A double-blind, placebo-controlled study on the effects of lutein and zeaxanthin on neural processing speed and efficiency.

Lutein and zeaxanthin are major carotenoids in the eye but are also found in post-receptoral visual pathways. It has been hypothesized that these pigments influence the processing of visual signals within and post-retina, and that increasing lutein and zeaxanthin levels within the visual system will lead to increased visual processing speeds. To test this, we measured macular pigment density (as a biomarker of lutein and zeaxanthin levels in brain), critical flicker fusion (CFF) thresholds, and visual motor reaction time in young healthy subjects (n = 92). Changes in these outcome variables were also assessed after four months of supplementation with either placebo (n = 10), zeaxanthin only (20 mg/day; n = 29) or a mixed formulation containing 26 mg/day zeaxanthin, 8 mg/day lutein, and 190 mg/day mixed omega-3 fatty acids (n = 25). Significant correlations were found between retinal lutein and zeaxanthin (macular pigment) and CFF thresholds (p<0.01) and visual motor performance (overall p<0.01). Supplementation with zeaxanthin and the mixed formulation (considered together) produced significant (p<0.01) increases in CFF thresholds (∼12%) and visual motor reaction time (∼10%) compared to placebo. In general, increasing macular pigment density through supplementation (average increase of about 0.09 log units) resulted in significant improvements in visual processing speed, even when testing young, healthy individuals who tend to be at peak efficiency.

Diazepam suppresses the acquisition but not the expression of 'fear-potentiation' of the acoustic startle response in man.

Sudden auditory stimuli elicit a short-latency muscular response (acoustic startle response) which is enhanced during presentation of a Pavlovian conditioned stimulus (CS) that has previously been paired with an aversive unconditioned stimulus (US) ('fear-potentiation'). In rodents, acute treatment with benzodiazepines blocks both the acquisition of fear-potentiation and the expression of fear-potentiation induced by prior exposure to CS/US pairing. We examined the effect of diazepam on the acquisition and expression of fear-potentiation of the acoustic startle response in man. Forty-six male volunteers (18-30 years) participated in two sessions separated by 7 days. In session 1, they were exposed to 20 2-s presentations of a light (CS), 50% of which terminated with an electric shock to the wrist (1.8 mA, 50 ms: US). Somatosensory potentials evoked by the US were recorded from the scalp at Cz, and skin conductance responses from electrodes taped to the second and fourth fingers. In session 2, the CS was presented 20 times without the US; a random 50% of CS presentations terminated with a sound pulse (40-ms 115-dB 1-kHz); an equal number of sound pulses was presented without the CS. Electromyographic responses of the orbicularis oculi muscle to the acoustic stimuli were recorded from electrodes placed on the lower eyelid, late-latency auditory evoked potentials were recorded at Cz, and skin conductance responses from electrodes taped to the second and fourth fingers. In each session, alertness was measured using visual analogue self-rating scales and critical flicker fusion frequency. Subjects received placebo or diazepam 10mg in the two sessions in a double-blind protocol: group 1 (n 12) placebo/placebo; group 2 (n 11) placebo/diazepam; group 3 (n 12) diazepam/placebo; group 4 (n 11) diazepam/diazepam. Diazepam reduced alertness as measured by visual-analogue self-rating scales and critical flicker fusion frequency. In session 1, diazepam reduced the amplitude of the somatosensory potentials and skin conductance responses evoked by the CS. In session 2, the acoustic startle response, the N1/P2 auditory evoked response and the skin conductance response evoked by the sound stimuli were enhanced in the presence of the CS. This fear-potentiation was attenuated in subjects who received diazepam in session 1, but was not affected by the treatment given in session 2. The results indicate that diazepam blocks the acquisition of fear-potentiation of startle responses in man, as in animals, but does not prevent the expression of a previously learned response.

Effects of lorazepam on fear-potentiated startle responses in man.

Sudden intense sensory stimuli elicit a cascade of involuntary responses, including a short-latency skeletal muscular response ('eyeblink startle response') and longer-latency autonomic responses. These responses are enhanced when subjects anticipate an aversive event compared to periods when subjects are resting ('fear potentiation'). It has been reported previously that the anxiolytic diazepam can suppress fear-potentiation of the eyeblink startle response in human volunteers. The present experiment aimed to confirm and extend these observations by examining the effect of another benzodiazepine, lorazepam, on the eyeblink and skin conductance components of the acoustic startle, and on fear-potentiation of these responses. Eighteen male volunteers participated in three weekly sessions in which they received oral treatment with placebo, lorazepam (1 mg) and lorazepam (2 mg), according to a balanced three-period, crossover, double-blind design. Two hours after ingestion of the treatments, electromyographic responses of the orbicularis oculi muscle and skin conductance responses were evoked by sound pulses during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with significant increase in the amplitude of the electromyographic (EMG) and skin conductance responses; there were also increases in baseline skin conductance, the number and amplitude of 'spontaneous' skin conductance fluctuations and self-rated anxiety. Lorazepam attenuated the effect of THREAT on self-rated anxiety and on the amplitude of the EMG response, but had no significant effect on fear-potentiation of the skin conductance responses. These results extend previous findings of the effect of diazepam on the fear-potentiated eyeblink startle response to lorazepam, and suggest that fear-potentiation of the later autonomic component of the startle response may be less sensitive to benzodiazepines than the fear-potentiated eyeblink response and self-rated anxiety.

