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.

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.

Dexamphetamine influences funneling illusion based on psychometric score.

OBJECTIVES: Our team previously showed that like the experience of the rubber hand illusion (RHI) in people with schizophrenia and their offspring¸ dexamphetamine administration to healthy volunteers increases the stimulus binding windows (BWs) in RHI. It is not clear if similar expansions of BWs are present for unimodal illusions. Studies have also shown that subjective or objective effects of amphetamine would be linked to between-person variations in personality measures. Therefore, we aimed to examine the effect of dexamphetamine (DEX), a dopamine-releasing stimulant, on illusory perception using unimodal sensory stimuli (Tactile Funneling Illusion [TFI]) across both temporal and spatial variables. We further examined the relationship between changes in psychometric scores and changes in illusion perception induced by dexamphetamine. METHODS: Healthy subjects (N = 20) participated in a randomized, double-blind, counter-balanced, placebo-controlled, cross-over study. The effects of dexamphetamine (0.45 mg/kg, PO, q.d.) on funneling and error of spatial localization (EL) were examined using TFI. Psychotomimetic effects were assessed using a battery of psychological measures. RESULTS: Dexamphetamine did not significantly increased the funneling illusion (p = 0.88) or EL (p = 0.5), relative to placebo. However, the degree of change in psychometric scores following dexamphetamine positively correlated with changes in funneling (ρ = 0.48, p = 0.03, n = 20), mainly at 0 ms delay condition (ρ = 0.6, p = 0.004, n = 20). CONCLUSION: Unlike multimodal illusions, alteration of BWs does not occur for unimodal illusions after administration of a dopamine-releasing agent. However, our findings indicate that moderate release of dopamine, through its psychotomimetic effect, indirectly influences unimodal illusion.

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.

When one's sense of agency goes wrong: Absent modulation of time perception by voluntary actions and reduction of perceived length of intervals in passivity symptoms in schizophrenia.

Passivity symptoms in schizophrenia are characterised by an absence of agency for actions, thoughts and other somatic experiences. Time perception and intentional binding have both been linked to agency and schizophrenia but have not been examined in passivity symptoms. Time perception and intentional binding were assessed in people with schizophrenia (n=15 with, n=24 without passivity symptoms) and 43 healthy controls using an interval estimation procedure (200, 400 and 600ms intervals) with active, passive and observed movements. People with passivity symptoms did not display action-modulation of time perception, while those without passivity symptoms estimated intervals to be the same after active and observed movements. Additionally, both clinical samples reported intervals to be shorter with increasing interval length. We propose that impaired predictive processes may produce an overreliance on external cues and, together with shorter perceived intervals, lead to the subjective loss of agency.

Body representations in schizophrenia: an alteration of body structural description is common to people with schizophrenia while alterations of body image worsen with passivity symptoms.

INTRODUCTION: Individuals with schizophrenia, particularly those with passivity symptoms, often feel that their actions and thoughts are controlled by an external agent. Recent evidence has elucidated the role of body representations in the aetiology of passivity symptoms, yet one representation - body structural description - has not yet been examined. Additionally, body image has rarely been examined outside of bodily illusions (e.g., rubber hand experiments) and external validation is required. METHODS: Body structural description was assessed with an in-between task and a matching body parts by location task, and body image with a questionnaire examining body distortion experiences (containing subscales assessing boundary loss, depersonalisation and body size distortions). Individuals with schizophrenia (20 with current, 12 with past and 21 with no history of passivity symptoms) and 48 healthy controls participated in the study. RESULTS: People with schizophrenia (as a group) made more errors on the in-between task, but not on the matching body parts by location task. Individuals with current passivity symptoms reported greater distortions on all subscales relative to the other clinical samples, except for experiences of boundary loss which were common to both passivity symptom groups. CONCLUSIONS: The results indicate that body structural description may be altered in schizophrenia generally and body image alterations are worsened in passivity symptoms, and these alterations likely contribute to the emergence of passivity symptoms.

Auditory brainstem responses of ephrin-A2, ephrin-A5(-/-) and ephrin-A2A5(-/-) mice.

