Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing

Key Points

Question

Are psychoticlike experiences in adolescents associated with altered prefrontal and striatal activation during reward processing?

Findings

In this cohort study of 298 adolescents, those with an elevated rate of psychoticlike experiences at age 14 years demonstrated reduced activation in prefrontal and limbic cortical areas during reward processing compared with adolescents with no psychoticlike experiences. However, by age 19 years, the group with the elevated rate of psychoticlike experiences showed differentially increased activation of the right prefrontal cortex and reduced activation of dorsal striatum.

Meaning

Adolescents with an elevated rate of psychoticlike experiences show differential activation in frontostriatal brain areas engaged during reward processing compared with control adolescents; given the nonclinical nature of the sample, the increase in prefrontal cortical activation from early to late adolescence may reflect a compensatory cognitive mechanism in the presence of abnormal striatal reward processing to contextualize these abnormal experiences.

Abstract

Importance

Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses.

Objective

To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task.

Design, Setting, and Participants

A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017.

Main Outcomes and Measures

Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined.

Results

Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation (F_{1, 93} = 5.559; P = .02; F_{1, 93} = 5.009; P = .03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction (F_{1, 93} = 7.448; P = .01).

Conclusion and Relevance

The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

This cohort study examines the rate of psychoticlike experiences in adolescents.

Introduction

Psychoticlike experiences (PLEs) describe transitory symptoms that, if they persist, lead to clinically relevant symptoms with functional impairment.¹ This contemporary view proposes that psychotic symptoms are not “all-or-nothing” pathologic phenomena, but rather fall within the spectrum of normal experiences, conceptualized as the continuum model of psychosis.² This view is supported by the high prevalence rate of delusional or hallucinatory experiences in the general population (10% and 30%), which is substantially higher than the prevalence rates of psychotic disorders.³ Late adolescence is a critical neurodevelopmental period in psychosis, with the classic age at onset being in early adulthood. Approximately 20% to 35% of individuals aged 12 to 35 years who meet clinical criteria for a prodromal risk syndrome (ie, the Comprehensive Assessment of the At-Risk Mental State structured questionnaire administered by clinicians) convert to psychosis within 2 years.⁴ The presence of psychotic symptoms at age 11 years and cannabis use by the age of 15 years were the 2 strongest predictors of psychosis outcomes at age 26 years.⁵ The most widely used community assessment of PLEs is the Community Assessment of Psychic Experiences Questionnaire (CAPE).⁶

Psychoticlike experiences offer a useful, nonclinical phenotype to study psychotic disorders⁷ with the advantages of a lack of exposure to the illness and antipsychotic medication, a critical phase of neurodevelopment for psychosis in drug-naive individuals. The aberrant salience model of psychosis suggests that positive psychotic symptoms occur when dysregulated dopamine firing in the mesocorticolimbic system gives rise to attribution of significance to irrelevant perceptual stimuli.⁸ Patients with first-episode psychosis exhibit abnormal physiologic responses associated with reward prediction error in the dopaminergic midbrain, striatum, and limbic system and subtle abnormalities in discriminating between motivationally salient and more neutral stimuli.⁹

A small functional magnetic resonance imaging (fMRI) study of individuals with PLEs (n = 27) at age 14 years using a reward task demonstrated increased amygdala/hippocampal activation in face perception tasks and reduced right dorsolateral prefrontal activation in response inhibition tasks.¹⁰ An earlier study suggested that PLEs arise as a consequence of decreased cognitive control,¹¹ a view that is supported by a more recent systematic review of schizophrenia.¹² In summary, the presence of psychosis symptoms is associated with decreases in striatal activation during reward tasks and a reduction in prefrontal activation in areas implicated in cognitive control. However, the frequency and intensity of psychotic symptoms differ from those in the general population sample through ultra-high-risk (UHR) states to schizophrenia and the latter is further differentiated by the presence of functional deterioration.¹³ If the cognitive control hypothesis is correct, one might anticipate dysregulation in subcortical reward processing in healthy adolescents that is compensated for by intact cognitive control mechanisms.

A combination of the aberrant salience and cognitive control hypotheses suggests that the presence of aberrant salience may generate PLEs, but these experiences are contextualized appropriately (ie, with no significant functional consequences) if cognitive control mechanisms are operating efficiently. Failure of cognitive control mechanisms would manifest as clinically relevant symptoms with consequent functional deterioration evidenced as psychotic illness.