Effects of quetiapine and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (PPI). Here, we report the effects of the 'atypical' antipsychotic drug quetiapine and the 'conventional' antipsychotic haloperidol on these responses. Sixteen males (aged 19-38 years) participated in four sessions at 7-day intervals, in which they received quetiapine 12.5 mg, quetiapine 25 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 2 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage PPI was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Quetiapine 12.5 mg and 25 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses; haloperidol had no effect on EMG response amplitude or PPI. Neither drug affected N1/P2 amplitude or PPI of this response. Quetiapine, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not quetiapine, elevated serum prolactin level. The ability of quetiapine to attenuate the startle response may reflect its sedative action.

Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers.

OBJECTIVES: To assess the cognitive and psychomotor effects of single oral doses of valerian in healthy volunteers in comparison with a placebo and the hypnotic agent triazolam. METHODS: In a double-blind, placebo-controlled, four-way crossover study nine healthy subjects (5 males, 4 females) received in random order valerian 500 mg, valerian 1000 mg, triazolam 0.25 mg and placebo. Doses were separated by a wash-out period of at least 1 week. Subjects were tested before each dose and at 2, 4 and 8 h after the dose of each compound using the critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), symbol search test (SST), digit span test (DST) and visual analogue scales of mood. RESULTS: Repeated measures ANOVA was used to examine the changes in performance on tests over time and significant effects were further analysed using simple main effects analysis with least significant difference corrections. Statistically significant differences were only noted for the cognitive tests: SST (F(3, 8)=3.182, p<0.05) and DSST (F(3, 8)=9.688, p<0.005). In both cases the differences between groups were due to the effects of triazolam. CONCLUSION: These data confirm that at recommended therapeutic doses, triazolam has detrimental effects on cognitive processes in healthy volunteers as found in previous studies. Valerian was without effect on either cognitive or psychomotor performance in healthy volunteers at the doses used in this study. Should the hypnotic activity of valerian be confirmed in randomized double-blind trials it may be a less troublesome alternative to benzodiazepines in the treatment of insomnia.

Effects of ketanserin and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the serotonin (5-HT)2 receptor antagonist ketanserin and the D2 dopamine receptor blocking antipsychotic drug haloperidol on these responses. Fifteen males (aged 18-35 years) participated in four sessions at 7-day intervals, in which they received ketanserin 20 mg, ketanserin 40 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after ingestion of haloperidol or 1 h after ingestion of ketanserin. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials), and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Ketanserin 40 mg significantly reduced the amplitude of the EMG response and both doses of ketanserin significantly suppressed prepulse inhibition of the response; haloperidol had no effect on EMG response amplitude or prepulse inhibition. Neither drug affected N1/P2 amplitude or prepulse inhibition of this response. Ketanserin, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not ketanserin, elevated serum prolactin level. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The ability of ketanserin to attenuate the startle response may reflect its sedative action, as other drugs with sedative properties have also been found to attenuate the startle response in man. The ability of ketanserin to suppress prepulse inhibition of the startle response is consistent with previous evidence for the involvement of 5-HTergic mechanisms in the regulation of prepulse inhibition in man.

A preliminary investigation on the acute pharmacodynamic effects of hypericum on cognitive and psychomotor performance.

Research has indicated that the herb St John's Wort (Hypericum perforatum) has comparable efficacy to conventional antidepressants in the treatment of depression. Although clinical studies have demonstrated that hypericum has a superior side-effect profile compared to standard antidepressants, no study has directly compared the cognitive and psychomotor effects of hypericum with those of other antidepressants. The aim of the current study was to examine the acute effects of hypericum on cognitive and psychomotor function, and to compare its effects with those of amitriptyline. Thirteen healthy volunteers received an acute dose of placebo, amitriptyline (25 mg, positive control) or hypericum (900 mg or 1800 mg) in a double-blind, placebo-controlled design. Cognitive and psychomotor tests and subjective measures of sedation were administered before and 1, 2 and 4 hours after drug administration. Amitriptyline impaired performance on a battery of psychological tests, which included critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), profile of mood states (POMS) and the line analogue rating scale (LARS), while hypericum had neutral effects on performance in these tests. However, hypericum induced a dose-related impairment on DSST. Current findings suggest that clinical doses of hypericum do not impair attention, sensorimotor function or information processing.

