (VD); e também que polimorfismos em um gene do eixo HHA, o gene promotor do receptor do tipo 1 do hormônio liberador de corticotrofina (CRHR1), estariam associados com sintomas depressivos no puerpério para prever os níveis de cortisol; e finalmente que as alterações verificadas no funcionamento do eixo HHA de puérperas deprimidas teriam relação com a neuroquímica do GCA. Os resultados indicaram que (1) ao redor do sexto mês após o parto, o CAR e a VD estavam atenuados em puérperas deprimidas comparadas com puérperas eutímicas, e com controles saudáveis não-puérperas; (2) os metabólitos presentes no GCA tinham correlação com as medidas do eixo HHA nas puérperas deprimidas; e (3) a presença de sintomas depressivos em associação com polimorfismos do CRHR1 previram alterações nos níveis de cortisol. No geral, estes resultados sugerem que as alterações do eixo HHA de puérperas deprimidas no puerpério tardio estão associadas com fatores genéticos e com a neuroquímica funcional do GCA / Postpartum depression (PPD) has been associated with changes in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the involvement of brain structures, or other mechanisms underlying these changes. A key assumption is that stress inherent to the puerperal period, individual vulnerability, and especially the hormonal changes resulting from the end of pregnancy play an important causal role in the alterations of the HPA axis and in the incidence of PPD. Studies on major depressive disorder show that functional changes in brain areas, such as the anterior cingulate gyrus (ACG), are related to depressed mood, and other researchers investigated the relation between the neurochemistry of the ACG and the activity of the HPA axis. Research on the HPA axis genes of interest have also reported associations between polymorphisms in these genes and changes in cortisol levels. The present study tested the hypothesis that depressed women in the remote postpartum period would show attenuation in the functioning of the HPA axis, measured by cortisol levels 30 minutes after awakening (cortisol awakening response, CAR) and by diurnal variation (DV) throughout the day; and also that polymorphisms in a gene of the HPA axis, the promoter gene of the corticotropin releasing hormone receptor type 1 (CRH-R1), would present association with depressive symptoms in the postpartum period to predict the levels of cortisol; and finally that the changes in the functioning of the HPA axis of postpartum depressed women have a relationship with the neurochemistry of the ACG. Results indicated that (1) around the sixth month after delivery, CAR and DV were attenuated in depressed postpartum women compared with euthymic postpartum women and with non-postpartum healthy control women; (2) metabolites present in the ACG showed correlation with measures of the HPA axis in depressed postpartum women; and (3) the presence of depressive symptoms in association with CRHR1 polymorphisms predicted changes in cortisol levels. Overall, these results suggest that changes in the functioning of the HPA axis of depressed postpartum women in the remote postpartum period are associated with genetic factors and with the functional neurochemistry of the ACG

A depressão periparto (PPD) é subtipo altamente prevalente e subdiagnosticado do transtorno depressivo maior (MDD), e causa um importante sofrimento para a mulher, sua família e seu filho. Uma interação complexa entre hormônios, neurotransmissores e fatores genéticos e ambientais pode estar envolvida na etiologia da PPD. Contudo, estudos de neuroimagem na PPD ainda são escassos, particularmente os que identificam alterações neuroquímicas. Sabe-se que a região do córtex pré frontal dorsolateral (dlPFC) está relacionada à funções executivas no circuito pré frontal, e juntamente com o giro do cíngulo anterior (ACG) faz parte das vias neuronais envolvidas no processamento emocional, desde a geração, regulação e reavaliação do estado afetivo. Existem evidências de que ambas as áreas estejam disfuncionais na MDD. A avaliação neuroquímica obtida pela espectroscopia de próton por ressonância magnética (MRS) permite inferir o metabolismo, a neurotransmissão e a viabilidade do tecido neuronal de interesse destas áreas fronto-límbicas. Objetivo: comparar puérperas com depressão