Differential association of traits of fear and anxiety with norepinephrine- and dark-induced pupil reactivity.

The relation between fear and anxiety remains unclear, though psychometric data strongly suggest they are independent emotional systems. Because central norepinephrine (NE) projection systems are at the core of models of both fear and anxiety, the present experiment explored whether this independence extends to NE functioning. Two different aspects of NE functioning were assessed in a healthy young adult sample (N = 18): pupillary reactivity to (a) a specific NE alpha-1 agonist challenge to assess receptor reactivity and (b) a darkness challenge to assess contributions of central NE. Pupillary reactivity to the former was strongly and specifically related to A. Tellegen's (1982) Multidimensional Personality Questionnaire (MPQ) Harm Avoidance scale (i.e., trait fear), whereas the latter was strongly and specifically related to MPQ Negative Emotionality (i.e., trait anxiety). Implications for conceptualizing fear and anxiety as emotional systems are discussed.

Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion.

Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, "experience-expectant," and "experience-dependent." Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.

Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions.

Neurocognitive research has focused on monoaminergic influences over broad behavior patterns. For example, dopamine (DA) generally facilitates informational transfer within limbic and cortical networks to promote reward-seeking behavior. Specifically, DA activity in prefrontal cortex modulates the ability for nonhuman primates and humans to perform spatial working memory tasks. Serotonin (5HT) constrains the activity of DA, resulting in an opposing relationship between DA and 5HT with respect to emotional and motor behaviors. A role for 5HT in constraining prefrontally guided spatial working memory (WM) processes in humans has not been empirically demonstrated but is a logical avenue for study if these principles of neurotransmitter activity hold within cortical networks. In this study, normal humans completed a visuospatial WM task under pharmacological challenge with (i) bromocriptine, a DA agonist and (ii) fenfluramine, a serotonin agonist, in a double-blind, repeated-measures, placebo-controlled design. Findings indicate that bromocriptine facilitated spatial delayed, but not immediate, memory performance. Fenfluramine resulted in impaired delayed spatial memory. These effects were not due to nonspecific arousal, attentional, sensorimotor or perceptual changes. These findings suggest that monoaminergic neurotransmitters (DA and 5HT) may interact within cortical networks to modulate the expression of specific cognitive behaviors, particularly effortful processes associated with goal-directed activity.

Dopamine and the structure of personality: relation of agonist-induced dopamine activity to positive emotionality.

Modern trait theories of personality include a dimension reflecting positive emotionality (PE) based on sensitivity to signals of incentive-reward. In animals, responsivity within an emotional system analog of PE is dependent on brain dopamine (DA) activity. To determine whether human PE trait levels are also associated with central DA, effects of a specific DA D2 receptor agonist were assessed in Ss who were widely distributed along the trait dimension of PE. The degree of agonist-induced reactivity in two distinct central DA indices was strongly and specifically associated with trait levels of PE, but not with other personality traits. The results suggest that the trait structure of personality may be related to individual differences in brain DA functioning.

Heat-loss response to a thermal challenge in seasonal affective disorder.

This study extends earlier findings of poorly facilitated postexercise heat loss during the winter in seasonal affective disorder (SAD). While depressed in the winter, 19 SAD subjects exhibited a significantly impaired postexercise heat loss relative to 10 control subjects. During the summer while euthymic, SAD subjects did not significantly differ from control subjects in postexercise heat loss. Since thermoregulatory heat loss is a highly dopamine-dependent process, these results support earlier findings of poorly facilitated dopamine availability in SAD during the winter and suggest a centrally mediated effect of light in SAD.

Regional electroencephalographic asymmetries in bipolar seasonal affective disorder before and after exposure to bright light.

Electroencephalographic (EEG) asymmetries found in nonseasonal depression were examined in seasonal affective disorder before and after bright-light exposure. Subjects with seasonal depression demonstrated the expected pattern of frontal asymmetry both when depressed and following light-induced remission. Right-hemisphere EEG coherence, by contrast, served as a state-dependent indicator of seasonal depression.

Behavioral engagement level, variability, and diurnal rhythm as a function of bright light in bipolar II seasonal affective disorder: an exploratory study.

Six patients with bipolar II seasonal affective disorder (SAD) and seven normal control subjects rated their moods in winter at six fixed times each week-day during 1 week of dim and 2 weeks of bright light. The scales rated represent the mood dimension specifically associated with depression, a dimension here called behavioral engagement (BE). Compared with controls, depressed SAD subjects (1) showed lower BE levels across all rating times of the day, (2) were more likely to show diurnal variation in BE, (3) displayed more between-day instability in BE diurnal rhythm, and (4) exhibited greater short-term lability (change within 3 hours) in BE. Bright light reduced or eliminated all group differences in BE level and variability.

