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Rationale: Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity., Objectives: The current study investigated the acute effects of Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN)., Methods: In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBD low ]; (5) THC 12 mg + CBD 400 mg [THC + CBD high ]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each)., Results: Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users., Conclusions: The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The brain-derived neurotrophic factor (BDNF) protein is essential for neuronal development. Val66Met (rs6265) is a functional polymorphism at codon 66 of the BDNF gene that affects neuroplasticity and has been associated with cognition, brain structure and function. The aim of this study was to clarify the relationship between BDNF Val66Met polymorphism and neuronal oscillatory activity, using the electroencephalogram (EEG), in a normative cohort. Neurotypical (N = 92) young adults were genotyped for the BDNF Val66Met polymorphism and had eyes open resting-state EEG recorded for four minutes. Focal increases in right fronto-parietal delta, and decreases in alpha-1 and right hemispheric alpha-2 amplitudes were observed for the Met/Met genotype group compared to Val/Val and Val/Met groups. Stronger frontal topographies were demonstrated for beta-1 and beta-2 in the Val/Met group versus the Val/Val group. Findings highlight BDNF Val66Met genotypic differences in EEG spectral amplitudes, with increased cortical excitability implications for Met allele carriers.

Background: The most important two medicinal cannabinoids are Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown., Aims: To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users., Methods: The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study., Results: Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered., Conclusions: The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the 'real-world' setting., (© 2019 Royal Australasian College of Physicians.)

The COMT Val158Met polymorphism affects the availability of synaptic dopamine in the prefrontal cortex and has been widely studied as a genetic risk factor for psychosis. Schizotypy is associated with an increased risk of psychosis, with some studies implicating similar neurobiological mechanisms to schizophrenia. The present study sought to interrogate the link between the COMT Val158Met polymorphism and schizotypy using electroencephalogram (EEG) to identify neurophysiological mechanisms underpinning psychosis risk. Neurotypical (N = 91) adults were genotyped for the COMT Val158Met polymorphism, completed the Schizotypal Personality Questionnaire (SPQ), and had eyes open resting-state EEG recorded for 4 min. SPQ suspiciousness subscale scores were higher for individuals homozygous for Val/Val and Met/Met versus Val/Met genotypes. Delta, theta, alpha-2, beta-1, and beta-2 amplitudes were lower for Val/Val than Met/Met individuals. Lower theta amplitudes were correlated with higher total SPQ scores (P = 0.050), and multiple regression revealed that higher delta, and lower theta and beta-2 amplitudes (but not COMT genotype) best predicted total SPQ scores (P = 0.014). This study demonstrates the importance of COMT genotype in determining trait suspiciousness and EEG oscillatory activity. It also highlights relationships between dopaminergic alterations, EEG and schizotypy that are dissimilar to those observed in schizophrenia., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. While adverse impacts of cannabis use are generally attributed to Δ 9 -tetrahydrocannabinol, emerging naturalistic evidence suggests cannabidiol (CBD) is neuroprotective and may ameliorate brain harms associated with cannabis use, including protection from hippocampal volume loss. This study examined whether prolonged administration of CBD to regular cannabis users within the community could reverse or reduce the characteristic hippocampal harms associated with chronic cannabis use. Materials and Methods: Eighteen regular cannabis users participated in an ∼10-week open-label pragmatic trial involving daily oral administration of 200 mg CBD, with no change to their ongoing cannabis use requested. Participants were assessed at baseline and post-CBD treatment using structural magnetic resonance imaging. Automated longitudinal hippocampal segmentation was performed to assess volumetric change over the whole hippocampus and within 12 subfields. Results: No change was observed in left or right hippocampus as a whole. However, left subicular complex (parasubiculum, presubiculum, and subiculum) volume significantly increased from baseline to post-treatment ( p =0.017 uncorrected) by 1.58% (Cohen's d =0.63; 2.83% in parasubiculum). Heavy cannabis users demonstrated marked growth in the left subicular complex, predominantly within the presubiculum, and right cornu ammonis (CA)1 compared to lighter users. Associations between greater right subicular complex and total hippocampal volume and higher plasma CBD concentration were evident, particularly in heavy users. Conclusions: Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis. While replication is required in a larger, placebo-controlled trial, these findings support a protective role of CBD against brain structural harms conferred by chronic cannabis use. Furthermore, these outcomes suggest that CBD may be a useful adjunct in treatments for cannabis dependence and may be therapeutic for a range of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer's disease, and major depressive disorder)., Competing Interests: No competing financial interests exist.

