Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4

Behavioral strategies require gating of premature responses to optimize outcomes. Several brain areas control impulsive actions, but the neuronal basis of natural variation in impulsivity between individuals remain largely unknown. Here, by combining a Go/No-Go behavioral assay with resting state (rs) functional MRI in mice, we identified the subthalamic nucleus (STN), a known gate for motor control in the basal ganglia, as a major hot spot for trait impulsivity. In vivo recorded STN neural activity encoded impulsive action as a separable state from basic motor control, characterized by decoupled STN/Substantia nigra pars reticulata (SNr) mesoscale networks. Optogenetic modulation of STN activity bi-directionally controlled impulsive behavior. Pharmacological and genetic manipulations showed that these impulsive actions are modulated by metabotropic glutamate receptor 4 (mGlu4) function in STN and its coupling to SNr in a behavioral trait-dependent manner, and independently of general motor function. In conclusion, STN circuitry multiplexes motor control and trait impulsivity, which are molecularly dissociated by mGlu4. This provides a potential mechanism for the genetic modulation of impulsive behavior, a clinically relevant predictor for developing psychiatric disorders associated with impulsivity.

Distinct Effects of Executive Functioning, Impulsivity and Anxiety on Global and Local Reading Comprehension

Reading comprehension (RC) is a cognitive ability linked with higher-order cognitive functions referred to as executive functions (EFs) and is also associated with educational achievement. To date, there is little research exploring links between reading comprehension, EFs, and personality traits. This study attempts to fill this gap by elucidating the role of EFs, trait impulsivity, and trait anxiety in RC among university students. To achieve a more in-depth examination, RC is divided into its global and local subskills. Ninety university students (83% female) completed self-report questionnaires on EFs, impulsivity, and anxiety, a neuropsychological task for cognitive flexibility, and global/local RC assessments. Our results indicated distinct associations between poor general EFs and poor global RC, poor cognitive flexibility and poor local RC, and, finally, between high impulsivity and adequate global RC. Individual differences in global and local information processing strategies in the context of attentional processes and personal traits of the university students, is discussed.

The Role of Trait Impulsivity and Novelty-Seeking as Predisposing Factors to the Acquisition and Reinstatement of MDMA Self-Administration

<p>It has been suggested that the response to novelty and impulsivity predict the latency to acquisition and maintenance of drug self-administration, respectively. The aim of this thesis was to examine the relationship between these two traits and (1) the latency to acquisition and (2) maintenance (drug seeking) of 3,4-methylenedioxymethamphetamine (MDMA) self–administration. Impulsivity, measured as premature responding on the 5-choice serial reaction time task (5-CSRTT), and novelty seeking, measured as the locomotor response in a novel environment, were measured prior to self-administration. Due to characteristics of the rat strain and test equipment the 5-CSRTT was configurated in the first part of this study and modified from the standard version. Following training in this task animals were implanted with a siliastic catheter and were subsequently screened for their response to a novel environment prior to MDMA self-administration. Latency to acquisition was determined as the number of test sessions required to self-administer an initial criterion of 90 infusions of 1.0 mg/kg/infusion as well as an additional 150 infusions of 0.5 mg/kg/infusion MDMA. For some rats, the ability of MDMA (0, 5.0 or 10.0 mg/kg, IP) to produce drug seeking was subsequently measured and for others, impulsivity was again measured following self-administration. Novelty seeking predicted cocaine self-administration but was not significantly correlated with either the acquisition or drug-seeking measures of MDMA self-administration. Impulsivity was not significantly correlated with the latency to acquire self-administration of MDMA but was significantly and positively correlated with the magnitude of MDMA produced drug-seeking. Furthermore, MDMA self-administration produced a number of notable, but transient, deficits in the 5-CSRTT; there was an increase in omission rate and a delayed increase in premature responses in particular. These findings suggest that impulsivity, but not sensation seeking, might be a risk factor for the development of compulsive drug-seeking following withdrawal from MDMA self-administration. A surprising finding from this study was a high acquisition rate amongst rats that acquired the 5-CSRTT prior to self-administration. This difference was examined in a separate set of experiments. This effect could not be explained by an effect of handling, food restriction, or exposure to sweetened condensed milk and might possibly be due to differences in instrumental learning.</p>

The Role of Trait Impulsivity and Novelty-Seeking as Predisposing Factors to the Acquisition and Reinstatement of MDMA Self-Administration

