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.

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.

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.

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.

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.

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.

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.

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.

Effect of the menstrual cycle stage on the melatonin suppression by dim white light.

Patients with bipolar disorder have been shown to have a supersensitive melatonin suppression to dim white light (200 and 500 lux) compared to normal healthy subjects. Previous studies suggest menstrual cycle dependent changes in the melatonin rhythm, but it is not known if the melatonin sensitivity to light changes during the menstrual cycle. The present study investigated the melatonin suppression to dim white light (200 lux) in different stages of the menstrual cycle. No significant differences in the percent suppression of melatonin were found across the stages of the menstrual cycle (p = .97). Our findings suggest that the menstrual cycle hormonal changes do not affect the melatonin sensitivity to dim light in healthy controls.

Cholinergic modulation of speed of early information processing: the effect of donepezil on inspection time.

RATIONALE: Selective cholinergic receptor agonists and antagonists have been shown to modulate inspection time, a measure of speed of early information processing. OBJECTIVE: The present study aimed to examine the effects of globally increasing cholinergic function with the acetylcholinesterase inhibitor donepezil on inspection time. METHODS: Fourteen healthy subjects participated in a randomised double-blind, placebo controlled trial in which all subjects were tested under either acute placebo or donepezil (5 mg) treatment conditions. Testing was conducted pre- and 90 min post-drug administration. RESULTS: There was a significant decrease in inspection time in the donepezil condition compared to the placebo condition (F = 12.86; P < 0.01). DISCUSSION: The decrease or improvement of inspection time following donepezil administration is consistent with the role of the cholinergic system in modulating speed of information processing, and adds evidence that inspection time may serve as a physiological index of the integrity of the cholinergic system.

Effects of the nicotinic antagonist mecamylamine on inspection time.

RATIONALE: Several lines of evidence suggest that nicotinic acetylcholine receptors (nAchRs) are involved in speed of information processing, and inspection time appears to be particularly sensitive to nicotinic manipulation. OBJECTIVE: The present study sought to examine the effects of the nAchR antagonist mecamylamine on inspection time. Furthermore, the extent to which the anticholinesterase donepezil would reverse the effects of mecamylamine on inspection time was also examined. METHODS: A double-blind, repeated measures design was employed. Subjects (n = 6) received placebo, mecamylamine (20 mg PO) or mecamylamine (20 mg PO) and donepezil (5 mg PO). Inspection time and physiological measures were then assessed. RESULTS: The mecamylamine condition and the mecamylamine and donepezil condition were associated with an increase in heart rate, when compared to the placebo condition. There was a significant slowing of inspection time in the mecamylamine condition; compared to placebo, which was partly reversed by donepezil. CONCLUSIONS: The slowing of inspection time following mecamylamine is consistent with the role of nAchRs in speed of information processing, and add to the evidence that IT may in part index nAchR system integrity.

The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects.

RATIONALE: Extracts of Bacopa monniera have been reported to exert cognitive enhancing effects in animals. However, the effects on human cognition are inconclusive. OBJECTIVE: The current study examined the chronic effects of an extract of B. monniera (Keenmind) on cognitive function in healthy human subjects. METHODS: The study was a double-blind placebo-controlled independent-group design in which subjects were randomly allocated to one of two treatment conditions, B. monniera (300 mg) or placebo. Neuropsychological testing was conducted pre-(baseline) and at 5 and 12 weeks post drug administration. RESULTS: B. monniera significantly improved speed of visual information processing measured by the IT task, learning rate and memory consolidation measured by the AVLT (P<0.05), and state anxiety (P<0.001) compared to placebo, with maximal effects evident after 12 weeks. CONCLUSIONS: These findings suggest that B. monniera may improve higher order cognitive processes that are critically dependent on the input of information from our environment such as learning and memory.

Evidence for 5-HT1A receptor control of pineal melatonin concentrations in the rat.

The effect of some serotonin agonists on day and night-time melatonin in the pineal gland was investigated in male rats. Dose dependent increases in nocturnal melatonin concentrations were observed for all serotonin agonists investigated. Statistically significant increases were observed only for D-fenfluramine (20 mg/kg) and the full 5-HT1A agonists S(+)-20499 (10 mg/kg, 20 mg/kg) and flesinoxan (20 mg/kg). Both paroxetine and D-fenfluramine dose dependently increased day-time pineal melatonin, but only for D-fenfluramine (20 mg/kg) was there a statistically significant increase. The data suggest that acute increases in synaptic serotonin concentrations can be used to manipulate day- or night-time melatonin. Data suggests an influence of the 5-HT1A receptor subtype in mediating nocturnal melatonin concentrations, perhaps through a functional coupling to beta1-adrenoceptors on the pineal gland.

Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology.

Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ ion concentrations. At a receptor level, chronic treatment with hypericum downregulates beta1-adrenoceptor, upregulates post-synaptic 5-HT1A receptors and 5-HT2 receptors. Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other mechanisms may also contribute alone or in combination to exert the overall antidepressant action.

The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age.

The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy normal subjects.

The Ayurvedic medicine Bacopa monniera (Brahmi) has been shown to exert cognitive enhancing effects in animals. The current study examined the acute effects of an extract of Bacopa monniera on cognitive function in normal healthy human subjects. The study was a double-blind, placebo-controlled independent group design in which subjects were randomly allocated to one of two treatment conditions, Bacopa monniera (300 mg) (n = 18) or placebo (n = 20). Neuropsychological testing was conducted before and 2 h after drug administration. No significant changes were found on any of the tests. The findings suggest that Bacopa monniera, at least for the dose administered, has no acute effects on cognitive functioning in normal healthy subjects. Copyright 2001 John Wiley & Sons, Ltd.

Inspection time: a neuropsychophysiological test for measuring the functional integrity of the cholinergic system.

Inspection time (IT) is a measure of the speed of early information processing, demonstrating reliable correlation with psychometric intelligence. We now provide evidence that it may serve as a marker for the integrity of the cholinergic system. Cholinergic agonists improve and antagonists impair IT, while modulators of the monoamine systems are without effect. Furthermore impairments in IT correlate with disease severity in Alzheimer's disease, a disorder of compromised cholinergic system function. Taken together, available data suggest that IT may be a useful physiological marker of functional status of the cholinergic system.

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.