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Funder: GlaxoSmithKline; Id: http://dx.doi.org/10.13039/100004330, Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract‐based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group‐by‐age interaction effect was found showing greater reductions with age in the alcohol‐dependent group within corpus callosum, overlapping with the group difference. We found no evidence of recovery with abstinence. A comparison of alcohol‐only‐ and alcohol‐polydrug‐dependent groups found no differences in FA. Overall, our findings show that AD is associated with lower FA and suggest that these alterations are primarily driven by lifetime alcohol consumption and cigarette smoking, showing no relationship with exposure to other substances such as cocaine, opiates or cannabis. Reductions in FA across the adult lifespan are more pronounced in AD and offer further support for the notion of accelerated ageing in relation to alcohol dependence. These findings highlight there may be lasting structural differences in white matter in alcohol dependence, despite continued abstinence.

© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey-matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed-based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala-SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala-SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala-SN/VTA RSFC and accelerated age-related grey-matter atrophy through potentially distinct mechanisms.

Background: Chronic stimulant use has been associated with disruptions in fronto-striatal systems implicated in as- sociative learning [1]. Experimental studies have also shown that individuals with stimulant drug addiction experience difficulties in selecting the appropriate action following feedback [2]. However, the precise impairments in feedback learning in stimulant-addicted individuals are still unclear. A possible explanation might lie in an abnormal prediction error mechanism, as stimulant drugs directly target striatal dopaminergic neurons [3].

Introduction: Evidence suggests that abnormalities in reward processing and increased impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised. This study used fMRI to investigate the BOLD response during reward and inhibitory control tasks and how such responses were associated with subjective and behavioural measures of impulsivity in abstinent alcohol, cocaine and polydrug addiction. We hypothesized a negative correlation between non-drug related reward anticipation and impulsivity measures in polydrug and alcohol dependence compared with healthy controls owing to increased impulsivity and thus more inhibitory control effort needed to maintain successful abstinence. Methods: Abstinent alcohol dependent (AD, n=27), polydrug dependent (PD, n=57) and healthy control (HC, n=65) participants were recruited [1] (REC number 11/H0707/9). Participants completed a battery of impulsivity measures; the Barratt Impulsiveness Scale (BIS-11) and the Urgency, Premeditation, (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPS-P) to measure trait impulsivity, the Kirby Delay Discounting task to measure choice impulsivity and the Stop Signal Task (SST) to measure impulsive action. Participants also underwent fMRI scanning (3-T) using the monetary incentive delay (MID) and Go/No-go (GNG) tasks. An a-priori region of interest approach was used to image BOLD response during the following contrasts: reward anticipation>neutral anticipation and no-go/go in the rIFG, OFC and caudate. Data was analysed using ANOVA or Kruskal- Wallis tests (with Tukey or Mann-Whitney U post-hoc tests respectively) and Pearson's or Spearman's rank correlations, as appropriate. Holm-Bonferroni correction was applied. Results: There were significant group differences in the BIS-11 (pneutral anticipation and no-go>go contrasts. In the overall population, significant but weak positive correlations were observed between BOLD response for the reward anticipation>neutral anticipation and no-go>go contrast in the rIFG (r=0.208, p=0.001), OFC (r=0.219, p=0.008) and caudate (r=0.208, p=0.012). Interestingly, while these associations were observed in the HC group no such associations existed in the AD and PD groups. Finally, no significant associations were observed between subjective impulsivity measures and BOLD signal change during either task. Conclusion: The overall findings of this study suggest that there is a relationship between BOLD response during reward processing and inhibitory control. However, in contrast to our hypothesis this association was positive and was not observed in AD or PD individuals, suggesting that such an association is dysregulated in addiction. Further work is required to better understand the association between BOLD response during reward processing and impulse control. This study was funded by the MRC (G1000018) with support from GSK.

Compulsivity is associated with failures in goal-directed control, an important cognitive faculty that protects against developing habits. But might this effect be explained by co-occurring anxiety? Previous studies have found goal-directed deficits in other anxiety disorders, and to some extent when healthy individuals are stressed, suggesting this is plausible. We carried out a causal test of this hypothesis in two experiments (between-subject N=88; within-subject N=50) that used the inhalation of hypercapnic gas (7.5% CO2) to induce an acute state of anxiety in healthy volunteers. In both experiments, we successfully induced anxiety, assessed physiologically and psychologically, but this did not affect goal-directed performance. In a third experiment (N=1413), we used a correlational design to test if real-life anxiety-provoking events (panic attacks, stressful events) impair goal-directed control. While small effects were observed, none survived controlling for individual differences in compulsivity. These data suggest that anxiety has no meaningful impact on goal-directed control.

