Neuroimaging oxytocin modulation of social reward learning in schizophrenia.

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. To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. 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. 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. 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

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

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

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Reduced susceptibility to the sound-induced flash fusion illusion in schizophrenia

Schizophrenia is characterised by the presence of abnormal complex sensory perceptual experiences. Such experiences could arise as a consequence of dysfunctional multisensory integration. We used the sound-induced flash illusion paradigm, which probes audiovisual integration using elementary visual and auditory cues, in a sample of individuals with schizophrenia (n=40) and matched controls (n=22). Signal detection theory analyses were performed to characterise patients’ and controls’ sensitivity in distinguishing 1 and 2 flashes under varying auditory conditions. Both groups experienced significant fission illusions (whereby one visual flash, accompanied by two auditory beeps, is misperceived as two flashes) and fusion illusions (whereby two flashes, accompanied by one beep, are perceived as one flash). Patients showed significantly lower fusion illusion rates compared to HC, while the fission illusion occurred similarly frequently in both groups. However, using an SDT approach, we compared illusion conditions with unimodal visual conditions, and found that illusory visual perception was overall more strongly influenced by auditory input in HC compared to patients for both illusions. This suggests that multisensory integration may be impaired on a low perceptual level in SZ

White matter changes in treatment refractory schizophrenia:Does cognitive control and myelination matter?

Widespread white matter abnormalities have been reported in schizophrenia, a disorder frequently characterised as a dysconnection syndrome. White matter connectivity in schizophrenia has been predominantly investigated using diffusion weighted imaging, with reductions in fractional anisotropy throughout the brain often interpreted as an indicator of abnormal myelination. However, diffusion weighted imaging lacks specificity and as such a number of microstructural factors besides myelin may be contributing to these results. We utilised multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in medicated patients with chronic schizophrenia, stratified by treatment response status, and healthy controls, in order to assess myelin water fraction (MWF) in these groups. In addition, we assessed cognitive control using the Stroop task to investigate how response inhibition relates to myelination in patients and controls. Both treatment resistant (n = 22) and treatment responsive (n = 21) patients showed reduced MWF compared to healthy controls (n = 24) in bilateral fronto-occipital fasciculi, particularly evident in the vicinity of the striatum und extending to the cerebellum, with no difference between patient groups. Patients showed greater reaction time interference on the Stroop task compared to healthy controls, with no difference between patient groups. Stroop interference was significantly negatively correlated with MWF in the corpus callosum across groups, and MWF differences in this region mediated the behavioural group effects on the Stroop task. These findings support the suitability of mcDESPOT as a myelin-specific measure of abnormal connectivity in schizophrenia, and suggest that treatment resistant schizophrenia is not characterised by more severe abnormalities in myelination or cognitive control compared to treatment responsive schizophrenia

Differential neural reward mechanisms in treatment-responsive and treatment-resistant schizophrenia

AbstractBackgroundThe significant proportion of schizophrenia patients refractory to treatment, primarily directed at the dopamine system, suggests that multiple mechanisms may underlie psychotic symptoms. Reinforcement learning tasks have been employed in schizophrenia to assess dopaminergic functioning and reward processing, but these have not directly compared groups of treatment-refractory and non-refractory patients.MethodsIn the current functional magnetic resonance imaging study, 21 patients with treatment-resistant schizophrenia (TRS), 21 patients with non-treatment-resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilizing emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE)-related neural activation and the differential impact of emotional bias on these reward signals were compared between groups.ResultsPatients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favoring happy faces. The pattern of RPE signaling was similar in the HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation in striatal, thalamic, precentral, parietal, and cerebellar regions. TRS patients, but not NTR patients, showed a positive relationship between emotional bias and RPE signal during negative feedback in bilateral thalamus and caudate.ConclusionTRS can be dissociated from NTR on the basis of a different neural mechanism underlying reinforcement learning. The data support the hypothesis that a favorable response to antipsychotic treatment is contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality of a non-dopaminergic mechanism – a glutamatergic mechanism would be a possible candidate.</jats:sec

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

Mapping cortical surface features in treatment resistant schizophrenia with in vivo structural MRI

Decreases in cortical volume (CV), thickness (CT) and surface area (SA) have been reported in individuals with schizophrenia by in vivo MRI studies. However, there are few studies that examine these cortical measures as potential biomarkers of treatment resistance (TR) and treatment response (NTR) in schizophrenia. This study used structural MRI to examine differences in CV, CT, and SA in 42 adults with schizophrenia (TR = 21, NTR = 21) and 23 healthy controls (HC) to test the hypothesis that individuals with TR schizophrenia have significantly greater reductions in these cortical measures compared to individuals with NTR schizophrenia. We found that individuals with TR schizophrenia showed significant reductions in CV and CT compared to individuals with NTR schizophrenia in right frontal and precentral regions, right parietal and occipital cortex, left temporal cortex and bilateral cingulate cortex. In line with previous literature, the temporal lobe and cingulate gyrus in both patient groups showed significant reductions of all three measures when compared to healthy controls. Taken together these results suggest that regional changes in CV and CT may index mechanisms specific to TR schizophrenia and potentially identify patients with TR schizophrenia for earlier treatment