Increased body mass index is associated with specific regional alterations in brain structure.

BACKGROUND: Although obesity is associated with structural changes in brain grey matter, findings have been inconsistent and the precise nature of these changes is unclear. Inconsistencies may partly be due to the use of different volumetric morphometry methods, and the inclusion of participants with comorbidities that exert independent effects on brain structure. The latter concern is particularly critical when sample sizes are modest. The purpose of the current study was to examine the relationship between cortical grey matter and body mass index (BMI), in healthy participants, excluding confounding comorbidities and using a large sample size. SUBJECTS: A total of 202 self-reported healthy volunteers were studied using surface-based morphometry, which permits the measurement of cortical thickness, surface area and cortical folding, independent of each other. RESULTS: Although increasing BMI was not associated with global cortical changes, a more precise, region-based analysis revealed significant thinning of the cortex in two areas: left lateral occipital cortex (LOC) and right ventromedial prefrontal cortex (vmPFC). An analogous region-based analysis failed to find an association between BMI and regional surface area or folding. Participants' age was also found to be negatively associated with cortical thickness of several brain regions; however, there was no overlap between the age- and BMI-related effects on cortical thinning. CONCLUSIONS: Our data suggest that the key effect of increasing BMI on cortical grey matter is a focal thinning in the left LOC and right vmPFC. Consistent implications of the latter region in reward valuation, and goal control of decision and action suggest a possible shift in these processes with increasing BMI.

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Speed of facial affect intensity recognition as an endophenotype of first-episode psychosis and associated limbic-cortical grey matter systems.

BACKGROUND: Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP). METHOD: Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed. RESULTS: The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives. CONCLUSIONS: Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.

Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters.

BACKGROUND: Patients with major depressive disorder (MDD) show deficits in processing of facial emotions that persist beyond recovery and cessation of treatment. Abnormalities in neural areas supporting attentional control and emotion processing in remitted depressed (rMDD) patients suggests that there may be enduring, trait-like abnormalities in key neural circuits at the interface of cognition and emotion, but this issue has not been studied systematically. METHOD: Nineteen euthymic, medication-free rMDD patients (mean age 33.6 years; mean duration of illness 34 months) and 20 age- and gender-matched healthy controls (HC; mean age 35.8 years) performed the Emotional Face N-Back (EFNBACK) task, a working memory task with emotional distracter stimuli. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure neural activity in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC), ventral striatum and amygdala, using a region of interest (ROI) approach in SPM2. RESULTS: rMDD patients exhibited significantly greater activity relative to HC in the left DLPFC [Brodmann area (BA) 9/46] in response to negative emotional distracters during high working memory load. By contrast, rMDD patients exhibited significantly lower activity in the right DLPFC and left VLPFC compared to HC in response to positive emotional distracters during high working memory load. These effects occurred during accurate task performance. CONCLUSIONS: Remitted depressed patients may continue to exhibit attentional biases toward negative emotional information, reflected by greater recruitment of prefrontal regions implicated in attentional control in the context of negative emotional information.

Examining brain-cognition effects of ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task.

Ginkgo Biloba extract (GBE) is increasingly used to alleviate symptoms of age related cognitive impairment, with preclinical evidence pointing to a pro-cholinergic effect. While a number of behavioral studies have reported improvements to working memory (WM) associated with GBE, electrophysiological studies of GBE have typically been limited to recordings during a resting state. The current study investigated the chronic effects of GBE on steady state visually evoked potential (SSVEP) topography in nineteen healthy middle-aged (50-61 year old) male participants whilst completing an object WM task. A randomized double-blind crossover design was employed in which participants were allocated to receive 14 days GBE and 14 days placebo in random order. For both groups, SSVEP was recorded from 64 scalp electrode sites during the completion of an object WM task both pre- and 14 days post-treatment. GBE was found to improve behavioural performance on the WM task. GBE was also found to increase the SSVEP amplitude at occipital and frontal sites and increase SSVEP latency at left temporal and left frontal sites during the hold component of the WM task. These SSVEP changes associated with GBE may represent more efficient processing during WM task completion.

Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the µ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-ß-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

High-dose glycine impairs the prepulse inhibition measure of sensorimotor gating in humans.

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.

Augmenting serotonin neurotransmission with citalopram modulates emotional expression decoding but not structural encoding of moderate intensity sad facial emotional stimuli: an event-related potential (ERP) investigation.

