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Two-weeks of intensified training significantly increased training volume, load and strain eliciting a state of overreaching in trained male cyclists.Intensified training caused deteriorations in physical performance but did not influence cognitive measures.Mood and recovery-stress balance were negatively affected by intensified training but recovered back to baseline following a two-week taper at a reduced training volume.A two-week taper period following two-weeks of intensified training did not result in improved physiological measures, physical performance parameters or mood above initial baseline values highlighting the need for careful consideration over the purpose, desired outcomes and necessity of intensified training on an individualised basis.

O'Neill, BV, Davies, KM, and Morris-Patterson, TE. Singapore sling: F1 race team cognitive function and mood responses during the Singapore grand prix. J Strength Cond Res 34(12): 3587-3592, 2020-The current investigation measured cognitive performance and subjective ratings of mood and sleep in Formula 1 (F1) race team members during the 2013 Singapore Grand Prix. Two weeks before the Singapore Grand Prix, subjects (n = 16; mean age 33.5 years, range 22-48 years) underwent baseline cognitive assessments and a questionnaire on mood and sleep quality/duration. These assessments were repeated on the race weekend before practice (S1) and after qualifying (S2). A significant increase in simple reaction time (SRT), i.e., slowing of total response time was observed from baseline to S1 (33.69 ± 6.52 ms; p < 0.001) and from baseline to S2 (34.63 ± 8.19 ms; p = 0.002). Mood-related effects were observed with subjective stress levels increased from baseline to S1 (18.06 ± 6.18; p = 0.032) and a decrease in how refreshed the race team members felt between S1 and S2 (18.56 ± 6.14; p = 0.029). In addition, a negative association between change in SRT and change in quality of sleep (R = 0.47; p = 0.016) as well as negative association in how refreshed individuals reported feeling and SRT between S1 and S2 (R = 0.37; p = 0.017). The findings suggest that the demands presented by an F1 race environment have significant effects on cognitive function and mood; however, the exact cause of any decrements would most likely be a combination and interaction of multiple factors. Future research should endeavor to adopt a holistic approach and investigate physiological and cognitive endpoints to fully explore the demands of this challenging motor sport.

Intensified periods of competition are common in many team sports, potentially leading to increased fatigue and reduced performance. The purpose of this study was to investigate the effect of repeated high-intensity sprint interval exercise on cognitive function, mood and perceptions of energy and fatigue. Twenty-four trained rugby players completed multiple bouts of repeated sprints across two consecutive days. Prior to and following each set of maximal effort sprints or equivalent control duration, a battery of cognitive tasks assessing simple and choice reaction time, visuo-spatial working memory and inhibition were completed as well as visual analogue scales that assessed mood, energy, and fatigue. Accuracy of incongruent Stroop responses was significantly lower across day 2 compared to day 1 and the control condition. Four-choice reaction time was slower across day 2 whilst feelings of alertness, contentedness, and physical and mental energy were reduced while ratings of physical and mental fatigue increased. These findings suggest that intensified periods of high-intensity sprint interval exercise have detrimental effects on executive function, mood and perceptions of physical and mental energy, and fatigue. These deleterious effects have the potential to impact performance and may increase the propensity for injury/accidents in certain sporting and non-sporting contexts.

Purpose It is well established that mental fatigue impairs performance during lab-based endurance tests lasting less than 45 min. However, the effects of mental fatigue on longer duration endurance events and in field settings are unknown. The aim of this study was to investigate the effect of mental fatigue on performance during a half-marathon race. Methods Forty-six male amateur runners (means ± SD: age 43.8 ± 8.6 years, $$\dot V{O_{2peak}}$$ V ˙ O 2 p e a k 46.0 ± 4.1 ml/kg/min) completed a half-marathon after being randomly allocated to performing a 50-min mentally fatiguing task (mental fatigue group) or reading magazines for 50 min (control group). Running speed, heart rate, and perceived effort were measured during the race. Results Runners in the mental fatigue group completed the half-marathon approximately 4 min slower (106.2 ± 12.4 min) than those in the control group (102.4 ± 10.2 min), but this difference was not statistically significant (Cohen’s d = 0.333; p = 0.265). However, equivalence was not established [t(40.88) = 0.239, p = 0.594] and equivalence testing analysis excluded a beneficial effect of mental fatigue on half-marathon performance. Conclusion Due to its posttest-only design and the achievable sample size, the study did not have enough power to provide evidence that the observed 4-min increase in half-marathon time is statistically significant. However, equivalence testing suggests that mental fatigue has no beneficial effect on half-marathon performance in male amateur runners, and a harmful effect cannot be excluded. Overall, it seems prudent for endurance athletes to avoid mentally fatiguing tasks before competitions.

