The effects of dexamphetamine on the resting-state electroencephalogram and functional connectivity.

The catecholamines-dopamine and noradrenaline-play important roles in directing and guiding behavior. Disorders of these systems, particularly within the dopamine system, are associated with several severe and chronically disabling psychiatric and neurological disorders. We used the recently published group independent components analysis (ICA) procedure outlined by Chen et al. (2013) to present the first pharmaco-EEG ICA analysis of the resting-state EEG in healthy participants administered 0.45 mg/kg dexamphetamine. Twenty-eight healthy participants between 18 and 41 were recruited. Bayesian nested-domain models that explicitly account for spatial and functional relationships were used to contrast placebo and dexamphetamine on component spectral power and several connectivity metrics. Dexamphetamine led to reductions across delta, theta, and alpha spectral power bands that were predominantly localized to Frontal and Central regions. Beta 1 and beta 2 power were reduced by dexamphetamine at Frontal ICs, while beta 2 and gamma power was enhanced by dexamphetamine in posterior regions, including the parietal, occipital-temporal, and occipital regions. Power-power coupling under dexamphetamine was similar for both states, resembling the eyes open condition under placebo. However, orthogonalized measures of power coupling and phase coupling did not show the same effect of dexamphetamine as power-power coupling. We discuss the alterations of low- and high-frequency EEG power in response to dexamphetamine within the context of disorders of dopamine regulation, in particular schizophrenia, as well as in the context of a recently hypothesized association between low-frequency power and aspects of anhedonia. Hum Brain Mapp 37:570-588, 2016. © 2015 Wiley Periodicals, Inc.

Dexamphetamine selectively increases 40 Hz auditory steady state response power to target and nontarget stimuli in healthy humans.

BACKGROUND: An emerging endophenotype of schizophrenia is the reduction of both power and phase locking of the 40 Hz auditory steady state response (ASSR), and there have been a number of reports linking increased γ activity with positive psychotic symptoms. Schizophrenia and, more specifically, positive psychotic symptoms have been closely linked to increased dopamine (DA) neurophysiology. Therefore, we gave dexamphetamine to healthy participants to determine the effect that increased DA transmission would have on the ASSR. METHODS: We administered 0.45 mg/kg of dexamphetamine orally in a double-blind placebo-controlled crossover study. Stimuli were 20 Hz and 40 Hz click trains presented in an auditory oddball-type stimulus format (probability of stimulus presentation: 0.2 for targets, 0.8 for nontargets). RESULTS: We included 44 healthy volunteers (18 women) in the study. Dexamphetamine significantly increased the 40 Hz power for both target and nontarget ASSR stimuli. Dexamphetamine did not significantly affect the 40 Hz phase-locking factor (PLF) or the 20 Hz power and PLF. Whereas there were significant effects of selective attention on power and PLF for 20 and 40 Hz ASSR, there were no significant interactions between dexamphetamine and selective attention. LIMITATIONS: Dexamphetamine releases both noradrenaline and DA with equal potency. Further research with selective dopaminergic and noradrenergic agents will better characterize the effects of monoamines on γ activity. CONCLUSION: The results demonstrate a frequency-specific effect of dexamphetamine on the ASSR. This finding is consistent with previous research that has found an association between increased γ and positive symptoms of psychosis. However, this result also raises the possibility that previous 40 Hz ASSR findings in people with schizophrenia may be confounded by effects of antipsychotic medication. Possible neural mechanisms by which dexamphetamine specifically increases 40 Hz power are also discussed. AUSTRALIAN AND NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12608000610336.

Cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression--a pilot study.

BACKGROUND: The aim of the current study was to investigate the cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in 10 treatment-resistant depression patients. METHODS: Patients received forty 20-min sessions of fast-frequency (10 Hz) rTMS of the left dorsolateral prefrontal cortex (DLPFC) over 20 days. Concept-shift ability (accuracy and duration of performance) was assessed daily with a Modified Concept-Shifting Task (mCST) in patients and in eight healthy volunteers. General cognitive functioning test (Repeatable Battery for the Assessment of Neuropsychological Status; RBANS), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAM-D) were applied before the first and after the last rTMS. RESULTS: Compared to before rTMS on the first 10 days, the patients performed the mCST significantly more accurately after rTMS on the last 10 days (p < .001, partial eta squared=.78) while the same comparison in healthy volunteers was not statistically significant (p = .256, partial eta squared=.18). A significant improvement in immediate memory on RBANS and reduction in BDI and HAM-D scores were also observed after the last compared to before the first rTMS. CONCLUSION: The rTMS is associated with an improvement in selective cognitive functions that is not explained by practice effects on tasks administered repeatedly. TRIAL REGISTRATION: Name: "Repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of depression, assessed with HAM-D over a four week period."URL: www.actr.org.au REGISTRATION NUMBER: ACTRN012605000145606.

