CSF 5-HIAA and aggression in female macaque monkeys: species and interindividual differences

Rationale: While the relationship among CSF 5-HIAA, impulsivity, and aggression is well characterized in males, its investigation in females is limited, and no studies have assessed its generalizability across primates by making simultaneous comparisons between and within closely-related species. Objectives: We tested three hypotheses. First, that female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques. Second, that females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression. Third, that subjects with high CSF 5-HIAA concentrations would be higher in social dominance within their respective groups than would subjects with low CSF 5-HIAA concentrations. Methods: We obtained CSF samples from 61 individually housed female primates of two closely related species: rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). We later placed subjects in unisex social groups, and correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and acquisition of social dominance rank. Results: Between-species analyses indicated higher CSF 5-HIAA concentrations in pigtailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. Conclusions: These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity, as species that show relatively high rates of severe aggression also tend to have low concentrations of CSF 5-HIAA. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning. Received: 30 December 1998 / Final version: 3 June 1999     

Using a clinically aggressive sample to examine the association between impulsivity, executive functioning, and verbal learning and memory

Impulsive behavior has been conceptualized from several vantage points including biological, sociological and psychological phenomenon. A comprehensive review of the empirical literature revealed that there is a paucity of research examining the association between working memory, executive functioning and impulsivity. A total sample of 170 aggressive outpatient participants was recruited for the study. Participants were administered a comprehensive neuropsychological battery. Principal components analysis of the 19 CVLT indices revealed five factors, accounting for 68% of the total variance. Results from the canonical correlation revealed one significant canonical variate with loadings from three CVLT factors (General Verbal Learning, Response Discrimination, and Proactive Interference), two executive functioning measures (Trail Making Test and Controlled Oral Word Association Test), and one impulsivity subscale (Attentional Impulsiveness). The findings of this study underscore the importance of memory functioning in determining impulsive aggressive behavior.     

Exposure to Family Violence and Temperament Factors as Predictors of Adult Psychopathology and Substance Use Outcomes

This study examines the potential for a negative psychological impact as a result of childhood exposure to family violence. Psychopathological outcomes in adulthood, such as alcohol problems and depression, are examined in light of reports of childhood physical abuse and exposure to parental violence. A national household probability sample of over 3,000 respondents were asked whether they had, as children, observed violence or threats of violence between their parents or whether they had directly experienced violence from one or both parents. Observed threats of violence was the most potent predictor of depression and current heavy drinking in women. Among men, observed threats of violence predicted current heavy drinking, and alcohol dependence symptoms; personal experience of violence predicted depression. Impulsivity was a main effect predictor of virtually all outcome variables for men and women, but typically did not interact with experience or observation of violence. Findings suggest that individuals who remember childhood experiences of indirect violence from parental conflicts have higher rates of pathological adult outcomes. Impulsivity and sensation seeking are highly related to these outcomes over and above violence history. Family conflict variables and temperament variables are highly correlated with one another but make independent contributions.     

P50, N100, and P200 sensory gating: Relationships with behavioral inhibition, attention, and working memory

P50, N100, and P200 auditory sensory gating could reflect mechanisms involved in protecting higher-order cognitive functions, suggesting relationships between sensory gating and cognition. This hypothesis was tested in 56 healthy adults who were administered the paired-click paradigm and two adaptations of the continuous performance test (Immediate/Delayed Memory Task, IMT/DMT). Stronger P50 gating correlated with fewer commission errors and prolonged reaction times on the DMT. Stronger N100 and P200 gating correlated with better discriminability on the DMT. Finally, prolonged P200 latency related to better discriminability on the IMT. These findings suggest that P50, N100, and P200 gating could be involved in protecting cognition by affecting response bias, behavioral inhibition, working memory, or attention.     

Cerebrospinal fluid GABA concentration: relationship with impulsivity and history of suicidal behavior, but not aggression, in human subjects

The objective of this study was to assess the relationship between cerebrospinal fluid concentrations of the neurotransmitter gamma-aminobutyric acid (GABA) and measures of impulsivity and related behaviors (aggression and suicidality) in healthy volunteer and personality disordered subjects. CSF GABA levels, and measures of impulsivity, aggression, and history of suicidal behavior were obtained by morning lumbar puncture in 57 healthy volunteer subjects and in subjects with personality disorder. CSF GABA levels were not found to correlate with measures of aggression but were found to correlate directly with measures of impulsivity; e.g., a composite measure of impulsivity in all subjects (r = 0.35, df = 46, P = 0.015) and in personality disordered subjects examined separately (r = 0.39, df = 30, P = 0.029). In the personality disorder group, CSF GABA levels were higher among subjects with a history of suicidal behavior compared with those without this history. These data suggest that central GABAergic function correlates directly with impulsiveness and history of suicidal behavior, but not aggressiveness, in personality disordered subjects. This may be consistent with observations that high doses of benzodiazepines can lead to “behavioral disinhibition” in human subjects. Further work assessing this and other aspects of the central GABA system in personality disordered subjects are warranted.     