Eph receptors and ephrin ligands are large families of cell surface proteins which have established roles in axonal growth and guidance. These are well characterized in the visual and somatosensory systems but are less well documented in the auditory pathway. We examined the possible functional role of two ephrin genes (ephrin-A2 and ephrin-A5) in the auditory system by measuring auditory brainstem responses (ABR) to tone bursts from 6 to 30 kHz in ephrin-A2(-/-), ephrin-A5(-/-) and ephrin-A2A5(-/-) (knockout) mice. At high frequencies, the ephrin-A2A5(-/-) mice exhibited thresholds that were significantly lower than in wild-type mice by approximately 20 dB, suggesting ephrin-A2 and ephrin-A5 may have frequency-specific effects on the auditory system. There were also alterations in ABR wave peak amplitudes that were specific to each mouse strain which suggested both peripheral and central involvement of EphA-ephrin-A signalling in auditory function.

A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates.

Treatment of Parkinson's disease with dopaminergic agents, such as l-DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinson's disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure-psychoactivity relationships, we designed a series of α-substituted MDMA analogues, one of which, bearing an α-cyclopropyl substituent (UWA-101), enhanced the quality of l-DOPA actions in animal models. Indeed, UWA-101 was more effective than MDMA. Unlike MDMA, UWA-101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA-101 displayed a unique receptor/transporter binding profile relative to MDMA, with a >5-fold decrease in affinity for NET and 5-HT(2A) receptors and a 10-fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA-101 inhibited both 5-HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA-101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinson's disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for long-term therapy.

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.

The effects of caffeine and d-amphetamine on spatial span task in healthy participants.

Studies that examined the effect of amphetamine or caffeine on spatial working memory (SWM) and verbal working memory (VWM) have used various tasks. However, there are no studies that have used spatial span tasks (SSTs) to assess the SWM effect of amphetamine and caffeine, although some studies have used digit span tasks (DST) to assess VWM. Previous reports also showed that increasing dopamine increases psychosis-like experiences (PLE, or schizotypy) scores which are in turn negatively associated with WM performance in people with high schizotypy and people with schizophrenia. Therefore, the present study aimed to examine the influence of d-amphetamine (0.45 mg/kg, PO), a dopamine releasing stimulant, on SST, DST, and on PLE in healthy volunteers. In a separate study, we examined the effect of caffeine, a nonspecific adenosine receptor antagonist with stimulant properties, on similar tasks. METHODS: Healthy participants (N = 40) took part in two randomized, double-blind, counter-balanced placebo-controlled cross-over pilot studies: The first group (N = 20) with d-amphetamine (0.45 mg/kg, PO) and the second group (N = 20) with caffeine (200 mg, PO). Spatial span and digit span were examined under four delay conditions (0, 2, 4, 8 s). PLE were assessed using several scales measuring various aspects of psychosis and schizotypy. RESULTS: We failed to find an effect of d-amphetamine or caffeine on SWM or VWM, relative to placebo. However, d-amphetamine increased a composite score of psychosis-like experiences (p = 0.0005), specifically: Scores on Brief Psychiatric Rating Scale, Perceptual Aberrations Scale, and Magical Ideation Scale were increased following d-amphetamine. The degree of change in PLE following d-amphetamine negatively and significantly correlated with changes in SWM, mainly at the longest delay condition of 8 s (r = -0.58, p = 0.006). CONCLUSION: The present results showed that moderate-high dose of d-amphetamine and moderate dose of caffeine do not directly affect performances on DST or SST. However, the results indicate that d-amphetamine indirectly influences SWM, through its effect on psychosis-like experiences. CLINICAL TRIAL REGISTRATION NUMBER: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry) for caffeine study, and ACTRN12608000610336 for d-amphetamine study.

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.

Nabilone Impairs Spatial and Verbal Working Memory in Healthy Volunteers.