Effects of haloperidol and clozapine on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the 'conventional' antipsychotic drug haloperidol and the 'atypical' antipsychotic clozapine on these responses. Fifteen males (aged 19-54 years) participated in four sessions at 7-day intervals, in which they received clozapine 3 mg, clozapine 6 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Clozapine 6 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses. Clozapine 6 mg did not affect the amplitude of the N1/P2 potential, but significantly attenuated prepulse inhibition of that response. Clozapine 3 mg and haloperidol had no significant effect on either response. Clozapine 3 mg and 6 mg, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Clozapine 6 mg reduced salivation. Haloperidol, but not clozapine, elevated serum prolactin levels. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The abililty of clozapine to attenuate the startle response may reflect its sedative action. The basis of the abililty of clozapine to suppress prepulse inhibition of the N1/P2 potential remains uncertain.

A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality.

RATIONALE: The effects of caffeine, especially caffeinated coffee, on human performance have been extensively studied. However, few studies have been naturalistic representations of how tea/coffee is normally consumed in terms of dose and time of consumption. OBJECTIVES: This study investigated the effects of day-long consumption of tea, coffee and water on cognitive and psychomotor performance, and sleep quality at night. METHODS: Thirty healthy volunteers received equal volume drinks equivalent to either 1 or 2 cups of tea (containing 37.5 mg or 75 mg caffeine), or coffee (75 mg or 150 mg caffeine), or water, in a randomised five-way crossover design. Drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours). A psychometric battery consisting of critical flicker fusion (CFF), choice reaction time (CRT) and subjective sedation (LARS) tests, was administered pre-dose and at frequent time points post-dose. The Leeds Sleep Evaluation Questionnaire (LSEQ) was completed each morning and a wrist actigraph was worn for the duration of the study. RESULTS: Caffeinated beverages maintained CFF threshold over the whole day (P<0.05), independent of caffeine dose or beverage type. During the acute phase of beverage ingestion, caffeine significantly sustained performance compared to water after the first beverage for CFF and subjective sedation (P<0.05), and after the second beverage for the Recognition component of the CRT task (P<0.05). Additionally, there were significant differences between tea and coffee at 75 mg caffeine after the first drink. Compared to coffee, tea produced a significant increase in CFF threshold between 30 and 90 min post-consumption (P<0.01). However, following the second beverage caffeinated coffee at 75 mg significantly improved reaction time (P<0.05), compared to tea at the same dose, for the Recognition component of the CRT task. Caffeinated beverages had a dose dependent negative effect on sleep onset (P<0.001), sleep time (P<0.001) and sleep quality (P<0.001). CONCLUSIONS: These results indicate that ingestion of caffeinated beverages may maintain aspects of cognitive and psychomotor performance throughout the day and evening when caffeinated beverages are administered repeatedly. This study also demonstrates that day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep. Other differences between tea and coffee were more subtle, and require further investigation.

The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers.

This study investigated the effects of acute doses of Ginkgo biloba extract (GBE) on memory and psychomotor performance in a randomized, double-blind and placebo controlled 5-way cross-over design. Thirty-one volunteers aged 30-59 years received GBE 150 mg (50 mg t. d.s), GBE 300 mg (100 mg t.d.s.), GBE 120 mg mane and GBE 240 mg mane and placebo for 2 days. Following baseline measures, the medication was administered at 0900 h for the single doses and at 0900, 1500 and 2100 h for the multiple doses. The psychometric test battery was administered pre-dose (0830 h) and then at frequent intervals until 11 h post dose. The results confirm that the effects of GBE extract on aspects of cognition in asymptomatic volunteers are more pronounced for memory, particularly working memory. They also show that these effects may be dose dependent though not in a linear dose related manner, and that GBE 120 mg produces the most evident effects of the doses examined. Additionally, the results suggest that the cognitive enhancing effects of GBE are more likely to be apparent in individuals aged 50-59 years.

Comparative study of the psychomotor and antistress effects of ritanserin, alprazolam and diazepam in healthy subjects: some trait anxiety-independent responses.