Inducing impulsivity leads high and low restrained eaters into overeating, whereas current dieters stick to their diet

Previous research has related impulsivity to overeating and obesity. However, the precise nature of this relation has not been examined yet. One possibility is that impulsivity causes overeating and hence contributes to overweight. To test this possibility we induced impulsivity versus inhibition to see whether this would affect food intake. In the first study participants were cognitively primed with the concepts “impulsivity” or “inhibition”. Caloric intake was significantly higher in the Impulsivity Condition compared to the Inhibition Condition. This effect was even stronger for highly restrained participants. In the second study impulsivity was manipulated via behavioural instructions. Restrained and unrestrained nondieters acted as expected: their caloric intake was significantly higher when impulsivity was induced compared to inhibition. Current dieters sharply reduced their caloric intake following the impulsivity induction. These results are in accordance with Lowe's model that, contrary to restraint theory, states that restraint and current dieting are different constructs that affect eating regulation differently. At least for nondieters it can be concluded that heightened impulsivity versus inhibition leads to a higher food intake in the lab.     

Are all drug addicts impulsive? Effects of antisociality and extent of multidrug use on cognitive and motor impulsivity

The purpose of this investigation was to examine the influence of antisociality and extent of multidrug use on cognitive and motor impulsivity among substance-dependent individuals (SDIs) that used primarily cocaine and/or heroin. One hundred currently abstinent male SDIs participated in the study. Extent of multidrug use and degree of antisociality, assessed with the Socialization Scale of the California Psychological Inventory (So-CPI), were used to classify participants into one of four groups: high antisocial/low multidrug use, high antisocial/high multidrug use, low antisocial/low multidrug use, and low antisocial/high multidrug use. All subjects completed the Iowa Gambling Task to assess cognitive impulsivity and the Stroop Task to measure motor impulsivity. Contrary to expectations, antisociality was associated with more advantageous performance on the Iowa Gambling Task, independent of extent of multidrug use. In contrast, greater multidrug use was associated with general psychomotor slowing on the Stroop Task. Results suggest that a subclinical form of antisociality may have a paradoxically facilitating effect on decision-making and cognitive impulsivity among SDIs.     

Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test

Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. The 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. The selective norepinepherine reuptake inhibitor, atomoxetine, represents the first non-stimulant based drug approved for Attention Deficit Hyperactivity Disorder (ADHD) and has replaced methylphenidate (Ritalin) as the first line in pharmacotherapy for the treatment of ADHD. Methylphenidate and atomoxetine have different cortical and sub-cortical neurochemical signatures that could predict differences in cognitive and non-cognitive functions. The present experiments investigated the effects of acute methylphenidate and atomoxetine in male long Evans rats in the 5-choice serial reaction time (5CSRT) test that is hypothesized to serve as a model of vigilance and impulsivity behaviors associated with ADHD. Long Evans rats were trained to perform at 75% correct responses with fewer than 20% missed trials in the 5CSRT test (500 ms stimulus duration, 5 s inter-trial interval (ITI)). By varying the ITI (10, 7, 5, and 4 s) on drug test days, impulsivity (as defined by premature responses) was dramatically increased with a concomitant decrease in attention (percent correct). Subsequently, animals were treated with methylphenidate (2.5 and 5 mg/kg, i.p.) or atomoxetine (0.1, 0.5 and 1 mg/kg, i.p.) using this design. In Experiment 1, treatment with methylphenidate modestly improved overall attention but the highest dose of methylphenidate (5.0 mg/kg) significantly increased impulsivity. In contrast, treatment with atomoxetine induced a marked decrease in impulsivity whilst modestly improving overall attention. Interestingly, no effect was observed on measures of performance (e.g. motivation/sedation) with atomoxetine, whilst moderate hyperactivity (faster overall response latencies; magazine, correct, incorrect) was observed in the methylphenidate group. Those data suggest that the 5CSRT test can be used to differentiate stimulant and non-stimulant pharmacotherapies on measures of impulsivity.     

Combined effects of age and BMI are related to altered cortical thickness in adolescence and adulthood

Overweight and obesity are associated with functional and structural alterations in the brain, but how these associations change across critical developmental periods remains unknown. Here, we examined the relationship between age, body mass index (BMI) and cortical thickness (CT) in healthy adolescents (n = 70; 14–19 y) and adults (n = 75; 25–45 y). We also examined the relationship between adiposity, impulsivity, measured by delay discounting (DD), and CT of the inferior frontal gyrus (IFG), a region key to impulse control. A significant age-by-BMI interaction was observed in both adolescents and adults; however, the direction of this relationship differed between age groups. In adolescents, increased age-adjusted BMI Z-score attenuated age-related CT reductions globally and in frontal, temporal and occipital regions. In adults, increased BMI augmented age-related CT reductions, both globally and in bilateral parietal cortex. Although DD was unrelated to adiposity in both groups, increased DD and adiposity were both associated with reduced IFG thickness in adolescents and adults. Our findings suggest that the known age effects on CT in adolescence and adulthood are moderated by adiposity. The association between weight, cortical development and its functional implications would suggest that future studies of adolescent and adult brain development take adiposity into account.