Background: In many health settings, administration of medicinal cannabis poses significant implementation barriers including drug storage and safety for administering staff and surrounding patients. Different modes of administration also provide different yet potentially significant issues. One route that has become of clinical interest owing to the rapid onset of action and patient control of the inhaled amount (via breath timing and depth) is that of vaporisation of cannabinoid products. Although requiring a registered therapeutic device for administration, this is a relatively safe method of intrapulmonary administration that may be particularly useful for patients with difficulty swallowing, and for those in whom higher concentrations of cannabinoids are needed quickly. A particular concern expressed to researchers undertaking clinical trials in the hospital is that other patients, nurses, and clinical or research staff may be exposed to second-hand vapours in the course of administering vaporised products to patients., Objective: The objective of this study was to take samples from two research staff involved in administering vaporised Δ 9 -tetrahydrocannabinol to participants in a clinical trial, to examine and quantitate cannabinoid presence., Methods: Blood samples from two research staff were taken during the exposure period for three participants (cannabis users) over the course of approximately 2.5 h and analysed using tandem mass spectrometry., Results: Blood samples taken over a vaporised period revealed exposure below the limit of detection for Δ 9 -tetrahydrocannabinol and two metabolites, using tandem mass spectrometry analytical methods., Conclusions: These results are reassuring for hospital and clinical trial practices with staff administering vaporised cannabinoid products, and helpful to ethics committees wishing to quantify risk.

Introduction: Chronic cannabis use has been associated with impaired cognition and elevated psychological symptoms, particularly psychotic-like experiences. While Δ 9 -tetrahydrocannabinol (THC) is thought to be primarily responsible for these deleterious effects, cannabidiol (CBD) is purported to have antipsychotic properties and to ameliorate cognitive, symptomatic, and brain harms in cannabis users. However, this has never been tested in a prolonged administration trial in otherwise healthy cannabis users. Here, we report the first study of prolonged CBD administration to a community sample of regular cannabis users in a pragmatic trial investigating potential restorative effects of CBD on psychological symptoms and cognition. Materials and Methods: Twenty frequent cannabis users (16 male, median age 25 years) underwent a 10-week open-label trial of 200 mg of daily oral CBD treatment, while continuing to use cannabis as usual. The majority of participants were daily cannabis users who had used cannabis for several years (median 5.5 years of regular use). Participants underwent psychological and cognitive assessments at baseline (BL) and post-treatment (PT) and were monitored weekly throughout the trial. Results: CBD was well tolerated with no reported side effects; however, participants retrospectively reported reduced euphoria when smoking cannabis. No impairments to cognition were found, nor were there deleterious effects on psychological function. Importantly, participants reported significantly fewer depressive and psychotic-like symptoms at PT relative to BL, and exhibited improvements in attentional switching, verbal learning, and memory. Increased plasma CBD concentrations were associated with improvements in attentional control and beneficial changes in psychological symptoms. Greater benefits were observed in dependent than in nondependent cannabis users. Conclusions: Prolonged CBD treatment appears to have promising therapeutic effects for improving psychological symptoms and cognition in regular cannabis users. Our findings require replication given the lack of a placebo control in this pragmatic trial, but suggest that CBD may be a useful adjunct treatment for cannabis dependence., Competing Interests: No competing financial interests exist.