Purpose:To assess changes in body composition and monitor cognitive function, subjective well-being, and physiological stress, as measured by salivary hormones and markers of mucosal immunity, during an Antarctic expedition. Methods:A 36-y-old man (188.2 cm height, 94.5 kg body mass) took part in a world-record attempt. A total-body dual-energy X-ray absorptiometry scan and measurement of 8 skinfolds and 5 girths were performed before and after the expedition. In addition, daily subjective data were recorded (sleep quality, total hours of sleep, energy levels, perceived exertion, mood, muscle soreness, and muscle/joint pain) along with distance covered and hours of physical activity per day. As a measure of cognitive function, the athlete completed a computerized battery of tasks (Axon Sports Cognitive Priming Application) every third morning. Saliva samples were collected before, during, and after the expedition to determine salivary cortisol (sCort), testosterone (sT), alpha amylase (sAA), and secretory immunoglobulin A (sIgA). Results:The athlete lost 5.3 kg body mass and sum of 8 skinfolds decreased from 73 mm to 59 mm from preexpedition to postexpedition. Psychomotor speed declined over the course of the expedition. sT increased and sCort decreased throughout, and sAA and sIgA peaked toward the end of the expedition. Conclusions:This case study provides novel data about the physiological and cognitive impact of an Antarctic expedition. The findings may inform strategies for future expeditions, allowing individuals undertaking expeditions of this nature to better prepare for success.

Sphingomyelin (SM) supports brain myelination, a process closely associated with cognitive maturation. The presence of SM in breast milk suggests a role in infant nutrition; however, little is known about SM contribution to healthy cognitive development. We investigated the link between early life dietary SM, later cognitive development and myelination using an exploratory observational study of neurotypical children. SM levels were quantified in infant nutrition products fed in the first three months of life and associated with myelin content (brain MRI) as well as cognitive development (Mullen scales of early learning; MSEL). Higher levels of SM were significantly associated with higher rates of change in verbal development in the first two years of life (r= 0.65,p< 0.001), as well as, higher levels of myelin content at 12–24 months, delayed onset and/or more prolonged rates of myelination in different brain areas. Second, we explored mechanisms of action using in vitro models (Sprague Dawley rat pups). In vitro data showed SM treatment resulted in increased proliferation [p= 0.0133 andp= 0.0434 at 4 and 10 din vitro(DIV)], maturation (p= 0.467 at 4 d DIV) and differentiation (p= 0.0123 andp= 0.0369 at 4 and 10 DIV) of oligodendrocyte precursor cells (OPCs), as well as increased axon myelination (p= 0.0005 at 32 DIV). These findings indicate an impact of dietary SM on cognitive development in healthy children, potentially modulated by oligodendrocytes and increased axon myelination. Future research should include randomized controlled trials to substantiate efficacy of SM for cognitive benefits together with preclinical studies examining SM bioavailability and brain uptake.