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance‐dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened “top‐down” control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no‐go (GNG) task we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent poly substance‐dependent (poly‐SUD) individuals, and controls during a randomized double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly‐SUD groups respectively. Self‐reported trait impulsivity in the poly‐SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly‐SUD groups, which are predicted by trait impulsivity in the poly‐SUD group.

What is a habit? One problem with the concept of habit has been that virtually everyone has their own ideas of what is meant by such a term. Whilst not eschewing folk psychology, it is useful to re-examine dictionary definitions of 'habit'. The Oxford Dictionary of English defines habit as "a settled or regular tendency or practice, especially one that is hard to give up" and also "an automatic reaction to a specific situation". The latter, reassuringly, is not too far from what has come to be known as stimulus-response theory.

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

What is a habit? One problem with the concept of habit has been that virtually everyone has their own ideas of what is meant by such a term. Whilst not eschewing folk psychology, it is useful to re-examine dictionary definitions of 'habit'. The Oxford Dictionary of English defines habit as "a settled or regular tendency or practice, especially one that is hard to give up" and also "an automatic reaction to a specific situation". The latter, reassuringly, is not too far from what has come to be known as stimulus-response theory.

BACKGROUND: Excessive checking is a common, debilitating symptom of obsessive–compulsive disorder. To further examine cognitive processes underpinning checking behaviour, and clarify how and why checking develops, we designed a novel operant paradigm for rats, the observing response task. The present study used the observing response task to investigate checking behaviour following excitotoxic lesions of the medial prefrontal cortex, nucleus accumbens core and dorsal striatum, brain regions considered to be of relevance to obsessive–compulsive disorder. METHODS: In the observing response task, rats pressed an ‘observing’ lever for information (provided by light onset) about the location of an ‘active’ lever that provided food reinforcement. Following training, rats received excitotoxic lesions of the regions described above and performance was evaluated post-operatively before histological processing. RESULTS: Medial prefrontal cortex lesions selectively increased functional checking with a less-prominent effect on non-functional checking and reduced discrimination accuracy during light information periods. Rats with nucleus accumbens core lesions made significantly more checking responses than sham-lesioned rats, including both functional and non-functional checking. Dorsal striatum lesions had no direct effect on checking per se, but reduced both active and inactive lever presses, and therefore changed the relative balance between checking responses and instrumental responses. CONCLUSIONS: These results suggest that the medial prefrontal cortex and nucleus accumbens core are important in the control of checking, perhaps via their role in processing uncertainty of reinforcement, and that dysfunction of these regions may therefore promote excessive checking behaviour, possibly relevant to obsessive-compulsive disorder.

Summary Confidence and actions are normally tightly interwoven—if I am sure that it is going to rain, I will take an umbrella—therefore, it is difficult to understand their interplay. Stimulated by the ego-dystonic nature of obsessive-compulsive disorder (OCD), where compulsive actions are recognized as disproportionate, we hypothesized that action and confidence might be independently updated during learning. Participants completed a predictive-inference task designed to identify how action and confidence evolve in response to surprising changes in the environment. While OCD patients (like controls) correctly updated their confidence according to changes in the environment, their actions (unlike those of controls) mostly disregarded this knowledge. Therefore, OCD patients develop an accurate, internal model of the environment but fail to use it to guide behavior. Results demonstrated a novel dissociation between confidence and action, suggesting a cognitive architecture whereby confidence estimates can accurately track the statistic of the environment independently from performance., Highlights • Action can be functionally dissociated from confidence • Patients with obsessive-compulsive disorder (OCD) show exaggerated action updating • Confidence in OCD is intact and reflects information that is not used to control action • Degree of action-confidence dissociation correlates with symptom severity in OCD, Vaghi, Luyckx et al. provide evidences of a novel dissociation between confidence and action in OCD patients with confidence accessing information that is not used to guide action.