Antidepressants targeting the serotonergic system have been shown to modulate biases in emotional processing. The effects of serotonergic modulation on the temporal course of emotional processing (accruing within milliseconds) are unknown. Furthermore, it is unknown how serotonin affects different stages of facial emotional processing. The current study investigated the effects of acute serotonin augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion 'expression decoding' (N250 and a late slow-wave positive potential [LPP]) of happy and sad facial stimuli, relative to neutral facial stimuli. The study was a double-blind, placebo-controlled, cross-over design, in which 14 healthy male participants completed a facial recognition task under two acute treatment conditions: 1) placebo (PLB) and 2) 20 mg citalopram (CIT). ERP recording were conducted while subjects viewed neutral, happy and sad facial stimuli. Findings indicated that under PLB, the N170 was not modulated by valence (happy or sad versus neutral), but the N250 and LPP were enhanced for processing happy (relative to neutral) faces. Citalopram had no effect on the N170, but it enhanced the LPP for processing sad (relative to neutral) faces. These findings suggest that serotonin enhancement has selective and temporal effects on emotional face processing, with evidence for modulating processes associated with 'expression decoding' but not 'structural encoding'. The enhanced cortical response to perception of moderately intense sad facial expressions following citalopram administration may relate to the cognitive processing of the social relevance or significance of such ambiguous stimuli.

The relationship between nicotinic receptors and cognitive functioning in healthy aging: An in vivo positron emission tomography (PET) study with 2-[(18)F]fluoro-A-85380.

Extensive experimental and neuropathological evidence supports the general hypothesis that decline in the basal forebrain cholinergic system contributes significantly to age-related cognitive impairment. Postmortem studies suggest reductions in neuronal nicotinic acetylcholine receptors (nAChRs, particularly the alpha(4)beta(2) subtype) with aging. This study aimed to determine the distribution of alpha(4)beta(2)-subtype nAChRs in vivo by 2-FA PET in healthy subjects (aged 21-83) and to establish whether there is an age-related decline in nAChRs. Furthermore, the relationship between PET measures of 2-FA binding and neurobehavioral measures of cognitive function was investigated. All participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of 2-FA (200 MBq). Brain regional 2-FA binding was assessed through a simplified estimation of distribution volume (DV(S)). As expected, increasing age was associated with poorer cognitive performance, particularly on tasks assessing episodic memory and attentional processes. No significant age-related differences in regional nAChR DV(S) were found. Furthermore, no significant correlations were found between cognitive measures and nAChR DV(S). These results are consistent with recent studies suggesting the stability of cholinergic markers during senescence. It is plausible that changes in alpha(4)beta(2) nAChRs do occur with advancing age, but are beyond detection by the clinical 2-FA PET approach adopted here. However, this approach may be appropriate for use in pathologies considered to undergo extensive nAChR loss such as Alzheimer's disease and Parkinson's disease.

Galantamine-induced improvements in cognitive function are not related to alterations in alpha(4)beta (2) nicotinic receptors in early Alzheimer's disease as measured in vivo by 2-[18F]fluoro-A-85380 PET.

INTRODUCTION: The nicotinic acetylcholine receptor (nAChR) system plays a regulatory role in a number of cognitive processes. Cholinesterase inhibitors (i.e., galantamine) that potentiate cholinergic neurotransmission improve cognitive function in Alzheimer's disease (AD); however, the relationship between these effects and associated changes in nAChRs are yet to be established in vivo. MATERIALS AND METHODS: 2-[18F]Fluoro-A-85380 (2-FA) binds to nAChRs and with positron emission tomography (PET) imaging provides a composite measure of receptor density and ligand affinity. This study aimed to: (1) quantify nAChRs in vivo in 15 drug-naïve patients with mild AD before and after chronic treatment with galantamine, using 2-FA and PET, and (2) examine the relationship between treatment-induced changes in nAChRs and improvements in cognitive function. Participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of approximately 200 MBq of 2-FA on two occasions (before and after 12 weeks, galantamine treatment). A 3-day washout period preceded the second scan. Brain regional 2-FA binding was assessed through a simplified estimation of distribution volume (DV(S)). RESULTS: Performance on global measures of cognition significantly improved following galantamine treatment (p < 0.05). This improvement extended to specific cognitive measures of language and verbal learning. No significant differences in nAChR DV(S) before and after galantamine treatment were found. The treatment-induced improvement in cognition was not correlated with regional or global nAChR DV(S), suggesting that changes in nAChRs may not be responsible for the improvements in cognition following galantamine in patients with mild AD.

Relationship between nicotinic receptors and cognitive function in early Alzheimer's disease: a 2-[18F]fluoro-A-85380 PET study.

