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The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as ‘integrated’ FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the ‘cartographic profile’ of time windows and k‐means clustering, and sub‐network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub‐network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub‐network comprised brain areas implicated in bottom‐up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk., A framework for extracting epochs of integrated functional connectivity was used to test network differences between healthy control and clinical high‐risk (CHR) groups, as well as associations with longitudinal changes in symptom and functioning scores in CHR participants. A sub‐network suggestive of bottom‐up sensory processing was found to be associated with changes in positive psychotic symptoms in the CHR group. We suggest this to be a useful approach in searching for network‐based biomarkers of psychosis risk.

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

BACKGROUND: The inappropriate attribution of salience to what would normally be irrelevant or neutral stimuli is a robust feature of psychotic disorders and is linked to altered subcortical dopaminergic signaling. Preclinical models suggest that the latter is driven by interactions within a hippocampal-striatum-midbrain circuit. Although novelty has been less investigated as a dimension of salience processing in psychosis than reward, preclinical evidence indicates that dopaminergic neurons in the midbrain code the salience of unexpected stimuli and respond to novel stimuli. Our first aim was to examine whether subjects at clinical high risk (CHR) for psychosis show altered activation and effective connectivity in the putative hippocampal-striatum-midbrain circuit using fMRI during the processing of novelty salience. The second aim was to examine the relationship between activation and effective connectivity within this circuit and the subsequent onset of a psychotic disorder, by following our CHR participants clinically for around 5 years after scanning to determine their clinical outcome. METHODS: Seventy-six CHR participants and 31 healthy controls (HC) were studied using fMRI while performing a task that engaged novelty salience processing. The CHR sample was then followed clinically for a mean of 59.7 months (~5 years): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups using the contrast Novel versus Neutral trials (indicating ‘pure’ novelty), using SPM12 and dynamic casual modelling (DCM12). Effects were considered significant at a voxel-wise threshold of p < 0.05 family-wise error corrected (FWE). RESULTS: In CHR individuals, the hippocampal response to pure novelty was significantly attenuated compared to that in HC (p = 0.041 FWE). DCM12 revealed that pure stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, pure stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis (CHR-T) than in CHR subjects who did not become psychotic. DISCUSSION: These data indicate that both hippocampal activation and hippocampal-striatal-midbrain effective connectivity in the context of pure novelty salience are perturbed in people at CHR for psychosis, and that the later onset of psychosis is associated with alterations in midbrain-striatal connectivity. These findings are consistent with data from preclinical models of psychosis implicating alterations in a hippocampal–striatal-midbrain circuit in the development of psychosis.

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

Background: The Ultra High Risk (UHR) state is a combination of genetic and clinical risk factors that are associated with an imminent high risk for psychotic disorder. Clinical features in UHR individuals are assessed using specialized semistructured interviews, such as the Comprehensive Assessment of At Risk Mental State (CAARMS). Previous studies have found that the range of symptoms measured by the CAARMS can be reduced to underlying symptom dimensions and these underlying psychopathological dimensions have been linked to higher risk of transition to psychosis, however neither of the two alternative factor structures in UHR have been replicated and to date there has been no investigation of the neurobiological correlates of symptom dimensions in UHR.

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Background: Preclinical and neuropathological research in psychosis suggest that prefrontal and hippocampal GABAergic deficits in fast-spiking, parvalbumin-positive interneurons play a central role in the development of the elevations in striatal dopamine function typically observed in psychosis. This multimodal study aimed to examine in vivo prefrontal GABAergic levels in antipsychotic naive subjects at clinical high risk for psychosis (CHR) and their association with hippocampal resting-state perfusion and severity of prodromal symptomatology.

This article provides an overview of heart failure (HF) and pharmacological treatment of systolic left ventricular dysfunction. The purpose of this article is to provide nurses the knowledge of current treatment recommendations and the Five Million Lives campaign sponsored by the National Institute of Healthcare Improvement. This initiative is a national campaign to protect 5 million patients from medical harm by promoting evidence-based standards of practice to improve the healthcare of Americans. HF has become part of this national initiative and the National Institute of Healthcare Improvement in conjunction with the American College of Cardiology/American Heart Association has implemented guidelines to improve the care of HF patients. Nurses would be expected to be familiar with these guidelines, as regulatory agencies will be using these guidelines as a benchmark to evaluate the quality of care provided to patients with this diagnosis.