Dexamphetamine reduces auditory P3 delta power and phase-locking while increasing gamma power.

Auditory P3 amplitude reduction is one of the most robust and replicated findings in schizophrenia. Recent evidence suggests that these reductions are due to reductions in both power and phase-locking at delta and theta frequencies. We have previously shown that the auditory, but not visual, P3 is reduced in healthy participants given the catecholamine releasing agent dexamphetamine. Our aim was to determine whether the auditory P3 amplitude reduction induced by dexamphetamine has similar power and phase locking characteristics to that seen in schizophrenia. Forty-four healthy participants were given 0.45 mg/kg dexamphetamine and placebo, in a double-blinded, placebo-controlled, cross-over design. The task was a three-stimulus auditory odd-ball task, target stimuli were the major stimuli of interest. Individual target trials underwent wavelet analysis to give power and phase-locking of delta (3 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz) and gamma (30-50 Hz) frequencies for a 50 ms time window centred around the peak of the target P3. Delta power around the P3 peak was significantly reduced when participants were given dexamphetamine. Delta phase-locking was also reduced but only when analysis was targeted at the location of the peak P3 amplitude. In contrast, theta power and phase-locking were not affected by dexamphetamine. These findings suggest that increased catecholamine activity may be responsible for the power and phase-locking reductions of the auditory P3 delta component in patients with schizophrenia. Interestingly, dexamphetamine significantly increased gamma power around the P3 peak. We attempt to link this finding with the gamma alterations that have been found in patients with schizophrenia.

Revisiting the suitability of antisaccade performance as an endophenotype in schizophrenia.

Poor performance on the antisaccade task has been proposed as a candidate endophenotype in schizophrenia. Caveats to this proposal, however, include inconsistent findings in first-degree relatives of individuals with schizophrenia, and substantial heterogeneity in individuals with the disorder. In this study, we examined antisaccade performance in patients and relatives, and sought to establish whether antisaccade measures could differentiate between two patients clusters identified in the Western Australian Family Study of Schizophrenia with either pervasive cognitive deficits (CD) or cognitively spared (CS). Ninety-three patients (CD=47, CS=46), 99 relatives and 62 healthy controls carried out a standard antisaccade task. Results showed: (i) significantly greater error rate, and prolonged latencies to correct responses and self-correction saccades in patients compared with controls; (ii) high error rates in relatives of poorly performing patients; (iii) longer latencies of self-correction saccades in relatives compared to controls; and (iv) higher error rate and longer latencies of self-correction saccades in the CD subgroup compared with CS. Unaffected relatives as a group were unimpaired in error rate as compared to healthy controls. These findings suggest that the antisaccade error rate and latency of self-correction saccades are useful measures in specific applications of genetic research in schizophrenia, without fully meeting endophenotype co-familiality requirements.

Dexamphetamine effects on separate constructs in the rubber hand illusion test.

RATIONALE: Corporeal awareness is an integral component of self-consciousness and is distorted in several neurological and psychiatric disorders. Research regarding the neural underpinnings of corporeal awareness has made much progress recently using the rubber hand illusion (RHI) procedure. However, more studies are needed to investigate the possibility of several dissociable constructs related to the RHI specifically, and corporeal awareness generally. OBJECTIVES: Considering dopamine's involvement in many perceptual-motor learning processes, as well as its apparent relationship with disorders such as schizophrenia that are linked to body ownership disturbances, we gave 0.45 mg/kg dexamphetamine (a dopamine transporter reverser) to 20 healthy participants to examine the effects of increased dopamine transmission on the RHI. METHODS: The effect of dexamphetamine on separate quantitative constructs underlying RHI were examined including embodiment of rubber hand, loss of ownership of real hand, perception of movement, affect, deafference, and proprioceptive drift. The experiment was a double-blind, placebo-controlled, cross-over design. RESULTS: Dexamphetamine increased participants' ratings of embodiment (particularly "ownership") of the rubber hand and was associated with the experience of loss of ownership of the person's real hand. There were significant increases from asynchronous to synchronous stroking for the measures of movement and proprioceptive drift after placebo but not dexamphetamine. There were no changes in the measures of other constructs. CONCLUSIONS: These results show a novel pharmacological manipulation of separate constructs of the RHI. This finding may aid in our understanding of disorders that have overlapping disturbances in both dopamine activity and body representations, particularly schizophrenia.