periparto (grupo PPD) com puérperas saudáveis (grupo HP) quanto à avaliação neuroquímica no dlPFC esquerdo e no ACG bilateral. Métodos: 36 puérperas do grupo PPD e 25 puérperas do grupo HP foram submetidas à duas entrevistas psiquiátricas estruturadas e à aplicação de questionários e escalas psicométricas, sendo a segunda avaliação realizada seccionalmente à MRS. A MRS foi adquirida pro MRI com campo de 3 Tesla, estando o volume de interesse (VOI) posicionado no dlPFC esquerdo e no ACG bilateral e processada pelo software LCModel. Os resultados neuroquímicos expressos em valores absolutos e normalizados pela creatina (razão metabólito/creatina) foram analisados por ANCOVA, incluindo a idade, o tempo de puerpério e o tipo de contraceptivo, enquanto covariáveis. Resultados: No dlPFC, o grupo PPD apresentou menores valores de Glu/Cr (-0,17; p=0,05), Glx (-0,95 mM; p=0,04), Glx/Cr (-0,22; p=0,03), NAA (-0,60 mM; p<0,01), e NAA/Cr (-0,13; p=0,02) em relação ao grupo HP. No ACG, o uso de hormônios contraceptivos somente com progestágenos resultou em um aumento dos valores de Glu (2,18 mM; p=0,03), Glx (1,84 mM; p=0,03), e redução de Cho/Cr (-0,08; p=0,03) quando comparados ao grupo que não utilizou somente progestágenos, independentemente dos grupos HP e PPD. Conclusão: Os níveis reduzidos de Glu e NAA no grupo PPD estão relacionados, respectivamente, à disfunção metabólica glutamatérgica e neuroglial no dlPFC, o que pode explicar sintomas cognitivos também relacionados à PPD, tal como já verificado no MDD. O uso de hormônios contraceptivos com progestágenos isoladamente interferiu com a neuroquímica do ACG, mas não se relacionou com a PPD. Embora o aumento do glutamato possa sugerir uma hiperfuncionalidade do ACG, e a redução da Cho/Cr representar diminuição de \"turnover\" da membrana lipídica ou da transdução sináptica, seu significado clínico e fisiopatológico ainda é incerto. Estes resultados contribuem com a compreensão dos substratos neuroquímicos de PPD / Peripartum depression (PPD) is a highly prevalent subtype of major depressive disorder (MDD) related to a significant loss for mother, family and baby. An Interaction between hormones, genetic, and environmental factors must be involved in its etiology. However, neuroimaging studies on PPD are still rare, particularly those that identify neurochemical changes. However, neuroimaging studies in PPD are still rare, particularly those that identify neurochemical changes. It is known that the region of the dorsolateral prefrontal cortex (dlPFC) is related to executive functions in the prefrontal circuit, and together with the anterior cingulate gyrus (ACG) is part of the neural pathways involved in emotional processing, including the generation, regulation, and reappraisal of affective state. And, there is evidence that both areas are dysfunctional in MDD. The neurochemical evaluation obtained by spectroscopy of proton magnetic resonance (MRS) allows to infer metabolism, neurotransmission and the viability of the neuronal tissue of interest these frontal-limbic areas. Objective: Compare postpartum women with peripartum depression (PPD group) with healthy postpartum women (HP group) regarding the neurochemical evaluation in the left dlPFC and bilateral ACG. Methods: 36 postpartum women of PPD group and 25 postpartum women of the HP group were subjected to two structured psychiatric interviews and questionnaires and psychometric scales, with the second evaluation performed sectionally at MRS. The MRS was obtained by 3-T MRI system with the volume of interest (VOI) positioned on the left dlPFC and bilateral ACG and processed by LC Model software. The neurochemical results expressed in absolute values and normalized by creatine (reason metabolite/creatine) were analyzed using ANCOVA, including age, postpartum time, the type of contraceptive as covariates. Results: In the dlPFC, PPD group presented significantly lower values of Glu/Cr (-0.17; p=0.05), Glx (-0.95mM; p=0.04), Glx/Cr (-0.22; p=0.03), NAA (-0.60mM; p<0.01), and NAA/Cr (-0.13; p=0.02) than HP. In ACG, progestogens isolated contraceptive hormones use resulted in significantly increased Glu (2.18mM; p=0.03), Glx (1.84mM; p=0.03), and reduced Cho/Cr (-0.08; p=0.03), compared to women without use them, regardless of diagnostic