Cognitive function in late versus early postmenopausal stage.

OBJECTIVES: There are relatively few studies of cognitive performance in the first few postmenopausal years and insufficient data on whether there is differential decline in different cognitive abilities. The aim of the present analysis was to determine the nature of cognitive decline across a range of functions within a period of 5 years from early to late postmenopausal stage. METHODS: In a cross-sectional study, 189 postmenopausal women, who had experienced a natural menopause, were not taking hormonal medication and had not done so in the previous 12 months, were divided according to their postmenopausal stage into early (stage +1, < or =5 years since the last menstrual period, aged 55.4+/-0.3 years, n=80), or late (stage +2, >5 years since the last menstrual period, aged 59.8+/-0.4 years, n=109) postmenopausal stages. Participants completed a comprehensive battery of tests measuring attention, episodic and semantic memory, planning and mental flexibility. Participants also completed self-ratings of mood, sleepiness and menopausal symptoms. RESULTS: There were no differences between the groups in their performance in tests of attention, verbal fluency or memory. However, in the two tests of executive function (planning and mental flexibility) the women in the late postmenopausal stage performed significantly worse than the women in the early postmenopausal stage. These differences remained significant when effects of age and IQ were taken into account by analyses of covariance. There were no differences between the groups in their ratings of mood or of habitual sleepiness, or of feeling sleepy at the start of testing. However, by the end of testing the women in the late postmenopausal stage rated themselves as feeling sleepier than did the women in the early postmenopausal stage. The group differences in executive function remained significant when these differences in sleepiness were accounted for. CONCLUSIONS: Although there were no differences in attention, verbal fluency and memory, executive function was significantly poorer in the late postmenopausal stage women, suggesting that this aspect of cognition deteriorates more rapidly than other functions. This change was independent of change in age, suggesting that hormonal changes between the early and late postmenopausal stages may be responsible.

Nicotine and cannabinoids: parallels, contrasts and interactions.

After a brief outline of the nicotinic and cannabinoid systems, we review the interactions between the pharmacological effects of nicotine and cannabis, two of the most widely used drugs of dependence. These drugs are increasingly taken in combination, particularly among the adolescents and young adults. The review focuses on addiction-related processes, gateway and reverse gateway theories of addiction and therapeutic implications. It then reviews studies on the important period of adolescence, an area that is in urgent need of further investigation and in which the importance of sex differences is emerging. Three other areas of research, which might be particularly relevant to the onset and/or maintenance of dependence, are then reviewed. Firstly, the effects of the two drugs on anxiety-related behaviours are discussed and then their effects on food intake and cognition, two areas in which they have contrasting effects. Certain animal studies suggest that reinforcing effects are likely to be enhanced by joint consumption of nicotine and cannabis, as also may be anxiolytic effects. If this was the case in humans, the latter might be viewed as an advantage particularly by adolescent girls, although the increased weight gain associated with cannabis would be a disadvantage. The two drugs also have opposite effects on cognition and the possibility of long-lasting cognitive impairments resulting from adolescent consumption of cannabis is of particular concern.

Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome.

Fourteen patients (7 male, 7 female, 22-63 years), classified as having chronic fatigue syndrome (CFS), but without concurrent major depression, significant sleepiness or use of psychoactive medication, completed a double-blind, placebo-controlled, crossover study of the effects of the selective wakefulness-promoting agent, modafinil (200 and 400mg/day). The treatment periods were each 20 days, with washout periods of 2 weeks. The primary aim was to determine effects on cognition and the secondary aim was to determine effects on self-ratings of fatigue, quality of life and mood. Modafinil had mixed effects in two cognitive tasks. In a test of sustained attention, treatment with 200mg reduced the latency to correctly detect sequences, but 400mg increased the number of missed targets. In a test of spatial planning, the 200mg dose resulted in a slower initial thinking time for the easiest part of the task, whereas 400mg reduced the initial thinking time for the hardest part of the test. Lastly, in a test of mental flexibility and one of motor speed, patients performed worse whilst on modafinil (400mg), compared with the placebo period. No effects were observed on the performance of other psychometric tests or on self-ratings of fatigue, quality of life or mood, but this may have been due to insufficient statistical power. It is discussed whether the limited and mixed cognitive effects that we observed could have occurred by chance, or whether a subgroup of CFS patients with daytime sleepiness would have shown greater benefits.