Polar lipids are amphiphilic lipids with a hydrophilic head and a hydrophobic tail. Polar lipids mainly include phospholipids and sphingolipids. They are structural components of neural tissues, with the peak rate of accretion overlapping with neurodevelopmental milestones. The critical role of polar lipids in cognitive development is thought to be mediated through the regulation of signal transduction, myelination, and synaptic plasticity. Animal products (egg, meat, and dairy) are the major dietary sources of polar lipids for children and adults, whereas human milk and infant formula provide polar lipids to infants. Due to the differences observed in both concentration and proportion of polar lipids in human milk, the estimated daily intake in infants encompasses a wide range. In addition, health authorities define neither intake recommendations nor guidelines for polar lipid intake. However, adequate intake is defined for 2 nutrients that are elements of these polar lipids, namely choline and DHA. To date, limited studies exist on the brain bioavailability of dietary polar lipids via either placental transfer or the blood-brain barrier. Nevertheless, due to their role in pre- and postnatal development of the brain, there is a growing interest for the use of gangliosides, which are sphingolipids, as a dietary supplement for pregnant/lactating mothers or infants. In line with this, supplementing gangliosides and phospholipids in wild-type animals and healthy infants does suggest some positive effects on cognitive performance. Whether there is indeed added benefit of supplementing polar lipids in pregnant/lactating mothers or infants requires more clinical research. In this article, we report findings of a review of the state-of-the-art evidence on polar lipid supplementation and cognitive development. Dietary sources, recommended intake, and brain bioavailability of polar lipids are also discussed.

Objective This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. Methods Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. Results The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. Conclusion Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

Background Bowling overs are the primary recorded measure for workloads in cricket for youth through to professionals. However, the validity of this measure has never been tested. Additionally, despite the cognitive component of cricket being suggested to be very high, changes in psychomotor processing speed has again not been explored. Methods Eight professional English county cricket bowlers participated in the study. Participants wore global positioning systems with a tri-axial accelerometer during a Twenty20 match and training. Bowling overs were expressed relative to external forces. Additionally, cognitive function (as measured by psychomotor speed) was assessed pre and post Twenty20 game and training. Results When expressed relative to high intensity running distance or external forces from the tri-axial accelerometer, the cost of each over (6 deliveries) was over 100% higher in a Twenty20 game compared to training. Psychomotor speed was unchanged although error within the cognitive task increased post Twenty20 (391±82±547±104 ms) and training (414±110±561±238 ms). This data suggests that reaction time is unchanged from cricket but the chance of making the incorrect decision is increased. Conclusions Movements in fielding should be quantified or bowling workloads adjusted to account for the high intensity fielding associated with Twenty20 cricket. Cognitive function was impaired following bowling, suggesting practitioners may also monitor psychomotor changes when assessing fatigue and allow appropriate time to mentally recover.

High-intensity exercise is generally considered to have detrimental effects on cognition. However, high fitness levels are suggested to alleviate this effect.The specific objective of this review was to evaluate the literature on the effect of acute high-intensity exercise on cognitive performance in trained individuals.Studies were sourced through electronic databases, reference lists of retrieved articles, and manual searches of relevant reviews. Included studies examined trained participants, included a high-intensity exercise bout, used a control or comparison group/condition, and assessed cognitive performance via general laboratory tasks during or ≤10min following exercise cessation.Ten articles met the inclusion criteria. Results indicated that the effect of acute high-intensity exercise on cognitive performance in trained individuals is dependent on the specific cognitive domain being assessed. Generally, simple tasks were not affected, while the results on complex tasks remain ambiguous. Accuracy showed little tendency to be influenced by high-intensity exercise compared to measures of speed.Multiple factors influence the acute exercise-cognition relationship and thus future research should be highly specific when outlining criteria such as fitness levels, exercise intensity, and exercise mode. Furthermore, greater research is needed assessing more cognitive domains, greater exercise durations/types, and trained populations at high intensities.

We examined the effects of video-based training in elite footballers' decision-making by presenting videos with training and testing scenarios at above real-time speeds. We also examined different training protocols to establish how much training is beneficial. We found that above real-time training improved accuracy and response time in football decision-making. In terms of scheduling, we found that the benefits were short lasting and did not last beyond 2 weeks.

Background: High-intensity exercise is generally considered to have detrimental effects on cognition. However, high-fitness levels are suggested to alleviate this effect. Objectives: The specific objective of this review was to evaluate the literature on the effect of acute high-intensity exercise on cognitive performance in trained individuals. Methods: Studies were sourced through electronic databases, reference lists of retrieved articles and manual searches of relevant reviews. Included studies examined trained participants; included a high-intensity exercise bout; used a control or comparison group/condition; and assessed cognitive performance via general laboratory tasks during or ≤10 minutes following exercise cessation. Results: Ten articles met inclusion criteria. Results indicated that the effect of acute high-intensity exercise on cognitive performance in trained individuals is dependent on the specific cognitive domain being assessed. Generally, simple tasks were not affected whilst the results on complex tasks remain ambiguous. Furthermore, accuracy showed little tendency to be influenced by high-intensity exercise compared to measures of speed. Conclusion: Multiple factors influence the acute exercise-cognition relationship and thus future research should be highly specific when outlining criteria such as fitness levels, exercise intensity and exercise mode. Furthermore, greater research is needed assessing more cognitive domains, greater exercise durations/types, and trained populations at high-intensities.