The aim of the study was to determine whether PLEs in adolescence are associated with altered prefrontal and striatal activation during reward processing. We used the IMAGEN database¹⁴ sample of 1434 healthy adolescents to examine the association between elevated CAPE-42 scores and striatal and prefrontal activation associated with salience and cognitive control, respectively. Two hypotheses were evaluated: the presence of high PLEs will be associated with decreased activation of the prefrontal cortex and striatum during reward processing^15,16 and the pattern of activation in the prefrontal cortex and striatum will vary between high and low PLE groups over time between early and late adolescence, consistently with reports in the literature on patients with psychosis.

Methods

Participants and Settings

Neuroimaging and clinical data of healthy adolescents were obtained from the IMAGEN database.¹⁴ The IMAGEN study received ethical approval by the ethics research committees of the academic centers at which the study was conducted (London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany). All adult participants provided written consent; minors provided oral consent and written consent was obtained by their parents or legal guardians. The present study was conducted from January 1, 2016, to January 1, 2017, from deidentified data. Access to IMAGEN database for the conduction of the present study did not require a separate informed consent; a waiver was applied owing to anonymized data. We used data from age 14 and 19 year points. A total of 1434 adolescents was initially selected based on quality controls and completeness of their behavioral and neuroimaging data sets. Two subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the CAPE 42 items instrument (CAPE-42) at age 19 years were included in the analysis. The epidemiologic features of our sample are described in Table 1.

Table 1. Participant Characteristics and CAPE-42 Score Stratification.

Characteristic	CAPE-42 Total Score Stratification
	High (n = 149)a			Low (n = 149)b
	Mean	SE	SD	Mean	SE	SD
Male, No. (%)	50 (33.6)			84 (56.4)
Right handed, No. (%)	128 (85.9)			123 (82.6)
Age, y
Baseline	14.47	0.03	0.39	14.43	0.03	0.38
Follow-up	19.02	0.06	0.76	18.98	0.06	0.74
WISC baseline score c
Verbal	111.15	1.32	15.66	106.72	1.27	15.24
Performance	108.49	1.33	15.79	105.2	1.20	14.42
ADRS total score, follow-upd	15.89	0.24	2.96	19.7	0.06	0.72
AUDIT total score, follow-upe	7.5	0.44	5.34	5.26	0.32	3.87
DAST total score, follow-upf	1.59	0.21	2.52	0.54	0.08	1.02
CAPE-42 score, follow-upg
Total	111.64	1.74	21.26	9.54	0.39	4.75
Positive symptoms	33.09	1.27	15.48	3.23	0.24	2.98
Bizarre delusions	13.17	0.97	11.82	0.37	0.09	1.09
Social delusions	19.91	0.54	6.57	2.87	0.21	2.61
Negative symptoms	46.37	0.93	11.37	2.22	0.21	2.61
Depressive symptoms	32.18	0.61	7.49	4.09	0.21	2.54

Abbreviations: ADRS, Adolescent Depression Rating Scale; AUDIT, Alcohol Use Disorders Identification Test; CAPE-42, Community Assessment of Psychic Experiences Questionnaire, 42 items instrument; DAST, Drug Abuse Screening Test for Cannabis; WISC, Wechsler Intelligence Scale for Children.

^aScorers in upper 10% of CAPE-42 total score.

^bScorers in lower 10% of CAPE-42 total score.

^cThe average score is 100; higher scores indicate higher than average intelligence and lower scores indicate lower levels of intelligence.³⁷

^dScores range from 0 to 60; higher scores indicate higher levels of adolescent depression.³⁸

^eScores range from 0 to 40; higher scores indicate greater levels of alcohol abuse.³⁹

^fScores range from 0 to 10; higher scores indicate greater levels of cannabis abuse.⁴⁰

^gScores range from 0 to 294; higher scores indicate elevated presence of prodromal psychotic symptoms.⁶

Measures

The CAPE-42 questionnaire⁶ was used as a measure of PLEs in our adolescent population at age 19 years. In its extended version CAPE-42 includes 42 items that are grouped in 3 dimensions: positive, negative, and depressive. Each item is scored for frequency and severity in a scale from 0 to 7; total scores range from 0 to 294. Higher scores indicate an elevated presence of prodromal psychotic symptoms.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) includes highly sensitive, precise, and objective measures of cognitive function.¹⁷ Our study focused on the Affective Go-NoGo Task (AGN), providing an assessment of the information processing biases for positive and negative stimuli; this task was chosen as a proxy for “hot” cognition, as related to the inhibitory/affective function of frontal and limbic areas of the brain.