Facilitation of working memory in humans by a d2 dopamine receptor agonist.

Recent studies on the neurobiology of cognition have focused on the ability of the prefrontal cortex (PFC) to support processes of working memory, i.e, mnemonic processes by which information relevant for a correct response is temporarily maintained to be reevaluated or updated on a trial-by-trial basis. Of most recent interest is the role played by dopamine (DA) in spatial working memory processes of the principal sulcal region of the PFC. Although D1 DA receptors appear to modulate these mnemonic processes in monkeys, several lines of research suggest that D2 DA receptors could also be relevant to cognitive functions. Therefore, we assessed the effects of a specific D2 receptor agonist (bromocriptine) and placebo on visuospatial delayed response performance in human subjects. During delay periods of 0 or 8 sec, subjects were required to remember the spatial location of rapidly presented visual cues displayed in peripheral vision within a 360° circumference. The extent to which D2 receptor activation by bromocriptine facilitated working memory in the 8-sec delay condition relative to placebo performance was assessed. As a means of providing validation of bromocriptine's D2 receptor effect, maximum inhibition of prolactin (PRL) secretion, which is inhibited specifically by activation of D2 receptor sites, was determined. Additionally, tasks having no working memory component were administered to rule out nonspecific effects of bromocriptine on sensory, arousal, attentional, and motor factors. Results demonstrated a significant facilitatory effect of bromocriptine on spatial delayed response performance (i.e., 8-sec delay performance). Results could not be explained by nonspecific effects of bromocriptine. Thus, findings of this study suggest that spatial working memory is facilitated by D2 receptor activation. The role that DA may play in human cognitive processes is discussed within the larger theoretical framework of DA's general role in the facilitation of goal-directed behavior. In the case of cognition, DA may facilitate processes that serve to guide motivated behavior through complex environments.

Dimensional measurement of seasonal variation in mood and behavior.

Recent epidemiologic studies have found that the behaviors that characterize seasonal affective disorder (SAD) show seasonal variation in 92%-95% of the general population, suggesting that seasonal variation in behavior and mood is a continuous, dimensional variable extending throughout the general population, defined at the upper extreme by SAD. Research into population seasonality will require a dimensional measure of seasonal variation in mood and behavior that produces a broad, finely graded distribution of seasonality scores sensitive to individual differences throughout the entire range of scores. Accordingly, the Inventory of Seasonal Variation (ISV) was developed as such a measure. This study demonstrated that the ISV has high internal structural validity and is highly sensitive to individual differences in seasonality across its entire range of scores in the normal population. This latter characteristic is not shared by other existing measures of seasonality. Initial external validity of the ISV was supported in that the mean of ISV scores of a SAD sample was found to lie at the 97th percentile of the normal population of scores. Analysis of ISV scores revealed that a winter pattern of seasonality was reported by over 95% of subjects, a pattern that was more pronounced in women than men, while a summer type of seasonality was reported by only 0.6% of the general population.

Seasonal independence of low prolactin concentration and high spontaneous eye blink rates in unipolar and bipolar II seasonal affective disorder.

Twenty-four subjects with seasonal affective disorder (SAD: bipolar II, n = 14; unipolar, n = 10) and 20 normal controls were assessed for early follicular basal serum prolactin (PRL) concentration in winter and summer. Luteal basal PRL concentration was assessed in winter. The PRL values represented the mean of three values derived during a 45-minute period. A subset of 17 subjects with SAD and 11 controls were also assessed for spontaneous eye blinking via a polygraphic recording in winter and summer. In winter, compared with controls, subjects with SAD were characterized by significantly lower follicular (10.1 vs 4.5 micrograms/L, respectively) and luteal (14.4 vs 7.4 micrograms/L, respectively) PRL values and by significantly higher eye blink rates (30 vs 61 blinks per 3 minutes, respectively). In summer, controls and subjects with SAD showed similar significant differences in follicular PRL values (9.3 vs 3.9 micrograms/L, respectively) and eye blink rates (25 vs 67 blinks per 3 minutes, respectively). No significant differences in PRL values or eye blink rates were found between the bipolar II and unipolar forms of SAD in either season. Results were discussed in terms of dopamine functioning.

Seasonal and mood independence of low basal prolactin secretion in premenopausal women with seasonal affective disorder.

To test hypotheses of opposing roles of dopamine and serotonin in prolactin secretion in seasonal affective disorder, the authors determined basal serum prolactin concentrations for premenopausal women, eight with and 14 without seasonal affective disorder, in late afternoon during the follicular phase of the menstrual cycle (and a subgroup during the luteal phase) in winter and summer. Despite their significantly higher Hamilton depression scale scores in winter than in summer, the patients had significantly lower prolactin concentrations than the control subjects in both seasons. These results suggest that low prolactin secretion may be a trait characteristic in seasonal affective disorder.

