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 Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events.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.

The effects of glycine on auditory mismatch negativity in schizophrenia.

Glycine increases N-methyl-d-aspartate receptor (NMDAR) mediated glutamatergic function. Mismatch negativity (MMN) is a proposed biomarker of glutamate-induced improvements in clinical symptoms, however, the effect of glycine-mediated NMDAR activation on MMN in schizophrenia is not well understood. This study aimed to determine the effects of acute and 6-week chronic glycine administration on MMN in schizophrenia patients. MMN amplitude was compared at baseline between 22 patients (schizophrenia or schizoaffective disorder; receiving stable antipsychotic medication; multi-centre recruitment) and 21 age- and gender-matched controls. Patients underwent a randomised, double-blind, placebo-controlled clinical trial with glycine added to their regular antipsychotic medication (placebo, n=10; glycine, n=12). MMN was reassessed post-45-minutes of first dose (0.2g/kg) and post-6-weeks treatment (incremented to 0.6g/kg/day). Clinical symptoms were assessed at baseline and post-6-weeks treatment. At baseline, duration MMN was smaller in schizophrenia compared to controls. Acute glycine increased duration MMN (compared to placebo), whilst this difference was absent post-6-weeks treatment. Six weeks of chronic glycine administration improved PANSS-Total, PANSS-Negative and PANSS-General symptoms compared to placebo. Smaller baseline duration MMN was associated with greater PANSS-Negative symptoms and predicted (at trend level) PANSS-Negative symptom improvement post-6-weeks glycine treatment (not placebo). These findings support the benefits of chronic glycine administration and demonstrate, for the first time, that acute glycine improves duration MMN in schizophrenia. This result, together with smaller baseline duration MMN predicting greater clinical treatment response, suggests the potential for duration MMN as a biomarker of glycine-induced improvements in negative symptoms in schizophrenia.

Attention to language: novel MEG paradigm for registering involuntary language processing in the brain.

Previous research indicates that, under explicit instructions to listen to spoken stimuli or in speech-oriented behavioural tasks, the brain's responses to senseless pseudowords are larger than those to meaningful words; the reverse is true in non-attended conditions. These differential responses could be used as a tool to trace linguistic processes in the brain and their interaction with attention. However, as previous studies relied on explicit instructions to attend or ignore the stimuli, a technique for automatic attention modulation (i.e., not dependent on explicit instruction) would be more advantageous, especially when cooperation with instructions may not be guaranteed (e.g., neurological patients, children etc). Here we present a novel paradigm in which the stimulus context automatically draws attention to speech. In a non-attend passive auditory oddball sequence, rare words and pseudowords were presented among frequent non-speech tones of variable frequency and length. The low percentage of spoken stimuli guarantees an involuntary attention switch to them. The speech stimuli, in turn, could be disambiguated as words or pseudowords only in their end, at the last phoneme, after the attention switch would have already occurred. Our results confirmed that this paradigm can indeed be used to induce automatic shifts of attention to spoken input. At ~250ms after the stimulus onset, a P3a-like neuromagnetic deflection was registered to spoken (but not tone) stimuli indicating an involuntary attention shift. Later, after the word-pseudoword divergence point, we found a larger oddball response to pseudowords than words, best explained by neural processes of lexical search facilitated through increased attention. Furthermore, we demonstrate a breakdown of this orderly pattern of neurocognitive processes as a result of sleep deprivation. The new paradigm may thus be an efficient way to assess language comprehension processes and their dynamic interaction with those of attention allocation. It does it in an automatic and task-free fashion, indicating its potential benefit for assessing uncooperative clinical populations.

Fast reconfiguration of high-frequency brain networks in response to surprising changes in auditory input.

How do human brain networks react to dynamic changes in the sensory environment? We measured rapid changes in brain network organization in response to brief, discrete, salient auditory stimuli. We estimated network topology and distance parameters in the immediate central response period, <1 s following auditory presentation of standard tones interspersed with occasional deviant tones in a mismatch-negativity (MMN) paradigm, using magnetoencephalography (MEG) to measure synchronization of high-frequency (gamma band; 33-64 Hz) oscillations in healthy volunteers. We found that global small-world parameters of the networks were conserved between the standard and deviant stimuli. However, surprising or unexpected auditory changes were associated with local changes in clustering of connections between temporal and frontal cortical areas and with increased interlobar, long-distance synchronization during the 120- to 250-ms epoch (coinciding with the MMN-evoked response). Network analysis of human MEG data can resolve fast local topological reconfiguration and more long-range synchronization of high-frequency networks as a systems-level representation of the brain's immediate response to salient stimuli in the dynamically changing sensory environment.

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.

Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala, and ventral striatum.