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the alpha(4)beta(2) subtype) with ageing and in Alzheimer's disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DV(S)). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p<.05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.

Evidence for synergistic modulation of early information processing by nicotinic and muscarinic receptors in humans.

Impairments in early information processing are a hallmark feature of diverse neuropsychiatric disorders including schizophrenia and Alzheimer's disease (AD). Several lines of evidence implicate a dysfunction of the cholinergic system in these disorders, particularly in AD where there is known degeneration in major cholinergic pathways. Inspection time (IT), a measure of early visual information processing speed, has been shown to be sensitive to cholinergic manipulation. The current study employed the IT task to (1) examine the independent roles of nicotinic and muscarinic receptors in modulating information processing and (2) investigate the interaction of nicotinic and muscarinic receptor systems in modulating information processing. Twelve healthy participants completed a randomized, double-blind, placebo-controlled study under four drug conditions; (1) placebo, (2) mecamylamine (15 mg; oral), (3) scopolamine (0.4 mg, s.c.), (4) mecamylamine (15 mg) + scopolamine (0.4 mg). IT measures were examined at baseline and 2.5 h post drug administration. Selective blockade of nicotinic receptors with mecamylamine did not significantly impair IT, whereas selective blockade of muscarinic receptors with scopolamine produced a significant but small impairment in IT. Combined blockade of both receptor types with scopolamine and mecamylamine produced a large impairment in IT performance. The results indicate that both nicotinic and muscarinic receptors are involved in modulating IT, and that the two systems may function synergistically to modulate early visual information processing. These findings suggest that functional abnormalities in both nicotinic and muscarinic systems may underlie deficits in early visual information processing seen in disorders such as Alzheimer's disease and schizophrenia.

Gender differences in the cortical electrophysiological processing of visual emotional stimuli.

The processing of visual emotional stimuli has been investigated previously; however, gender differences in the processing of emotional stimuli remain to be clarified. The aim of the current study was to use steady-state probe topography (SSPT) to examine steady-state visually evoked potentials (SSVEPs) during the processing of pleasant and unpleasant images relative to neutral images, and to determine whether this processing differs between males and females. Thirty participants (15 males and 15 females) viewed 75 images low on the arousal dimension (categorised as pleasant, neutral or unpleasant) selected from the International Affective Picture System (IAPS), whilst a 13-Hz sinusoidal white visual flicker was superimposed over the visual field and brain electrical activity was recorded from 64 electrode sites. Results suggest that pleasant and unpleasant images relative to neutral images are associated with reductions in frontal latency and occipital amplitude. In addition, electrophysiological gender differences were observed despite there being no differences found between males and females on subjective mood or behavioural ratings of presented images (valence and arousal dimensions). The main gender difference reported in the current study related to the processing of unpleasant images (relative to neutral images) which is associated with widespread frontal latency reductions (predominantly right sided) in females but not in males. Our results suggest that gender differences do exist in the processing of visual emotional stimuli, and illustrate the importance of taking these differences into account during investigations of emotional processing. Finally, these gender differences may have implications for the pathophysiology of mood disorders such as depression.

Cortical neurophysiology of anticipatory anxiety: an investigation utilizing steady state probe topography (SSPT).

The precise role of the cortex in human anxiety is not well characterised. Previous imaging research among healthy controls has reported alterations in regional cerebral blood flow (rCBF) within the prefrontal and temporal cortices during periods of anxious anticipation; however, the temporal dynamics of this activity has yet to be examined in detail. The present study examined cortical Steady State Probe Topography (SSPT) changes associated with anticipatory anxiety (AA), allowing examination of the temporal continuity and the excitatory or inhibitory nature of AA activations. We recorded Steady State Visually Evoked Potentials (SSVEPs) at 64 scalp locations, skin conductance, and self reported anxiety among 26 right-handed males while relaxed and during the anticipation of an electric shock. Relative to the baseline condition, the AA condition was associated with significantly higher levels of self-reported anxiety and increased phasic skin conductance levels. Across the seven second imaging window, AA was associated with increased SSVEP latency within medial anterior frontal, left dorsolateral prefrontal and bilateral temporal regions. In contrast, increased SSVEP amplitude and decreased SSVEP latency were observed within occipital regions. The observed SSVEP latency increases within frontal and temporal cortical regions are suggestive of increased localised inhibitory processes within regions reciprocally connected to subcortical limbic structures. Occipital SSVEP latency decreases are suggestive of increased excitatory activity. SSVEP amplitude increases within occipital regions may be associated with an attentional shift from external to internal environment. The current findings provide further support for the involvement of frontal, anterior temporal, and occipital cortical regions during anticipatory anxiety, and suggest that both excitatory and inhibitory processes are associated with AA alterations.