We examined the effects of video-based training in elite footballers’ decision-making by presenting videos with training and testing scenarios at above real-time speeds. We also examined different training protocols to establish how much training is beneficial. We found that above real-time training improved accuracy and response time in football decision-making. In terms of scheduling, we found that the benefits were short lasting and did not last beyond 2 weeks.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Behavioural and psychological factors related to eating have been associated with obesity, although their relationship to anthropometric measures, more specifically fat mass, has not been fully examined. This study examined the relationship between fat mass (n=98; 75M, 23 F) and behavioural measures of eating and obesity related psychological traits (n=337; 226M, 111 F) in overweight and obese individuals (Mean BMI 30.5±4.0; BMI range 25-46kg/m(2)). Two sets of principal component analyses (PCA) were performed: one on validated questionnaires of eating behaviour and psychological traits and a second on fat mass and body weight related anthropometric measures (BMI, weight) and the aforementioned questionnaire measures. From the initial PCA (n=337), the primary principal component, P1 (R(2) value of 0.33), represented a latent variable associated with overeating or binge eating behaviour. In a second PCA (questionnaire measures augmented by anthropometric variables, n=98), a single component was identified, P1(+) (R(2) of 0.28), similar to that identified as P1 in the previous analysis and this component was highly correlated with fat mass (ρ=0.68). These findings suggest that levels of body fat and eating behaviour (namely, binging or overeating) are strongly related and, at least in a subgroup of individuals, obesity may be driven by behavioural factors associated with eating in combination with pre-existing environmental and genetic factors.

The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.

Objectives. To investigate the effect of manipulating the brain dopamine system, using a D3 receptor antagonist, on approach responses to food cues in overweight and obese individuals. Methods. Twenty-six healthy overweight and obese participants were randomly assigned to receive either a single dose of dopamine D3 receptor antagonist, GSK598809 (175mg), or placebo in the first assessment session; and vice versa in the second session. Using a stimulus-response compatibility task, approach bias was indexed by response latency to move an image of a manikin towards, versus away from, pictures of food, relative to non-food stimuli. Results. Data from the first session (which were unaffected by repeated testing) indicated that approach bias scores were significantly reduced in overweight and obese participants who received GSK598809, compared with those who received placebo. Data from the second session were confounded by an effect of treatment-order and, consequently, were uninformative for the hypotheses. Conclusions. Between-subjects comparison of drug versus placebo conditions indicated that GSK598809 attenuated approach bias to food cues, which is consistent with reduction in their motivational attractiveness. Findings, albeit preliminary, concur with the view that D3 receptor antagonists may prove useful as therapeutic agents for reducing appetitive responses to food cues in obesity.

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D₃ receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D₃ receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D₃ receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

Objective: The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP. Methods: Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified. Results: Mean N1/P2 slopes for female participants were higher than those for male participants (p

An impaired capacity to filter or ‘gate’ sensory information is a core deficit in cognitive function associated with schizophrenia. These deficits have been linked in part to N-methyl-d-aspartate (NMDA) receptor dysfunction. An association between high levels of glycine, a positive allosteric modulator of the NMDA receptor, and sensorimotor gating impairments (i.e. prepulse inhibition (PPI) deficit) have been reported in animal models of schizophrenia as well as patients with schizophrenia. This study examined the acute effects of modulating the glycine site of the NMDA receptor (with high-dose glycine) on sensory gating as measured by PPI. Sixteen healthy male subjects (final sample size of 12) participated in a double-blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by at least a 5-day washout period; placebo and 0.8 g/kg glycine. PPI was recorded 45 min post treatment using electromyography of the eye-blink response. Relative to placebo, high-dose glycine significantly impaired sensorimotor gating as demonstrated by a decrease in PPI ( t(11) = −2.983, p < 0.05). Administration of a high dose of glycine is associated with impairments in PPI supporting earlier observations in animals and patients with schizophrenia. This result, when taken together with findings in patients, suggests that high synaptic levels of glycine may have some clinically relevant detrimental effects and suggests a potential dissociation of clinical symptomatology and sensory information processing as a function of NMDA receptor modulation in schizophrenia.

