Salience Attribution and its Relationship to Cannabis-Induced Psychotic Symptoms

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHODS: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test (SAT), a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory (PSI). Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and 6 controls with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups (F1,32 = 1.12, p=.30 [implicit]; F1,32=1.09, p=.30 [explicit]). Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r=.61, p=.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15= 5.8, p=.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r=-.91, p=.01), whereas this relationship was non-significant within users (difference between correlations: Z=-2.05, p=.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use

Understanding the mechanisms underlying cognitive control in psychosis

Background Cognitive control (CC) involves a top–down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia. Methods This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity. Results The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia. Conclusion These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC

Neural correlates of positive and negative symptoms through the illness course: an fMRI study in early psychosis and chronic schizophrenia

Psychotic illness is associated with cognitive control deficits and abnormal recruitment of neural circuits subserving cognitive control. It is unclear to what extent this dysfunction underlies the development and/or maintenance of positive and negative symptoms typically observed in schizophrenia. In this study we compared fMRI activation on a standard Stroop task and its relationship with positive and negative symptoms in early psychosis (EP, N = 88) and chronic schizophrenia (CHR-SZ, N = 38) patients. CHR-SZ patients showed reduced frontal, striatal, and parietal activation across incongruent and congruent trials compared to EP patients. Higher positive symptom severity was associated with reduced activation across both trial types in supplementary motor area (SMA), middle temporal gyrus and cerebellum in EP, but not CHR-SZ patients. Higher negative symptom severity was associated with reduced cerebellar activation in EP, but not in CHR-SZ patients. A negative correlation between negative symptoms and activation in SMA and precentral gyrus was observed in EP patients and in CHR-SZ patients. The results suggest that the neural substrate of positive symptoms changes with illness chronicity, and that cognitive control related neural circuits may be most relevant in the initial development phase of positive symptoms. These findings also highlight a changing role for the cerebellum in the development and later maintenance of both positive and negative symptoms

Cognitive correlates of abnormal myelination in psychosis

Psychotic illness has consistently been associated with deficits in cognitive function and reduced white matter integrity in the brain. However, the link between white matter disruptions and deficits in cognitive domains remains poorly understood. We assessed cognitive performance and white matter myelin water fraction (MWF) using multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in recent-onset psychosis patients and age-matched healthy controls (HC). Psychosis patients showed deficits in working memory, phonological and semantic fluency, general intelligence quotient and reduced MWF in the left temporal white matter compared to HC. MWF in the left inferior fronto-occipital fasciculus and inferior longitudinal fasciculus was positively associated with intelligence quotient and verbal fluency in patients, and fully mediated group differences in performance in both phonological and semantic verbal fluency. There was no association between working memory and MWF in the left temporal white matter. Negative symptoms demonstrated a negative association with MWF within the left inferior and superior longitudinal fasciculi. These findings indicate that psychosis-related deficits in distinct cognitive domains, such as verbal fluency and working memory, are not underpinned by a single common dysfunction in white matter connectivity

Influence of music on driver psychology and safety-relevant behaviours: a multi-study inductive content analysis

Supplemental data for this article is available online at https://doi.org/10.1080/1463922X.2021.2009933 .Copyright © 2021 The Author(s). Underpinned by pragmatism and symbolic interactionism, an inductive content analysis was conducted to assess driving experiences under a variety of music conditions. Many quantitative studies have addressed the effects of music on drivers, but there has been a conspicuous dearth of qualitative research to provide a more nuanced understanding of music-related phenomena. Data collection took place over three simulated driving studies, each with different tasks/participants (Study 1 – n = 34, Study 2 – n = 46, and Study 3 – n = 27). The inductive content analysis was conducted by two members of the research team and a peer debriefing was conducted by a third. Findings show that music can have a range of affective, behavioural and cognitive effects (both positive and negative), that are moderated by the driving environment (i.e. urban vs. highway) and aspects of the musical stimulus (i.e. inclusion/non-inclusion of lyrics, loudness and tempo). Participants were mindful of the implications of in-vehicle music vis-à-vis the safety–performance–pleasure trade-off. The analysis suggested a perceived beneficial effect of music and consequent contribution to driving style/safety-related performance. Younger drivers’ apparent reliance on music as a means by which to regulate their emotion highlights an education need in terms of optimising selections.UKRI Economic and Social Research Council grant (ES/R005559/1); Direct Line Group (UK)