<p>It has been suggested that the response to novelty and impulsivity predict the latency to acquisition and maintenance of drug self-administration, respectively. The aim of this thesis was to examine the relationship between these two traits and (1) the latency to acquisition and (2) maintenance (drug seeking) of 3,4-methylenedioxymethamphetamine (MDMA) self–administration. Impulsivity, measured as premature responding on the 5-choice serial reaction time task (5-CSRTT), and novelty seeking, measured as the locomotor response in a novel environment, were measured prior to self-administration. Due to characteristics of the rat strain and test equipment the 5-CSRTT was configurated in the first part of this study and modified from the standard version. Following training in this task animals were implanted with a siliastic catheter and were subsequently screened for their response to a novel environment prior to MDMA self-administration. Latency to acquisition was determined as the number of test sessions required to self-administer an initial criterion of 90 infusions of 1.0 mg/kg/infusion as well as an additional 150 infusions of 0.5 mg/kg/infusion MDMA. For some rats, the ability of MDMA (0, 5.0 or 10.0 mg/kg, IP) to produce drug seeking was subsequently measured and for others, impulsivity was again measured following self-administration. Novelty seeking predicted cocaine self-administration but was not significantly correlated with either the acquisition or drug-seeking measures of MDMA self-administration. Impulsivity was not significantly correlated with the latency to acquire self-administration of MDMA but was significantly and positively correlated with the magnitude of MDMA produced drug-seeking. Furthermore, MDMA self-administration produced a number of notable, but transient, deficits in the 5-CSRTT; there was an increase in omission rate and a delayed increase in premature responses in particular. These findings suggest that impulsivity, but not sensation seeking, might be a risk factor for the development of compulsive drug-seeking following withdrawal from MDMA self-administration. A surprising finding from this study was a high acquisition rate amongst rats that acquired the 5-CSRTT prior to self-administration. This difference was examined in a separate set of experiments. This effect could not be explained by an effect of handling, food restriction, or exposure to sweetened condensed milk and might possibly be due to differences in instrumental learning.</p>

Reward-Related Decision-Making in Current and Past Disordered Gambling: Implications for Impulsive Choice and Risk Preference in the Maintenance of Gambling Disorder

Impulsive reward-related decision-making (RRDM) is robustly associated with gambling disorder (GD), although its role in the development and perpetuation of GD is still being investigated. This project sought to examine the possible roles of impulsive and risky choice, two aspects of RRDM, in the perpetuation of GD. Additionally, the potential moderating role of comorbid substance misuse was considered. A total of 434 participants with symptoms of current GD and symptoms of concurrent substance use disorder (SUD; n = 105), current GD with past SUD (n = 98), past GD with current SUD (n = 53), or past GD with past substance use disorder (SUD; n = 92), and 96 healthy controls were recruited through MTurk. Participants completed a randomly adjusting delay discounting (a measure of impulsive choice) and probabilistic discounting (a measure of risky choice) task and self-report questionnaires of gambling participation, GD and SUD symptomology, and trait impulsivity. Although control participants showed significantly greater delay discounting compared to individuals with a current or history of GD, no significant group differences emerged between individuals with current GD or a history of GD. Individuals with current GD showed significantly less probabilistic discounting compared to individuals with a history of GD and control participants showed the greatest rates of probabilistic discounting. These effects remained after controlling for lifetime gambling symptom severity and trait impulsivity. Overall, these findings suggest a potential maintaining role of risky choice in gambling disorder, but do not support a maintaining role for impulsive choice.

Trait Impulsivity and Choice Impulsivity in Young Adults with Probable Binge Eating Disorder

Background Binge Eating Disorder (BED) as a public health problem has been included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Akin to addictive disorders, impulsivity-related neuropsychological constructs might be potentially involved in the onset and development of BED. However, it remains unclear which facets of impulsivity are connected to overeating and binge eating behaviors among non-clinical populations. The present study aimed to detect the relationship between impulsivity and BED both on the personality-trait and behavioral-choice levels in undiagnosed young adults. Methods Fifty-eight individuals with probable BED and 60 healthy controls, matched on age, gender, and educational level, were assessed by using a series of self-report measurements, including the Barratt Impulsiveness Scale (BIS-11), UPPSP Impulsive Behaviors Scale (UPPSP), Delay Discounting Test (DDT), and Probability Discounting Test (PDT). Results Multivariate analysis of variance models revealed that compared with healthy controls, the BED group showed elevated scores on the BIS-11 Attentional and Motor impulsiveness, and on the UPPSP Negative Urgency, Positive Urgency, and Lack of Perseverance. However, BED subjects had similar discounting rates on the DDT and PDT with healthy controls. Regression models found that Negative Urgency was the only positive predictor of BED. Conclusions These findings suggested that typical facets of trait impulsivity, which have been recognized in addictive disorders, were associated with BED in young adults, whereas choice impulsivity was not aberrantly seen in BED. This study might promote a better understanding of the pathogenesis of BED.