Cognitive effects of modafinil in student volunteers may depend on IQ.

The results of two previous studies on the effects of modafinil, a selective wakefulness-promoting agent, in healthy university students were combined in a retrospective analysis. This allowed determination of whether the effects of modafinil were dependent on IQ and whether the larger sample size (n=89) would reveal more cognitive benefits. A battery of cognitive tests was completed 2-3 h after dosing. In the whole sample, modafinil (200 mg) significantly reduced the number of missed targets in a test of sustained attention (RVIP). However, interestingly, several interactions between modafinil and IQ emerged. Modafinil (100 and 200 mg) significantly improved target sensitivity in the RVIP test, but only in the group of 'lower' IQ (mean+/-sem=106+/-0.6), not in the 'higher' IQ group (mean+/-sem=115.5+/-0.5). Furthermore, there were significant modafinil x IQ interactions in two further tests. Modafinil significantly reduced speed of responding in a colour naming of dots, and in clock drawing, but only in the 'lower' IQ group. Thus, the cognitive benefits of modafinil seem particularly marked in tests of vigilance and speed, in which sleepiness would be an important factor. Furthermore, the results indicate that high IQ may limit detection of modafinil's positive effects.

Endocannabinoid system and stress and anxiety responses.

Cannabinoid agonists induce complex and often contradictory effects on anxiety in humans and experimental animals. The data from animal tests provide evidence of dose-dependent bidirectional modulation of anxiety by the cannabinoid system and the importance of environmental context. The mechanisms mediating the effects of cannabinoids on anxiety-related responses appear to involve CB1 and non-CB1 cannabinoid receptors. In addition, the CRH, GABA(A), cholecystokinin, opioid and serotonergic systems have also been implicated. Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity. Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states and may constitute a novel pharmacological target for anti-anxiety therapy.

Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?

In a double-blind, parallel groups study, 60 healthy student volunteers (29 men and 31 women, aged 19-22 years) were randomly allocated to receive placebo, 100 or 200 mg modafinil. Two hours later, in the early evening, they completed an extensive cognitive battery. The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session, and there were no treatment-associated changes in these or in mood ratings during the tests. Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency. These results suggest that the benefits of modafinil are not clearly dose-related, and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory, which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals.

Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers.

RATIONALE: Acute doses of Ginkgo biloba have been shown to improve attention and memory in young, healthy participants, but there has been a lack of investigation into possible effects on executive function. In addition, only one study has investigated the effects of chronic treatment in young volunteers. OBJECTIVES: This study was conducted to compare the effects of ginkgo after acute and chronic treatment on tests of attention, memory and executive function in healthy university students. METHODS: Using a placebo-controlled double-blind design, in experiment 1, 52 students were randomly allocated to receive a single dose of ginkgo (120 mg, n=26) or placebo (n=26), and were tested 4 h later. In experiment 2, 40 students were randomly allocated to receive ginkgo (120 mg/day; n=20) or placebo (n=20) for a 6-week period and were tested at baseline and after 6 weeks of treatment. In both experiments, participants underwent tests of sustained attention, episodic and working memory, mental flexibility and planning, and completed mood rating scales. RESULTS: The acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern-recognition memory task; however, there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests. CONCLUSIONS: In line with the literature, after acute administration ginkgo improved performance in tests of attention and memory. However, there were no effects after 6 weeks, suggesting that tolerance develops to the effects in young, healthy participants.

Cognitive improvement after 6 weeks of soy supplements in postmenopausal women is limited to frontal lobe function.

OBJECTIVE: To assess the effects of 6 weeks of treatment with soy supplements on mood, menopausal symptoms, and cognition in postmenopausal women not taking other forms of hormone therapy. DESIGN: In a double-blind, placebo-matched parallel groups study, 50 postmenopausal women (aged 51-66 y) were randomly allocated to receive daily treatment with a soy supplement (Novasoy, 60 mg total isoflavone equivalents/day) or matching placebo capsules. They were tested at baseline before treatment began and after 6 weeks of treatment in tests of attention, memory, and frontal lobe function, and completed questionnaires to assess sleepiness, mood, and menopausal symptoms. RESULTS: After 6 weeks of treatment, there was a significant (P < 0.02) reduction in somatic menopausal symptoms in the group taking soy supplements, but there were no other significant effects of soy on menopausal symptoms or mood. On the test of nonverbal short-term memory, the soy group showed greater improvement than the placebo group (P < 0.03), but there were no effects of soy on long-term memory, category generation, or sustained attention. However, the soy treatment produced significantly better performance on the two tests of frontal lobe function, those of mental flexibility (simple rule reversal, P < 0.05; complex rule reversal, P < 0.03) and of planning ability (P < 0.05). CONCLUSIONS: The results suggest that the main improvement after 6 weeks of soy supplementation was in frontal lobe function. Significant improvements in the same three measures of frontal lobe function were previously found after 12 weeks of soy supplements in postmenopausal women. The effects of soy on memory seem less robust.

Limited cognitive benefits in Stage +2 postmenopausal women after 6 weeks of treatment with Ginkgo biloba.

Gingko biloba has cognitive benefits both in populations suffering from dementia and after acute treatment in healthy volunteers, with some evidence indicating that those with poorer cognitive performance show greater benefit. We have previously found that 1 week of treatment with ginkgo improved attention, memory and mental flexibility in post-menopausal women, but the evidence for any beneficial effects of longer treatment is less well-established. The present study aimed to determine whether cognitive benefits, similar to those previously found after 1 week of treatment, would persist after 6 weeks of treatment, and whether those with poorer cognitive performance would benefit more. In a placebo-controlled, double-blind study, postmenopausal women (aged 51-67 years) were randomly allocated to receive a standardized extract of ginkgo (LI 1370, Lichtwer Pharma, Marlow, UK) (one capsule/day of 120 mg, n = 45) or matching placebo (n = 42) for 6 weeks. According to an established reproductive staging system, subjects were divided into those in the early (Stage +1; mean age 55 years) and late (Stage +2: mean age 61 years) stages of menopause. At baseline and after 6 weeks of treatment, subjects completed tests of mental flexibility, planning, memory and sustained attention, and ratings of mood, sleepiness, bodily and menopausal symptoms. The only significant effects of ginkgo were in the test of mental flexibility, in which there were significant menopausal stage-ginkgo interactions. This was because subjects in Stage +2 required fewer trials to complete the task and made fewer errors after ginkgo treatment, whereas those in Stage +1 showed no benefits. Subjects in Stage +2 had poorer performance at baseline compared to those in Stage +1 both in this task and the test of planning ability. The beneficial effects of ginkgo were limited to the test of mental flexibility and to those with poorer performance.

Animal tests of anxiety.

Animal tests of anxiety are used to screen novel compounds for anxiolytic or anxiogenic activity, to investigate the neurobiology of anxiety, and to assess the impact of other occurrences such as exposure to predator odors or early rearing experiences. This unit presents protocols for the most commonly used animal tests of anxiety. The Geller-Seifter conflict test, the social interaction test, light/dark exploration, the elevated plus-maze, defensive burying, and the thirsty rat conflict. The protocols are described in terms of drug screening tests, but can be modified easily for other purposes.

Binge drinking and sex: effects on mood and cognitive function in healthy young volunteers.

This study compared the mood and cognitive performance of male and female teetotal and binge drinking students. The binge drinkers had significantly lower self-ratings of trait anxiety and depression and of state alertness at the time of testing than did the teetotallers. The females had significantly higher ratings of trait and state anxiety, but there were no Sex x Bingeing interactions on mood. The binge drinkers made significantly fewer correct responses in a test of sustained attention and recalled fewer line drawings. There was a significant Sex x Binge interaction in a spatial recognition task because the male, but not the female, binge drinkers were slower to make correct responses. Males performed better than females in both the spatial and pattern recognition memory tasks. There were three tests of executive function. In a spatial working memory task, males performed better than females, but there were no effects of binge drinking. There were no effects in a test of mental flexibility. However, in a test of planning, the binge drinkers were significantly slower than the teetotallers were. Thus, compared with a group of teetotallers, the binge drinkers had lower trait anxiety and depression and poorer performance in tests of sustained attention, episodic memory and planning ability.