Steady-state visually evoked potential topography during processing of emotional valence in healthy subjects.

The International Affective Picture System (IAPS) is increasingly used in brain imaging studies to examine emotional processes. This task allows valence and arousal content to be systematically investigated; however, previous studies have generally failed to select images that vary in one dimension as well as hold constant the variability on the other dimension. In addition, no studies have investigated the temporal structure associated with the conscious, ongoing processing of emotional stimuli following systematic selection of IAPS images. The aim of the present study was therefore to use steady-state probe topography (SSPT) to examine the steady-state visually evoked potentials (SSVEPs) associated with the processing of pleasant and unpleasant images low in arousal content. Seventy-five IAPS images, categorized as unpleasant, neutral, or pleasant, were presented to 16 healthy subjects while brain activity was recorded from 64 scalp sites. Analysis subtracted the activity associated with the presentation of neutral images from the activity associated with the presentation of pleasant as well as unpleasant images. Results demonstrate that both pleasant and unpleasant valence is associated with transient, widespread, and bilateral frontal SSVEP latency reductions. Unpleasant images were also associated with a transient bilateral anterior frontal amplitude decrease. Latency reductions are interpreted as increases in neural information processing speed, while amplitude reductions are interpreted in the current paper as analogous to an event-related desynchronisation commonly associated with the alpha bandwidth. These key findings support previous literature in terms of there being substantial overlap in frontal neural circuitry when the brain processes pleasant and unpleasant valence relative to neutral valence.

Test-retest reliability of the emotional stroop task: examining the paradox of measurement change.

The Emotional Stroop (ES) task (I. H. Gotlib & C. D. McCann, 1984) has been proposed as an experimental measure to assess the processing of emotion or the bias in attention of emotion-laden information. However, study results have not been consistent. To further examine its reliability for empirical research, the authors of this study administered the ES task to 33 participants on 2 separate occasions separated by 1 week. Results indicated that retest reliabilities for reaction times (RTs) derived from the 3 separate emotion conditions (manic, neutral, and depressive) across the 1 week interval were very high. However, consistent with previous research, the reliabilities were very low for the interference indices (manic and depressive). These low reliabilities reflect the very high intercorrelation between the RTs derived from the 3 conditions. The authors concluded that a better indicator of the reliability for this task is the individual RTs from each emotion condition.

The pharmacology of human working memory.

Experimental studies conducted primarily on non-human primates have begun to address the anatomical and neurochemical correlates of working memory. There is an associated growing body of experimental literature investigating whether modulating key neurotransmitters can facilitate working memory in humans. This paper reviews evidence that acute modulation of dopamine in particular, but also noradrenaline, acetylcholine and serotonin may influence working-memory performance in humans. Differences in neurochemical specificity with regard to stages of working memory, type of working memory (spatial or non-spatial) and cortical effects are also discussed. This evidence has contributed to neuropharmacological understanding of working memory in humans. The important therapeutic consequences of a better understanding of facilitation of working memory is discussed in reference to schizophrenia, Parkinson's disease and Alzheimer's disease.

An investigation into the acute nootropic effects of Hypericum perforatum L. (St. John's Wort) in healthy human volunteers.

Hypericum perforatum L. (St. John's Wort) is a complex herb that has been used for centuries for its putative medicinal properties, and has current therapeutic relevance as a treatment of mild to moderate depression. Recently, two studies in rodents have suggested that hypericum may also have memory-enhancing effects. It has a complex pharmacology, in that acute administration modulates numerous neurotransmitter systems that have previously been observed to either augment or impair a variety of memory processes in humans. This study aimed to examine whether acute administration of standardized hypericum extract could exert a nootropic effect in normal human subjects. The study employed a double-blind, crossover, repeated-measures design. Twelve healthy young subjects completed the Cognitive Drug Research (CDR) memory battery, following administration of placebo, 900 mg and 1800 mg hypericum (Blackmore's Hyperiforte). The findings suggested that hypericum does not have an acute nootropic effect in healthy humans at these doses. However, there was some evidence for an impairing effect on accuracy of numeric working memory and delayed picture recognition at the higher dose. This observed impairment could be due to a sensitivity of these specific tasks to modulation by neurotransmitters that have been noted to have memory-impairing effects (e.g. y-aminobutyric acid (GABA), serotonin).