The adapted monetary incentive delay (MID) task is a widely used assessment of rewarded learning. It measures participant reactions to a brief visual target. The MID task includes reward anticipation and receipt of feedback of win or no-win outcomes.

Stratification of the Sample

We defined 2 subgroups with high or low PLEs, based on total CAPE-42 scores. Because the CAPE-42 total scores did not follow a normal distribution, we selected participants with high and low scores using the upper and lower deciles. This distinction resulted in 149 adolescents in the high PLEs group and 149 in the low PLEs group. The high group CAPE-42 total score ranged from 91 to 182, corresponding to an itemized score range of 2.17 to 4.33. Cutoff levels in the area of 2.0 per CAPE-42 item provide adequate positive predictive value for transition to psychosis¹⁸; the level formed the lower bound of the high PLEs group. The 2 groups were matched for handedness, age, and IQ.

fMRI Acquisition and Analysis

The scanning parameters and sequence protocol were chosen to be uniform for all sites and scanners. A full description of the scanning protocols, cross-site standardization and quality checks, and preprocessing of resulting data are provided elsewhere.¹⁹

First-Level Analysis

Two within-participant contrasts reflecting core reward processing, as previously described,^20,21 were selected for investigation. The fMRIs were conducted at ages 14 and 19 years, using SPM12 (http://www.fil.ion.ucl.ac.uk/spm; Wellcome Trust Centre for Neuroimaging): anticipation of large win – anticipation of no win and feedback of large win – feedback of no win.

Second-Level Analysis

Whole-brain analysis focused only on high and low CAPE-42 scorers and task-related regions of interest for the 2 first-level contrasts were collapsed across the high and low groups. This approach provides an unbiased estimate of the activation, as the group average positive/negative is orthogonal to high greater than low or low greater than high and is also supported by literature on functional localizers.²²

In a factorial analysis, the main effect of time, group, and the interaction of time × group on brain activation levels was examined by employing a mixed-model 2-way analysis of variance, with group as fixed and subject as random effects. Any main effects or interactions were further examined by post hoc paired, independent, 2-tailed t tests, with P < .05 as the statistically significant threshold. Additional exploratory analysis was also reported, when statistically significant.

Results

Two groups of adolescents (high PLEs, n = 149; 50 [33.6%] males and low PLEs, n = 149; 84 [56.4%) males]) were compared at ages 14 and 19 years. The 2 groups were matched for handedness, age, and IQ.

Results of fMRI Analysis

Five regions of interest (ROIs) based on previous studies of reward processing in psychosis and UHR for psychosis^15,16 and located in the prefrontal cortices, the limbic areas, and the striatum, were selected for factorial analysis. The ROIs (Montreal Neurological Institute space coordinates) were right caudate head (9, 8, 1), right middle frontal gyrus (33, 41, 40), right middle frontal gyrus (33, 44, 31), left middle frontal gyrus (−36, 47, 31), and left cingulate gyrus (−12, −28, 40) (Figure 1 and eFigure 1, eFigure 2, and eFigure 3 in the Supplement provide a visual representation of the ROIs and eTable 1 in the Supplement reports the results of the functional regions of interest brain analysis).

Figure 1. Regions of Interest Showing Differences in Brain Activation Between Low (L) and High (H) Psychoticlike Experiences Groups.

Coronal (A), sagittal (B), and axial (C) views. At age 14 years: right middle frontal gyrus (33, 41, 40 [red]) (L>H [low group has shown greater brain activation than high group]); right middle frontal gyrus (33, 44, 31 [blue]) (L>H); left cingulate gyrus (−12, −28, 40 [purple]) (L>H); and left middle frontal gyrus (L>H) (−36, 47, 31 [yellow]). At age 19 years: (9, 8, 1 [green]) right caudate head (L>H).

Right Caudate Head (9, 8, 1)

No effects of group × time, group, or time were found. Additional exploratory analysis showed higher brain activation of the low PLEs group compared with the high PLEs group at age 19 years during anticipation (t = −2.846; P = .01) (eTable 2 and eTable 3 in the Supplement).

Right Middle Frontal Gyrus (33, 41, 40)

There was an interaction effect of group × time (F_{1, 93} = 7.448; P = .01), showing significant increase in the high PLEs group from ages 14 to 19 years (t = −3.18; P = .003) with no change in the low PLEs group. Additional exploratory analysis exhibited higher brain activation of the low PLEs group compared with the high PLEs group at age 14 years during feedback (t = −5.069; P < .001) (Figure 2, Table 2, and eTable 3 and eTable 4 in the Supplement).

Figure 2. Mean Brain Activation Parameter Estimates at Ages 14 and 19 Years for Functional Regions of Interest.

Statistically significant changes at P = .05 level for the high psychoticlike experiences group only; SE bars are displayed. MID indicates monetary incentive delay.

Table 2. Mean Brain Activation Contrast Parameter Estimates Factorial Analysis.

Characteristic	Type III Sum of Squares	df	Mean Square	F Value	P Value	r Valuea
Frontal ROI (33, 41, 40) brain activation
Time	7.632	1	7.632	1.527	.22b	0.127
Group	4.108	1	4.108	3.598	.06b	0.193
Time × group	37.236	1	37.236	7.448	.008	0.272
Error (time)	464.966	93	5.000	NA	NA	NA
Error (group)	106.187	93	1.142	NA	NA	NA
Frontal ROI (33, 44, 31) brain activation
Time	25.604	1	25.604	5.009	.03	0.226
Group	2.323	1	2.323	1.821	.18b	0.139
Time × group	8.606	1	8.606	1.684	.20b	0.133
Error (time)	475.398	93	5.112	NA	NA	NA
Error (group)	118.659	93	1.276	NA	NA	NA
Frontal ROI (−36, 47, 31) brain activation
Time	33.354	1	33.354	5.559	.02	0.237
Group	2.24	1	2.24	1.77	.19b	0.137
Time × group	19.871	1	19.871	3.312	.07b	0.185
Error (time)	558.029	93	6	NA	NA	NA
Error (group)	117.68	93	1.265	NA	NA	NA

Abbreviations: ROI, region of interest; NA, not applicable.

^aPearson correlation coefficient.

^bNot statistically significant at a P = .05 level.

Right Middle Frontal Gyrus (33, 44, 31)

There was a main effect of time (F_{1, 93} = 5.009; P = .03), driven by an increase in brain activation from ages 14 to 19 years, significant only for the high PLEs group (t = −2.902, P = .01). Additional exploratory analysis exhibited higher brain activation of the low PLEs group compared with the high PLEs group at age 14 years during feedback (t = −3.029; P = .003) (Figure 2, Table 2, and eTable 3 and eTable 4 in the Supplement).

Left Middle Frontal Gyrus (−36, 47, 31)

There was a main effect of time (F_{1, 93} = 5.559; P = .02) that was driven by an increase in brain activation from ages 14 to 19 years, but was significant only for the high PLEs group (t = −2.851; P = .01). Additional exploratory analysis exhibited higher brain activation of the low PLEs group compared with the high PLEs group at age 14 years during feedback (t = −2.818; P = .01) (Figure 2, Table 2, and eTable 3 and eTable 4 in the Supplement).

Left Cingulate Gyrus (−12, −28, 40)

No effects of group × time, group, or time were reported. Additional exploratory analysis exhibited higher brain activation of the low PLEs group compared with the high PLEs group at age 14 years during feedback (t = −2.82; P = .01) (eTable 2 and eTable 3 in the Supplement).

Results CANTAB Measures Analysis

There was a significant effect of time on AGN total omissions for both positive (F_{1, 159} = 58.778; P < .001) and negative (F_{1, 159} = 50.236; P < .001) stimuli; however, there was no significant main effect of group and no interaction (Table 3). Post hoc analyses demonstrated the AGN total omissions for both positive and negative stimuli showed a decrease from ages 14 to 19 years across the high PLEs group (AGN positive: t = 4.529; P < .001; AGN negative: t = 3.745; P < .001) and the low PLEs group (AGN positive: t = 6.352; P < .001; AGN negative: t = 6.385; P < .001). The high PLEs group scored lower on AGN total omissions for both positive and negative stimuli at age 14 years (Table 3 and eTable 5, eTable 6, and eFigure 4 in the Supplement).

Table 3. CANTAB Measures Factorial Analysis^a.

CANTAB Variableb	Factors	Type III Sum of Squares	df, dfR	Mean Square	F Value	P Value	r Valuec
AGN total omissions negative	Time	3006.213	1, 159	3006.213	50.236	<.001	0.490
	Group	73.817	1, 159	73.817	2.498	.12d	0.124
	Time × group	144.599	1, 159	144.599	2.416	.12d	0.122
AGN total omissions positive	Time	3423.720	1, 159	3423.720	58.778	<.001	0.520
	Group	77.094	1, 159	77.094	2.919	.09d	0.134
	Time × group	77.335	1, 159	77.335	1.328	.25d	0.091

Abbreviations: AGN, Affective Go-NoGo Task; CANTAB, Cambridge Neuropsychological Test Automated Battery; dfR, df(error).

^aMixed-model, 2-way analysis of variance factorial analysis.

^bTotal number of missed responses to targets in the blocks specified by the value of target type (negative, positive).

^cPearson correlation coefficient.

^dNot statistically significant at a P = .05 level.

Discussion

Adolescents with high levels of PLEs at age 19 years demonstrated a novel significant increase in right frontal activation during a reward processing task between the ages of 14 and 19 years. They also exhibited decreased activation of the head of caudate during reward processing at 19 years, which is in line with earlier findings.²³ Previous studies in early adolescent high-risk populations have found decreased frontal brain activation compared with controls¹⁶; this is in line with our findings of lower frontal activation in our high PLEs group at age 14 years.

The contemporary view suggests that abnormal perceptions, such as PLEs, may be a relatively common occurrence and, in most cases, they are appropriately contextualized—a function of cognitive control—and no functional alterations occur. The pattern of decreased striatal activation and increased prefrontal activation supports the suggestion that the evolution of clinically relevant psychotic symptoms requires not only a deficit in striatal reward processing, but also a putative failure of compensatory frontal executive processes.^24,25 Thus, this increase in right frontal activation in PLEs may serve as a proxy of executive function—a compensatory mechanism to ensure that any unusual experiences secondary to reward processing deficits do not become incorrectly represented given the current context. The lack of any neuropsychological performance differences in executive functioning between the low and high PLE adolescent groups also lends additional support to this view. However, other possibilities are that this pattern of change in processing reward engages prefrontal cortex and striatum in a different way to generate PLEs in these individuals or that the differences reflect the allocation of potential resources in a proactive, healthy way.

In a study using an MID task, anticipation of reward loss-avoidance elicited significant activation of the ventral striatum in both controls and active participants with UHR for psychosis, with a tendency for less activation in the UHR group.¹⁵ Individuals with UHR have been shown to be more likely to attribute motivational salience to irrelevant stimulus features, and this bias (and ventral striatum responses) were correlated with delusionlike symptoms²⁶; ventral striatum/pallidum connectivity to the midbrain is also altered in people with UHR for psychosis.²⁷ Functional MRI studies with UHR individuals have shown ventral striatum hypoactivation and frontal hyperactivation during reward anticipation.^15,28

Early hypoactivation in frontal areas might represent a trait in the development of psychosis, as it is commonly reported across all phases of the psychosis continuum, from prodromal to schizophrenia. Hypofrontality²⁹ and functional dysconnectivity of frontostriatal circuitry³⁰ may represent a risk phenotype for psychosis. A meta-analysis of neurofunctional correlates of vulnerability to psychosis revealed hypoactivation of dorsolateral prefrontal cortex and ventrolateral prefrontal cortex as the most common finding in UHR and first-episode psychosis populations.³¹ Even in healthy individuals, aberrant frontostriatal prediction error signals correlate with delusionlike beliefs.³² Our longitudinal studies confirmed the involvement of 3 frontal areas, showing hypoactivation in the high PLEs group at age 14 years, which also manifested higher levels of activation at 19 years. This change might represent the outcome of a corrective mechanism, targeting brain areas with an activation deficit at an early phase.

