O mapeamento das respostas BOLD (Blood Oxygenation Level Dependent) constitui etapa importante nos experimentos de imagem funcional por ressonância magnética (Functional Magnetic Resonance Imaging fMRI) e de EEG-fMRI simultâneo. Em sua grande maioria, a análise de dados de fMRI e de EEG-fMRI está baseada no modelo linear geral (General Linear Model GLM), que procura localizar as respostas BOLD por meio de modelos definidos a priori. Porém, em muitos casos, como em pacientes, variações na forma e/ou atraso podem reduzir a confiabilidade dos resultados. Desse modo, o primeiro objetivo deste trabalho foi explorar métodos clássicos e propor novos métodos para análise de dados de fMRI e de EEG-fMRI simultâneo. Neste trabalho, um método modificado baseado na distância de Kullback-Leibler generalizada (dKLg) foi desenvolvido. Diferentemente do GLM, essa abordagem não requer um modelo para a resposta. Dados simulados foram utilizados para otimizá-lo e compará-lo ao GLM sob diferentes condições de resposta como a relação sinal ruído e a latência. Em seguida, o dKLg foi testado em dados reais, adquiridos em 14 voluntários assintomáticos, submetidos a tarefas motoras e auditivas padrões. Os resultados mostram a equivalência entre o dKLg e o GLM. Em seguida, essa estratégia foi testada em 02 pacientes com com estenose carotídea unilateral. Neste caso, o dKLg foi capaz de detectar regiões significativas ipsilaterais à estenose, não detectadas pelo GLM, em virtude do atraso do sinal BOLD. Em seguida, esses métodos foram aplicados sobre exames de EEG-fMRI realizados em 45 pacientes com epilepsia. Para esse conjunto de dados, mais uma abordagem foi elaborada, que utiliza a Análise de Componentes Independentes (Independent Component Analysis ICA). Denominado ICA-GLM, ele permite extrair de modo semi-automático a amplitude, duração e topografia das descargas epileptiformes interictais (Interictal Epileptiform Discharges IED), favorecendo a inclusão de sinais do EEG de menor destaque. Além dessa vantagem, ele ainda permite incluir modelos do sinal BOLD com diferentes latências, aumentando a abrangência da variabilidade das respostas encontradas em pacientes com epilepsia. A eficiência do ICA-GLM também foi comparado à do GLM e dKLg nos exames de EEG-fMRI. Embora os resultados tenham demonstrado a robustez do GLM, em alguns pacientes o dKLg foi mais eficiente para localizar regiões concordantes que não foram detectadas pelo GLM. Ainda, em boa parte dos casos o ICA-GLM detectou regiões mais extensas e com maior valor estatístico, quando comparado ao GLM. De forma geral, nota-se que o dKLg e ICA-GLM podem ser ferramentas complementares importantes ao GLM, aumentando a sensibilidade dos exames de EEG-fMRI como um todo. Outra etapa importante nas avaliações de EEG-fMRI em pacientes com epilepsia tem sido a utilização de imagens de fontes elétricas (Electrical Source Imaging ESI). Neste trabalho, os mapas de ESI foram obtidos por dois métodos de solução inversa distribuída nunca usados no cenários da EEG-fMRI: Bayesian Model Averaging (BMA) e constrained Low Resolution Electromagnetic Tomography (cLORETA). Além da construção dos mapas de ESI, avaliamos a utilidade de combinar as técnicas de ESI e de EEG-fMRI para promover a diferenciação entre fontes primárias e de propagação temporal. Essa análise permitiu avaliar a concordância entre as regiões detectadas pelo ESI e EEG-fMRI e diferenciar as respostas BOLD relacionadas aos componentes iniciais e posteriores da IED. Embora os resultados ainda sejam preliminares para eleger qual método seria mais eficiente (cLORETA ou BMA), a distância encontrada entre o máximo ESI e o cluster de EEG-fMRI mais próximo foi consistentemente similar, em ambos, com os dados recentes da literatura. / Functional magnetic resonance imaging (fMRI) and combined EEG-fMRI usually rely on the successful detection of Blood Oxygenation Level Dependent (BOLD) signal. Typically, the analysis of both fMRI and EEG-fMRI are based on the General Linear Model (GLM) that aims at localizing the BOLD responses associated to an a priori model. However, the responses are not always canonical, as is the case of those from patients, which may reduce the reliability of the results. Therefore, the first objective of the present study was to explore the usage of classical methods, such as the GLM, and to propose alternative strategies to the analysis of fMRI and combined EEG-fMRI. A first method developed was based on the computation of the generalized Kullback-Leibler distance (gKLd), which does not require the use of an a priori model. Simulated data was used to allow quantitative comparison between the gKLd and GLM under different response conditions such as the signal to noise ratio and delay. The gKLd was then tested on real data, first from 14 asymptomatic subjects, submitted to classical motor and auditory fMRI protocols. The results demonstrate that under these conditions the GLM and gKLd are equivalent. The same strategy was applied to 02 patients with unilateral carotid stenosis. Now the dKLg was capable of detecting the expected bilateral BOLD responses that were not detected by the GLM, as a consequence of the response delay imposed by the stenosis. Those comparisons were now extended to the evaluation of EEG-fMRI exams from 45 patients with epilepsy. For this data set, an additional method was used, based on the use of Independent Component Analysis (ICA), which was called ICA-GLM. It allows extracting semi-automatically the amplitude, duration and topography of EEG interictal Epileptiform Discharges (IED), favoring the use of less prominent signals. Moreover, it also allows the use of BOLD response models with different delays, expanding the variability of the responses to be detected in patients with epilepsy. ICA-GLM was also compared to GLM and dKLg in these EEG-fMRI evaluations. Although in general the results have demonstrated the robustness of the GLM, dKLg was more efficient in detecting the responses from some pacients, while the ICA-GLM mostly detected broader regions with more significant results when compared to GLM. In general, dKLg and ICA-GLM seem to offer an important complementary aspect to the GLM, increasing its sensibility in EEG-fMRI as a whole. Another important aspect of EEG-fMRI applied to patients with epilepsy has been the inspection of Electrical Source Imaging (ESI) to evaluate some dynamical aspects of the IED. Herein, ESI maps were obtained from two inverse distributed solutions that were not applied so far to EEG-fMRI: Bayesian Model Averaging (BMA) and constrained Low Resolution Electromagnetic Tomography (cLORETA). Besides, we also evaluated the combined information from ESI and EEG-fMRI in order to differentiate from primary sources to temporal propagation of the signal. Such analysis allowed us to inspect for the correspondence between regions detected by ESI e EEG-fMRI and to separate BOLD signals whose sources are related to the initial and later components of the IED. Although the results are preliminary to determine which ESI method (cLORETA or BMA) is more efficient, the distance between the maximum ESI and the closest EEG-fMRI cluster was consistently similar with those reported in the literature.

