From the ventral to the dorsal striatum: Devolving views of their roles in drug addiction

AbstractWe revisit our hypothesis that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntarily drug use to habitual, and ultimately compulsive drug use. We especially focus on the transitions in striatal control over drug seeking behaviour that underlie these transitions since functional heterogeneity of the striatum was a key area of Ann Kelley's research interests and one in which she made enormous contributions. We also discuss the hypothesis in light of recent data that the emergence of a compulsive drug seeking habit both reflects a shift to dorsal striatal control over behaviour and impaired prefontal cortical inhibitory control mechanisms. We further discuss aspects of the vulnerability to compulsive drug use and in particular the impact of impulsivity. In writing this review we acknowledge the untimely death of an outstanding scientist and a dear personal friend

Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity.

Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress

THE RELATIVE CONTRIBUTION OF GOAL-DIRECTED AND HABIT SYSTEMS TO PSYCHIATRIC DISORDERS

Psychiatric disorders may be caused by underlying imbalances between goal-directed and habit systems in the brain. Numerous studies have aimed to establish whether this is because of a goal-directed system deficit, enhanced habit system, or both. This transdiagnostic approach to studying psychiatric disorders is increasingly popular. Maladaptive habitual behaviour is present in many disorders. It is the principal observation in disorders of compulsivity and is also present in other psychiatric disorders that are not primarily characterised by compulsive behaviour. The psychopathology that causes these disorders might be similar and could be targeted with specific treatment. Traditional categorical classification systems of psychiatric disorders do not reflect similarities in neurobiological dysfunction. The comorbidity and overlap between psychiatric disorders means that a dimensional classifications system based on underlying brain system dysfunction might be more appropriate. In this paper, the neural and neuromodulatory systems that contribute to goal-directed and habit systems are discussed. Account is taken of model-based and model-free computational learning mechanisms that are thought to give rise to goal-directed and habitual control respectively. Different psychiatric disorders that have a deficit in goal-directed behaviour or habit systems are then explored to see if there are similarities in the underlying neural systems despite differences in clinical presentation. It concludes that the relative contribution of goal-directed and habit systems in psychiatric disorders is not evenly distributed. Similar dysfunction of these systems might cause different psychiatric disorders. This neurobiological finding might influence classification systems and research into potential treatments

Distinctive Personality Traits and Neural Correlates Associated with Stimulant Drug Use Versus Familial Risk of Stimulant Dependence

BackgroundStimulant drugs such as cocaine and amphetamine have a high abuse liability, but not everyone who uses them develops dependence. However, the risk for dependence is increased for individuals with a family history of addiction. We hypothesized that individuals without a family history of dependence who have been using cocaine recreationally for several years but have not made the transition to dependence will differ in terms of personality traits and brain structure from individuals who are either dependent on stimulants or at risk for dependence.MethodsWe compared 27 individuals without a familial risk of dependence who had been using cocaine recreationally with 50 adults with stimulant dependence, their nondependent siblings (n = 50), and unrelated healthy volunteers (n = 52) who had neither a personal nor a family history of dependence. All participants underwent a magnetic resonance imaging brain scan and completed a selection of personality measures that have been associated with substance abuse.ResultsIncreased sensation-seeking traits and abnormal orbitofrontal and parahippocampal volume were shared by individuals who were dependent on stimulant drugs or used cocaine recreationally. By contrast, increased levels of impulsive and compulsive personality traits and limbic-striatal enlargement were shared by stimulant-dependent individuals and their unaffected siblings.ConclusionsWe provide evidence for distinct neurobiological phenotypes that are either associated with familial vulnerability for dependence or with regular stimulant drug use. Our findings further suggest that some individuals with high sensation-seeking traits but no familial vulnerability for dependence are likely to use cocaine but may have relatively low risk for developing dependence

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

Brain networks underlying vulnerability and resilience to drug addiction.

