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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.

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.

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.

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 has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson’s disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission. Here, we study global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks. Thirty-three patients with idiopathic Parkinson’s disease were studied three times in a double-blind, placebo-controlled counter-balanced crossover design, following placebo, 40mg-oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30mg-oral citalopram (selective serotonin reuptake inhibitor). Neuropsychological assessments were performed outside the scanner. Seventy-six controls were scanned without medication to provide normative data for comparison to the patient cohort. Graph theoretical analysis of task-free brain connectivity, with a random 500-node parcellation, was used to measure the effect of disease in placebo-treated state (versus unmedicated controls) and pharmacological intervention (drug versus placebo). Relative to controls, patients on placebo had executive impairments (reduced fluency and inhibitory control), which was reflected in dysfunctional network dynamics in terms of reduced clustering coefficient, hub degree and hub centrality. In patients, atomoxetine improved fluency in proportion to plasma concentration (p=0.006, r2=0.24), and improved response inhibition in proportion to increased hub eigen centrality (p=0.044, r2=0.14). Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering (p=0.01, r2=0.22), modularity (p=0.043, r2=0.14) and path length (p=0.006, r2=0.25) increased in patients with milder forms of Parkinson’s disease, but decreased in patients with more advanced disease (UPDRS-III >30). This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. We propose that hub connectivity contributes to cognitive performance in Parkinson’s disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function.

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