Introduction: The emergence of anxiety during childhood is accompanied by the development of attentional biases to threat. However, the neural mechanisms underlying these biases are poorly understood. In addition, previous research has not examined whether state and trait anxiety are independently associated with threat-related biases. Methods: We compared ERP waveforms during the processing of emotional faces in a population sample of 58 6-11-year-olds who completed self-reported measures of trait and state anxiety and depression. Results: The results showed that the P1 was larger to angry than neutral faces in the left hemisphere, though early components (P1, N170) were not strongly associated with child anxiety or depression. In contrast, Late Positive Potential (LPP) amplitudes to angry (vs. neutral) faces were significantly and positively associated with symptoms of anxiety/depression. In addition, the difference between LPPs for angry (vs. neutral) faces was independently associated with state and trait anxiety symptoms. Discussion: The results showed that neural responses to facial emotion in children with elevated symptoms of anxiety and depression were most evident at later processing stages characterized as evaluative and effortful. The findings support cognitive models of threat perception in anxiety and indicate that trait elements of anxiety and more transitory fluctuations in anxious affect are important in understanding individual variation in the neural response to threat in late childhood.

Schizophrenia may be conceptualised using a dimensional approach to examine trait-like expression such as schizotypy within non-clinical populations to better understand pathophysiology. A candidate psychosis-risk marker, the auditory mismatch negativity (MMN) is thought to index the functionality of glutamatergic NMDA receptor mediated neurotransmission. Although the MMN is robustly reduced in patients with schizophrenia, the association between MMN and schizotypy in the general population is under-investigated. Thirty-five healthy participants completed the Schizotypal Personality Questionnaire (SPQ) and a multi-feature MMN paradigm (standards 82%, 50ms, 1000Hz, 80dB) with duration (100ms), frequency (1200Hz) and intensity (90dB) deviants (6% each). Spearman's correlations were used to explore the association between schizotypal personality traits and MMN amplitude. Few associations were identified between schizotypal traits and MMN. Higher Suspiciousness subscale scores tended to be correlated with larger frequency MMN amplitude. A median-split comparison of the sample on Suspiciousness scores showed larger MMN (irrespective of deviant condition) in the High compared to the Low Suspiciousness group. The trend-level association between MMN and Suspiciousness is in contrast to the robustly attenuated MMN amplitude observed in schizophrenia. Reductions in MMN may reflect a schizophrenia-disease state, whereas non-clinical schizotypy may not be subserved by similar neuropathology., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains underresearched. Associations between poorer performance and a range of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.

The ability to regulate our emotional responses is crucial to effective functioning in daily life. Whilst there has been extensive study of the brain potentials related to valenced stimuli, the neural basis of the ability to regulate actions elicited by these remains to be clarified. To address this, 40 volunteers undertook an approach-avoidance paradigm. In the congruent condition, participants approached pleasant and avoided unpleasant stimuli. In the incongruent condition, the opposite was the case, requiring the regulation of natural emotional response tendencies. Both behavioural and electrophysiological indices of emotional regulation were recorded. Congruency effects were observed at both the behavioural and electrophysiological level. Reaction times were faster and the LPP larger, when performing emotionally congruous relative to incongruous actions. Moreover, neural and behavioural effects were correlated. The current results suggest that the LPP congruency effect can be considered a neural marker of individual differences in emotion-driven action tendencies. We discuss whether this reflects emotion regulation, effort allocation, or correct mapping of stimulus response tendencies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ∆9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis., Methods: Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230 ° C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC., Results: THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation., Conclusions: While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD., Trial Registration: Current Controlled Trials ISRCTN24109245.