This review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenaline reuptake blocker atomoxetine. Functional neuroimaging evidence suggests a modulation of circuitry including the inferior prefrontal cortex by this drug. Parallel work in rats had shown that atomoxetine improves stop signal performance by affecting possibly homologous regions of the rodent prefrontal cortex. This parallel effect of atomoxetine in rodents and humans could potentially be exploited in other disorders in which impulsivity plays a role, such as stimulant abuse and Parkinson’s disease. A contrasting relative lack of involvement of 5-HT mechanisms in the stop signal reaction time task will also be described. Research in humans and experimental animals that demonstrate effects of serotoninergic agents such as the selective serotonin (5-HT) reuptake inhibitor citalopram on probabilistic learning and reversal (upon which atomoxetine has little effect) will also be reviewed, possibly relevant to the treatment of clinical depression, Finally, other promising examples of parallel studies of behavioural effects of CNS-active drugs in animals and humans will also be described.

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

Excessive drinking to intoxication is the major behavioral characteristic of those addicted to alcohol but it is not the only one. Indeed, individuals addicted to alcohol also crave alcoholic beverages and spend time and put much effort into compulsively seeking alcohol, before eventually drinking large amounts. Unlike this excessive drinking, for which treatments exist, compulsive alcohol seeking is therefore another key feature of the persistence of alcohol addiction since it leads to relapse and for which there are few effective treatments. Here we provide novel evidence for the existence in rats of an individual vulnerability to switch from controlled to compulsive, punishment-resistant alcohol seeking. Alcohol-preferring rats given access to alcohol under an intermittent 2-bottle choice procedure to establish their alcohol-preferring phenotype were subsequently trained instrumentally to seek and take alcohol on a chained schedule of reinforcement. When stable seeking-taking performance had been established, completion of cycles of seeking responses resulted unpredictably either in punishment (0.45 mA foot-shock) or the opportunity to make a taking response for access to alcohol. Compulsive alcohol seeking, maintained in the face of the risk of punishment, emerged in only a subset of rats with a predisposition to prefer and drink alcohol, and was maintained for almost a year. We show further that a selective and potent μ-opioid receptor antagonist (GSK1521498) reduced both alcohol seeking and alcohol intake in compulsive and non-compulsive rats, indicating its therapeutic potential to promote abstinence and prevent relapse in individuals addicted to alcohol.

Our daily lives involve high levels of repetition of activities within similar contexts. We buy the same foods from the same grocery store, cook with the same spices, and typically sit at the same place at the dinner table. However, when questioned about these routine activities, most of us barely remember the details of our actions. Habits are automatically triggered behaviours in which we engage without conscious awareness or deliberate control. Although habits help us to operate efficiently, breaking them requires great effort. We have developed a 27-item questionnaire to measure individual differences in habitual responding in everyday life. The Creature of Habit Scale (COHS) incorporates two aspects of the general concept of habits, namely routine behaviour and automatic responses. Both aspects of habitual behaviour were weakly correlated with underlying anxiety levels, but showed a more substantial difference in relation to goal-oriented motivation. We also observed that experiences of adversity during childhood increased self-reported automaticity, and this effect was further amplified in participants who also reported exposure to stimulant drugs. The COHS is a valid and reliable self-report measure of habits, which may prove useful in a number of contexts where discerning individuals' propensity for habit is beneficial.

Cognitive control has traditionally been associated with pFC based on observations of deficits in patients with frontal lesions. However, evidence from patients with Parkinson's disease indicates that subcortical regions also contribute to control under certain conditions. We scanned 17 healthy volunteers while they performed a task-switching paradigm that previously dissociated performance deficits arising from frontal lesions in comparison with Parkinson's disease, as a function of the abstraction of the rules that are switched. From a multivoxel pattern analysis by Gaussian Process Classification, we then estimated the forward (generative) model to infer regional patterns of activity that predict Switch/Repeat behavior between rule conditions. At 1000 permutations, Switch/Repeat classification accuracy for concrete rules was significant in the BG, but at chance in the frontal lobe. The inverse pattern was obtained for abstract rules, whereby the conditions were successfully discriminated in the frontal lobe but not in the BG. This double dissociation highlights the difference between cortical and subcortical contributions to cognitive control and demonstrates the utility of multivariate approaches in investigations of functions that rely on distributed and overlapping neural substrates.