Neuroanatomical Correlates of Binge-Eating Behavior: At the Roots of Unstoppable Eating

Binge-eating refers to episodes of uncontrolled eating accompanied by a perceived loss of control, which can be common in the general population. Given the profound negative consequences of persistent binge-eating such as weight and eating disorders, it is vital to determine what makes someone more vulnerable than others to engage in such a conduct. A total of 42 normal-weight individuals (21 with binge-eating episodes and 21 without binge-eating episodes) underwent a structural magnetic resonance imaging measurement and Voxel-based morphometry (VBM) was used to assess between-group differences in terms of gray matter volume (GMV), together with self-report impulsivity and binge-eating measures. The results showed binge-eating individuals as characterized by higher trait impulsivity and greater regional GMV in the left middle frontal gyrus: however, the GMV in this region appeared to be positively correlated only with measures of binge-eating but not with trait impulsivity measures. These findings provide novel insights on the neurobiological roots of BE in normal-weight individuals and highlight how this behavior can be associated with brain morphometric changes within prefrontal regions also in a non-clinical population. Overall, this study provides a further characterization of the neural correlates of binge-eating and novel insights into the treatment of its more severe pathological forms.

Impulsivity and Its Relationship With Lisdexamfetamine Dimesylate Treatment in Binge Eating Disorder

High trait impulsivity is thought to contribute to the sense of loss of control over eating and impulses to binge eat experienced by those with binge eating disorder (BED). Lisdexamfetamine dimesylate (LDX), a drug approved for treatment of moderate to severe BED, has been shown to decrease impulsive features of BED. However, the relationship between LDX-related reductions of binge eating (BE) episodes and impulsivity has not yet been explored. Forty-one adults aged 18–40years with moderate to severe BED completed questionnaires and tasks assessing impulsivity at baseline and after 8weeks of 50–70mg of LDX. Twenty age-matched healthy controls were also assessed at two timepoints for normative comparison. Data were analysed using linear mixed models. BED participants exhibited increased self-reported motor, non-planning, cognitive and food-related impulsivity relative to controls but no differences in objective task-based measures of impulsivity. Food-related and non-planning impulsivity was significantly reduced by LDX, but not to normative levels. Individuals with higher baseline levels of motor and non-planning impulsivity, and loss of control over eating scores experienced the greatest reduction in BE frequency after 8weeks of LDX. Further, there were significant associations between the degree to which subjective loss of control over eating, non-planning impulsivity and BE frequency reduced after 8weeks of LDX. These data suggest that specific subjective measures of impulsivity may be able to predict who will have the greatest benefit from LDX treatment and that reductions in BE frequency may be moderated by concurrent reductions in non-planning impulsivity.

Toxoplasma gondii, Suicidal Behavior, and Intermediate Phenotypes for Suicidal Behavior

Within the general literature on infections and suicidal behavior, studies on Toxoplasma gondii (T. gondii) occupy a central position. This is related to the parasite's neurotropism, high prevalence of chronic infection, as well as specific and non-specific behavioral alterations in rodents that lead to increased risk taking, which are recapitulated in humans by T. gondii's associations with suicidal behavior, as well as trait impulsivity and aggression, mental illness and traffic accidents. This paper is a detailed review of the associations between T. gondii serology and suicidal behavior, a field of study that started 15 years ago with our publication of associations between T. gondii IgG serology and suicidal behavior in persons with mood disorders. This “legacy” article presents, chronologically, our primary studies in individuals with mood disorders and schizophrenia in Germany, recent attempters in Sweden, and in a large cohort of mothers in Denmark. Then, it reviews findings from all three meta-analyses published to date, confirming our reported associations and overall consistent in effect size [ranging between 39 and 57% elevation of odds of suicide attempt in T. gondii immunoglobulin (IgG) positives]. Finally, the article introduces certain links between T. gondii and biomarkers previously associated with suicidal behavior (kynurenines, phenylalanine/tyrosine), intermediate phenotypes of suicidal behavior (impulsivity, aggression) and state-dependent suicide risk factors (hopelessness/dysphoria, sleep impairment). In sum, an abundance of evidence supports a positive link between suicide attempts (but not suicidal ideation) and T. gondii IgG (but not IgM) seropositivity and serointensity. Trait impulsivity and aggression, endophenotypes of suicidal behavior have also been positively associated with T. gondii seropositivity in both the psychiatrically healthy as well as in patients with Intermittent Explosive Disorder. Yet, causality has not been demonstrated. Thus, randomized interventional studies are necessary to advance causal inferences and, if causality is confirmed, to provide hope that an etiological treatment for a distinct subgroup of individuals at an increased risk for suicide could emerge.