Neuroimaging in drug addiction: an eye towards intervention purposes
Professor Rita Goldstein, Icahn School of Medicine at Mount Sinai, USA
Drug addiction is a chronically relapsing disorder characterised by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, Dr Goldstein will present results of human neuroimaging studies, utilising a multimodal approach (neuropsychology, functional magnetic resonance imaging, positron emission tomography, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, Dr Goldstein’s multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk Dr Goldstein will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behaviour compromises in treatment seeking cocaine addicted individuals. Promising novel fMRI studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging in the empirical guidance for the development of effective neurorehabilitation strategies in cocaine addiction.
Addictive behaviour in experimental animals: prospects for translation
Professor Barry Everitt FMedSci FRS, University of Cambridge, UK
Drug addiction is characterised by loss of control over drug seeking behaviour such that it becomes less goal-directed and more habitual, elicited by drug associated conditioned stimuli (CSs) and ultimately compulsive; it is difficult to relinquish drug seeking habits and there is a high propensity to relapse in abstinence. These complex behavioural processes have been successfully modelled in animals, especially rats, by exploiting the fact that they will self-adminster drugs that are addictive in humans. The group has developed behavioural procedures that have allowed them to model the interactions between pavlovian and instrumental learning and memory processes that underlie addictive behaviour. This has enabled the group to define the circuitry mediating that the transition from goal-directed to habitual drug seeking, as well as the neural basis of the impact of drug CSs on drug seeking and relapse, and also the mechanisms resulting in compulisve drug seeking, such as loss of prefrontal inhibitory control. These animal experimental data increasingly align with data from imaging studies in humans, especially the impact of drug CSs that elicit craving and relapse. Pharmacological and/or psychological treatments that diminish the impact of drug CSs on drug seeking and relapse and or decrease the compulsive behaviour would clearly have clinical utility. Pharmacological agents from several drug classes, including a µ-opioid receptor antagonist, can prevent cocaine, heroin and alcohol seeking and thereby promote abstinence. Serotonin re-uptake inhibitors or a selective µ-opioid receptor antagonist can decrease compulsive cocaine or alcohol seeking, respectively. Increasing top-down inhibtory control can also reduce compulsive drug seeking in both rats and humans. More recently, the group has shown that retrieving drug memories by presenting drug CSs results in their destabilisation in the brain and that undergo restablilisation, or ‘reconsolidation’, in order to persist. Preventing drug memory reconsolidation, for example by anatagonising NMDA or ß-adrenoceptors given at memory retrieval, can result in the long-term reduction or elimination of the ability of drug CSs to elicit drug seeking and relapse. The potential, as well as challenges, of translation to the clinic of these putative treatment approaches will be discussed.
Neurobiology of compulsive eating
Dr Pietro Cottone, Boston University, USA
Compulsive eating behaviour is a transdiagnostic construct that is characteristic of medical and psychiatric conditions such as forms of obesity and eating disorders. It has been hypothesised that one of the mechanisms underlying compulsive eating involves highly palatable food acquiring negative reinforcing properties; that is, the need to alleviate a negative emotional state induced by withdrawal from high palatable food drives overeating. The group observed that rats undergoing chronic, intermittent access to highly palatable food showed hypophagia and decreased motivation for a less palatable food alternative. Withdrawal from palatable food was associated with spontaneous emotional signs of palatable food-withdrawal, including anxiety- and depressive-like behaviour. In addition, cycling rats showed a weakened ability for contextual spatial processing during withdrawal. According to a negatively reinforced mechanism, renewing access to highly palatable food normalised all withdrawal-dependent maladaptive behavioural outcomes, and induced overeating. Palatable-food withdrawal was also found to be accompanied by increased corticotropin-releasing factor (CRF) expression in the central nucleus of the amygdala and administration of a selective CRF1 receptor antagonist directly into this brain area was able to block both the overeating of palatable food and the negative emotional state. Interestingly, diet cycled rats also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus, as well as a withdrawal-dependent decrease of proliferating cells. These results suggest that withdrawal from palatable food, analogous to abstinence from abused drugs, causes profound behavioural and molecular neuroadaptations which promote and sustain compulsive eating.
Deep Brain Stimulation in obsessive compulsive disorder: a decade of experience
Professor Damiaan Denys, University of Amsterdam, The Netherlands
OCD is considered one of the most disabling psychiatric disorders, causing serious impairment in patients’ daily functioning and affecting professional, social, and personal lives. Thanks to a wide range of available pharmacologic treatments and cognitive behavioural therapy (CBT), most patients can be treated to a satisfactory level. However, 10% of patients experience inadequate response and remain severely ill. In the last decades, neuromodulating techniques have emerged as promising alternatives for the treatment of OCD. Different from the rather aspecific pharmacologic modulation of drug therapy, neuromodulation techniques enable modulation of distinct neuronal circuits by targeting specific brain structures. OCD may be particularly suitable for these interventions because of its strong link to discrete neuro-anatomic networks. Neuroimaging studies have consistently related OCD to aberrant activity within the orbitofronto-striato-thalamo-cortical (CSTC) network. A major advantage of neuromodulation is its potential of adjustable and reversible brain network manipulation. This lecture reviews studies on DBS for OCD.
Dissecting OCD mechanisms using advanced technologies in mice
Dr Susanne Ahmari, University of Pittsburgh, USA
Ahmari and colleagues explore the neural mechanisms underlying perseverative thoughts and actions. This topic is of general importance because compulsive behaviours are a central component of Obsessive Compulsive Disorder (OCD), as well as prominent, disabling, and notoriously-treatment resistant symptoms of many severe psychiatric disorders, including autism, schizophrenia, and addiction. Although OCD symptoms have been broadly linked to abnormal activity in cortical-basal ganglia circuits via human imaging studies, there is still a quite limited understanding of how maladaptive repetitive behaviours are encoded in the brain. The Ahmari lab is therefore using novel technologic approaches and statistical strategies to determine: 1) which neural circuits underlie maladaptive repetitive behaviours, 2) how these behaviours are encoded in the brain, and 3) when the neural code changes as these behaviours develop and resolve.
In previous work the Ahmari lab demonstrated that repeated pulses of brief but abnormal activity delivered by optogenetic stimulation of projections from orbitofrontal cortex (OFC) to ventromedial striatum (VMS) leads to long-lasting perseverative grooming, a mouse behaviour linked to OCD. This compulsive grooming behaviour was associated with increased neural activity in the striatum. Dr Ahmari will discuss how her lab is now using advanced in vivo approaches including optogenetics, electrophysiology, and head-mounted microscopy to identify the specific activity patterns, cell-types, and circuits responsible for this pathologic plasticity in the brain. She will also describe approaches to ground basic neuroscience experiments in findings from clinical studies.