groups. Conclusions: The reduced levels of Glu and NAA in the PPD group are related respectively to the glutamatergic and neuroglial metabolic dysfunction in the dlPFC, which may explain cognitive symptoms also related to PPD as already verified in MDD. Progestogens isolated contraceptive hormones use interfered with neurochemistry of ACG, but not associated with PPD. Although the increase of glutamate may suggest an overactive ACG, and lower Cho/Cr represent decrease of the lipid membrane turnover or synaptic transduction its clinical and pathophysiological significance remains uncertain. These results contribute to the understanding of the neurochemical substrates of PPD

Bildgebende Studien haben gezeigt, dass bei schizophrenen Patienten Positivsymptome mit Veränderungen mesolimbischer Aktivierungsmuster unter Einbeziehung des Nucleus accumbens in Zusammenhang stehen. Hierbei ist von besonderem Interesse, dass der Nucleus accumbens Teil des Belohnungssystems ist, wobei die integrale „Bewertung“ belohnungsanzeigender Reize präfrontalen kortikalen Strukturen, insbesondere dem anterioren Zingulum, zuzurechnen ist. Bereits in der Antizipationsphase potentiell belohnender Reize, werden vermutlich zur Berechnung von Prädiktionsabweichungen dopaminerge Signale in der VTA generiert und modulieren den Nucleus accumbens. Es gibt zahlreiche Hinweise, dass glutamaterge Neurone des anterioren Zingulums die Dopaminausschüttung im Nucleus accumbens beeinflussen, und dass diese Modulation bei Erkrankungen wie der Schizophrenie beeinträchtigt ist. Ziel der vorliegenden Arbeit war es, mittels funktioneller Magnetresonanztomographie und Protonen Magnetresonanzspektroskopie, Hinweise über den Zusammenhang zwischen der glutamatergen Neurotransmission des ACC und belohnungsassoziierter Dopaminausschüttung im Nucleus accumbens bei 23 gesunden Probanden und bei 23 unmedizierten schizophrenen Patienten zu erlangen. Die Ergebnisse weisen darauf hin, dass die gegenseitige Modulation von anteriorem Zingulum und Nucleus accumbens bei schizophrenen Patienten gestört ist. Dieses und weitere Ergebnisse wurden im theoretischen Rahmen der NMDA-Rezeptor-Hypoaktivität und einer gestörten Balance zwischen Dopamin-D1- und Dopamin-D2-Rezeptor-Aktivität als pathophysiologische Korrelate schizophrener Erkrankungen diskutiert. / Imaging studies have demonstrated that for schizophrenic patients a correlation exists between positive symptoms and changes in the patterns of mesolimbic activity. Especially the changes in the ncl. accumbens (Nac) were interpreted in connection with the reward system. The signals indicating reward are thought to be processed by the anterior cingulum (ACC). These structures attribute meaning to the reward signals. In the anticipation phase of a potentially rewarding stimulus, dopaminergic signals from the VTA are generated in prediction of expected or aberrant outcome, thus modulating the Nac. Data indicate a direct modulation of the Nac. by glutamatergic neurons of the anterior cingulum. A major aim of this thesis is to establish a connection between the reward associated dopaminergic signals of the ncl. accumbens and the glutamatergic projections of the acc in unmedicated schizophrenic patients and healthy controls. The methods included measurements of proton magnetic resonance spectroscopy (1H-MRS) and functional MRI-scans done at a 3-Tesla tomograph. The paradigm applied was a modified version of the monetary incentive delay paradigm (Knutson et al. 2000). In healthy volunteers we found a significant negative correlation between the glutamate concentration in the ACC and the BOLD-contrast in the Nac (reward versus neutral), in contrast to the findings in schizophrenic patients. A significant higher BOLD-contrast was seen in the anticipation phase in healthy controls. The results were incorporated in a model of NMDA-R-Hypoaktivity. In addition to discussing the functional aspects for the structures involved the model was further expanded to include the hypothesis of a disturbed balance between dopamine-D1- and -D2-receptor activity and a dysfunctional hippocampal gating-process. The so constructed model suggests a profound striato-thalamo-cortical filter disturbance as the basis of the observed aberrations in the reward processing in schizophrenic disorders.