The new potential anxiolytic ritanserin was studied in a double-blind manner vs. alprazolam, diazepam and placebo in 23 healthy subjects. The subjects belonged either to a high anxiety level group or a low anxiety level group, in order to study the effect of the anxiety level on the pharmacodynamic responses. The assessments included cognitive function (memory tests), psychomotor performance [Critical Flicker Fusion (CFF), Choice Reaction Time (CRT)], subjective ratings of alertness and overnight sleep and stress paradigm. Ritanserin (10 mg), alprazolam (0.75 mg), diazepam (10 mg) and placebo were given as single oral doses following a latin square design. Groups were well contrasted on the Cattell anxiety scale and were not overlapping. On no psychometric variable have there been any interactions between the anxiety level and the drug factor. At baseline an anxiety-related difference between the two groups was observed: lower CFF value in the high anxiety group (-1.4 Hz). Both benzodiazepines impaired psychomotor assessment and memory function and increased sleepiness. Ritanserin decreased CFF values without significantly affecting CRT on which nevertheless a trend to impairment was observed. Memory tests, and subjective ratings of alertness were unaffected by ritanserin. A trend to an antistress effect was observed on electrodermogram after ritanserin. Both benzodiazepines decreased central nervous system arousal and memory while ritanserin was inactive except on CFF. Recent data support the hypothesis that 5-HT2 blockers decrease pupil diameter which is a well known covariate of flicker frequency.

A comparison of the CNS effects of enprofylline and theophylline in healthy subjects assessed by performance testing and subjective measures.

1. The effects of intravenous infusions of enprofylline, theophylline, and placebo on subjective ratings and on psychological test performance were studied in a double-blind crossover experiment in 12 healthy subjects who abstained from caffeine throughout the experimental procedures. 2. Mean plasma concentrations of enprofylline were: mean 2.9 mg l-1 (range 1.9-3.4). Those for theophylline were: mean 12.1 mg l-1 (range 9.0-14.4). 3. Performance on the auditory vigilance task showed a significant improvement with theophylline compared with both enprofylline and placebo. The correct detection rates (out of 90) were 50.3, 43.4 and 39.1 respectively. A similar effect was seen with finger tapping rates: 404, 394 and 390 taps min-1 respectively. Other measures showed no significant effects, although choice reaction time showed a trend towards faster responses with theophylline. 4. Subjective ratings showed that subjects were significantly more alert with theophylline than with enprofylline. Subjects reported themselves as significantly more dizzy and ill with both active drugs compared with placebo. 5. These results suggest that emprofylline largely lacks the CNS stimulant effects of theophylline, but that the incidence of other unwanted effects of the drugs may be similar.

The effect of betel nut on human performance.

The effects of low doses of betel nut on early-stage visual information processing were examined, using a cross-over experimental design. Three assessment measures were used, critical flicker fusion (an index of the efficiency of the visual processing system), heart rate, and analogue scales of subjective alertness. Only heart rate was shown to be significantly elevated, immediately following betel nut administration. From these results, it was concluded that there is no evidence to suggest that betel nut usage facilitates visual information processing at low-dose levels in habituated subjects, but there is some evidence that peripheral stimulation occurs.

The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers.

Eight healthy female volunteers received Ginkgo biloba extract (G.B.E.) 120, 240, 600 mg and placebo according to a randomized, double-blind crossover design. One hour following treatment, subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS) and a Sternberg memory scanning test. No statistically significant changes from placebo were observed on CFF, CRT or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with G.B.E. 600 mg when compared to placebo and results suggested a localized effect of the drug on the serial comparison stage of the reaction process.

[Effect of phenazepam on psychophysiological reactions]. / Vliianie fenazepama na psikhofiziologicheskie reaktsii.

After intensive psychophysical sports exercise phenazepam given to 18 male athletes at a dose of 0.0005 g reduced the latent period of ordinary motor reactions to the sound and improved visual-motor coordination as judged from the test of reacting to the moving object, and also slightly increased the critical frequency of light flickering confluence and time of digital recognition. At a dose of 0.002 g phenazepam led to contrary changes in the parameters cited. No residual action was recorded in the morning after phenazepam administration overnight as a hypnotic agent at a dose of 0.002 g.

Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects-a review.

This literature review presents summary methodological and statistical data on 33 studies in which critical flicker frequency (CFF) thresholds were used to evaluate the effects of acute oral doses of single psychotropic drugs in normal human subjects. In all, 96 drug-dose-study combinations are represented. CFF was found to be altered to a statistically significant degree (P is less than 0.05) in 51 (65%) of the 79 instances in which inferential statistical methods were used to evaluate the results. As expected, stimulants increased CFF while hypnotics decreased it. There is also a discussion of important methodological considerations in the design of psychopharmacological studies employing CFF. While many studies have shown CFF to be sensitive to the effects of psychotropic drugs, there have not always been adequate controls for extraneous factors (especially, set and suggestion, changes in pupillary diameter, and the presence of other commonly used drugs). Finally, consideration is given to the attempts to increase the sensitivity of the CFF test to drug effects.