Background: Cannabis use is associated with the development of psychotic symptoms and increased risk for schizophrenia. The mismatch negativity (MMN) is a brain event-related potential marker of change detection thought to index glutamatergic N-methyl-D-aspartate receptor-mediated neurotransmission, which is known to be deficient in schizophrenia. This study examined auditory MMN in otherwise healthy chronic cannabis users compared with nonuser control subjects., Methods: Forty-two chronic cannabis users and 44 nonuser healthy control subjects completed a multi-feature MMN paradigm, which included duration, frequency, and intensity deviants (deviants 6%; standards 82%). The MMN was compared between users and control subjects as well as between long- and short-term users and age- and gender-matched control subjects. Associations between MMN, cannabis use measures, and symptoms were examined., Results: The MMN amplitude was significantly reduced to frequency but not duration or intensity deviants in overall cannabis users relative to control subjects. Frequency MMN was similarly attenuated in short- and long-term users relative to control subjects. Long-term users also exhibited reduced duration MMN relative to control subjects and short-term users and this was correlated with increased duration of exposure to cannabis and increased psychotic-like experiences during intoxication. In short-term users, a younger age of onset of regular cannabis use and greater frequency of use were associated with greater psychotic-like experiences and symptomatic distress., Conclusions: These results suggest impaired sensory memory that might reflect N-methyl-D-aspartate receptor dysfunction in chronic cannabis users. The pattern of MMN alterations in cannabis users differed from that typically observed in patients with schizophrenia, indicating overlapping but distinct underlying pathology., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Chronic cannabis use has been associated with neurocognitive deficits, alterations in brain structure and function, and with psychosis. This study investigated the effects of chronic cannabis use on P50 sensory-gating in regular users, and explored the association between sensory gating, cannabis use history and the development of psychotic-like symptoms. Twenty controls and 21 regular cannabis users completed a P50 paired-click (S1 and S2) paradigm with an inter-pair interval of 9s. The groups were compared on P50 amplitude to S1 and S2, P50 ratio (S2/S1) and P50 difference score (S1-S2). While cannabis users overall did not differ from controls on P50 measures, prolonged duration of regular use was associated with greater impairment in sensory gating as indexed by both P50 ratio and difference scores (including after controlling for tobacco use). Long-term cannabis users were found to have worse sensory gating ratios and difference scores compared to short-term users and controls. P50 metrics did not correlate significantly with any measure of psychotic-like symptoms in cannabis users. These results suggest that prolonged exposure to cannabis results in impaired P50 sensory-gating in long-term cannabis users. While it is possible that these deficits may have pre-dated cannabis use and reflect a vulnerability to cannabis use, their association with increasing years of cannabis use suggests that this is not the case. Impaired P50 sensory-gating ratios have also been reported in patients with schizophrenia and may indicate a similar underlying pathology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The default mode network (DMN) is characterised by coherent very low frequency (VLF) neural oscillations in the resting brain. The attenuation of this activity has been demonstrated following the transition from rest to performance of a broad range of cognitive goal-directed tasks. Whether the activity of resting state VLF oscillations is attenuated during non-cognitive goal-directed tasks such as waiting for rewarding outcomes is not known. This study examined the VLF EEG power from resting to performance of attention demanding task and two types of goal-directed waiting tasks. The association between the attenuation of VLF EEG power and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms was examined. Direct current EEG (DC-EEG) data were collected from 32 healthy young adults (half high and half low ADHD symptom scorers) during (i) a rest state, (ii) while performing a cognitive demanding reaction time task (2CRT), and (iii) while undertaking each of two different goal-directed waiting conditions: "forced-to-wait (FW)" and "choose-to-wait (CW)" tasks. The spatial distribution of VLF EEG power across scalp was similar to that seen in previous resting VLF EEG studies. Significant rest-to-task attenuation of VLF EEG power occurred during the 2CRT and the CW task, but not during the FW task. The association between self-ratings of ADHD symptoms and waiting-induced attenuation was not significant. This study suggests VLF EEG power attenuation that occurs following rest-to-task transition is not simply determined by changes in cognitive load. The goal-directed nature of a task, its motivated nature and/or the involvement of effortful attention may also contribute. Future studies should explore the attenuation of resting state VLF oscillations during waiting and impulsive choice., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Objective: This study has been specifically designed to investigate very low frequency neuronal oscillations (VLFO, <0.5 Hz) during resting states and during goal-directed tasks of graded difficulty levels, quantify the changes that the slow waves undergo in these conditions and compare them with those for higher frequency bands (namely delta, theta and alpha)., Methods: To this end we developed a multistage signal processing methodology comprising blind source separation coupled with a neural network based feature extraction and classification method., Results: Changes in the amplitude and phase of brain sources estimates in the VLF band between rest and task were enhanced with increased task difficulty, but remained lower than those experienced in higher frequency bands. The slow wave variations were also significantly correlated with task performance measures, and hence with the level of task-directed attention., Conclusions: These findings suggest that besides their prominent sensitivity to external stimulation, VLFOs also contribute to the cortical ongoing background activity which may not be specifically related to task-specific attention and performance., Significance: Our work provides important insight into the association between VLF brain activity and conventional EEG frequency bands, and presents a novel framework for assessing neural activity during various mental conditions and psychiatric states., (Copyright © 2012 International Federation of Clinical Neurophysiology. All rights reserved.)