Background: Memory impairments and psychosis-like experiences can be adverse effects of cannabis use. However, reports on the cognitive impact of cannabis use are not consistent. There are also limited studies on the psychotomimetic effects of cannabinoid compounds to reveal the association between cannabis and psychosis. Therefore, we investigated the effect of acute cannabinoid intoxication on verbal working memory (VWM) and spatial working memory (SWM) following oral doses of the synthetic cannabinoid agonist, nabilone (1-2 mg, oral). We further investigated the effect of nabilone on psychosis-like experiences (schizotypy scores) and associations of schizotypy with VWM and SWM. Methods: Healthy participants (n=28) completed spatial and digit span tasks across different delay conditions (0, 6, 12, and 18 sec) after receiving nabilone (1-2 mg, PO) or placebo in a randomized, double-blind, counterbalanced, crossover manner. A subset of participants completed a short battery of schizotypy measures (n=25). Results: Nabilone impaired VWM (p=0.03, weak effect size η2=0.02) and SWM (p=0.00016, η2=0.08). Nabilone did not significantly change overall schizotypy scores. Schizotypy scores were negatively correlated with working memory (WM) averaged across all delays and both modalities, under placebo (ρ=-0.41, p=0.04). In addition, there were significant negative correlations between occasions of cannabis use and overall WM averaged scores across drug treatments (ρ=-0.49, p=0.007) and under placebo (ρ=-0.45, p=0.004). The results showed that the drug effect in the less frequent cannabis users was more pronounced on the SWM (p<0.01) and VWM (p<0.01), whereas there appeared to be little drug effect in the frequent cannabis users. Conclusion: Low doses of synthetic cannabinoid impaired SWM and VWM, indicating that exogenous activation of the cannabinoid system influences cognitive performance. Further, the results replicated previous findings that schizotypy is correlated with deficits in WM. Clinical Trial Registry Name: Nabilone and caffeine effects on the perceptions of visually, auditory, tactile and multimodal illusions in healthy volunteers. Clinical Trial Registration Number: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry).

Practice effects on the modified concept shifting task (mCST): a convenient assessment for treatment effects on prefrontal cognitive function.

BACKGROUND: Trail-making tests, such as the Concept Shifting Task (CST), can be used to test the effects of treatment on cognitive performance over time in various neuropsychological disorders. However, cognitive performance in such experimental designs might improve as a result of the practice obtained during repeated testing rather than the treatment itself. The current study investigated if practice affects the accuracy and duration of performance on the repeatedly administered Concept Shifting Task modified to make it resistant to practice (mCST). The mCST was administered to 54 healthy participants twice a day, before and after a short break, for eight days. RESULTS: The ANOVA and meta-analysis showed that there was no improvement in the mCST accuracy on the last vs. the first trial (Hedges' g = .14, p = .221) or within the session (after vs. before the break on all days; g = .01, p = .922). However, the participants performed the task faster on the last vs. the first trial (g = -.75, p < .001) and after vs. before the break on all days (g = -.12, p = .002). CONCLUSIONS: Repeated administration of the mCST does not affect the accuracy of performance on the test. However, practice might contribute to faster performance on the mCST over time and within each session.

Cannabis use and sensorimotor gating in patients with schizophrenia and healthy controls.

OBJECTIVE: Schizophrenia patients and healthy cannabis users show different attention-dependant alterations in prepulse inhibition (PPI). It is of interest then to examine PPI in patients with schizophrenia who use cannabis, given the hypothesized association between cannabis use and schizophrenia. METHODS: Prepulse inhibition was measured in 34 healthy cannabis users, 32 healthy non-using controls, 20 patients with schizophrenia who were current cannabis users, and 44 non-using patients with schizophrenia. PPI was measured across a range of startling stimulus intensities, during two attention set conditions. Curves of best fit were fitted to the startle magnitudes, across the stimulus intensities. A number of reflex parameters were extracted from these logistic functions. RESULTS: Similar to healthy cannabis users, cannabis-using patients showed altered PPI of Threshold, only when instructed to sustain attention to the auditory stimuli. Conversely, non-using patients with schizophrenia showed reduced PP of R(MAX) only when instructed to ignore the auditory stimuli. CONCLUSION: Cannabis use in patients with schizophrenia is associated with a similar pattern of attention-dependant alterations in PPI to that observed in healthy cannabis users. This is different to those observed in patients with schizophrenia who do not use cannabis and may be as a result of a dysfunction of sustained attention.

Setting the beat of an internal clock: Effects of dexamphetamine on different interval ranges of temporal processing in healthy volunteers.

