Revisiting deficits in threat and safety appraisal in obsessive-compulsive disorder.

Current behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD. A clinical sample of individuals with OCD (N = 45) and matched healthy controls (N = 45) underwent functional magnetic resonance imaging. While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan. We found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE = .001). These findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.

Longitudinal changes in neural gain and its relationship to cognitive control trajectory in young adults with early psychosis.

The mixed cognitive outcomes in early psychosis (EP) have important implications for recovery. In this longitudinal study, we asked whether baseline differences in the cognitive control system (CCS) in EP participants would revert toward a normative trajectory seen in healthy controls (HC). Thirty EP and 30 HC undertook functional MRI at baseline using the multi-source interference task-a paradigm that selectively introduces stimulus conflict-and 19 in each group repeated the task at 12 months. Activation of the left superior parietal cortex normalized over time for the EP group, relative to HC, coincident with improvements in reaction time and social-occupational functioning. To examine these group and timepoint differences, we used dynamic causal modeling to infer changes in effective connectivity between regions underlying the MSIT task execution, namely visual, anterior insula, anterior cingulate, and superior parietal cortical regions. To resolve stimulus conflict, EP participants transitioned from an indirect to a direct neuromodulation of sensory input to the anterior insula over timepoints, though not as strongly as HC participants. Stronger direct nonlinear modulation of the anterior insula by the superior parietal cortex at follow-up was associated with improved task performance. Overall, normalization of the CCS through adoption of more direct processing of complex sensory input to the anterior insula, was observed in EP after 12 months of treatment. Such processing of complex sensory input reflects a computational principle called gain control, which appears to track changes in cognitive trajectory within the EP group.

Cognitive Control System Gates Insula Processing of Affective Stimuli in Early Psychosis.

BACKGROUND AND HYPOTHESIS: Impairments in the expression, experience, and recognition of emotion are common in early psychosis (EP). Computational accounts of psychosis suggest disrupted top-down modulation by the cognitive control system (CCS) on perceptual circuits underlies psychotic experiences, but their role in emotional deficits in EP is unknown. STUDY DESIGN: The affective go/no-go task was used to probe inhibitory control during the presentation of calm or fearful faces in young persons with EP and matched controls. Computational modeling of functional magnetic resonance imaging (fMRI) data were performed using dynamic causal modeling (DCM). The influence of the CCS on perceptual and emotional systems was examined using parametric empirical bayes. STUDY RESULTS: When inhibiting motor response to fearful faces, EP participants showed higher brain activity in the right posterior insula (PI). To explain this, we used DCM to model effective connectivity between the PI, regions from the CCS activated during inhibition (dorsolateral prefrontal cortex [DLPFC] and anterior insula [AI]), and a visual input region, the lateral occipital cortex (LOC). EP participants exerted a stronger top-down inhibition from the DLPFC to the LOC than controls. Within the EP cohort, increased top-down connectivity between the LOC and AI was associated with a higher burden of negative symptoms. CONCLUSIONS: Young persons with a recent onset of psychosis show a disturbance in the cognitive control of emotionally salient stimuli and the suppression of irrelevant distractors. These changes are associated with negative symptoms, suggesting new targets for the remediation of emotional deficits in young persons with EP.

Mechanisms of imbalanced frontostriatal functional connectivity in obsessive-compulsive disorder.

The diagnosis of obsessive-compulsive disorder (OCD) has been linked with changes in frontostriatal resting-state connectivity. However, replication of prior findings is lacking, and the mechanistic understanding of these effects is incomplete. To confirm and advance knowledge on changes in frontostriatal functional connectivity in OCD, participants with OCD and matched healthy controls underwent resting-state functional, structural and diffusion neuroimaging. Functional connectivity changes in frontostriatal systems were here replicated in individuals with OCD (n = 52) compared with controls (n = 45). OCD participants showed greater functional connectivity (t = 4.3, PFWE = 0.01) between the nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC) but lower functional connectivity between the dorsal putamen and lateral prefrontal cortex (t = 3.8, PFWE = 0.04) relative to controls. Computational modelling suggests that NAcc-OFC connectivity changes reflect an increased influence of NAcc over OFC activity and reduced OFC influence over NAcc activity (posterior probability, Pp > 0.66). Conversely, dorsal putamen showed reduced modulation over lateral prefrontal cortex activity (Pp > 0.90). These functional deregulations emerged on top of a generally intact anatomical substrate. We provide out-of-sample replication of opposite changes in ventro-anterior and dorso-posterior frontostriatal connectivity in OCD and advance the understanding of the neural underpinnings of these functional perturbations. These findings inform the development of targeted therapies normalizing frontostriatal dynamics in OCD.