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone ($\textit{n}$=18, alcohol) and in combination with cocaine and/or opioid dependence ($\textit{n}$=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence ($\textit{n}$=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

Whereas contemporary neuroimaging evidence supports a role for dysfunctioning prefrontal-amygdaloid-striatal circuitry in affective disorders, precise psychological functions of this interaction have still to be revealed, thus providing barriers to producing new treatments for these debilitating conditions. The great advantage of murine models of psychiatric disorders is the availability of the novel neuroscience tools, including optogenetics and designer receptors exclusively activated by designer drugs (DREADDs), which enable the molecular features of specific functional circuits identified in human neuroimaging studies to be further characterized and novel molecular targets for drug discovery to be identified.

Human decision-making arises from both reflective and reflexive mechanisms, which underpin goal-directed and habitual behavioural control. Computationally, these two systems of behavioural control have been described by different learning algorithms, model-based and model-free learning, respectively. Here, we investigated the effect of diminished serotonin (5-hydroxytryptamine) neurotransmission using dietary tryptophan depletion (TD) in healthy volunteers on the performance of a two-stage decision-making task, which allows discrimination between model-free and model-based behavioural strategies. A novel version of the task was used, which not only examined choice balance for monetary reward but also for punishment (monetary loss). TD impaired goal-directed (model-based) behaviour in the reward condition, but promoted it under punishment. This effect on appetitive and aversive goal-directed behaviour is likely mediated by alteration of the average reward representation produced by TD, which is consistent with previous studies. Overall, the major implication of this study is that serotonin differentially affects goal-directed learning as a function of affective valence. These findings are relevant for a further understanding of psychiatric disorders associated with breakdown of goal-directed behavioural control such as obsessive-compulsive disorders or addictions.

Background:\ud There is evidence of executive function impairment in obsessive compulsive disorder (OCD) that potentially contributes to symptom development and maintenance. Nevertheless, the precise nature of these executive impairments and their neural basis remains to be defined.\ud \ud \ud Method:\ud We compared stopping and shifting, two key executive functions previously implicated in OCD, in the same task using functional magnetic resonance imaging, in patients with virtually no co-morbidities and age-, verbal IQ- and gender-matched healthy volunteers. The combined task allowed direct comparison of neural activity in stopping and shifting independent of patient sample characteristics and state variables such as arousal, learning, or current symptom expression.\ud \ud \ud Results:\ud Both OCD patients and controls exhibited right inferior frontal cortex activation during stopping, and left inferior parietal cortex activation during shifting. However, widespread under-activation across frontal-parietal areas was found in OCD patients compared to controls for shifting but not stopping. Conservative, whole-brain analyses also indicated marked divergent abnormal activation in OCD in the caudate and thalamus for these two cognitive functions, with stopping-related over-activation contrasting with shift-related under-activation.\ud \ud \ud Conclusions:\ud OCD is associated with selective components of executive function, which engage similar common elements of cortico-striatal regions in different abnormal ways. The results implicate altered neural activation of subcortical origin in executive function abnormalities in OCD that are dependent on the precise cognitive and contextual requirements, informing current theories of symptom expression.

Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems

Though stimulant drugs such as cocaine are considered highly addictive, some individuals report recreational use over long periods without developing dependence. Difficulties in response inhibition have been hypothesized to contribute to dependence, but previous studies investigating response inhibition in recreational cocaine users have reported conflicting results. Performance on a stop-signal task was examined in 24 recreational cocaine users and 32 healthy non-drug using control participants matched for age, gender and verbal intelligence during functional magnetic resonance imaging scanning. The two groups were further matched on traumatic childhood histories and the absence of family histories of addiction. Results revealed that recreational cocaine users did not significantly differ from controls on any index of task performance, including response execution and stop-signal reaction time, with the latter averaging 198 ms in both groups. Functional magnetic resonance imaging analyses indicated that, compared with controls, stopping in the recreational users was associated with increased activation in the pre-supplementary motor area but not the right inferior frontal cortex. Thus, findings imply intact response inhibition abilities in recreational cocaine users, though the distinct pattern of accompanying activation suggests increased recruitment of brain areas implicated in response inhibition. This increased recruitment could be attributed to compensatory mechanisms that enable preserved cognitive control in this group, possibly relating to their hypothetical resilience to stimulant drug dependence. Such overactivation, alternatively, may be attributable to prolonged cocaine use leading to neuroplastic adaptations.

Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.