Drug studies are powerful models to investigate the neuropharmacological mechanisms underlying temporal processing in humans. This study administered dexamphetamine to 24 healthy volunteers to investigate time perception at different time scales, along with contributions from working memory. Healthy volunteers were administered 0.45 mg/kg dexamphetamine or placebo in a double-blind, crossover, placebo-controlled design. Time perception was assessed using three experimental tasks: a time-discrimination task, which asked participants to determine whether a comparison interval (1200 ± 0, 50, 100, 150, 200 ms) was shorter or longer than a standard interval (1200 ms); a retrospective time estimation task, which required participants to verbally estimate time intervals (10, 30, 60, 90 and 120 s) retrospectively; and a prospective time-production task, where participants were required to prospectively monitor the passing of time (10, 30, 60, 90 and 120 s). Working memory was assessed with the backwards digit span. On the discrimination task, there was a change in the proportion of long-to-short responses and reaction times in the dexamphetamine condition (but no association with working memory), consistent with an increase in the speed of an internal pacemaker, and an overestimation of durations in the timing of shorter intervals. There was an interaction between dexamphetamine, working memory, and performance on the estimation and production tasks, whereby increasing digit span scores were associated with decreasing interval estimates and increased produced intervals in the placebo condition, but were associated with increased interval estimates and decreased produced intervals after dexamphetamine administration. These findings indicate that the dexamphetamine-induced increase in the speed of the internal pacemaker was modulated by the basal working memory capacity of each participant. These findings in healthy humans have important implications for the role of dopamine, and its contributions to timing deficits, in models of psychiatric disorders.

Sex differences in the cardiometabolic health of cannabis users with a psychotic illness.

BACKGROUND: Growing evidence shows cannabis use is associated with lower rates of metabolic dysregulation. Despite cannabis impacting each sex differently, few studies have examined the metabolic profile of male and female cannabis users separately. Our aim was to investigate sex differences in the impact of cannabis use on metabolic syndrome in adults with psychotic illness. METHOD: Data from 1078 men and 735 women interviewed in the second Australian national survey of psychosis were analyzed using multiple logistic regression to model separately, for each sex, the influence of no, occasional and frequent past-year cannabis use on metabolic syndrome, adjusting for potential covariates including antipsychotic medication, smoking, and physical activity. RESULTS: The proportion of women and men with metabolic syndrome was 58.1% and 57.6% respectively. Unadjusted analyses showed frequent cannabis use was associated with significantly lower odds of metabolic syndrome for both sexes. In adjusted analyses, the association between metabolic syndrome and frequent cannabis use remained significant for men (AOR = 0.49, 95% CI = 0.31-0.78), but not for women (AOR = 0.68, 95% CI = 0.37-1.24). Frequent cannabis use was associated with lower odds of abdominal obesity, hypertension and elevated triglyceride levels in men only. CONCLUSIONS: The differences we found suggest cannabinoid regulation of energy balance may be sex-dependent and highlight the importance of examining cannabis use in men and women separately. At the same time, the negative association between cannabis and psychosis onset and relapse should not be dismissed.

Self- and other-agency in people with passivity (first rank) symptoms in schizophrenia.

Individuals with passivity (first-rank) symptoms report that their actions, thoughts and sensations are influenced or controlled by an external (non-self) agent. Passivity symptoms are closely linked to schizophrenia and related disorders yet they remain poorly understood. One dominant framework posits a role for deficits in the sense of agency. An important question is whether deficits in self-agency can be differentiated from other-agency in schizophrenia and passivity symptoms. This study aimed to evaluate self- and other-agency in 51 people with schizophrenia (n=20 current, 10 past, 21 no history of passivity symptoms), and 48 healthy controls. Participants completed the projected hand illusion (PHI) with active and passive movements, as well as immediate and delayed visual feedback. Experiences of agency and loss of agency over the participant's hand and the image ('the other hand') were assessed with a self-report questionnaire. Those with passivity symptoms (current and past) reported less difference in agency between active and passive movements on items assessing agency over their own hand (but not agency over the other hand). Relative to the healthy controls, the current and never groups continued to experience the illusion with delayed visual feedback suggesting impaired timing mechanisms regardless of symptom profile. These findings are consistent with a reduced contribution of proprioceptive predictive cues to agency judgements specific to self representations in people with passivity symptoms, and a subsequent reliance on external visual cues in these judgements. Altogether, these findings emphasise the multifactorial nature of agency and the contribution of multiple impairments to passivity symptoms.

