Journal of Psychopharmacology

Muthukumaraswamy, Suresh D

doi: 10.1177/0269881114536790pmid: 24920134

Magnetoencephalography (MEG) is a neuroimaging technique that allows direct measurement of the magnetic fields generated by synchronised ionic neural currents in the brain with moderately good spatial resolution and high temporal resolution. Because chemical neuromodulation can cause changes in neuronal processing on the millisecond time-scale, the combination of MEG with pharmacological interventions (pharmaco-MEG) is a powerful tool for measuring the effects of experimental modulations of neurotransmission in the living human brain. Importantly, pharmaco-MEG can be used in both healthy humans to understand normal brain function and in patients to understand brain pathologies and drug-treatment effects. In this paper, the physiological and technical basis of pharmaco-MEG is introduced and contrasted with other pharmacological neuroimaging techniques. Ongoing developments in MEG analysis techniques such as source-localisation, functional and effective connectivity analyses, which have allowed for more powerful inferences to be made with recent pharmaco-MEG data, are described. Studies which have utilised pharmaco-MEG across a range of neurotransmitter systems (GABA, glutamate, acetylcholine, dopamine and serotonin) are reviewed.

Ioannidis, Konstantinos ;Chamberlain, Samuel R ;Müller, Ulrich

doi: 10.1177/0269881114541014pmid: 24989644

Caffeine is one of the most widespread psychotropic substances in the world. It exerts multiple effects on the brain including adenosine receptor antagonism, and thereby has been found to modulate aspects of cognition, including attention, in animal models and in healthy human volunteers. This review considers what is known of the effects of caffeine on symptoms and cognitive functions in attention-deficit hyperactivity disorder (ADHD), a prototypical disorder of cognitive dysfunction. We consider the merits of investigating further caffeine’s therapeutic potential as a monotherapy or as an adjunctive agent in ADHD. The potential benefits of re-opening a dialogue regarding the use of caffeine in ADHD clinical practice are highlighted, along with potential implications for the use of adenosine receptor antagonists in ADHD and other disorders characterised by cognitive impairment.

Asherson, Philip ;Bushe, Chris ;Saylor, Keith ;Tanaka, Yoko ;Deberdt, Walter ;Upadhyaya, Himanshu

doi: 10.1177/0269881114542453pmid: 25035246

Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double-blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10–16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (−12.2 vs −8.1; Conners’ Adult ADHD Rating Scale–Investigator-Rated: Screening Version (CAARS-Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were −13.2 vs −9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement ≥30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) ≤3 were 34.8% vs 22.3% in the short-term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements ≥40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates.

Schmid, Yasmin ;Hysek, Cédric M ;Simmler, Linda D ;Crockett, Molly J ;Quednow, Boris B ;Liechti, Matthias E

doi: 10.1177/0269881114542454pmid: 25052243

Social cognition is important in everyday-life social interactions. The social cognitive effects of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and methylphenidate (both used for neuroenhancement and as party drugs) are largely unknown. We investigated the acute effects of MDMA (75 mg), methylphenidate (40 mg) and placebo using the Facial Emotion Recognition Task, Multifaceted Empathy Test, Movie for the Assessment of Social Cognition, Social Value Orientation Test and the Moral Judgment Task in a cross-over study in 30 healthy subjects. Additionally, subjective, autonomic, pharmacokinetic, endocrine and adverse drug effects were measured. MDMA enhanced emotional empathy for positive emotionally charged situations in the MET and tended to reduce the recognition of sad faces in the Facial Emotion Recognition Task. MDMA had no effects on cognitive empathy in the Multifaceted Empathy Test or social cognitive inferences in the Movie for the Assessment of Social Cognition. MDMA produced subjective ‘empathogenic’ effects, such as drug liking, closeness to others, openness and trust. In contrast, methylphenidate lacked such subjective effects and did not alter emotional processing, empathy or mental perspective-taking. MDMA but not methylphenidate increased the plasma levels of oxytocin and prolactin. None of the drugs influenced moral judgment. Effects on emotion recognition and emotional empathy were evident at a low dose of MDMA and likely contribute to the popularity of the drug.