Regular drug use can lead to addiction, but not everyone who takes drugs makes this transition. How exactly drugs of abuse interact with individual vulnerability is not fully understood, nor is it clear how individuals defy the risks associated with drugs or addiction vulnerability. We used resting-state functional MRI (fMRI) in 162 participants to characterize risk- and resilience-related changes in corticostriatal functional circuits in individuals exposed to stimulant drugs both with and without clinically diagnosed drug addiction, siblings of addicted individuals, and control volunteers. The likelihood of developing addiction, whether due to familial vulnerability or drug use, was associated with significant hypoconnectivity in orbitofrontal and ventromedial prefrontal cortical-striatal circuits-pathways critically implicated in goal-directed decision-making. By contrast, resilience against a diagnosis of substance use disorder was associated with hyperconnectivity in two networks involving 1) the lateral prefrontal cortex and medial caudate nucleus and 2) the supplementary motor area, superior medial frontal cortex, and putamen-brain circuits respectively implicated in top-down inhibitory control and the regulation of habits. These findings point toward a predisposing vulnerability in the causation of addiction, related to impaired goal-directed actions, as well as countervailing resilience systems implicated in behavioral regulation, and may inform novel strategies for therapeutic and preventative interventions.This research was funded by a Medical Research Council (MRC) grant (G0701497), financially supported by the NIHR Cambridge Biomedical Research Centre, and conducted within the Behavioural and Clinical Neuroscience Institute (BCNI). CM was supported by the Wellcome Trust grant to KDE (105602/Z/14/Z) and the NIHR Cambridge Biomedical Research Centre. JS was partly supported by the NIHR CLAHRC East of England and by the Charles University PRVOUK programme P38. TWR is a recipient of a Wellcome Trust Senior Investigator Award (104631/z/14/z). TWR discloses consultancy with Cambridge Cognition, Greenfield Bioventures and Unilever; he receives royalties for CANTAB from Cambridge Cognition, research grants from Shionogi and GlaxoSmithKline and editorial honoraria from Springer Verlag and Elsevier. ETB is a National Institute for Health Research Senior Investigator

Fronto-striatal circuits in response-inhibition: Relevance to addiction.

Disruptions to inhibitory control are believed to contribute to multiple aspects of drug abuse, from preexisting vulnerability in at-risk individuals, through escalation to dependence, to promotion of relapse in chronic users. Paradigms investigating the suppression of actions have been investigated in animal and human research on drug addiction. Rodent research has focused largely on impulsive behaviors, often gauged by premature responding, as a viable model highlighting the relevant role of dopamine and other neurotransmitters primarily in the striatum. Human research on action inhibition in stimulant dependence has highlighted impaired performance and largely prefrontal cortical abnormalities as part of a broader pattern of cognitive abnormalities. Animal and human research implicate inhibitory difficulties mediated by fronto-striatal circuitry both preceding and as a result of excessive stimulus use. In this regard, response-inhibition has proven a useful cognitive function to gauge the integrity of fronto-striatal systems and their role in contributing to impulsive and compulsive features of drug dependence.This is the final version. It was first published by Elsevier at http://dx.doi.org/10.1016/j.brainres.2014.09.01

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Compulsivity in obsessive-compulsive disorder and addictions.

Compulsive behaviors are driven by repetitive urges and typically involve the experience of limited voluntary control over these urges, a diminished ability to delay or inhibit these behaviors, and a tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is not only a central characteristic of obsessive-compulsive disorder (OCD) but is also crucial to addiction. Based on this analogy, OCD has been proposed to be part of the concept of behavioral addiction along with other non-drug-related disorders that share compulsivity, such as pathological gambling, skin-picking, trichotillomania and compulsive eating. In this review, we investigate the neurobiological overlap between compulsivity in substance-use disorders, OCD and behavioral addictions as a validation for the construct of compulsivity that could be adopted in the Research Domain Criteria (RDoC). The reviewed data suggest that compulsivity in OCD and addictions is related to impaired reward and punishment processing with attenuated dopamine release in the ventral striatum, negative reinforcement in limbic systems, cognitive and behavioral inflexibility with diminished serotonergic prefrontal control, and habitual responding with imbalances between ventral and dorsal frontostriatal recruitment. Frontostriatal abnormalities of compulsivity are promising targets for neuromodulation and other interventions for OCD and addictions. We conclude that compulsivity encompasses many of the RDoC constructs in a trans-diagnostic fashion with a common brain circuit dysfunction that can help identifying appropriate prevention and treatment targets.This work was supported in part by the NIH (P20 DA027844), the Connecticut State Department of Mental Health and Addictions Services, and the Yale Gambling Center of Research Excellence grant from the National Center for Responsible Gaming

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.This study was funded by the WT fellowship grant for VV (093705/Z/ 10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. YW is supported by the Fyssen Fondation and MRC Studentships. PD is supported by the Gatsby Charitable Foundation. JEG has received grants from the National Institute of Drug Abuse and the National Center for Responsible Gaming. TWR and BJS are supported on a WT Programme Grant (089589/Z/09/Z). The BCNI is supported by a WT and MRC grant.This is the final published version. It's also available from Molecular Psychiatry at http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201444a.html