Impulsivity in disorders of food and drug misuse.

BACKGROUND: Evidence suggests some overlap between the pathological use of food and drugs, yet how impulsivity compares across these different clinical disorders remains unclear. Substance use disorders are commonly characterized by elevated impulsivity, and impulsivity subtypes may show commonalities and differences in various conditions. We hypothesized that obese subjects with binge-eating disorder (BED) and abstinent alcohol-dependent cohorts would have relatively more impulsive profiles compared to obese subjects without BED. We also predicted decision impulsivity impairment in obesity with and without BED. METHOD: Thirty obese subjects with BED, 30 without BED and 30 abstinent alcohol-dependent subjects and age- and gender-matched controls were tested on delay discounting (preference for a smaller immediate reward over a larger delayed reward), reflection impulsivity (rapid decision making prior to evidence accumulation) and motor response inhibition (action cancellation of a prepotent response). RESULTS: All three groups had greater delay discounting relative to healthy volunteers. Both obese subjects without BED and alcohol-dependent subjects had impaired motor response inhibition. Only obese subjects without BED had impaired integration of available information to optimize outcomes over later trials with a cost condition. CONCLUSIONS: Delay discounting appears to be a common core impairment across disorders of food and drug intake. Unexpectedly, obese subjects without BED showed greater impulsivity than obese subjects with BED. We highlight the dissociability and heterogeneity of impulsivity subtypes and add to the understanding of neurocognitive profiles across disorders involving food and drugs. Our results have therapeutic implications suggesting that disorder-specific patterns of impulsivity could be targeted.V.V. is a Wellcome Trust Intermediate Fellow in Clinical Neurosciences (Wellcome Trust grant no. WT093705MA). Y.W. is supported by the Fyssen Fondation. N.A.H. is a Wellcome Trust Intermediate Fellow in Clinical Neurosciences. The BCNI is supported by both the Wellcome Trust and Medical Research Council.This is the accepted manuscript. The final version is available from CUP at http://dx.doi.org/10.1017/S003329171400183

Behavioral and Neural Mechanisms of Serotonin Modulation of Impulsivity and Reward

Despite its prevalence in many psychiatric disorders, such as attention deficit hyperactivity disorder, suicidal depression, schizophrenia, and aggression and motivational disorders, impulsivity and its biological bases remain poorly understood. Subdivisions of impulsivity, including impulsive action (reduced response inhibition) and impulsive choice (reduced delay of gratification), sometimes present in an uncorrelated manner. This complexity renders pathological impulsivity difficult to treat, as different underlying causes likely result in different phenotypic presentations, despite being placed under one umbrella term. In order to study the behavior and biology of one particular facet of impulsivity, this dissertation utilizes the serotonin 1B receptor (5-HT1BR; an inhibitory G-protein coupled receptor) knockout mouse model, which presents with a specific elevation in impulsive action but not impulsive choice. In Chapter 1, I show that mice lacking the 5-HT1BR have increased impulsive action accompanied by enhanced motivation and responsiveness to palatable rewards, indicating that they may have dysregulation of subjective reward valuation. In Chapter 2, I then explore the 5- HT1BR knockout model from the perspective of behavioral inhibition, demonstrating that knockout mice have intact inhibitory learning despite having difficulty withhold responding for reward. Of particular interest to this particular presentation of impulsive action, therefore, is serotonin neuromodulation of reward circuitry in the brain. In Chapter 3, I first show behaviorally that normalizing reward value in 5-HT1BR knockout mice reduces impulsive action to the level of controls. Neurally, I then complete a series of experiments with targeted knockouts in reward-related brain regions, specifically projections to and from the nucleus accumbens shell, in addition to combined 5-HT1BR genetic heteroreceptor and viral autoreceptor knockout. Only combined Emx1+ heteroreceptor and autoreceptor knockout results in increased motivation and impulsivity similar to the whole brain knockout. On the other hand, combined VGAT+ heteroreceptor and autoreceptor knockout increases hedonic taste reactvity. This suggests that modified serotonin release in addition to multiple 5-HT1B heteroreceptor population losses synergistically modulate neural signaling to increase reward valuation and impulsive action. Together, these studies provide insight into the behavioral and biological bases of impulsive action and propose a framework for better understanding specific presentations of impulsivity

Decreased olfactory discrimination is associated with impulsivity in healthy volunteers