Thermoregulatory response to thermal challenge in seasonal affective disorder: a preliminary report.

It has recently been proposed that alterations in central dopamine (DA) functional activity may, in part, account for certain behavioral changes observed in seasonal affective disorder (SAD) during the winter. To explore this possibility, a preliminary study of thermoregulatory heat loss to an endogenous heat challenge--a strongly DA-dependent process--was undertaken in groups of four SAD woman and four nonpsychiatric control women across three conditions (winter, after successful phototherapy, and summer). Homeostatic heat loss during recovery from heat challenge in SAD, but not in control, subjects was found to be a significant function of light condition and of clinical state. Thermoregulatory heat loss in SAD subjects was significantly blunted in winter during depression, was similar in efficiency to control subjects after a successful antidepressant response to phototherapy, and tended to be more efficient than controls in summer during a euthymic state. Results raise the possibility that a common effect of phototherapy and summer light conditions is a facilitation of central DA activity in SAD.

General behavior inventory identification of unipolar and bipolar affective conditions in a nonclinical university population.

Validated the General Behavior Inventory (GBI), revised to identify unipolar as well as bipolar affective conditions, in a nonclinical sample (n = 201) against naive, interview-derived diagnoses. For bipolar and unipolar conditions, respectively, the GBI had high positive (.94, .87) and negative (.99, .93) predictive power with the effect of prevalence considered, adequate sensitivity (.78, .76), high specificity (.99, .99), and adequate selection ratios for sampling of affective and nonaffective subjects from nonclinical populations for research purposes. The utility of the GBI in several different research contexts is discussed.

Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels.

We have examined serum levels of oestradiol (E2), sex-hormone binding globulin (SHBG) and human chorionic gonadotrophin (hCG) during early pregnancy in relation to smoking status at the time of sampling in a series of 147 women. Smoking was associated with significantly depressed serum levels of E2, SHBG and hCG: in smokers, E2 levels were on average 17.6% lower (P = 0.037), SHBG levels were 12.4% lower (P = 0.15), and hCG levels were 21.5% lower (P = 0.044). There appeared to be a steady decline in these values with increasing cigarette consumption. These lower hormone levels in smokers may explain certain adverse effects of smoking in pregnancy.

Effect of phototherapy on spontaneous eye blink rate in subjects with seasonal affective disorder.

Eye blink rate was measured in four subjects with seasonal affective disorder and in four control subjects before and after phototherapy. The subjects with seasonal disorder blinked twice as often as the control subjects before therapy but no differently after phototherapy.

Maternal hormone levels in early gestation of cryptorchid males: a case-control study.

A case-control study was conducted to assess maternal hormonal factors associated with increased risk of bearing a cryptorchid son. Serum samples were collected during the first trimester of pregnancy from participants in the US Collaborative Perinatal Study. Twenty-five mothers of normal offspring (controls) were individually matched on medical center, age, parity, weight and length of gestation at the time of sampling to women bearing sons who had a diagnosis of cryptorchidism at one year of age or older. Compared with controls, mothers of cryptorchid sons (cases) had significantly greater percentages of non-protein bound (P = 0.010) and albumin-bound (P = 0.014) estradiol during the first trimester of the index pregnancy. On average, cases had 16% more bioavailable oestradiol than controls. Levels of human chorionic gonadotropin, testosterone, non-protein bound testosterone and sex-hormone binding globulin did not differ between the two groups. The data presented support the hypothesis that cryptorchidism results from elevated maternal oestrogen levels early in pregnancy.

Cryptorchidism, and epidemiologic study with emphasis on the relationship to central nervous system dysfunction.

This case-control study examines the relation of cryptorchidism to central nervous system dysfunction. Elevated odd ratios were found for cerebral palsy (RR = 34), low IQ (RR = 2.7), and low motor function measured by the Bayley test (RR = 3.6). Low IQ and cerebral palsy were independent risk factors for cryptorchidism. Breech labor (RR = 2.6), a gestation less than 34 weeks (RR = 2.0), and being a twin (RR = 4.1) were also independent risks. Other risk factors were estrogen use by the mother (RR = 3.3) and a maternal Quetelet index less than 24 (RR = 1.6). All of these risks were statistically significant. These factors suggest that cryptorchidism may be caused either by sex steroid action directly on the testes or by CNS damage, which in turn causes suppression of pituitary gonadotropins. The increased occurrence of cryptorchidism in twins and small babies indicates that retarded general fetal development can be another mechanism for maldescent of the testes.