Quality prescribing in early psychosis: key pharmacotherapy principles.

OBJECTIVE: To present a practical, easy-to-implement clinical framework designed to support evidence-based quality prescribing for people with early psychosis. METHOD: Identification and explanation of key principles relating to evidence-based pharmacotherapy for people with early psychosis. These were derived from the literature, practice guidelines and clinical experience. RESULTS: Key principles include (1) medication choice informed by adverse effects; (2) metabolic monitoring at baseline and at regular intervals; (3) comprehensive and regular medication risk-benefit assessment and psychoeducation; (4) early consideration of long-acting injectable formulations (preferably driven by informed patient choice); (5) identification and treatment of comorbid mood disorders and (6) early consideration of clozapine when treatment refractory criteria are met. CONCLUSIONS: Current prescribing practices do not align with the well-established evidence for quality pharmacotherapy in early psychosis. Adopting evidence-based prescribing practices for people with early psychosis will improve outcomes.

Sub-optimal modulation of gain by the cognitive control system in young adults with early psychosis.

Executive dysfunctions in early psychosis (EP) are subtle but persistent, hindering recovery. We asked whether changes in the cognitive control system (CCS) disrupt the response to increased cognitive load in persons with EP. In all, 30 EP and 30 control participants undertook multimodal MRI. Computational models of structural and effective connectivity amongst regions in the CCS were informed by cortical responses to the multi-source interference task, a paradigm that selectively introduces stimulus conflict. EP participants showed greater activation of CCS regions, including the superior parietal cortex, and were disproportionately slower at resolving stimulus conflict in the task. Computational models of the effective connectivity underlying this behavioral response suggest that the normative (control) group resolved stimulus conflict through an efficient and direct modulation of gain between the visual cortex and the anterior insula (AI). In contrast, the EP group utilized an indirect path, with parallel and multi-region hops to resolve stimulus conflict at the AI. Individual differences in task performance were dependent on initial linear gain modulations in the EP group versus a single nonlinear modulation in the control group. Effective connectivity in the EP group was associated with reduced structural integration amongst those connections critical for task execution. CCS engagement during stimulus conflict is hampered in EP owing to inefficient use of higher-order network interactions, with high tonic gain impeding task-relevant (phasic) signal amplification.

Protocol update and statistical analysis plan for CADENCE-BZ: a randomized clinical trial to assess the efficacy of sodium benzoate as an adjunctive treatment in early psychosis.

BACKGROUND: CADENCE-BZ is a multi-centre, parallel-group, double-blind randomized controlled trial designed to examine the clinical efficacy and safety of an accessible food preservative, sodium benzoate, as an add-on treatment for patients with early psychosis. The original study protocol was published in 2017. Here, we describe the updated protocol along with the Statistical Analysis Plan (SAP) for the CADENCE-BZ trial prior to study completion. METHODS AND MATERIALS: Two important changes were made to the original protocol: (1) improvements to our statistical analysis plan permitted a reduction in sample size; and (2) a revision in the secondary outcomes with the intent of reducing redundancy and excluding those measures that were not appropriate as outcomes. CONCLUSIONS: We provide the updated SAP prior to the completion of the study with the intent of increasing the transparency of the data analyses for CADENCE-BZ. The final participants are currently completing the study and the results will be published in the near future. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12615000187549 ). Registered on 26th February 2015.

Sifting through the surfeit of neuroinflammation tracers.

The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [11C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [11C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.

Pandemic influenza H1N1 2009 in north Queensland--risk factors for admission in a region with a large indigenous population.

This study describes the epidemiology of laboratory-confirmed pandemic influenza H1N1 within north Queensland, Australia. We collected data on all specimens tested for influenza (including H1N1) by polymerase chain reaction between May and August 2009 at Townsville Hospital. Patients requiring admission to hospital and a proportion of non-admitted patients had clinical characteristics recorded. Multi-variable logistic regression analysis was used to identify independent predictors for admission. Patients requiring admission were on average older, less likely to be of Aboriginal or Torres Strait Islander descent and more likely to be pregnant, female or suffer from diabetes mellitus. Oseltamivir provision was significantly higher within the Aboriginal or Torres Strait Islander patient population. However, when the relative sizes of the local Indigenous and non-Indigenous populations were considered, the relative risk of hospital admission for Indigenous people was found to be 7.9 (4.7-13.2) in comparison to non-indigenous.