In clinical populations, olfactory abilities parallel executive function, implicating shared neuroanatomical substrates within the ventral prefrontal cortex. In healthy individuals, the relationship between olfaction and personality traits or certain cognitive and behavioural characteristics remains unexplored. We therefore tested if olfactory function is associated with trait and behavioural impulsivity in nonclinical individuals. Eighty-three healthy volunteers (50 females) underwent quantitative assessment of olfactory function (odour detection threshold, discrimination, and identifcation). Each participant was rated for trait impulsivity index using the Barratt Impulsiveness Scale and performed a battery of tasks to assess behavioural impulsivity (Stop Signal Task, SST; Information Sampling Task, IST; Delay Discounting). Lower odour discrimination predicted high ratings in non-planning impulsivity (Barratt Non-Planning impulsivity subscale); both, lower odour discrimination and detection threshold predicted low inhibitory control (SST; increased motor impulsivity). These fndings extend clinical observations to support the hypothesis that defcits in olfactory ability are linked to impulsive tendencies within the healthy population. In particular, the relationship between olfactory abilities and behavioural inhibitory control (in the SST) reinforces evidence for functional overlap between neural networks involved in both processes. These fndings may usefully inform the stratifcation of people at risk of impulse-control-related problems and support planning early clinical interventions

Binge drinking is associated with attenuated frontal and parietal activation during successful response inhibition in fearful context

Binge drinking is associated with increased impulsivity and altered emotional processing. The current study investigated, in a group of university students who differed in their level of binge drinking, whether the ability to inhibit a pre-potent response and to delay gratification is disrupted in the presence of emotional context. We further tested whether functional connectivity within intrinsic resting-state networks was associated with alcohol use. Higher incidence of binge drinking was associated with enhanced activation of the lateral occipital cortex, angular gyrus, the left frontal pole during successful response inhibition irrespective of emotional context. This observation suggests a compensatory mechanism. However, higher binge drinking attenuated frontal and parietal activation during successful response inhibition within a fearful context, indicating the selective emotional facilitation of inhibitory control. Similarly, higher binge drinking was associated with attenuated frontopolar activation when choosing a delayed reward over an immediate reward within the fearful, relative to the neutral, context. Resting-state functional data analysis revealed that binge drinking decreased coupling between right supramarginal gyrus and Ventral Attention Network, indicating alcohol-associated disruption of functional connectivity within brain substrates directing attention. Together, our results suggest that binge drinking makes response inhibition more effortful, yet emotional (more arousing) contexts may mitigate this; disrupted functional connectivity between regions underlying adaptive attentional control, is a likely mechanism underlying these response inhibition effects associated with binge drinking

Unidirectional relationship between heroin self-administration and impulsive decision-making in rats

Rationale: There is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown. Objective: We studied the relationship between impulsive choice and vulnerability to heroin taking and seeking. Materials and methods: Rats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly. Results and discussion: High impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking. Conclusion: These data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait. © 2011 The Author(s)

Impulsivity and body fat accumulation are linked to cortical and subcortical brain volumes among adolescents and adults

Obesity is associated not only with metabolic and physical health conditions, but with individual variations in cognition and brain health. This study examined the association between body fat (an index of excess weight severity), impulsivity (a vulnerability factor for obesity), and brain structure among adolescents and adults across the body mass index (BMI) spectrum. We used 3D T1 weighted anatomic magnetic resonance imaging scans to map the association between body fat and volumes in regions associated with obesity and impulsivity. Participants were 127 individuals (BMI: 18–40 kg/m2; M = 25.69 ± 5.15), aged 14 to 45 years (M = 24.79 ± 9.60; female = 64). Body fat was measured with bioelectric impendence technology, while impulsivity was measured with the UPPS-P Impulsive Behaviour Scale. Results showed that higher body fat was associated with larger cerebellar white matter, medial orbitofrontal cortex (OFC), and nucleus accumbens volume, although the latter finding was specific to adolescents. The relationship between body fat and medial OFC volume was moderated by impulsivity. Elevated impulsivity was also associated with smaller amygdala and larger frontal pole volumes. Our findings link vulnerability and severity markers of obesity with neuroanatomical measures of frontal, limbic and cerebellar structures, and unravel specific links between body fat and striatal volume in adolescence

Investigation of neuronal structures and networks on the modulation of decision-making and impulse control by temporary inactivation via local microinfusion of the GABAA receptor agonist muscimol in rats