Mood changes after cognitive testing in late middle-age: impacts of sex and habitual alcohol consumption.

Men and women (50-67 years) completed drinking diaries and, on the basis of this, were divided into low (<2 units/day, 1 UK unit=8 g alcohol) and moderate (2-5 units/day) alcohol groups. They completed analogue rating scales of mood and bodily symptoms before and after two extended computerised cognitive tests. After the tests, the women showed significantly greater increases in self-ratings on the factors of anxiety and discontentment and felt significantly less alert than did the men. They also showed significantly greater increases in bodily symptoms of somatic anxiety and ratings of aggressive mood than did the men. There were no significant effects of alcohol or Sex x Alcohol interactions on the self-ratings, but the men showed significant positive correlations of alcohol and negative mood. On both the cognitive tests, there were significant Sex x Alcohol interactions because the moderate-drinking men performed worse than the low-drinking men, whereas the moderate-drinking women performed better than the low-drinking women. Thus, the middle-aged women responded much more than did the men with negative mood changes to the psychological stress of cognitive testing, although their cognitive performance was not worse.

Does drinking have effects on mood and cognition in male and female students?

Self-ratings of mood and bodily symptoms were made by groups of IQ and education-matched male and female students [teetotal, low (2-9 units/week for both sexes; 1 UK unit=8 g alcohol) and moderate (12-34 units/week for males; 10-24 units/week for females) drinkers], before the start and at the end of cognitive testing. Multivariate analyses of variance (MANOVAs) showed that there were significant Alcohol x Time interactions, because the teetotal group responded to the cognitive tests with greater increases in the factors of somatic anxiety and aggressive mood than did the other two groups. Thus, the teetotallers had greater ratings of anxiety, sweating, palpitations, irritability, headache, feeling angry, quarrelsome, belligerent, resentful, hostile, spiteful and rebellious. No differences were found in immediate or delayed logical memory, in verbal fluency, trails, clock-drawing or mental flexibility tests. In tests of sustained attention [rapid visual information processing (RVIP)] and planning, males performed better than females. The moderate-alcohol group performed better than the low-alcohol group in RVIP and planning (completed significantly more tasks in the minimum moves), although in the hardest parts of the latter test, they took longer in planning the initial move. In conclusion, there was no evidence that the group drinking moderate levels of alcohol had any cognitive impairment and the teetotal group responded to the cognitive tests with the greatest increases in negative mood.

The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers.

Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers. In a double-blind parallel group design study, 45 non-sleep-deprived middle-aged volunteers (20 men and 25 women, aged 50-67 years) were randomly allocated to receive two capsules containing placebo, 100 or 200 mg modafinil, and 3 h later they completed 100 mm visual analogue scales of mood and bodily symptoms, before and after an extensive battery of cognitive tests [pen and paper and the Cambridge Neuropsychological Test Automated Battery (CANTAB)]. There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study. The group treated with modafinil (200 mg) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability (Clock Drawing Test) compared with the placebo group. However, subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift (ID/ED) task than both the other groups. Thus, this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers.

Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test.

In spite of the addictive properties of cannabinoids, under certain circumstances, they can evoke strong anxiogenic and aversive responses in humans and in animal tests of anxiety. Effects of different doses of CP 55,940 (10, 20, and 40 microg/kg) were tested in the low-light, familiar (LF) apparatus test condition of the social interaction test. The 40-microg/kg dose of CP 55,940 significantly decreased the time spent in social interaction, indicating an anxiogenic effect. This dose also had an independent effect of reducing locomotor activity. In rats tested undrugged 24 h after testing with 40 microg/kg, there was a significant anxiogenic effect, indicating conditioned anxiety. The group of rats injected with 40 microg/kg immediately after the social interaction test showed an unexpected significant anxiolytic effect when tested undrugged 24 h later. In an additional experiment, rats were tested in the high-light, familiar (HF) apparatus test condition after 10 or 40 microg/kg, and only those that were tested after 40 microg/kg showed an anxiogenic effect on the test day and a conditioned anxiogenic effect when tested undrugged 24 h later. Once again, those injected with 40 microg/kg after the social interaction test displayed an anxiolytic effect when tested undrugged 24 h later. We provide the first evidence for unconditioned and conditioned anxiogenic-like responses to a cannabinoid agonist in the social interaction test.