The purpose of this thesis is threefold: 1) A behavioral examination of the role of diacritics in Arabic, 2) A functional magnetic resonance imaging (fMRI) investigative study of diacritics in Arabic, and 3) An optimization algorithm for brain mapping and detecting brain function. Firstly, the role of diacritics in Arabic was examined behaviorally. The stimulus was a lexical decision task (LDT) that constituted of low, mid, and high frequency words and nonwords; with and without diacritics. Results showed that the presence of vowel diacritics slowed reaction time but did not affect word recognition accuracy. The longer reaction times for words with diacritics versus without diacritics suggest that the diacritics may contribute to differences in word recognition strategies. Secondly, an Event-related fMRI experiment of lexical decisions associated with real words with versus without diacritics in Arabic readers was done. Real words with no diacritics yielded shorter response times and stronger activation than with real words with diacritics in the hippocampus and middle temporal gyrus possibly reflecting a search from among multiple meanings associated with these words in a semantic store. In contrast, real words with diacritics had longer response times than real words without diacritics and activated the insula and frontal areas suggestive of phonological and semantic mediation in lexical retrieval. Both the behavioral and fMRI results in this study appear to support a role for diacritics in reading in Arabic. The third research work in this thesis is an optimization algorithm for fMRI data analysis. Current data-driven approaches for fMRI data analysis, such as independent component analysis (ICA), rely on algorithms that may have low computational expense, but are much more prone to suboptimal results. In this work, a genetic algorithm (GA) based on a clustering technique was designed, developed, and implemented for fMRI ICA data analysis. Results for the algorithm, GAICA, showed that although it might be computationally expensive; it provides global optimum convergence and results. Therefore, GAICA can be used as a complimentary or supplementary technique for brain mapping and detecting brain function by way of fMRI.