Attention-dependent reduction in prepulse inhibition of the startle reflex in cannabis users and schizophrenia patients--a pilot study.

Our previous report [Kedzior, K., Martin-Iverson, M., 2006. Chronic cannabis use is associated with attention-modulated reduction in prepulse inhibition of the startle reflex in healthy humans. J. Psychopharmacol. 20, 471-484.] indicates that chronic cannabis use in healthy humans is associated with deficits in the attentional modulation of prepulse inhibition of the acoustic startle reflex. The aim of the current study was to compare the attentional modulation of prepulse inhibition among healthy controls, otherwise-healthy cannabis users and schizophrenia patients (non-users) utilising the same attentional paradigm. Auditory startle reflex (the eye blink) was recorded from orbicularis oculi muscle while participants were attending to or ignoring 100 dB pulses and 70 dB prepulses separated by 20-200 ms. Cannabis users and schizophrenia patients showed a significant reduction in prepulse inhibition relative to controls while attending to, but not ignoring, auditory stimuli. These results suggest that the reduction in prepulse inhibition observed in cannabis users and in schizophrenia patients appears to be related to attentional dysfunction.

The impact of current cannabis use on general cognitive function in people with psychotic illness.

BACKGROUND: Despite growing research, it remains unclear if cannabis use is associated with additive cognitive impairment in people with psychotic illness and whether exposure in early adolescence is associated with poorer cognitive performance in adulthood. METHODS: This cross-sectional study of a nationally representative sample of 1199 adults with psychotic illness compared current cognition (digit symbol coding) of 297 current users of cannabis (used in the past year), 460 past users (used previously but not in the past year) and 442 non-users (never used). Multiple logistic regression was used to examine whether cognitive performance of cannabis-user groups varied by exposure age and diagnosis (non-affective/affective psychoses). RESULTS: Unadjusted analysis showed current cannabis users had significantly higher odds of impaired cognitive function compared to non-users (odds ratio=1.52, 95%CI=1.04-2.22). After adjusting for potential confounders, differences between the three groups were not significant. Exposure age was not significant in adjusted analysis. In participants with nonaffective psychoses, cognitive ability of current cannabis users did not differ from non-users. However, in participants with affective psychoses, using cannabis in the last year was a significant predictor of impaired cognitive function (odds ratio=2.25, 95%CI=1.05-4.84). CONCLUSION: Among people with psychotic illness, there was no significant difference in cognitive function between current, past and non-users of cannabis. However, when we compared cognitive performance of the three cannabis groups by diagnostic grouping, current cannabis use had a significant negative relationship with cognitive function in people with affective psychoses, but not in those with non-affective psychoses. This finding requires replication and further investigation.

Chronic cannabis use is associated with attention-modulated reduction in prepulse inhibition of the startle reflex in healthy humans.

Regardless of a wide research interest the nature of a relationship between cannabis use and schizophrenia is controversial. One of the physiological abnormalities in schizophrenia is attention-modulated deficit in prepulse inhibition (PPI), which is a normal reduction in the startle reflex magnitude when a non-startling stimulus (prepulse) precedes the startling stimulus (pulse). This experiment was designed to determine whether or not otherwise healthy people using cannabis would exhibit attention-modulated deficit in PPI. The startle reflex was recorded in carefully screened healthy humans attending to and ignoring auditory pulse and prepulse stimuli separated by short (20-200 ms) and long prepulse intervals (1600 ms). In contrast to 12 non-using controls, cannabis use in 16 healthy humans was associated with significant reduction in%PPI while attending to auditory stimuli, but not while ignoring them. The PPI was correlated with the duration of cannabis use but not with the concentration of cannabinoid metabolites in urine and the recency of cannabis use in the preceding 24 hours. Cannabis use was not associated with changes in prepulse facilitation of startle reflex magnitude (%PPF) at long prepulse intervals, prepulse facilitation of startle reflex latency and startle reflex magnitude in the absence of prepulses. These results suggest that chronic, but not acute, use of cannabis is associated with schizophrenia-like disruption in PPI in healthy controls. Such reduction in PPI is attention-dependent and does not reflect a global deficit in sensorimotor gating in cannabis users.