A depressão pós-parto (DPP) tem sido associada com alterações no funcionamento do eixo hipotálamo-hipófise-adrenal (HHA), mas pouco se sabe do envolvimento de estruturas cerebrais, ou outros mecanismos subjacentes a estas alterações. Uma hipótese fundamental é que o estresse inerente ao período puerperal, vulnerabilidade individual e, principalmente, as alterações hormonais decorrentes do final da gravidez desempenham um importante papel causal nas alterações do eixo HHA e na incidência da DPP. Estudos sobre o transtorno depressivo maior mostram que alterações funcionais em áreas cerebrais como o giro do cíngulo anterior (GCA) estão relacionadas com humor deprimido, e outros pesquisadores investigaram a relação entre a neuroquímica do GCA e a atividade do eixo HHA. Pesquisas sobre genes de interesse do eixo HHA também têm reportado associações entre polimorfismos nestes genes e alterações nos níveis de cortisol. O presente trabalho testou a hipótese de que mulheres deprimidas no puerpério remoto apresentariam atenuação no funcionamento do eixo HHA, medido pelos níveis de cortisol em 30 minutos após o despertar (CAR) e ao longo da variação diurna (VD); e também que polimorfismos em um gene do eixo HHA, o gene promotor do receptor do tipo 1 do hormônio liberador de corticotrofina (CRHR1), estariam associados com sintomas depressivos no puerpério para prever os níveis de cortisol; e finalmente que as alterações verificadas no funcionamento do eixo HHA de puérperas deprimidas teriam relação com a neuroquímica do GCA. Os resultados indicaram que (1) ao redor do sexto mês após o parto, o CAR e a VD estavam atenuados em puérperas deprimidas comparadas com puérperas eutímicas, e com controles saudáveis não-puérperas; (2) os metabólitos presentes no GCA tinham correlação com as medidas do eixo HHA nas puérperas deprimidas; e (3) a presença de sintomas depressivos em associação com polimorfismos do CRHR1 previram alterações nos níveis de cortisol. No geral, estes resultados sugerem que as alterações do eixo HHA de puérperas deprimidas no puerpério tardio estão associadas com fatores genéticos e com a neuroquímica funcional do GCA / Postpartum depression (PPD) has been associated with changes in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the involvement of brain structures, or other mechanisms underlying these changes. A key assumption is that stress inherent to the puerperal period, individual vulnerability, and especially the hormonal changes resulting from the end of pregnancy play an important causal role in the alterations of the HPA axis and in the incidence of PPD. Studies on major depressive disorder show that functional changes in brain areas, such as the anterior cingulate gyrus (ACG), are related to depressed mood, and other researchers investigated the relation between the neurochemistry of the ACG and the activity of the HPA axis. Research on the HPA axis genes of interest have also reported associations between polymorphisms in these genes and changes in cortisol levels. The present study tested the hypothesis that depressed women in the remote postpartum period would show attenuation in the functioning of the HPA axis, measured by cortisol levels 30 minutes after awakening (cortisol awakening response, CAR) and by diurnal variation (DV) throughout the day; and also that polymorphisms in a gene of the HPA axis, the promoter gene of the corticotropin releasing hormone receptor type 1 (CRH-R1), would present association with depressive symptoms in the postpartum period to predict the levels of cortisol; and finally that the changes in the functioning of the HPA axis of postpartum depressed women have a relationship with the neurochemistry of the ACG. Results indicated that (1) around the sixth month after delivery, CAR and DV were attenuated in depressed postpartum women compared with euthymic postpartum women and with non-postpartum healthy control women; (2) metabolites present in the ACG showed correlation with measures of the HPA axis in depressed postpartum women; and (3) the presence of depressive symptoms in association with CRHR1 polymorphisms predicted changes in cortisol levels. Overall, these results suggest that changes in the functioning of the HPA axis of depressed postpartum women in the remote postpartum period are associated with genetic factors and with the functional neurochemistry of the ACG

