F.G. Moeller

Reduced Anterior Corpus Callosum White Matter Integrity is Related to Increased Impulsivity and Reduced Discriminability in Cocaine-Dependent Subjects: Diffusion Tensor Imaging

Brain imaging studies find evidence of prefrontal cortical dysfunction in cocaine-dependent subjects. Similarly, cocaine-dependent subjects have problems with behaviors related to executive function and impulsivity. Since prefrontal cortical axonal tracts cross between hemispheres in the corpus callosum, it is possible that white matter integrity in the corpus callosum could also be diminished in cocaine-dependent subjects. The purpose of this study was to compare corpus callosum white matter integrity as measured by the fractional anisotropy (FA) on diffusion tensor imaging (DTI) between 18 cocaine-dependent subjects and 18 healthy controls. The Barratt Impulsiveness Scale (BIS-11) and a continuous performance test: the Immediate and Delayed Memory Task (IMT/DMT) were also collected. Results of the DTI showed significantly reduced FA in the genu and rostral body of the anterior corpus callosum in cocaine-dependent subjects compared to controls. Cocaine-dependent subjects also had significantly higher BIS-11 scores, greater impulsive (commission) errors, and reduced ability to discriminate target from catch stimuli (discriminability) on the IMT/DMT. Within cocaine dependent subjects there was a significant negative correlation between FA in the anterior corpus callosum and behavioral laboratory measured impulsivity, and there was a positive correlation between FA and discriminability. The finding that reduced integrity of anterior corpus callosum white matter in cocaine users is related to impaired impulse control and reduced ability to discriminate between target and catch stimuli is consistent with prior theories regarding frontal cortical involvement in impaired inhibitory control in cocaine-dependent subjects.

Tryptophan depletion and aggressive responding in healthy males

In order to study the effect of decreasing plasma tryptophan levels on aggressive responding in a controlled laboratory setting, we administered two doses (25 g and 100 g) of a tryptophan-free amino acid mixture to ten healthy male subjects after 24 h of a low tryptophan diet. Subjects were screened for current or past psychiatric, or non-psychiatric medical illness. Aggressive responding on a free-operant laboratory measure of aggression (the Point Subtraction Aggression Paradigm) and plasma tryptophan levels were measured before and after drinking the amino acid mixture. There was a significant increase in aggressive responding 5 h after the 100 g mixture and a significant increase in aggressive responding 6 h after the 25 g mixture compared to a baseline day when no drink was administered. There was also a significant decrease in plasma tryptophan at 5 hours after ingestion compared to baseline for both doses of amino acid mixture. This study supports the hypothesis that tryptophan depletion increases aggressive responding in healthy males in a laboratory setting; probably by decreasing brain serotonin.

The effects of tryptophan depletion and loading on laboratory aggression in men: time course and a food-restricted control.

Abstract Some studies have shown that sharp reduction of L-tryptophan (Trp) concentration in plasma results in increases in laboratory-measured aggression. Conversely, raising plasma Trp has blunted aggression. These effects are presumably due to impaired or enhanced serotonin synthesis and neurotransmission in the brain. In this study, the laboratory-measured aggressive behavior of eight men under both Trp depletion (T-) and Trp loading (T+) conditions was compared to their aggressive behavior under food-restricted control conditions (overnight fast without an amino acid beverage). Subjects were provoked by periodic subtraction of money which was attributed to a fictitious other participant, and aggression was defined as the number of retaliatory responses the subject made ostensibly to reduce the earnings of the (fictitious) other participant. Following ingestion of the T- beverage, aggressive responding was significantly elevated relative to the food-restricted control condition, and this increased aggressive behavior became more pronounced across behavioral testing sessions on a time-course which paralleled previously documented decreases in plasma Trp concentrations. In contrast, no changes were observed in aggressive responding under T+ conditions relative to food-restricted conditions. These within-subject behavioral changes under depleted plasma Trp conditions support earlier indications of a role of serotonin in regulating aggression.

Diffusion tensor imaging and decision making in cocaine dependence.

Background Chronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes. Methodology/Principal Findings In 15 cocaine-dependent and 18 control subjects, we examined relationships between decision-making performance on the Iowa Gambling Task (IGT) and white matter integrity as measured by diffusion tensor imaging (DTI). Whole brain voxelwise analyses showed that, relative to controls, the cocaine group had lower fractional anisotropy (FA) and higher mean of the second and third eigenvalues (λ⊥) in frontal and parietal white matter regions and the corpus callosum. Cocaine subjects showed worse performance on the IGT, notably over the last 40 trials. Importantly, FA and λ⊥ values in these regions showed a significant relationship with IGT performance on the last 40 trials. Conclusions Compromised white matter integrity in cocaine dependence may be related to functional impairments in decision making.

