Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association With Clinical Outcome

Abstract

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.

Increased Functional Coupling between VTA and Hippocampus during Rest in First-Episode Psychosis

“…CHR individuals showed reduced hippocampal activity during an event-related novelty/salience task which drives hippocampal-midbrain-striatal response. The authors found that CHR participants had significantly less activation with stimulus novelty in the anterior right hippocampus, but when using functional coupling as an approach to understand the circuit, CHR subjects showed greater VTA-hippocampal connectivity, along with reduced midbrain-striatum connectivity (Modinos et al, 2020). Thus, our findings extend this literature to indicate that patterns of connectivity not only persist into patient's first episode, but notably also generalize to task-free states.…”

“…Recently, research has begun to characterize interactions across the VTA and hippocampus in psychosis-related populations (for review, see Modinos et al, 2015). A study found that, during the processing of novel environments, individuals at clinical high risk (CHR) for developing psychosis exhibited attenuated functional coupling between the VTA and hippocampus; moreover, these alterations were greater in individuals that converted to having psychosis versus not (Modinos et al, 2020). Further, hippocampus-VTA connectivity was altered in a sample of individuals with chronic schizophrenia, finding a correlation with positive symptoms during resting state but importantly Nakamura and colleagues did not find differences across individuals with schizophrenia and controls as well as those with other neuropsychiatric disorders (Nakamura et al, 2020).…”

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis

“…A full description of the pre‐processing used is given in the Supplementary Materials Section 1. A high pass cut off of 128 s was included in this pipeline (discrete cosine basis during CompCor extraction) (Behzadi, Restom, Liau, & Liu, 2007), which is equivalent to bandpass filtering that had been used in previous research using the same task paradigm (Bunzeck & Düzel, 2006; Modinos et al, 2020).…”

“…Reaction time and error rate from this task indicates performance on target button presses and not instances of novelty stimulus presentation. Data from the present study using this task has previously been published using Dynamic Causal Modelling (Modinos et al, 2020).…”

Altered subcortical emotional salience processing differentiates Parkinson’s patients with and without psychotic symptoms

“…Some models propose that within the hippocampal-striatal-midbrain circuits, hippocampal dysfunction leads to an enhanced subcortical dopaminergic signalling through descending projections to the dorsal striatum (Lisman and Grace, 2005;Lodge and Grace, 2007). Supporting the involvement of these circuits, a recent study investigating novelty salience processing reported increased connectivity of hippocampal to striatal and midbrain regions, but decreased connectivity between the striatum and the midbrain in subjects at high risk of developing psychosis (Modinos et al, 2019). Furthermore, our previous work in firstepisode psychosis patients, using the same salience paradigm as Modinos et al, showed reduced midbrain, striatal and occipital activation while processing novelty and negative emotional salient stimuli (Knolle et al, 2018).…”