Background: The ability to anticipate and then secure future rewards and avoid future punishments by responding effectively to environmental demands is at the core of successful decision making. Disruptions to these processes have been shown to be implicated in a number of psychiatric conditions. In the current paper we use the electrophysiological monetary incentive delay task (e-MID) to decompose the neural response to (i) reinforcement anticipation, (ii) reinforcement-contingent target processing and (iii) reinforcement-related feedback., Methods: Thirty-eight adolescents and young adults performed an ERP-based analogue of the monetary incentive delay task. ERP components previously associated with motivationally salient cue (cue-P3 and contingent negative variation, CNV), target (P3) and feedback (success vs. failure; feedback-related negativity; FRN and the late positive potential; LPP) stimuli were examined., Results: Response times were shorter and less variable in the monetary gain and loss conditions. Distinctive ERP components were observed for each phase of reinforcement processing. First, cue-P3 was enhanced to monetary gain cues. Predicted alterations in cue-P3 following monetary loss cues and the CNV following cues of either monetary loss or gain were not observed. Target P3 was enhanced in both incentive conditions. The FRN was greater following monetary loss feedback. LPP amplitude was enhanced following feedback denoting monetary gain and the avoidance of monetary loss., Conclusion: Although behaviourally the effects of monetary loss and gain were similar, the e-MID task differentiated neural processing in terms of anticipation and feedback-related brain potentials. The e-MID task and the results of the current study provide a valuable complement to fMRI-based approaches to studying normal and abnormal brain correlates of reinforcement processing., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The ubiquitous tendency to choose immediate over delayed rewards can, in extremis, lead to maladaptive preferences for smaller sooner over larger later rewards (i.e., impulsive choice) in certain pathological groups. The delay aversion hypothesis provides one possible account of impulsive choice and argues that this tendency is motivated by the avoidance of the negative affective states associated with delay imposed prior to the delivery of a large reward. This model also predicts that on non-choice tasks individuals will be motivated to work harder and more efficiently, when given the opportunity to avoid delay. In the current paper we studied the neural markers of the motivational salience of the imposition and escape from delay using a simple reaction time task under two conditions: First where fast responses were expected to lead to delay escape and second where delay was inescapable., Methods: Forty participants performed the Escape Delay Incentive (EDI) task during which they were asked to respond as quickly as they could to a target stimulus. The EDI task included two conditions: first, a Delay Escape condition where fast responses led to the avoidance of delay and a Delay No-Escape condition in which a delay was presented on every trial irrespective of response speed. EEG was recorded from 66 equidistant electrode sites across the scalp. The neural response in these two conditions was compared in terms of contingent negative variation (CNV; preparation of motivated responses) and late positive potential, LPP; evaluation of performance feedback)., Results: As predicted individuals responded more quickly and showed enhanced CNV amplitude to Delay Escape compared with Delay No-Escape trials. Enhanced LPP amplitude was also observed when participants were not able to avoid the delay in the Delay Escape condition. ADHD symptoms were associated with larger CNV differences between Delay Escape and Delay No-Escape conditions. An association between ADHD symptoms and the LPP in the Delay Escape condition did not reach significance., Conclusion: The results of the current study suggest that delay escape is a potent reinforcer at both behavioural and neural levels. Future research should extend this analysis to clinical samples using a broader range of delays and across imaging modalities., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Patients with ADHD are typically more variable in their reaction times (RT) than control children. Signal processing analyses have shown that time series RT data of children with ADHD have a distinctive low frequency periodic structure suggestive of a pattern of occasional spontaneous performance lapses. Here we use a fine-grained analysis of spectral power across a broader frequency range to differentiate the periodic qualities of ADHD time series RT data from (a) 1/frequency noise, and (b) control performance. We also assess the familiality of these frequencies by using a proband-sibling design., Method: Seventy-one children with ADHD, one of their siblings, and 50 control participants completed a simple RT task. Power across the RT frequency spectrum was calculated. The frequencies significantly differentiating the two groups were identified. Familiality was assessed in two ways: first, by comparing probands with their unaffected siblings and controls, and, second, by investigating the siblings of neuropsychologically impaired and unimpaired children with ADHD., Results: Analyses converged to highlight the potential importance of the .20-.26 Hz band in differentiating the periodic structure of ADHD RT time series data from both 1/frequency noise and control performance. This frequency band also showed the strongest evidence of familiality., Conclusions: RT performance of children with ADHD had a distinctive periodic structure. The band identified as most differentiating and familial was at a higher frequency than in most previous reports. This highlights the importance of employing tasks with faster interstimulus intervals that will allow a larger portion of the frequency spectrum to be examined.