We used functional magnetic resonance imaging to explore brain responses to food images in overweight humans, examining independently the impact of a prescan meal ("satiety") and the anti-obesity drug sibutramine, a serotonin and noradrenaline reuptake inhibitor. We identified significantly different responses to these manipulations in amygdala, hypothalamus, and ventral striatum. Each region was specifically responsive to high-calorie compared to low-calorie food images. However, the ventral striatal response was attenuated by satiety (but unaffected by sibutramine), while the hypothalamic and amygdala responses were attenuated by drug but unaffected by satiety. Direct assessment of regional interactions confirmed the significance of this double dissociation. We explored the regional responses in greater detail by determining whether they were predictive of eating behavior and weight change. We observed that across the different regions, the individual-specific magnitude of drug- and satiety-induced modulation was associated with both variables: the sibutramine-induced modulation of the hypothalamic response was correlated with the drug's impact on both weight and subsequently measured ad libitum eating. The satiety-induced modulation of striatal response also correlated with subsequent ad libitum eating. These results suggest that hypothalamus and amygdala have roles in the control of food intake that are distinct from those of ventral striatum. Furthermore, they support a regionally specific effect on brain function through which sibutramine exerts its clinical effect.

Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial.

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration.

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.

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.

The cognitive effects of modulating the glycine site of the NMDA receptor with high-dose glycine in healthy controls.

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.

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.

Acute dopamine D(1) and D(2) receptor stimulation does not modulate mismatch negativity (MMN) in healthy human subjects.

RATIONALE: Schizophrenia is commonly associated with an impairment in pre-attentive change detection, as represented by reduced mismatch negativity (MMN), an auditory event related potential. While the neurochemical basis of MMN has been linked to the integrity of the glutamatergic system involving N-methyl-D-aspartate (NMDA) receptors, the role of the dopaminergic system and in particular, the role of D(1) and D(2) receptors on MMN is yet to be determined. OBJECTIVES: The aim of the present project was to investigate the acute effects of dopamine D(2) (bromocriptine) and D(1)/D(2) (pergolide) receptor stimulation on the human MMN in healthy subjects. METHODS: Fifteen healthy male subjects participated in a double-blind, placebo-controlled, cross-over design in which each subject was tested under three acute treatment conditions separated by a 1-week wash out period; placebo, bromocriptine (2.5 mg) and pergolide (0.1 mg). 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 neither D(2) receptor stimulation with bromocriptine, nor simultaneous D(1) and D(2) receptor stimulation with pergolide, modulated MMN. CONCLUSIONS: These findings suggest that acute D(1) and D(2) receptor stimulation does not modulate MMN. While the role of dopamine cannot be completely ruled out, the findings support the view that the aberrant MMN reported in schizophrenia may be linked primarily to glutamate dysfunction involving NMDA receptors.

High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans.

RATIONALE: 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. OBJECTIVES: 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. MATERIALS AND METHODS: 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 C(Z). RESULTS: 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 < 0.02). CONCLUSION: While the exact mechanism responsible for the effects of glycine on the LDAEP are not known, the findings suggest an inhibitory effect in the cortex, possibly via activation of NMDA receptors on GABA interneurons or inhibitory glycine receptors. The findings add to the growing literature exhibiting modulation of the LDAEP by multiple neurochemical systems in addition to the serotonergic system.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women.

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT(1A) receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function.

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.

The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans.

L-Theanine (delta-glutamylethylamide) is one of the predominant amino acids ordinarily found in green tea, and historically has been used as a relaxing agent. The current study examined the acute effects of L-theanine in comparison with a standard benzodiazepine anxiolytic, alprazolam and placebo on behavioural measures of anxiety in healthy human subjects using the model of anticipatory anxiety (AA). Sixteen healthy volunteers received alprazolam (1 mg), L-theanine (200 mg) or placebo in a double-blind placebo-controlled repeated measures design. The acute effects of alprazolam and L-theanine were assessed under a relaxed and experimentally induced anxiety condition. Subjective self-reports of anxiety including BAI, VAMS, STAI state anxiety, were obtained during both task conditions at pre- and post-drug administrations. The results showed some evidence for relaxing effects of L-theanine during the baseline condition on the tranquil-troubled subscale of the VAMS. Alprazolam did not exert any anxiolytic effects in comparison with the placebo on any of the measures during the relaxed state. Neither L-theanine nor alprazalam had any significant anxiolytic effects during the experimentally induced anxiety state. The findings suggest that while L-theanine may have some relaxing effects under resting conditions, neither L-theanine not alprazolam demonstrate any acute anxiolytic effects under conditions of increased anxiety in the AA model.

Effects of a combined extract of Ginkgo biloba and Bacopa monniera on cognitive function in healthy humans.

Extracts of Ginkgo biloba and Bacopa monniera have been shown to produce positive effects on cognitive function in healthy subjects. While the exact mechanisms are not known, it has been suggested that antioxidant properties and cholinergic modulation may play a role. In the current study the sub-chronic (2 weeks) and chronic (4 weeks) effects of an extract containing Ginkgo biloba (120 mg) and Bacopa monniera (300 mg) (Blackmores Ginkgo Brahmi) on cognitive function were examined. The study was a randomized, double-blind, placebo-controlled, independent group design in which 85 healthy subjects were allocated to one of two treatment conditions (placebo or combined Ginkgo biloba and Bacopa monniera extract). Testing was conducted at baseline and 2 and 4 weeks post treatment. The results showed that the combined extract relative to placebo did not demonstrate any significant effects on tests investigating a range of cognitive processes including attention, short-term and working memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness and decision making. These findings suggest that at least within the current treatment duration and doses, an extract containing Ginkgo biloba and Bacopa monniera had no cognitive enhancing effects in healthy subjects.