Estimulação Magnética Transcraniana profunda (EMTp) modula estruturas corticais mais profundas, como a Ínsula Posterior Superior (IPS) e o Córtex Cingulado Anterior (CCA) e tem sido usada para tratar condições não anteriormente sensíveis à EMT superficial. No entanto, até o momento, nenhum estudo avaliou os efeitos da EMTp na cognição após várias sessões de estimulação de maneira abrangente, especialmente em pacientes com disfunção cognitiva basal devido a lesões estruturais da SNC. Apresentamos resultados secundários de um estudo randomizado paralelo de três braços sobre os efeitos da EMTp ativa de 10Hz para o CCA ou IPS contra EMTp simulada na avaliação neuropsicológica de 98 pacientes com dor neuropática central submetidos a um curso de 12 semanas (16 sessões) de tratamento. Vários canais cognitivos foram avaliados em um desenho cego (atenção, controle inibitório, velocidade de processamento, flexibilidade mental, fluência verbal-fonêmica e semântica, memória operacional e episódica, cognição global e percepção visual) no início e após o último dia de estimulação. Nós observamos que não há efeitos do córtex Insular Posterior Superior (IPS) ou do Cíngulado Anterior (CCA) comparado com EMTp simulada na dor clínica, apesar do achado antinociceptivo significativo nos limiares térmicos após EMTp- IPS e um efeito ansiolítico significativo de EMTp- CCA comparado com estimulação simulada. Não encontramos efeitos significativos da estimulação ativa para o IPS ou para o CCA em comparação com a estimulação simulada em qualquer um dos domínios cognitivos. Os autores concluíram que a EMTp CCA/IPS de alta frequência e repetidas sessões de longa duração é segura em pacientes com lesões do SNC que apresentam lesões cerebrais estruturais e comprometimento cognitivo significantes / Deep-TMS (dTMS) modulates deeper cortical structures such as the posterior superior insular (PSI) and the anterior cingulate cortices (ACC) and has been used to treat conditions not previously responsive to superficial-TMS. However, to date no study has assessed the effects of dTMS on cognition after several sessions of stimulation in a comprehensive manner, especially in patients with baseline cognitive dysfunction due to SNC structural lesions. We present secondary outcome results form a three-arm parallel randomized trial on the effects of active10Hz dTMS to either the ACC or PSI against sham dTMS on neuropsychological assessment of 98 central neuropathic pain patients undergoing a 12-week (16 sessions) course of treatment. Several cognitive channels were assessed in a blinded design (attention, inhibitory control, processing speed, mental flexibility, verbal fluency-phonemic and semantic, working and episodic memory, global cognition and visual perception) at baseline and after the last day of stimulation. We observed that there were no effects of either posterior insular (PSI) or anterior cingulate cortex (ACC) compared to sham dTMS on clinical pain, despite the finding of a significant anti-nociceptive on thermal thresholds after PSI d- TMS and a significant anxiolytic effect of ACC d-TMS compared to sham stimulation. We found no significant effects of active stimulation to either the PSI or to the ACC compared to sham stimulation in any of the cognitive domains. Long-term repetitive-session high frequency ACC/PSI- dTMS is safe in patients with structural SNC lesions who have baseline significant structural brain lesions and cognitive impairment

<p>This dissertation explains why behavioral genetic research can be better informed by using characteristics in the human iris as biomarkers for personality, and is divided into five parts. Part I gives an introduction to the classical twin method and an overview of the findings that have led most developmental researchers to recognize that the normal variation of personality depends on a complex interplay between genetic and environmental factors. Part II highlights empirical findings that during the last twenty years have gradually moved genetic and environmental theory and research to evolve toward one another, and also presents the theory of genetics and experience that currently is used to explain how the interplay between genes and the environment works. Part III explains why, from a developmental perspective, it is of interest to identify candidate genes for personality, and gives a brief overview of genes that have been associated with personality. Problems associated with genetic research on the molecular level and how these apply to personality are also highlighted. Part IV examines molecular research on the iris and the brain, which suggests that genes expressed in the iris could be associated with personality, and explains how the use of iris characteristics can increase power to test candidate genes for personality by taking advantage of the self-organizing properties of the nervous system. The empirical foundation for the questions posed in this dissertation and also the empirical results are presented here. Part V discusses the associations found between iris characteristics and personality, and exemplifies how iris characteristics can be used within the theoretical frameworks presented in parts I, II, III and IV. In other words, Part V explains how iris characteristics – in addition to identify as well as test candidate genes for personality – can be used to investigate how people’s experiences in themselves are influenced by genetic factors.</p>

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.

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