Background: The default-mode network (DMN) is characterised by coherent very low frequency (VLF) brain oscillations. The cognitive significance of this VLF profile remains unclear, partly because of the temporally constrained nature of the blood oxygen-level dependent (BOLD) signal. Previously we have identified a VLF EEG network of scalp locations that shares many features of the DMN. Here we explore the intracranial sources of VLF EEG and examine their overlap with the DMN in adults with high and low ADHD ratings., Methodology/principal Findings: DC-EEG was recorded using an equidistant 66 channel electrode montage in 25 adult participants with high- and 25 participants with low-ratings of ADHD symptoms during a rest condition and an attention demanding Eriksen task. VLF EEG power was calculated in the VLF band (0.02 to 0.2 Hz) for the rest and task condition and compared for high and low ADHD participants. sLORETA was used to identify brain sources associated with the attention-induced deactivation of VLF EEG power, and to examine these sources in relation to ADHD symptoms. There was significant deactivation of VLF EEG power between the rest and task condition for the whole sample. Using s-LORETA the sources of this deactivation were localised to medial prefrontal regions, posterior cingulate cortex/precuneus and temporal regions. However, deactivation sources were different for high and low ADHD groups: In the low ADHD group attention-induced VLF EEG deactivation was most significant in medial prefrontal regions while for the high ADHD group this deactivation was predominantly localised to the temporal lobes., Conclusions/significance: Attention-induced VLF EEG deactivations have intracranial sources that appear to overlap with those of the DMN. Furthermore, these seem to be related to ADHD symptom status, with high ADHD adults failing to significantly deactivate medial prefrontal regions while at the same time showing significant attenuation of VLF EEG power in temporal lobes.

Background: Resting brain activity appears altered in Attention Deficit/Hyperactivity Disorder (ADHD). The default mode interference hypothesis (Sonuga-Barke and Castellanos, 2007) postulates that patterns of spontaneous very low frequency brain activity, typical of the resting brain, cause attention lapses in ADHD when they remain unattenuated following the transition from rest to active task performance. Here we test this hypothesis using DC-EEG., Methods: DC-EEG recordings of very low frequency brain activity (<1.5Hz) were compared for 16 male children with ADHD and 16 healthy controls during both rest and active task performance (two choice reaction time task)., Results: A previously identified very low frequency resting network of electrodes was replicated. At rest ADHD children showed less EEG power in very low frequency bands (i.e., .02-.2Hz). They also showed less attenuation of power at these frequency bands during rest-to-task transition. Reduced attenuation was associated with a number of measures of performance., Discussion: We confirmed the existence of altered very low frequency brain activity in ADHD. ADHD children may have deficits both in maintaining a resting brain when needed and 'protecting' an active brain from the intrusion of resting state brain activity., (Copyright 2010 Elsevier B.V. All rights reserved.)