The Influence of Menstrual-Cycle Phase on the Relationship Between Testosterone and Aggression

Plasma testosterone levels and aggressive behavior were measured in 12 women with and without perimenstrual affective symptomatology (e.g., depression, irritability) during the menstrual, midfollicular, ovulatory, and premenstrual phases of the menstrual cycle. The Point Subtraction Aggression Paradigm was used to quantify aggressive response to provocation. Subjects had two response options: a point-maintained option (100 presses earned a point worth 10 cents) and an aggressive response option (10 presses ostensibly subtracted a point from a fictitious partners counter). Subjects were provoked by the periodic subtraction of a point that was attributed to the responding of a fictitious opponent. Although plasma testosterone levels (determined by radioimmunoassay) increased significantly during the ovulatory phase, aggressive response to provocation remained unchanged across the menstrual cycle. Plasma testosterone did not differ between the 2 groups during any phase. A relationship between plasma testosterone levels and use of the aggressive response option was seen only during the midfollicular phase (Spearman r = .673, p = .017). These preliminary data suggest that: 1. The relationship in female subjects between endogenous testosterone and aggressive behavior is inconsistent; 2. self-report of perimenstrual symptomatology is a more consistent predictor of aggressive behavior across the menstrual cycle than plasma testosterone; and 3. perimenstrual emotional symptomatology is not related to testosterone levels.

Plasma L-Tryptophan Depletion and Aggression

There is a well-established relationship between aggression and lowered serotonin neuro-transmission. Recently developed methodologies for manipulating L-tryptophan levels (and brain serotonin) have been applied to human laboratory studies of aggression. Collectively, these studies provide further evidence for the serotonin-aggression relationship. Two important findings have been made recently: (1) subsets of individuals (e.g., persons self-rating high on aggressive or hostility scales) may differ in their susceptibility to aggression produced through plasma tryptophan depletion; and (2) alcohol in combination with L-tryptophan depletion has an additive effect on aggression. All previous studies have been conducted with men. Extending these studies to women appears to be the much-needed next step given that serotonergic levels appear to vary both as a function of the menstrual cycle phase and menstrual symptomatology.

Interactions between bipolar disorder and antisocial personality disorder in trait impulsivity and severity of illness

Swann AC, Lijffijt M, Lane SD, Steinberg JL, Moeller FG. Interactions between bipolar disorder and antisocial personality disorder in trait impulsivity and severity of illness.

Serotonin (5-hydroxytryptamine) 5-HT2A receptor: Association with inherent and cocaine-evoked behavioral disinhibition in rats

Alterations in the balance of functional activity within the serotonin [5-hydroxytryptamine (5-HT)] system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently show greater impulsivity relative to nondrug using control subjects. Preclinical studies suggest that the 5-HT2A receptor (5-HT2AR) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine. We hypothesized that the selective 5-HT2AR antagonist M100907 would reduce inherent levels of impulsivity and attenuate impulsive responding induced by cocaine in two animal models of impulsivity, the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. M100907 reduced rates of responding in the DRL task and premature responding in the 1-CSRT task. Conversely, cocaine disrupted rates of responding in the DRL task and increased premature responding in the 1-CSRT task. M100907 attenuated cocaine-induced increases in specific markers of behavioral disinhibition in the DRL and 1-CSRT tasks. These results suggest that the 5-HT2AR regulates inherent impulsivity, and that blockade of the 5-HT2AR alleviates specific aspects of elevated levels of impulsivity induced by cocaine exposure. These data point to the 5-HT2AR as an important regulatory substrate in impulse control.

Impulsivity and BOLD fMRI activation in MDMA users and healthy control subjects

The correlation between scores on the Barratt Impulsiveness Scale (BIS) and activation measured by functional magnetic resonance imaging in a dorsolateral prefrontal cortical (DLPFC) activating task was examined in 15 MDMA-using subjects and 19 controls. A significant correlation between BIS scores and DLPFC activation was found, supporting a role for the DLPFC in BIS-measured impulsivity.

Risk Factors for Clozapine Discontinuation Among 805 Patients in the VA Hospital System

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.