Detrimental effects on executive function and mood following consecutive days of repeated high-intensity sprint interval exercise in trained male sports players.

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.

Singapore Sling: F1 Race Team Cognitive Function and Mood Responses During the Singapore Grand Prix.

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.

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study.

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 ß-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.

Effects of two doses of glucose and a caffeine-glucose combination on cognitive performance and mood during multi-tasking.

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

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) 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 M(1) 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 M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Effect of intensified training on cognitive function, psychological state & performance in trained cyclists.

Athletes often undertake intensified training loads prior to competition with the goal of functionally overreaching for temporary performance enhancement; however, little is known about the impact of this on cognitive function. The aim of this study was to investigate the effect of intensified training induced fatigue on cognitive function, psychological state and performance in trained cyclists. Twenty-three trained male cyclists were randomly assigned to an intensified training group or a control group for two-weeks, followed by a two-week taper period. At baseline, one-week, two-weeks and post-taper, participants undertook a series of cognitive, performance, mood and recovery-stress assessments. The training intervention significantly increased training volume, load and strain by 108%, 116% and 151% respectively. Peak and mean power output on a maximal test and time trial significantly decreased by 4.8% and 9.4% following the two-week training intervention compared to baseline, in addition to a 169% change in total mood disturbance and significant disruption to recovery-stress balance. No change in any cognitive measure was observed across the study period. Following a two-week taper, performance, mood and well-being measures returned to baseline. Two weeks of intensified training resulted in overreaching as identified by performance and psychological measures. Cognitive function was not sensitive to intensified training promoting caution with its use as a measure for the early identification of overreaching.HighlightsTwo-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.

An Examination of the Associations between Nutritional Composition, Social Jet Lag and Temporal Sleep Variability in Young Adults.

While dietary intake has previously been related to various indices of poor sleep (e.g., short sleep duration, poor sleep quality), to date, few studies have examined chrononutrition from the perspectives of the relationship between dietary intake and social jet lag and temporal sleep variability. Moreover, recently it has been suggested that previous methods of measuring social jet lag have the potential to lead to large overestimations. Together, this precludes a clear understanding of the role of nutritional composition in the pathophysiology of poor sleep, via social jet lag and temporal sleep variability, or vice versa. The aim of the present study was to determine the relationships between nutrient intake and social jet lag (using a revised index, taking account of intention to sleep and sleep onset and offset difficulties), and temporal sleep variability. Using a cross-sectional survey, 657 healthy participants (mean age 26.7 ± 6.1 years), without sleep disorders, were recruited via an online platform and completed measures of weekly dietary intake, social jet lag, temporal sleep variability, stress/sleep reactivity and mood. Results showed limited associations between nutritional composition and social jet lag. However, levels of temporal sleep variability were predicted by consumption of polyunsaturated fats, sodium, chloride and total energy intake. The results suggest further examinations of specific nutrients are warranted in a first step to tailoring interventions to manage diet and temporal variabilities in sleep patterns.

The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.

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 relationship between fat mass, eating behaviour and obesity-related psychological traits in overweight and obese individuals.

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.

A Nutrient Formulation Affects Developmental Myelination in Term Infants: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Observational studies suggest differences between breast-fed and formula-fed infants in developmental myelination, a key brain process for learning. The study aims to investigate the efficacy of a blend of docosahexaenoic acid (DHA), arachidonic acid (ARA), iron, vitamin B12, folic acid, and sphingomyelin (SM) from a uniquely processed whey protein concentrate enriched in alpha-lactalbumin and phospholipids compared with a control formulation on myelination, cognitive, and behavioral development in the first 6 months of life. METHODS: These are 6-month results from an ongoing two-center, randomized controlled trial with a 12-month intervention period (completed for all participants). In this study, full term, neurotypical infants of both sexes (N = 81) were randomized into investigational (N = 42) or control groups (N = 39). In addition, non-randomized breast-fed children (N = 108) serve as a natural reference group. Main outcomes are myelination (MRI), cognitive (Bayley Scales of Infant and Toddler Development, 3rd edition [Bayley-III]), social-emotional development (Ages and Stages Questionnaires: Social-Emotional, 2nd edition [ASQ:SE-2]), sleep (Brief Infant Sleep Questionnaire [BISQ]), and safety (growth and adverse events [AEs]). RESULTS: The full analyses set comprises N = 66 infants. Significant differences in myelin structure, volume, and rate of myelination were observed in favor of the investigational myelin blend at 3 and 6 months of life. Effects were demonstrated for whole brain myelin and for cerebellar, parietal, occipital, and temporal regions, known to be functionally involved in sensory, motor, and language skills. No statistically significant differences were found for early behavior and cognition scores. CONCLUSIONS: This is the first study demonstrating the efficacy of a myelin nutrient blend in well-nourished, term infants on developmental myelination, which may be foundational for later cognitive and learning outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03111927.

Evidence for sex differences in the loudness dependence of the auditory evoked potential in humans.

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 < 0.0001). CONCLUSION: 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.

The loudness dependence auditory evoked potential is insensitive to acute changes in serotonergic and noradrenergic neurotransmission.

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.

Dietary Polar Lipids and Cognitive Development: A Narrative Review.

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.

Quantification of bowling workload and changes in cognitive function in elite fast bowlers in training compared with Twenty20 Cricket.

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.

Sphingomyelin in Brain and Cognitive Development: Preliminary Data.

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 and p = 0.0434 at 4 and 10 d in vitro (DIV)], maturation (p = 0.467 at 4 d DIV) and differentiation (p = 0.0123 and p = 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.

Differential effects of acute serotonin and dopamine depletion on prepulse inhibition and p50 suppression measures of sensorimotor and sensory gating in humans.

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.

Acute high-dose glycine attenuates mismatch negativity (MMN) in healthy human controls.

RATIONALE: 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. OBJECTIVES: 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. MATERIALS AND METHODS: 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%). RESULTS: 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. CONCLUSIONS: 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) as an in vivo biomarker of central serotonergic function in humans: rationale, evaluation and review of findings.

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.

An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline.

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.

Effects of selective and combined serotonin and dopamine depletion on the loudness dependence of the auditory evoked potential (LDAEP) in humans.

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 C(Z). 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.