In this review we are concerned specifically with the putative role of the default-mode network (DMN) in the pathophysiology of mental disorders. First, we define the DMN concept with regard to its neuro-anatomy, its functional organisation through low frequency neuronal oscillations, its relation to other recently discovered low frequency resting state networks, and the cognitive functions it is thought to serve. Second, we introduce methodological and analytical issues and challenges. Third, we describe putative mechanisms proposed to link DMN abnormalities and mental disorders. These include interference by network activity during task performance, altered patterns of antagonism between task specific and non-specific elements, altered connectively and integrity of the DMN, and altered psychological functions served by the network DMN. Fourth, we review the empirical literature systematically. We relate DMN dysfunction to dementia, schizophrenia, epilepsy, anxiety and depression, autism and attention deficit/hyperactivity disorder drawing out common and unique elements of the disorders. Finally, we provide an integrative overview and highlight important challenges and tasks for future research.

Rationale: Previous research investigating the effects of stimulants, such as methylphenidate (MPH), on children with attention deficit/hyperactivity disorder (AD/HD) has rarely included autonomic measures of arousal., Objective: Our aim was to clarify the effects of MPH on central and autonomic measures in AD/HD children during a continuous performance task (CPT) using a naturalistic open-label study., Method: Thirty-six boys (18 AD/HD and 18 control) participated in a CPT over two trial periods, allowing a more valid estimate of the effects of medication, rather than assuming that retesting per se has no substantial impact. MPH was administered to the AD/HD group 1 h prior to the second trial. Errors and reaction time (RT) were recorded as measures of performance, electrodermal activity as an autonomic nervous system measure and event-related potentials (ERPs) as an index of central nervous system activity., Results: AD/HD children made more errors than controls in the first session, but no group differences were found after medication. No significant differences were observed for RT. Skin conductance level was found to be lower in AD/HD children than controls, but this difference was also ameliorated after medication. Conversely, mean skin conductance response to target stimuli was found not to differ between groups during the initial test phase but became significantly different in phase 2. ERP data showed topographic differences between groups in N1, P2, N2 and P3 at the initial test phase, which were reduced at the second test., Conclusion: Stimulant medication ameliorated some of the dysfunctions in AD/HD children, which are reflected in behavioural and ERP measures. These results, in combination with general differences in electrodermal activity, support a hypo-arousal model of AD/HD, which can explain the action of MPH in these children.

Children with Attention Deficit/Hyperactivity Disorder (AD/HD) appear to be deficient in inhibitory processes, as reflected in behavioural and electrophysiological measures. This study examined the effect of methylphenidate (MPH) on response inhibition in children with AD/HD. Event-related potentials (ERPs) and skin conductance level (SCL) were recorded from 18 boys with AD/HD and 18 controls while they performed a cued Go/Nogo task with 70% Go probability. All participants performed the task twice, with an hour interval between test sessions. At the beginning of this interval children with AD/HD took their normal morning dose of MPH. The AD/HD group showed lower SCL than controls pre-medication, a difference not found subsequent to the administration of MPH. While the AD/HD group made more overall errors (omission+commission) pre-medication, and continued to make more omission errors than controls post-medication, the groups became comparable on the number of commission errors, suggesting MPH ameliorates deficits in response inhibition. Children with AD/HD displayed enhanced N1 and P2 amplitudes, and reduced N2 amplitudes relative to controls. These differences were not significant post-medication, at least partly attributable to the action of MPH. This study is unusual in the concurrent examination of electrodermal and electrophysiological measures of medication effects in children with AD/HD, with the retesting of both the AD/HD and control groups allowing a more valid estimate of the effects of medication, rather than assuming that retesting does not have a substantial impact.