Adverse events; Antiobesity; Antiobesity drugs; Anxiety; Bupropion; Cannabinoid receptor; CB1 receptor; Central; Contrave; Depression; Drugs; Ecopipam; Lorcaserin; μ-opioid receptor; Naltrexone; Obesity; Psychiatric; Psychological; Rimonabant; Sedation; Sibutramine; Side effects; Sleep; Taranabant; Tesofensine; Topiramate; Treatments; Zonisamide. SUMMARY Introduction: Central neurochemical systems including the monoamine, opi- oid, and cannabinoid systems have been promising targets for antiobesity drugs that modify behavioral components of obesity. In addition to modulating eating behavior, centrally acting antiobesity drugs are also likely to alter emo- tional behavior and cognitive function due to the high expression of recep- tors for the neurochemical systems targeted by these drugs within the fronto- striatal and limbic circuitry. Methods: This paper reviewed the neuropsychi- atric adverse effects of past and current antiobesity drugs, with a central mech- anism of action, linking the adverse effects to their underlying neural sub- strates and neurochemistry. Results: Antiobesity drugs were found to have varying neuropsychiatric adverse event profiles. Insomnia was the most com- mon adverse effect with drugs targeting monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some positive effects on mood and anxiety and may have added therapeutic benefits in obese patients with comorbid depression and anxiety symptoms. Sedation and tiredness were the most common adverse effects reported with drugs targeting the m-opioid re- ceptors (i.e., naltrexone) and combination therapies targeting the opioid and monoamine systems (i.e., Contrave TM ). Cognitive impairments were most fre- quently associated with the antiepileptic drugs, topiramate and zonisamide, consistent with their sedative properties. Drugs targeting the cannabinoid sys- tem (rimonabant and taranabant) were consistently associated with symp- toms of anxiety and depression, including reports of suicidal ideation. Simi- lar adverse events have also been noted for the D1/D5 antagonist ecopipam. Conclusion: These findings highlight the need to assess neuropsychiatric ad- verse events comprehensively using sensitive and validated methods early in the clinical development of candidate antiobesity drugs with a central mecha- nism of action.

Objectives The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a valid means of non-invasively assessing in vivo central serotonin (5-hydroxytryptamine, 5-HT) function in humans. The specificity and sensitivity of the LDAEP to changes in 5-HT neurotransmission have recently been explored directly in a number of pharmacological and genetic studies. Subsequently, this review was undertaken in an attempt to critically evaluate the potential role of the LDAEP as a marker of the central 5-HT function. Design Findings from clinical, experimental animal and human studies examining the relationship between the LDAEP and the 5-HT system as well as other neurochemical systems including dopaminergic, glutamatergic and the cholinergic systems were reviewed. Results The majority of evidence for an association between the LDAEP and 5-HT has come from animal studies. Indirect studies in clinical disorders of presumed serotonergic dysfunction have been circumstantial and inconsistent with more recent investigations utilising direct genetic association studies also providing conflicting reports. Pharmacological studies in humans provide overwhelming evidence that the LDAEP is insensitive to acute changes in 5-HT function, with additional evidence outlining sensitivity to other neurotransmitter systems including the glutamatergic system. Conclusions The available evidence suggests that the LDAEP lacks sensitivity and specificity to acute changes in serotonergic neurotransmission. Overall the findings do not provide strong support for its utility as a marker of central 5-HT function. However the LDAEP shows more promise as a potential predictor of antidepressant treatment response and this predictive ability may provide the basis for future research involving the LDAEP. Copyright # 2008 John Wiley & Sons, Ltd.