Individuals feel more empathy for those in their group (i.e., ingroup members) and less for those who are not (i.e., outgroup members). But evidence suggests that empathy is not merely selective to the other’s group, rather it fluctuates according to how the other’s group is perceived by the individual. This project was developed to investigate whether individuals truly differentiate between outgroups when it comes to empathy. Across several studies, I presented participants with images depicting others receiving physically painful stimulations. The other person in each case was a member of the ingroup or one of two outgroups, one of which was more of a competitive threat to the ingroup. In Study 3, I found that participants exhibited an ingroup bias, that is, greater levels of empathy to images of ingroup pain, compared to outgroup pain. In Study 4, I found that empathic responses also varied between the two outgroups: Empathy was significantly lower when targets were from the outgroup that was perceived as more of a competitive threat to the ingroup, than the other outgroup. This provided the first evidence that beliefs about outgroups, and not merely the ingroup-outgroup distinction, modulates empathic processing. I also investigated the extent to which threats that are incidental to the ingroup context affect empathy. Across two studies I showed reliable evidence that priming incidental feelings of fear was sufficient to elicit intergroup bias in self-reported empathy, specifically against the outgroup, i.e., reduced empathy for outgroup targets, rather than increased empathy for ingroup targets. Finally, I investigated the extent to which my findings could be accounted for by individual differences. In a series of ‘mini meta-analyses’, I provide evidence that in an intergroup context a shared group membership confers an empathic advantage when responding to a target’s pain, regardless of one’s sex or their scores on a measure of trait empathy.

Navigation through the environment requires the ability to select relevant information from a multitude of irrelevant stimuli. Under conditions of processing conflict, attention and cognitive control processes bias sensory input based on internal goals. These processes are supported by the interplay of a fronto-parietal attention network that exerts a top-down influence on information processing and a superior temporal network that operates in parallel and that responds in a stimulus-driven manner to behaviorally salient stimuli. It is often reported that nicotine can enhance top-down attention control and reduce distraction. In experiments 1 and 2, the effects of increasing control demands on behavior were assessed using electrophysiological (EEG) and behavioral measures in an auditory number parity decision task with different levels of distraction. Participants made forced choice ‘odd’ or ‘even’ number decisions, while ignoring preceding or simultaneous novel distractors. A group of non-smokers was compared to overnight abstinent smokers (9 hours) and after nicotine intake via 2 mg nicotine tablet or via smoke-inhaled nicotine. The results revealed that preceding distractors impaired task performance due to orienting to and reorienting from the distractor. Simultaneous distractors did not cause orientation of attention (indicated by absence of a P3a Event-Related Potential) and produced smaller increments in response latencies. However, this type of complex novel stimulus initiated processes of memory updating that significantly impaired response sensitivity and accuracy. Nicotine withdrawal enhanced these distraction effects, whereas nicotine intake, particularly via smoking, normalized performance. In experiment 3, dichotic listening performance in a group of non-smokers was compared to abstinent smokers (12 hours) using behavioral, EEG and functional Magnetic Resonance Imaging (fMRI) measures. The perceptual salience of the stimuli was manipulated by systematically varying the Inter-aural Intensity Difference (IID) between them. The analysis pointed to distinct brain networks that differentially activate depending on the level of competition between sensory inputs and these effects were additionally modulated by nicotine withdrawal. Nicotine withdrawal impaired behavioral performance supported by evidence of enhanced use of memory and attention resources, and some evidence of task-independent default mode network activation. Overall, the findings suggest that withdrawal from nicotine, particularly in heavy smokers, is associated with impairments in cognitive control and that subsequent intake of nicotine serves mainly to normalize performance.

Effective memory representations must be specific to prevent interference between episodes that may overlap in terms of place, time, or items present. Pattern separation, a computational process performed by the hippocampus overcomes this interference by establishing non-overlapping memory representations. This project explores pattern separation and how it is impacted by age and sleep. Experiment 1. Structures of the medial temporal lobe (MTL) are known to be involved in declarative memory processes. However, little is known about how age-related changes in MTL structures, white matter integrity, and functional connectivity affect pattern separation processes in the MTL. In the present study, we used magnetic resonance imaging (MRI) to measure the volumes of MTL regions of interest, including hippocampal subfields (dentate gyrus, CA3, CA1, and subiculum) in healthy older and younger adults. Additionally, we used diffusion tensor imaging to measure white matter integrity for both groups. Finally, we used functional MRI to acquire resting functional connectivity measures for both groups. We show that, along with age, the volume of left CA3/dentate gyrus predicts memory performance. Differences in fractional anisotropy and the strength of resting functional connections between the hippocampus and other cortical structures implicated in memory processing were not significant predictors of performance. As previous studies have only hinted, it seems that the size of left CA3/dentate gyrus contributes more to successful discrimination between similar mnemonic representations than other hippocampal sub-fields, MTL structures, and other neuroimaging correlates. Accordingly, the implications of aging and atrophy on lure discrimination capacities are discussed. Experiment 2. Although it is widely accepted that declarative memories are consolidated during sleep, the effects of sleep on pattern separation have yet to be elucidated. We used whole-brain, high-resolution functional neuroimaging to investigate the effects of sleep on a task that places high demands on pattern separation. Sleep had a selective effect on memory specificity and not general recognition memory. Activity in brain regions related to attention, visual acuity, and visual recall demonstrated an interaction between sleep and delay. Surprisingly, there was no effect of sleep on hippocampal activity using a group-level analysis. To further understand the role of the hippocampus on our task, we performed a representational similarity analysis. We investigated whether hippocampal activity associated with looking at novel stimuli correlated more with similar-looking (lure) stimuli or repeated stimuli. Results indicate that while a single night's sleep does not significantly impact hippocampal responses, the hippocampus does treat lure stimuli similarly as it does novel stimuli.

The prevalence of chronic pain is known to increase with advancing age, with over 50% of community dwelling older adults (aged 65 years and over) and up to 80% of those residing in nursing homes estimated to be suffering some form of persistent or recurring pain complaint. In addition to a greater likelihood of pain, advancing age is associated with increased reports of pain interference. It is possible to ascribe age-related changes in pain report and impact to increased disease prevalence and severity in older people. However, there is also evidence that ageing has effects on pain perception, central pain processing, and plasticity of pain responses that are not explained by co-morbid disease. / The increased prevalence of chronic pain in older adults represents a major public health concern. As a result of increased life expectancy and the post-World War II baby boom, there will be a dramatic change in the demographic structure of our population over the coming decades, with older adults representing the fastest-growing segment of our communities. The proportion of the total population over the age of 65 in Australia has risen from 9% in 1976, to 12% in 2001, and is predicted to reach 16% by the year 2016. Pain that is undetected or under-treated can adversely affect quality of life for older adults, leading to diminished mood, impaired cognition, behavioural problems, as well as increased functional dependence. This in turn contributes to greater demands for daily personal care and a resultant increase in health-care costs. / Pain management is a particularly salient issue in the case of older adults with dementia, who are at increased risk of undetected pain on account of impaired cognition and communication skills. Indeed, clinical reports show that patients with Alzheimer’s disease (AD) are routinely administered fewer pain-relief medications compared with their cognitively-intact peers. Understandably, reports of reduced analgesia in AD have sparked considerable research interest, and over recent years there has been a marked increase in the number of studies aimed at better characterising the experience of pain in patients with AD. However, despite these efforts, the effects of neurodegeneration on pain processing, and the specific ways in which the disease process impacts on brain responses to noxious stimulation and the ensuing experience of pain have not been previously determined. / Improved management of pain is fundamental to the clinical care of older adults, particularly those with dementia. However, the potential to adequately counteract pro-nociceptive processes and facilitate endogenous inhibitory mechanisms in the treatment of ongoing pain in older adults will only become possible once the effects of ageing and age-related neurodegeneration on central pain processing are identified and described. The overarching goal of this thesis was therefore to improve current understanding of the ways in which normal ageing and Alzheimer’s disease impact on the perception and central nervous system processing of pain. The findings of this thesis provide valuable new insights into the impact of ageing and AD on the central mechanisms contributing to pain perception, and may therefore contribute toward better management and treatment of pain in this vulnerable and rapidly growing sector of our community. / Thesis outline: Chapter 2 provides a review of the background literature and rationale for the thesis. The chapter begins with a discussion of current understanding of pain as a multidimensional phenomenon shaped by sensory, emotional and cognitive components, and leads into a description of neural mechanisms of nociception, as well as the supraspinal processes involved in the elaboration of nociceptive signals into these aspects of pain. The impact of ageing on the structure and function of central nervous system regions underlying these processes are discussed, along with the findings from previous clinical and empirical data which suggest age-related changes in pain perception. Current understanding of the neuropathological and clinical aspects of AD is reviewed, with particular emphasis on potential ways in which the disease may impact on central nociceptive processing and the behavioural response to pain. This is followed by a review of the previous clinical and empirical literature examining pain perception in AD. Finally, the aims of the current thesis are outlined. / Chapter 3 describes the general methods which were employed in the subsequent empirical chapters in order to address the aims of the thesis. The equipment and psychophysical procedures used to assess pain perception in healthy young and older adults and patients with AD are described. The basic principals of magnetic resonance imaging (MRI) are then outlined, and the utility of structural and functional MRI for assessing age-related and disease-related changes to brain regions involved in pain perception and processing are discussed. The empirical studies which were undertaken to identify the impact of ageing and AD on central pain processing are presented in the next three chapters. / Chapter 4 begins with psychophysical studies comparing sensory and emotional responses to pain in healthy young and older adults, and follows with MRI investigations of age-related differences in brain volumetry and pain-related brain activity. Studies of pain sensitivity and pain-evoked brain activity in patients with AD compared with age-matched controls are presented in Chapter 5. Following on from these findings of AD-related differences in pain-evoked brain activation, the study described in Chapter 6 used functional connectivity analysis in order to assess the impact of AD on the functional integration of brain regions underlying the sensory, emotional, and cognitive aspects of pain. / The key findings presented in the preceding three chapters are summarized in a general discussion in Chapter 7. The implications of the findings, in terms of the clinical management of pain in older adults with and without Alzheimer’s disease are discussed. The opportunity is also taken to discuss some of the limitations of the present research, and finally, recommendations are made for future research directions.