Impulsivity is determined by deficits in decision-making (impulsive choice) and impulse control (impulsive action). Using reversible inactivation via microinfusion of the GABAA receptor agonist muscimol the thesis aimed to elucidate the participation of the ventral medial prefrontal cortex (vmPFC), the nucleus accumbens (NAc) core and shell as well as the connections of the vmPFC and the NAc subregions in both forms of impulsivity in rats. The present results indicate that impulse control is regulated by both structures, while impulsive decision-making is principally modulated by the NAc, and not the vmPFC. The current investigation suggests both functional dissociations and close interactions between the vmPFC and NAc in terms of impulsive action, depending on the involved accumbal subregion. The NAc shell constitutes the critical region mediating both types of impulsivity, whereas the NAc core seems to be implicated in non-specific impairments beyond impulsive choice. Consequently, this work points towards various specific frontostriatal systems differentially contributing to delay-based decision-making and particularly impulse control

Comparison of neural substrates of temporal discounting between youth with Autism Spectrum Disorder and with Obsessive-Compulsive Disorder

Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share abnormalities in hot executive functions such as reward-based decision-making, as measured in the temporal discounting task (TD). No studies, however, have directly compared these disorders to investigate common/distinct neural profiles underlying such abnormalities. We wanted to test whether reward-based decision-making is a shared transdiagnostic feature of both disorders with similar neurofunctional substrates or whether it is a shared phenotype with disorder-differential neurofunctional underpinnings. Age and IQ-matched boys with ASD (N = 20), with OCD (N = 20) and 20 healthy controls, performed an individually-adjusted functional magnetic resonance imaging (fMRI) TD task. Brain activation and performance were compared between groups. Boys with ASD showed greater choice-impulsivity than OCD and control boys. Whole-brain between-group comparison revealed shared reductions in ASD and OCD relative to control boys for delayed-immediate choices in right ventromedial/lateral orbitofrontal cortex extending into medial/inferior prefrontal cortex, and in cerebellum, posterior cingulate and precuneus. For immediate-delayed choices, patients relative to controls showed reduced activation in anterior cingulate/ventromedial prefrontal cortex reaching into left caudate, which, at a trend level, was more decreased in ASD than OCD patients, and in bilateral temporal and inferior parietal regions. This first fMRI comparison between youth with ASD and with OCD, using a reward-based decision-making task, shows predominantly shared neurofunctional abnormalities during TD in key ventromedial, orbital- and inferior fronto-striatal, temporo-parietal and cerebellar regions of temporal foresight and reward processing, suggesting trans-diagnostic neurofunctional deficits

5-HT2A Receptors Modulate Dopamine D2-mediated Maternal Effects

Serotonin 5-HT2A receptors are expressed throughout the mesolimbic and mesocortical dopamine pathways, and manipulation of this receptor system has a profound impact on dopamine functions and dopamine-mediated behaviors. It is highly likely that 5-HT2A receptors may also modulate the D2-mediated maternal effects. The present study investigated this issue and also explored the possible behavioral mechanisms. We tested the effects of two D2 drugs (an agonist quinpirole: 0.5, 1.0 mg/kg, and a potent D2 antagonist haloperidol: 0.05, 0.10 mg/kg, sc) and their combinations with two 5-HT2A drugs (a selective 5-HT2A agonist TCB-2: 2.5 mg/kg, and 5-HT2A antagonist MDL100907, 1.0 mg/kg, sc) on maternal behavior in Sprague-Dawley postpartum females. Individually, TCB-2 (2.5 mg/kg, sc) and quinpirole (0.5 and 1.0 mg/kg, sc) reduced pup preference and disrupted home-cage maternal behavior. In contrast, haloperidol (0.10 mg/kg, sc) only disrupted home-cage maternal behavior, but did not suppress pup preference. MDL100907 (1.0 mg/kg, sc) by itself had no effect on either pup preference or maternal behavior. When administered in combination, pretreatment of TCB-2 did not alter quinpirole’s disruption of pup preference and home-cage maternal behavior (possibly due to the floor effect), however, it did enhance haloperidol’s disruption of pup retrieval in the home cage. MDL100907 had no effect both quinpirole’s and haloperidol’s disruption of pup preference and home-cage maternal behavior. Interestingly, haloperidol attenuated TCB-2’s disruptive effect on pup preference. These findings suggest that activation of 5-HT2A receptors tends to enhance D2-mediated maternal disruption, whereas blockade of 5-HT2A receptors is less effective. They also suggest that 5-HT2A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors. The possible behavioral and neural mechanisms by which 5-HT2A-and D2-mediated maternal effects and their interaction are discussed