Background: This study assessed the effects of two doses of glucose and a caffeine–glucose combination on mood and performance of an\ud ecologically valid, computerised multi-tasking platform.\ud Materials and methods: Following a double-blind, placebo-controlled, randomised, parallel-groups design, 150 healthy adults (mean age\ud 34.78 years) consumed drinks containing placebo, 25 g glucose, 60 g glucose or 60 g glucose with 40 mg caffeine. They completed a multitasking\ud framework at baseline and then 30 min following drink consumption with mood assessments immediately before and after the multitasking\ud framework. Blood glucose and salivary caffeine were co-monitored.\ud Results: The caffeine–glucose group had significantly better total multi-tasking scores than the placebo or 60 g glucose groups and were\ud significantly faster at mental arithmetic tasks than either glucose drink group. There were no significant treatment effects on mood. Caffeine\ud and glucose levels confirmed compliance with overnight abstinence/fasting, respectively, and followed the predicted post-drink patterns.\ud Conclusion: These data suggest that co-administration of glucose and caffeine allows greater allocation of attentional resources than\ud placebo or glucose alone. At present, we cannot rule out the possibility that the effects are due to caffeine alone Future studies should aim\ud at disentangling caffeine and glucose effects

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D₃ receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D₃ receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D₃ receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

The dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity. Here, we used functional Magnetic Resonance Imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of overweight and obese binge-eating subjects. Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula. However, brain activation to food images was not modulated by GSK598809. The results demonstrate that D(3) receptor manipulation does not modulate brain responses to food images in overweight and obese subjects.

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP.Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified.Mean N1/P2 slopes for female participants were higher than those for male participants (p 0.0001).These findings suggest that the LDAEP is modulated by sex potentially because of differences in serotonergic neurotransmission, and these differences may account for some of the inconsistent findings linking serotonin function and LDAEP.

Background The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as an electrophysiological marker for assessing serotonergic function in vivo in humans, although accumulating evidence suggests that it is insensitive to acute changes in serotonergic neurotransmission. Very little is known about the sensitivity of the LDAEP to other neurotransmitter systems including the noradrenergic system. The current study examined the effects of noradrenergic modulation as well as serotonergic modulation on the LDAEP. Methods The study utilised a double-blind placebo-controlled design in which the LDAEP in 17 healthy males and females was tested following acute administration of each of citalopram (20 mg), reboxetine (4 mg) and placebo. Results Neither citalopram nor reboxetine modulated the LDAEP relative to placebo treatment (p > 0.05). Conclusion These findings suggest that the LDAEP is insensitive to acute changes in serotonergic or noradrenergic neurotransmission and thus is a poor pharmacodynamic marker of these systems. Copyright # 2010 John Wiley & Sons, Ltd.

Schizophrenia is commonly associated with impairments in pre-attentive change detection, as represented by reduced mismatch negativity (MMN). While the neurochemical basis of MMN has been linked to N-methyl-d-aspartic acid (NMDA) receptor function, the roles of the dopaminergic and/or the serotonergic systems are not fully explored in humans. The aim of the present study was to investigate the effects of acutely depleting dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) alone or simultaneously by depleting their amino acid precursors on MMN in healthy participants. Sixteen healthy male subjects participated in a double-blind, placebo-controlled, cross-over design in which each subject’s duration MMN was assessed under four acute treatment conditions separated by a 5-day washout period: balanced amino acid control (no depletion), tyrosine/phenylalanine depletion (to reduce DA neurotransmission), tryptophan depletion (to reduce 5-HT neurotransmission) and tryptophan/tyrosine/phenylalanine depletion (to reduce DA and 5-HT neurotransmission simultaneously). Acute depletion of either DA and 5-HT alone or simultaneously had no effect on MMN. These findings suggest that modulation of the dopaminergic and serotonergic systems acutely does not lead to changes in MMN.

Objective This study examined sensory and cognitive processing in adolescents, young adults and older adults, when exposed to 2nd (2G) and 3rd (3G) generation mobile phone signals. Methods Tests employed were the auditory 3-stimulus oddball and the N-back. Forty-one 13–15year olds, forty-two 19–40year olds and twenty 55–70year olds were tested using a double-blind cross-over design, where each participant received Sham, 2G and 3G exposures, separated by at least 4days. Results 3-Stimulus oddball task: Behavioural : accuracy and reaction time of responses to targets were not affected by exposure. Electrophysiological : augmented N1 was found in the 2G condition (independent of age group). N-back task: Behavioural : the combined groups performed less accurately during the 3G exposure (compared to Sham), with post hoc tests finding this effect separately in the adolescents only. Electrophysiological : delayed ERD/ERS responses of the alpha power were found in both 3G and 2G conditions (compared to Sham; independent of age group). Conclusion Employing tasks tailored to each individual's ability level, this study provides support for an effect of acute 2G and 3G exposure on human cognitive function. Significance The subtlety of mobile phone effect on cognition in our study suggests that it is important to account for individual differences in future mobile phone research.

Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing such that perceptual bias is shifted away from negative and towards positive emotional material. However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown.The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli.This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg).Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP).Citalopram and reboxetine have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli.

Objective The underlying effect of serotonergic neurotransmission has been implicated in several psychiatric disorders. The inability to routinely and non-invasively determine the integrity of the serotonergic system in vivo has limited our understanding of disorders with a putative serotonergic abnormality. The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a reliable measure of central serotonin function in humans. While animal studies suggest that the LDAEP is sensitive to changes in central serotonin neurotransmission, evidence in humans has been indirect and inconsistent. The aim of this study was to assess the sensitivity of the LDAEP to acute augmentation in central serotonergic neurotransmission in humans. Methods The study used a double-blind, placebo-controlled cross-over design, in which healthy subjects were tested under four acute treatment conditions, with pharmacologically equivalent single doses of placebo, escitalopram (10 mg), citalopram (20 mg) and sertraline (50 mg) to examine the direct effect of acute enhancement of synaptic serotonin on the LDAEP. Furthermore, the outcome of the serotonergic modulatory effects on the LDAEP was also examined using two methods (dipole source analysis (DSA) vs. scalp analysis). Results Escitalopram, citalopram and sertraline had no effects on the LDAEP and were independent of the analysis method used. Conclusion These findings question the sensitivity of the LDAEP to acute changes in serotonin neurotransmission and its validity as a reliable measure of central serotonin function in humans. Copyright © 2008 John Wiley & Sons, Ltd.

Background The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a possible in vivo measure of central serotonin function. However, more recent studies suggest that the LDAEP may be modulated by multiple neuromodulatory systems in addition to the serotonergic system. Accordingly we further examined the effects of selective serotonin, dopamine and simultaneous serotonin and dopamine depletion on the LDAEP in healthy subjects. Methods The study employed a placebo-controlled, double-blind, cross over design. Fourteen subjects were tested under four acute treatment conditions: placebo (balanced amino acid drink), tryptophan (serotonin) depletion (ATD), tyrosine/phenylalanine (dopamine) depletion (ATPD) and combined tryptophan/tyrosine/phenylalanine (serotonin and dopamine) depletion (CMD). Testing was conducted 5.5 h post-depletion and changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at CZ. Results Greater than 80% plasma precursor depletion was achieved across all conditions. Despite significant depletion of monoamine precursors, ATD, (p = 0.318), ATPD (p = 0.061) and CMD (p = 0.104) had no effects on the LDAEP (60–100 dB). Conclusion Acute serotonin and dopamine depletion did not modulate the LDAEP. This finding adds support to growing evidence that the LDAEP is insensitive to acute changes in serotonin and dopamine neurotransmission. Copyright © 2008 John Wiley & Sons, Ltd.

N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition, although findings have not been convincing. We used the Cognitive Drug Research computerised assessment system to examine the effects of high-dose glycine on a number of cognitive processes in healthy young subjects. The study was a randomised placebo controlled repeated measures design in which each subject received acute placebo or glycine (0.8 g/kg) orally, with treatment conditions separated by a 5-day washout period. No significant effects of glycine were found on measures of working memory, declarative memory, attention or perceptual processing. These findings, together with those of previous studies, cast doubt over the ability of acute high-dose glycine to improve cognitive function in healthy subjects and suggest that the optimum dose of glycine for improving cognition may vary between different populations, possibly due to differences in endogenous glycine levels and the functional status of NMDA receptors.