Neuroimaging oxytocin modulation of social reward learning in schizophrenia

Background Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms. Aims To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. Method We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human. Results During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms. Conclusions During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia

Psychological and psychophysiological effects of music intensity and lyrics on simulated urban driving

© 2021 The Authors. The main aim of this study was to investigate the effect of musical characteristics (i.e., presence of lyrics and loudness) in the context of simulated urban driving. Previous work has seldom isolated musical characteristics and examined these both singularly and interactively. We investigated the potentially distracting effects of processing lyrics through exposing young drivers to the same piece of music with/without lyrics and at different sound intensities (60 dBA [soft] and 75 dBA [loud]) using a counterbalanced, within-subjects design (N = 34; Mage = 22.2 years, SD = 2.0 years). Six simulator conditions were included that comprised low-intensity music with/without lyrics, high-intensity music with/without lyrics, plus two controls – ambient in-car noise and spoken lyrics. Between-subjects variables of driving style (defensive vs. assertive) and sex (women vs. men) were explored. A key finding was that the no lyrics/soft condition yielded lower affective arousal scores when compared to the other music conditions. There was no main effect of condition for HRV data (SDNN and RMSSD). Exploratory analyses showed that, for assertive drivers, NASA-TLX Performance scores were lower in the no lyrics/soft condition compared to the lyrics/loud condition. Moreover, women exhibited higher mean heart rate than men in the presence of lyrics. Although some differences emerged in subjective outcomes, these were not replicated in HRV, which was used as an objective index of emotionality. Drivers should consider the use of soft, non-lyrical music to optimise their affective state during urban driving.UKRI Economic and Social Research Council grant (ES/R005559/ 1); Direct Line Group (UK)

A Novel Virtual Reality Assessment of Functional Cognition: Validation Study.

BACKGROUND: Cognitive deficits are present in several neuropsychiatric disorders, including Alzheimer disease, schizophrenia, and depression. Assessments used to measure cognition in these disorders are time-consuming, burdensome, and have low ecological validity. To address these limitations, we developed a novel virtual reality shopping task-VStore. OBJECTIVE: This study aims to establish the construct validity of VStore in relation to the established computerized cognitive battery, Cogstate, and explore its sensitivity to age-related cognitive decline. METHODS: A total of 142 healthy volunteers aged 20-79 years participated in the study. The main VStore outcomes included verbal recall of 12 grocery items, time to collect items, time to select items on a self-checkout machine, time to make the payment, time to order coffee, and total completion time. Construct validity was examined through a series of backward elimination regression models to establish which Cogstate tasks, measuring attention, processing speed, verbal and visual learning, working memory, executive function, and paired associate learning, in addition to age and technological familiarity, best predicted VStore performance. In addition, 2 ridge regression and 2 logistic regression models supplemented with receiver operating characteristic curves were built, with VStore outcomes in the first model and Cogstate outcomes in the second model entered as predictors of age and age cohorts, respectively. RESULTS: Overall VStore performance, as indexed by the total time spent completing the task, was best explained by Cogstate tasks measuring attention, working memory, paired associate learning, and age and technological familiarity, accounting for 47% of the variance. In addition, with λ=5.16, the ridge regression model selected 5 parameters for VStore when predicting age (mean squared error 185.80, SE 19.34), and with λ=9.49 for Cogstate, the model selected all 8 tasks (mean squared error 226.80, SE 23.48). Finally, VStore was found to be highly sensitive (87%) and specific (91.7%) to age cohorts, with 94.6% of the area under the receiver operating characteristic curve. CONCLUSIONS: Our findings suggest that VStore is a promising assessment that engages standard cognitive domains and is sensitive to age-related cognitive decline

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies