The main findings of our analysis are summarised in Table 4. Overall, the group with lower CAPE scores showed increased activation, compared to the group with higher CAPE scores in the left insula (age 14), the left caudate, the right prefrontal and the right parahippocampal areas (age 19); the high CAPE score group exceeded the low CAPE score group in activation only in the right insula (age 14).

Table 4 Overall Results of Mean Brain Activation and CANTAB Measures Factorial and Exploratory Analysis. Full size table

19-year-old subjects with increased CAPE scores, indexing higher PLEs (measured only at age 19), demonstrated attenuated activation of the right superior frontal gyrus, the right parahippocampal gyrus/amygdala and the left caudate, compared to their peers with lower CAPE scores, indexing lower PLEs – when examined using fMRI during a facial emotion perception test. These regions form components of a broader neural circuit responsible for social cognition and behaviour, encompassing the amygdalae, the VMPFC, the cingulate cortex, somatosensory cortices, the fusiform gyrus and the superior temporal sulcus27. Misidentification of facial expressions represent a crucial deficit in this process, and as observed extensively in the schizophrenia literature, can give rise to impaired social interactions and the subsequent elaboration of paranoid and persecutory beliefs. The right parahippocampal gyrus, was also observed to show increased activation in controls, compared to schizophrenia patients, during the perception of fearful faces14. In our study, we noticed increased activation in the right parahippocampal gyrus including foci within the amygdala in the low PLEs group, at the age of 19, during perception of angry faces. These observations provide neuroimaging evidence supporting the extended psychosis phenotype encompassing preclinical and clinical presentations.

While the low PLEs group showed a regular trajectory of increasing activation over time in the right prefrontal and right insular cortices with brain maturation, the high PLEs group demonstrated decreased activation of the right parahippocampal/amygdala and left insular activation over the same time. This normal increase in frontal activation from age 14 to 19 years is thought to reflect a consequence of the increasing prefrontal cortical control evidenced by the routine improvement in behavioural impulsivity measures to affective stimuli assessed by the Affective Go-NoGo task. Besides, lack of change (or more precisely, a non-significant decrease) in the right insular activation for the high PLEs group between the ages of 14 and 19 results in a ‘normalisation’ of an overactivation at age 14, as the low PLEs group demonstrates a significant increase in right insular activation between the two timepoints. Our longitudinal analysis confirmed that in the high PLEs group, brain activation of a parahippocampal area including foci within the amygdala showed an attenuation between the ages of 14 and 19; the same area also demonstrated significantly decreased activation in the low PLEs group, at the age of 19. This variation could potentially underpin an ‘aberrant’ developmental process, leading to under-recruitment of critical limbic areas during perception of angry faces, introducing a risk for the future emergence of psychosis. Between the ages of 14 and 19, the high PLEs group compared to the low PLEs group showed no significant change in activation of the prefrontal cortex [6 65 31]; the same area remained under-active at the age of 19 in the high PLEs group, which could represent a residual deficit in frontal activation.

Hypoactivation in frontal areas might represent a trait (pattern of brain activation which persist along various timepoints) in the development of psychosis, as it appears in all phases of the continuum, from preclinical to schizophrenia. Frontal hypoactivation or ‘hypo-frontality’ has been extensively researched in schizophrenia, in relation to a variety of behaviours, including motivation, executive functions and psychotic symptomatology28. Another position is that during working memory tasks, patients with schizophrenia can either recruit more extended prefrontal resources, or fail to sustain recruitment of adequate prefrontal areas, compared to controls, which eventually results in poorer behavioural outcomes29. Functional dysconnectivity of fronto-striatal circuitry may represent a risk phenotype for psychosis. First-episode psychosis is associated with pronounced dysregulation of cortico-striatal systems, characterized most prominently by hypo-connectivity of dorsal and hyper-connectivity of ventral fronto-striatal circuits30. A meta-analysis of neurofunctional correlates of vulnerability to psychosis revealed hypoactivation of DLPFC and VLPFC as the most common finding in Ultra-High Risk (UHR) and First-Episode Psychosis (FEP) populations31. Our cross-sectional results indeed revealed hypoactivation of prefrontal [6 65 31] and striatal [−12 5 10] regions in the high PLEs group at age 19, a finding consistent with perturbed fronto-striatal connectivity.

Aberrant activation of the amygdala during a face recognition is probably one of neuroimaging hallmarks of psychosis. In our study, we identified a large cluster centred in the right parahippocampal gyrus, including the amygdalae, hippocampal, and parahippocampal areas, which demonstrated a peak activation at a right parahippocampal region, [33–46], which demonstrated significantly lower activation for the high PLEs group at the age of 19. A study employing a similar IMAGEN sample as ours revealed that subjects with PLEs demonstrated, among other findings, increased hippocampus/amygdala activation during processing of neutral faces, compared to controls16. It is of note however that the authors of this study employed a smaller sample (n = 27), assessed PLEs at age 14 only and used a less extended questionnaire focusing on perceptual abnormalities and delusional thoughts. It’s relevant that we are assessing a non-clinical group of subjects; thus, our findings are likely to correspond to preliminary brain alterations in a trajectory toward psychosis and predate changes that are later seen more consistently across the psychosis continuum.

Our finding of lower left caudate activation at age 19 in the high PLEs group, is of interest. A similar finding in this region has been reported by another study, showing that UHR individuals had decreased left caudate activation during processing of prosodic voice with negative emotional valence, compared to increases activation in controls32.

The neuropsychological assessment showed a decrease in AGN scores from age 14 to age 19 in both the high and low PLEs groups, which indicates an improvement in affective/inhibitory control. This change corresponds to findings of decreased limbic activation [33, −46, −5] from age 14 to age 19 in the high PLEs group, and increased frontal activation [6, 31, 65] from age 14 to age 19 in the low PLEs group. Knowing that processing of emotional material is largely mediated by limbic areas of the brain, while the frontal lobes can exert a top-down inhibitory control in subcortical areas, here we detect a dual pattern of achieving improved emotional processing, by either increasing ‘higher’ cortical control (high PLEs group) or decreasing ‘lower’ limbic activation (low PLEs group). Hyperactivation in the limbic system can account for an inability to regulate emotions, and as discussed earlier, emotion regulation difficulties can lie at the core of vulnerability to psychosis15.

Interestingly, the high PLEs group exhibited a lower rate of omissions in the AGN task, indexing increased affective/inhibitory control, compared to the low PLEs group at age 14. This observation cannot be accounted by the limited corresponding findings of increased right insular activation [42 8 −14] and decreased left insular activation [−36 11 −5] in the same group at the same age; neither can be interpreted within the boundaries of the continuum model of psychosis. However, similar inconsistencies between neuroimaging findings and cognitive-behavioural measures point towards the differences in sensitivity of the two approaches to detect an underlying brain process33.

Limitations

There is a number of limitations in our study. Firstly, we selected CAPE upper and lower deciles to stratify our sample, as these correspond to cut-off levels roughly equivalent to those associated with psychosis proneness in literature (detailed in the section describing the stratification of our sample). The decision to dichotomize our population was mainly driven by the need to identify the most/least prone to psychosis individuals in a naturalistic sample, given that CAPE-42 scores were still moderate in it. Despite the limitations introduced by the use of dichotomization, this was deemed as the most appropriate method to explore the extremes of the psychosis continuum in our naturalistic sample. Nevertheless, we eventually ended up with a high PLEs group having a still low average total score of 112, considering the full potential range of scoring (0–294). In addition, as we stratified our sample retrospectively, based on CAPE-42 scores at age 19 year, and in light of the absence of available scores at age 14 years or intermediate ages, it was impossible to observe the evolution of PLEs between the two timepoints. We have rather arbitrarily viewed the high-PLEs phenotype as a representative for the prodrome for psychosis; however, PLEs can have multiple clinical outcomes, thus leading to a variety of psychopathologies, other than florid psychosis or can also be associated with non-clinical phenotypes as manifested by a mean lifetime prevalence of>5% of psychotic experiences in the general population34. Obviously, the lack of transition to psychosis data restricts the use of our high PLEs group as a measure of the UHR population. There was a greater representation of males in our low vs high PLEs groups; despite male predominance being a common epidemiological finding in this clinical field35, this may impede the generalisability of our results. Moreover, we did not control for gray matter volumetric changes.

In our study we focused on contrasts involving angry faces aiming at emotional aspects of faces’ processing. It would be of interest for future studies to analyse contrasts allowing the detection differences in baseline activation (i.e. neutral faces vs control stimuli) which can be suggestive of an aberrant salience processing36.