Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Bi-directional and multi-modal effects of dexamphetamine on spatial binding windows in healthy individuals.

OBJECTIVES: Stimuli that are separated by a short window of space or time, known as spatial and temporal binding windows (SBW/TBWs), may be perceived as separate. Widened TBWs are evidenced in schizophrenia, although it is unclear if the SBW is similarly affected. The current study aimed to assess if dexamphetamine (DEX) may increase SBWs in a multimodal visuo-tactile illusion, potentially validating usefulness as an experimental model for multimodal visuo-tactile hallucinations in schizophrenia, and to examine a possible association between altered binding windows (BWs) and working memory (WM) suggested by previous research. METHODS: A placebo-controlled, double-blinded, and counter-balanced crossover design was employed. Permuted block randomisation was used for drug order. Healthy participants received DEX (0.45 mg/kg, PO, b.i.d.) or placebo (glucose powder) in capsules. The Rubber Hand Illusion (RHI) and Wechsler Adult Intelligence Scale Spatial Span was employed to determine whether DEX would alter SBWs and WM, respectively. Schizotypy was assessed with a variety of psychological scales. RESULTS: Most participants did not experience the RHI even under normal circumstances. Bi-directional and multimodal effects of DEX on individual SBWs and schizotypy were observed, but not on WM. CONCLUSIONS: Bidirectional multimodal effects of DEX on the RHI and SBWs were observed in individuals, although not associated with alterations in WM.

Dexamphetamine widens temporal and spatial binding windows in healthy participants.

BACKGROUND: The pathophysiology of psychosis is complex, but a better understanding of stimulus binding windows (BWs) could help to improve our knowledge base. Previous studies have shown that dopamine release is associated with psychosis and widened BWs. We can probe BW mechanisms using drugs of specific interest to psychosis. Therefore, we were interested in understanding how manipulation of the dopamine or catecholamine systems affect psychosis and BWs. We aimed to investigate the effect of dexamphetamine, as a dopamine-releasing stimulant, on the BWs in a unimodal illusion: the tactile funneling illusion (TFI). METHODS: We conducted a randomized, double-blind, counterbalanced placebo-controlled crossover study to investigate funnelling and errors of localization. We administered dexamphetamine (0.45 mg/kg) to 46 participants. We manipulated 5 spatial (5-1 cm) and 3 temporal (0, 500 and 750 ms) conditions in the TFI. RESULTS: We found that dexamphetamine increased funnelling illusion (p = 0.009) and increased the error of localization in a delay-dependent manner (p = 0.03). We also found that dexamphetamine significantly increased the error of localization at 500 ms temporal separation and 4 cm spatial separation (p interaction = 0.009; p 500ms|4cm v. baseline = 0.01). LIMITATIONS: Although amphetamine-induced models of psychosis are a useful approach to understanding the physiology of psychosis related to dopamine hyperactivity, dexamphetamine is equally effective at releasing noradrenaline and dopamine, and, therefore, we were unable to tease apart the effects of the 2 systems on BWs in our study. CONCLUSION: We found that dexamphetamine increases illusory perception on the unimodal TFI in healthy participants, which suggests that dopamine or other catecholamines have a role in increasing tactile spatial and temporal BWs.

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.

Multi-modal and bi-directional effects of a synthetic Δ9-Tetrahydrocannabinol (THC) analogue, Nabilone, on spatio-temporal binding windows: Evidence from the projected hand illusion.

Abnormally widened spatial and temporal binding windows (SBW/TBWs; length of space/time whereby stimuli are considered part of the same percept) are observed in schizophrenia. TBW alterations have been associated with altered sense of agency (hereafter referred to as agency), and an associative relationship between embodiment (body ownership) and agency has been proposed. SBWs/TBWs are investigated separately, but no evidence exists of these being separate in mechanism, system or function. The underlying neural substrate of schizophrenia remains unclear. The literature claims either pro-psychotic or anti-psychotic effects of Δ9-Tetrahydrocannabinol (THC) in patients and healthy individuals, but major support for cannabis in the aetiology of schizophrenia is associative, not causal. To clarify if THC is pro- or anti-psychotic, this single-blind, placebo-controlled within-subjects cross-over study tested several hypotheses. 1) Competing hypotheses that a synthetic THC analogue, Nabilone (NAB, 1-2 mg), would alter measures of agency and embodiment in healthy volunteers (n = 32) similarly, or opposite, to that of in patients with schizophrenia. 2) That there would be significant associations between any NAB-induced alterations in individual agency and embodiment measures in the Projected Hand Illusion (PHI). 3) That there is a unitary spatio-temporal binding window (STBW). A large proportion of individuals did not experience the PHI. Multimodal and bi-directional effects of NAB on the PHI were observed. Evidence of a unitary spatio-temporal binding window (STBW) was observed. NAB widened the STBW in some but narrowed it in others as a function of space and delay. No associations were found between agency and embodiment.

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.

Sleep profiles and CBT-I response in schizophrenia and related psychoses.

This study investigated sleep subtypes in schizophrenia, and their response to Cognitive Behavioural Therapy for Insomnia (CBT-I) treatment. Sleep profiling was conducted using latent class analysis on baseline Pittsburgh Sleep Quality Index data (N = 74 outpatients with schizophrenia who were poor sleepers, 52% male, mean age = 41.4 years). Of these, 40 took part in CBT-I treatment. Analyses revealed three sleep subtypes based on total sleep time (TST), sleep efficiency (SE), and sleep onset latency (SOL) parameters: Cluster 1 ('classic severe insomnia', 44.6%), Cluster 2 ('insomnia with normal sleep duration', 37.8%), and Cluster 3 ('insomnia with hypersomnia', 17.6%). Gains analysis of pre- and post-treatment data from CBT-I participants revealed improvements in sleep and psychopathology in all three clusters, although there were some group differences in the areas and magnitude of improvement. Cluster 1 showed the greatest benefits with longer TST and improved SE. Cluster 2 showed a comparatively blunted treatment response although TST moved closer to recommended sleep guidelines. Cluster 3 showed significant reductions in TST. Altogether, this is the first demonstration of different sleep profiles in schizophrenia and their influence on treatment response to CBT-I. It also supports the notion that therapies should be tailored to the person and their insomnia presentation.

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers.

RATIONALE: Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects. OBJECTIVES: The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli. METHODS: A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES50) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity. RESULTS: Dexamphetamine increased the threshold and ES50 of the response to pulse-alone trials in both sexes and reduced R MAX exclusively in females. Dexamphetamine modestly increased PPI of the R MAX across both attention conditions. PPI of R MAX was reduced during the ATTEND condition compared to the IGNORE condition. CONCLUSIONS: Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.

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.

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.

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.