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal ‘gating’ function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

Schizophrenia is commonly associated with impairments in pre-attentive change detection as represented by reduced mismatch negativity (MMN). The neurochemical basis of MMN has been linked to N-methyl-d-aspartate (NMDA) receptor function. Glycine augments NMDA receptor function via stimulation of the glycine modulatory site of the NMDA receptor and has been shown to effectively reduce negative symptoms in schizophrenia. However, no study has investigated the possible effects of high-dose glycine on MMN. Further, the physiological consequences of administering high-dose glycine in subjects with normal NMDA receptor function are unknown. The aim of the present project was to investigate the acute effects of a single large dose of glycine on the human MMN in healthy subjects. Sixteen healthy male subjects participated in a double blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by a 1-week washout period; placebo and 0.8 g/kg glycine. The subjects were exposed to a duration-MMN paradigm with 50-ms standard tones (91%) and 100-ms deviant tones (9%). The results showed that glycine significantly attenuated duration MMN amplitude at frontal electrodes. There was no effect of glycine on MMN latencies or on amplitudes or latencies of N1, N2 and P3a. These findings suggest that an acute high dosage of glycine attenuates MMN in healthy controls, raising the possibility that optimal effects of glycine and other glycine agonists may depend on the integrity of the NMDA receptor system.

The loudness dependence of the auditory evoked Potential (LDAEP) has been suggested to be a putative marker of central serotonin function, with reported abnormalities in clinical disorders presumed to reflect serotonin dysfunction. Despite considerable research, very little is known about the LDAEP’s sensitivity to other neurotransmitter systems. Given the role of N-methyl-d-aspartate (NMDA) receptors in modulating pyramidal cell activity in cortico-cortico and thalamo-cortical loops, we examined the effect of targeting the glycine modulatory site of the NMDA receptor with high-dose glycine on the LDAEP in healthy subjects. The study was a double-blind, placebo-controlled repeated-measures design in which 14 healthy participants were tested under two acute treatment conditions, placebo and oral glycine (0.8 g/kg). Changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at CZ. Compared to placebo, high-dose glycine induced a weaker LDAEP (a pronounced decrease in the slope of the N1/P2 with increasing tone loudness; p

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.

The Loudness Dependence of the Auditory Evoked Potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans; however, its specificity for the serotonin system remains a topic of debate, with possible modulation of this purported serotonin marker by other neurotransmitters, including dopamine.We examined the effect of dopaminergic modulation on the LDAEP using the D1/D2/D3 dopamine receptor agonist pergolide and the D2/D3 agonist bromocriptine.The study was a double-blind, placebo-controlled repeated-measures design in which healthy participants were tested under three acute treatment conditions: placebo, bromocriptine (2.5 mg), and pergolide (0.1 mg). Changes in the amplitude of the N1/P2 at intensities (60, 70, 80, 90, and 100 dB) were examined at C Z.Acute stimulation of D1/D2/D3 receptors with pergolide and D2/D3 receptors with bromocriptine in comparison with placebo had no effect on the LDAEP.These findings indicate that acute stimulation of dopamine D1, D2, and D3 receptors does not modulate the LDAEP in humans. Although the findings suggest that the LDAEP may not be modulated by acute changes in dopamine neurotransmission, further studies are needed to fully characterize its dopaminergic sensitivity.

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans. The most convincing evidence for a direct relationship between serotonergic function and LDAEP to date has come from animal studies, while evidence in humans has been circumstantial and inconsistent. In the current study, we examine the direct effect of serotonergic modulation with the selective serotonin reuptake inhibitor (SSRI) citalopram on the LDAEP. The study was a double-blind placebo controlled design in which healthy participants were tested under two acute treatment conditions: placebo and citalopram (20 mg). Enhancement of serotonin function with citalopram in comparison to placebo decreased the slope of the LDAEP (i.e. weaker LDAEP). The findings provide direct evidence in humans, of a relationship between central serotonin function and the LDAEP, supporting findings previously observed in animals and clinical populations. Together the results provide further support for the validity of the LDAEP as a non-invasive in vivo measure of central serotonin function in humans.

Is the Loudness Dependence of the Auditory Evoked Potential a Sensitive and Selective In Vivo Marker of Central Serotonergic Function?