Animal tests of anxiety.

Animal tests of anxiety are used to screen novel compounds for anxiolytic or anxiogenic activity, to investigate the neurobiology of anxiety, and to assess the impact of other occurrences such as exposure to predator odors or early rearing experiences. This unit presents protocols for the most commonly used animal tests of anxiety. The Geller-Seifter conflict test, the social interaction test, light/dark exploration, the elevated plus-maze, defensive burying, and the thirsty rat conflict. The protocols are described in terms of drug screening tests, but can be modified easily for other purposes.

Effects on cognition and mood in postmenopausal women of 1-week treatment with Ginkgo biloba.

In a double-blind, placebo-controlled study, postmenopausal women (53-65 years old) were randomly assigned to 7-day treatment with Ginkgo (120 mg/day, n=15) or matched placebo (n=16). They were given a battery of cognitive tests and measurements of mood and menopausal symptoms at baseline (before treatment began) and at the end of 7 days. The group treated with Ginkgo was significantly better than the placebo group in a matching-to-sample test of nonverbal memory, but the groups did not differ in immediate or delayed paragraph recall or in delayed recall of pictures. In a test of frontal lobe function (rule shifting) and in the Paced Auditory Serial Addition Test (PASAT) (which measures sustained attention but also involves frontal lobe function), the group treated with Ginkgo performed significantly better than the placebo group. However, the groups did not differ in a test of planning. The treatments did not differ in their effects on the volunteers' ratings of menopausal symptoms, sleepiness, bodily symptoms or aggression. The benefits of Ginkgo on memory and frontal lobe function found in this study are modest but are unlikely to be secondary to major mood changes.

Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones.

We previously reported that a high soya diet improved memory and frontal lobe function in young volunteers, and since soya isoflavones are agonists at oestrogen receptors, they may improve these functions in postmenopausal women. Thirty-three postmenopausal women (50-65 years) not receiving conventional hormone replacement therapy (HRT) were randomly allocated in a double-blind parallel study to receive a soya supplement (60 mg total isoflavone equivalents/day) or placebo for 12 weeks. They received a battery of cognitive tests and completed analogue rating scales of mood and sleepiness, and a menopausal symptoms questionnaire before the start of treatment and then after 12 weeks of treatment. Those receiving the isoflavone supplement showed significantly greater improvements in recall of pictures and in a sustained attention task. The groups did not differ in their ability to learn rules, but the isoflavone supplement group showed significantly greater improvements in learning rule reversals. They also showed significantly greater improvement in a planning task. There was no effect of treatment on menopausal symptoms, self-ratings of mood, bodily symptoms or sleepiness. Thus, significant cognitive improvements in postmenopausal women can be gained from 12 weeks of consumption of a supplement containing soya isoflavones that are independent of any changes in menopausal symptoms, mood or sleepiness.

Age-associated sex differences in response to food deprivation in two animal tests of anxiety.

The effects of mild food deprivation (7 days of food restricted to once daily feeding to maintain body weights at 85% of free-feeding weights) were examined in adult male and female and adolescent female rats tested in the elevated plus maze and social interaction tests of anxiety. In adult male rats, food deprivation appeared to have an anxiolytic effect in the plus-maze as it significantly increased the percentage of entries onto open arms and the percentage of time spent on the open arms, without changing the number of closed arm entries. There were no effects of food deprivation in adult females, although in adolescent females food deprivation significantly increased the percentage of open arm entries rats. Adolescent female rats have female brains, but do not have circulating gonadal hormones and thus these results suggest that circulating female gonadal hormones are able to suppress some of the effects of mild food deprivation in the plus-maze. In the social interaction test, there were no effects of food deprivation in any group on the time spent in social interaction. There were opposite effects on locomotor activity in the adult male and female rats, with deprivation increasing activity in males and decreasing it in females. There were no effects of food deprivation on locomotor activity in the adolescent females, suggesting that circulating gonadal hormones were responsible for the bidirectional effects in the adult rats. In both tests there were age-associated differences in the female rats, with the adolescent females being less anxious (higher percentage of open arm entries and increased social interaction) than the adults.

Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models.

Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.