O’Daly, Owen G ;Joyce, Daniel ;Tracy, Derek K ;Stephan, Klaas E ;Murray, Robin M ;Shergill, Sukhwinder

doi: 10.1177/0269881114527360pmid: 24671338

Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.

van de Giessen, Elsmarieke ;Celik, Funda ;Schweitzer, Dave H ;van den Brink, Wim ;Booij, Jan

doi: 10.1177/0269881114531664pmid: 24785761

Introduction: The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted striatal dopamine release. Method: We measured striatal dopamine D2/3 receptor (DRD2/3) availability and amphetamine-induced striatal dopamine release in 15 obese and 15 age-matched, normal-weight women using [123I]iodobenzamide single photon emission computed tomography (SPECT) imaging. In addition, correlations with food craving were examined. Results: Baseline striatal DRD2/3 availability was lower in obese subjects (0.91±0.16) compared to controls (1.09±0.16; p=0.006). Amphetamine-induced dopamine release was significant in controls (7.5%±9.2; p=0.007) and not in obese subjects (1.2%±17.7; p=0.802), although the difference in release between groups (d=0.45) was not significant. Dopamine release positively correlated with the trait food craving in obese subjects. Conclusion: This study replicates previous findings of lower striatal DRD2/3 availability in obesity and provides preliminary data that obesity is associated with blunted dopamine release. The positive correlation between dopamine release and food craving in obesity may seem contradictory with the latter finding but is presumably related to heterogeneity within the obese subjects.

Pinkney, Verity; Wickens, Robin; Bamford, Susan; Baldwin, David S; Garner, Matthew

doi: 10.1177/0269881114532858pmid: 24899597

Inhalation of low concentrations of carbon dioxide (CO2) triggers anxious behaviours in rodents via chemosensors in the amygdala, and increases anxiety, autonomic arousal and hypervigilance in healthy humans. However, it is not known whether CO2 inhalation modulates defensive behaviours coordinated by this network in humans. We examined the effect of 7.5% CO2 challenge on the defensive eye-blink startle response. A total of 27 healthy volunteers completed an affective startle task during inhalation of 7.5% CO2 and air. The magnitude and latency of startle eye-blinks were recorded whilst participants viewed aversive and neutral pictures. We found that 7.5% CO2 increased state anxiety and raised concurrent measures of skin conductance and heart rate (HR). CO2 challenge did not increase startle magnitude, but slowed the onset of startle eye-blinks. The effect of CO2 challenge on HR covaried with its effects on both subjective anxiety and startle latency. Our findings are discussed with reference to startle profiles during conditions of interoceptive threat, increased cognitive load and in populations characterised by anxiety, compared with acute fear and panic.

Brunamonti, Emiliano ;Mione, Valentina ;Di Bello, Fabio ;De Luna, Paolo ;Genovesio, Aldo ;Ferraina, Stefano

doi: 10.1177/0269881114538543pmid: 24944084

One of the most remarkable traits of highly encephalized animals is their ability to manipulate knowledge flexibly to infer logical relationships. Operationally, the corresponding cognitive process can be defined as reasoning. One hypothesis is that this process relies on the reverberating activity of glutamate neural circuits, sustained by NMDA receptor (NMDAr) mediated synaptic transmission, in both parietal and prefrontal areas. We trained two macaque monkeys to perform a form of deductive reasoning – the transitive inference task – in which they were required to learn the relationship between six adjacent items in a single session and then deduct the relationship between nonadjacent items that had not been paired in the learning phase. When the animals had learned the sequence, we administered systemically a subanaesthetic dose of ketamine (a NMDAr antagonist) and measured their performance on learned and novel problems. We observed impairments in determining the relationship between novel pairs of items. Our results are consistent with the hypothesis that transitive inference premises are integrated during learning in a unified representation and that reducing NMDAr activity interferes with the use of this mental model, when decisions are required in comparing pairs of items that have not been learned.