The dopamine hypothesis of schizophrenia specified subcortical hyperdopaminergia combined with prefrontal hypodopaminergia as the cardinal features of the neuropathologic cause of schizophrenia; this hypothesis has been modified by inclusion of a presynaptic striatal dopamine dysregulation conceptualized as the final common pathway responsible for the misappraisal of stimuli characteristic of emergent psychosis.³³ In our study, we showed that aberrant activation in this neural circuit (frontal areas and caudate head) is present at ages 14 and 19 years in individuals with a prodromal psychotic phenotype.

Ethologic observations have traditionally distinguished between appetitive (anticipation or reward, motivational phase) and consummatory (outcome/feedback of reward, hedonic response) stages of reward processing involving ventral striatum and ventromedial frontal cortex.^34,35 In our studies, 3 ROIs that resulted from the feedback contrast were located in left and right middle frontal gyri; 1 ROI that resulted from the anticipation contrast was located in dorsal striatum. A recent, small fMRI study from the IMAGEN sample¹⁰ showed increased activation in the right anterior/middle cingulate gyrus and decreased activation in the left fusiform gyrus in the MID in individuals with PLEs. However, the authors of that study used a smaller sample, assessed PLEs at age 14 years, and used a less-extended assessment tool focusing on perceptual abnormalities and delusional thoughts.

The neuropsychological assessment showed that the low PLEs group manifested higher omission errors compared with the high PLEs group at age 14 years, suggestive of reduced inhibitory control, despite the cross-sectional neuroimaging finding of increased frontal brain activation. However, a decrease in AGN scores from ages 14 to 19 years, which corresponds to an improvement in affective/inhibitory control, was observed in both the high and low PLEs groups and was associated with the longitudinal neuroimaging finding of an increase in brain activation at frontal ROIs from ages 14 to 19 years, which was significant only for the high PLEs group. This finding lends support to the proposal that there were no significant differences in explicit cognitive control between the high and low PLEs groups compared with an implicit compensatory cognitive control mechanism that was seen only in the high PLEs group.

Limitations

There are some limitations in our study; we selected high and low decile scorers on CAPE-42 to identify the 2 most polarized groups that would best represent the relative high and low risk for psychosis phenotypes; however, CAPE-42 scores were moderate in our sample. Because our stratification was based on CAPE-42 scores at age 19 years and we did not have available scores at age 14 years or intermediate ages, it was not possible to track the evolution of PLEs between the 2 points. We have viewed the high PLEs phenotype as a proxy for the prodrome for psychosis; however, PLEs can have multiple clinical outcomes, thus leading to a variety of psychopathologic conditions other than psychosis. The lack of transition to psychosis data limits the use of our high PLEs group as a measure for the UHR population. There was a greater representation of the male sex in our low vs high PLEs groups, despite a male preponderance being a common epidemiologic trend in this clinical field.³⁶

Conclusions

Adolescents with high levels of PLEs performing a reward processing task demonstrate decreased activation of frontal and limbic areas at age 14 years and a differential increase in right middle frontal activation from ages 14 to 19 years. Given the nonclinical nature of this sample, this finding could represent a compensatory developmental change that permits cognitive control mechanisms to contextualize the PLEs sufficiently to preclude their evolution to clinical intensity. This finding lends support to a 2-stage process in the emergence of psychotic symptoms, with failure of cognitive control as the key event in transition to functionally relevant symptoms. The ongoing follow-up of this sample will permit evaluation of this change as a useful brain biomarker for the psychosis or other broader psychiatric phenotypes.

Supplement.

eFigure 1. MID Study, ROIs selected for analysis, Illustration (Coronal View)

eFigure 2. MID Study, ROIs selected for analysis, Illustration (Sagittal View)

eFigure 3. MID Study, ROIs selected for analysis, Illustration (Axial View)

eTable 1. MID Study, fROI Brain Analysis

eTable 2. MID Study, fROIs Factorial Analysis, Mixed Model 2-Way ANOVA

eTable 3. MID Study, Exploratory Cross-Sectional Analysis, Independent T-Tests

eTable 4. MID Study, Exploratory Longitudinal Analysis, Paired T-Tests

eTable 5. CANTAB Measures Exploratory Cross-Sectional Analysis, Independent T-Tests

eTable 6. CANTAB Measures Exploratory Longitudinal Analysis, Paired T-Tests

eFigure 4. CANTAB Measures: Mean AGN Total Omissions Positive and Negative Stimuli Scores at age 14 and 19