Evidence of abnormalities in mid-latency auditory evoked responses (MLAER) in cognitive subtypes of patients with schizophrenia.

Abnormalities in measures of mid-latency auditory evoked responses (MLAER) have frequently been reported in schizophrenia, while few studies have examined whether these measures could distinguish cognitive subtypes of schizophrenia. The aim of this study was to investigate whether patterns of performance on MLAER measures could differentiate a cognitive subtype of patients characterized by pervasive cognitive deficits (CD) from patients with only mild cognitive deficits (CS) and controls. An auditory paired-click conditioning test was administered to 55 schizophrenia patients (26 CD, 29 CS) and 49 healthy controls. Amplitudes, latencies and sensory gating indices of the P50, N100, and P200 MLAER were analysed. The results showed that CD patients exhibited smaller S1 amplitudes of N100 and P200 than controls, while CS patients were comparable to controls. Binary logistic regression identified the P200 S1 amplitude as a significant predictor of patients' membership in the CD subtype. However, none of the other MLAER measures could differentiate the two subtypes of schizophrenia. These findings suggest that the abnormal pathophysiologic mechanisms underlying the electrophysiological brain responses to auditory stimulation are associated with the pervasive cognitive deficits, which characterize the CD subtype of schizophrenia. This finding might provide additional electrophysiological endophenotypes for future genetic research of schizophrenia.

Dexamphetamine-induced reduction of P3a and P3b in healthy participants.

The reduced P3 is one of the most robust deficits involved in schizophrenia. Previous research with catecholaminergic agonists or releasers such as amphetamines have used doses too small to adequately demonstrate an effect on P3. In this study, we gave 0.45 mg/kg dexamphetamine to healthy volunteers (final n = 18) using both auditory and visual three-stimulus P3 procedures. Dexamphetamine significantly reduced P3 amplitudes to auditory target, rare non-target and standard stimulus amplitudes. The reduction in auditory P3 induced by dexamphetamine was proportional across stimulus types to placebo P3 values. There were no effects of dexamphetamine on visual P3. We demonstrate a reduced auditory P3 similar to that seen in schizophrenia and other psychotic illnesses. This possibly reflects a common pathology which is hypothesized within the P3 literature to be related to attention and working memory. Differences between auditory and visual P3 modulation may be related to regional variations in catecholamine or specifically dopamine receptor densities. One specific auditory P3 generator is the superior temporal cortex, an area with dopamine D(2) receptor enriched bands. This is contrasted with visual specific generators, such as the inferior temporal cortex and superior parietal cortex, which do not have these enriched bands.

The feasibility of a three-dimensional charting interface for general dentistry.

BACKGROUND: Most current paper- and computer-based formats for patient documentation use a two-dimensional dental chart, a design that originated almost 150 years ago in the United States. No studies have investigated the inclusion of a three-dimensional (3-D) charting interface in a general dental record. METHODS: A multidisciplinary research team with expertise in human-computer interaction, dental informatics and computer science conducted a 14-week project to develop and evaluate a proof of concept for a 3-D dental record. Through several iterations of paper- and computer-based prototypes, the project produced a high-fidelity (hi-fi) prototype that was evaluated by two dentists and two dental students. RESULTS: The project implemented a prototypical patient record built around a 3-D model of a patient's maxillofacial structures. Novel features include automatic retrieval of images and radiographs; a flexible view of teeth, soft tissue and bone; access to historical patient data through a timeline; and the ability to focus on a single tooth. CONCLUSIONS: Users tests demonstrated acceptance for the basic design of the prototype, but also identified several challenges in developing intuitive, easy-to-use navigation methods and hi-fi representations in a 3-D record. CLINICAL IMPLICATIONS: Test participants in this project accepted the preliminary design of a 3-D dental record. Significant further research must be conducted before the concept can be applied and evaluated in clinical practice.