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

Embodied cognition theorists suggest that cognition is bodily based and that the brain developed due to interaction with the environment, and thus evolved to facilitate sensorimotor processing. As such, one goal of embodied cognition research is to determine how the interaction between the body and the environment affects the storage and processing of semantic information. Recent neuroimaging research has shown that the sensorimotor and premotor cortices are activated somatotopically when responding to action-related stimuli. In addition, behavioural research has provided evidence in support of the theory of embodied cognition, in that the sensorimotor properties of a stimulus have been shown to affect performance on language tasks. The goal of the current research was to provide a novel and comprehensive examination of the theory of embodied cognition through the combination of multiple experimental paradigms. Several functional magnetic resonance imaging and behavioural experiments on healthy participants were carried out, as well as a behavioural study of two individuals who have undergone either a left or right hemispherectomy. The results from the functional neuroimaging experiments demonstrated that there are common regions of activation between motor movements and semantic processing, whereby sensorimotor and premotor regions that are responsible for arm and leg motor movements are also recruited when responding to arm- and leg-related action semantic knowledge. Thus these results are consistent with the theory of embodied cognition, suggesting that the motor system is involved in the processing of action-related semantic information. The behavioural results were also consistent with previous research showing that pictures have privileged access to action-related semantic knowledge. Additionally, the behavioural results with hemispherectomy patients provided evidence regarding the necessity versus sufficiency of the left and right hemispheres when responding to arm- and leg-related semantic knowledge. Finally, given that words rated as higher in body-object interaction were responded to faster than words rated as lower in body-object interaction, these results show evidence that language processing is grounded in bodily interaction and sensorimotor processing. Together, the results further advance the theory of embodied cognition, and moreover, provide an in-depth analysis of how arm- and leg-related stimuli are processed dependent upon presentation format.

Embodied cognition theorists suggest that cognition is bodily based and that the brain developed due to interaction with the environment, and thus evolved to facilitate sensorimotor processing. As such, one goal of embodied cognition research is to determine how the interaction between the body and the environment affects the storage and processing of semantic information. Recent neuroimaging research has shown that the sensorimotor and premotor cortices are activated somatotopically when responding to action-related stimuli. In addition, behavioural research has provided evidence in support of the theory of embodied cognition, in that the sensorimotor properties of a stimulus have been shown to affect performance on language tasks. The goal of the current research was to provide a novel and comprehensive examination of the theory of embodied cognition through the combination of multiple experimental paradigms. Several functional magnetic resonance imaging and behavioural experiments on healthy participants were carried out, as well as a behavioural study of two individuals who have undergone either a left or right hemispherectomy. The results from the functional neuroimaging experiments demonstrated that there are common regions of activation between motor movements and semantic processing, whereby sensorimotor and premotor regions that are responsible for arm and leg motor movements are also recruited when responding to arm- and leg-related action semantic knowledge. Thus these results are consistent with the theory of embodied cognition, suggesting that the motor system is involved in the processing of action-related semantic information. The behavioural results were also consistent with previous research showing that pictures have privileged access to action-related semantic knowledge. Additionally, the behavioural results with hemispherectomy patients provided evidence regarding the necessity versus sufficiency of the left and right hemispheres when responding to arm- and leg-related semantic knowledge. Finally, given that words rated as higher in body-object interaction were responded to faster than words rated as lower in body-object interaction, these results show evidence that language processing is grounded in bodily interaction and sensorimotor processing. Together, the results further advance the theory of embodied cognition, and moreover, provide an in-depth analysis of how arm- and leg-related stimuli are processed dependent upon presentation format.

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.