The association between aberrant salience and psychotic experiences in general population twins, and genetic vulnerability as a modifier.

BACKGROUND: Previous studies assessing the hypothesis that the construct of 'aberrant salience' is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results. METHODS: The TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task. RESULTS: Measures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282). CONCLUSIONS: Various studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called 'ultra-high risk' patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum.

Gender differences in the associations between childhood adversity and psychopathology in the general population.

PURPOSE: To explore gender differences of the associations between childhood adversity (CA) subtypes and psychiatric symptoms in the general population. METHODS: Data of 791 participants were retrieved from a general population twin cohort. The Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire were used to assess overall psychopathology with nine symptom domains scores and total CA with exposure to five CA subtypes, respectively. The associations between CA and psychopathology were analyzed in men and women separately and were subsequently compared. RESULTS: Total CA was associated with total SCL-90 and all symptom domains without significant gender differences. However, the analyses of CA subtypes showed that the association between emotional abuse and total SCL-90 was stronger in women compared to men [χ2(1) = 4.10, P = 0.043]. Sexual abuse was significantly associated with total SCL-90 in women, but emotional neglect and physical neglect were associated with total SCL-90 in men. Exploratory analyses of CA subtypes and SCL-90 subdomains confirmed the pattern of gender-specific associations. In women, emotional abuse was associated with all symptom domains, and sexual abuse was associated with all except phobic anxiety and interpersonal sensitivity. In men, emotional neglect was associated with depression, and physical neglect was associated with phobic anxiety, anxiety, interpersonal sensitivity, obsessive-compulsive, paranoid ideation, and hostility subdomains. CONCLUSION: CA is a trans-syndromal risk factor regardless of gender. However, differential associations between CA subtypes and symptom manifestation might exist. Abuse might be particularly associated with psychopathology in women, whereas neglect might be associated with psychopathology in men.

TwinssCan - Gene-Environment Interaction in Psychotic and Depressive Intermediate Phenotypes: Risk and Protective Factors in a General Population Twin Sample.

Meta-analyses suggest that clinical psychopathology is preceded by dimensional behavioral and cognitive phenotypes such as psychotic experiences, executive functioning, working memory and affective dysregulation that are determined by the interplay between genetic and nongenetic factors contributing to the severity of psychopathology. The liability to mental ill health can be psychometrically measured using experimental paradigms that assess neurocognitive processes such as salience attribution, sensitivity to social defeat and reward sensitivity. Here, we describe the TwinssCan, a longitudinal general population twin cohort, which comprises 1202 individuals (796 adolescent/young adult twins, 43 siblings and 363 parents) at baseline. The TwinssCan is part of the European Network of National Networks studying Gene-Environment Interactions in Schizophrenia project and recruited from the East Flanders Prospective Twin Survey. The main objective of this project is to understand psychopathology by evaluating the contribution of genetic and nongenetic factors on subclinical expressions of dimensional phenotypes at a young age before the onset of disorder and their association with neurocognitive processes, such as salience attribution, sensitivity to social defeat and reward sensitivity.

Evidence for interaction between genetic liability and childhood trauma in the development of psychotic symptoms.

PURPOSE: Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability. METHODS: The TwinssCan Study collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the co-twin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression. RESULTS: In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (χ2 = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ2 = 8.8, df = 2, p = 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive). CONCLUSION: The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.

Effects of mindfulness-based cognitive therapy on self-reported suicidal ideation: results from a randomised controlled trial in patients with residual depressive symptoms.

INTRODUCTION: The aim of the present study was to investigate the effects of mindfulness-based cognitive therapy (MBCT) on suicidal ideation in an open-label randomised controlled trial of patients with residual depressive symptoms. Furthermore, this study aimed at examining whether an effect of MBCT on suicidal ideation was dependent on a reduction in depression severity, worry and rumination, or an increase in mindfulness. METHODS: One hundred and thirty participants were randomised to a treatment arm (treatment as usual plus MBCT) or a wait list arm. Change in depression, change in worry, change in rumination and change in mindfulness were entered as covariates in a repeated measures ANOVA in order to assess to what degree MBCT-induced changes in suicidal ideation were independent from changes in these parameters. RESULTS: There was a significant group×time (pre vs. post) interaction on suicidal ideation indicating a significant reduction of suicidal ideation in the MBCT group, but not in the control group. The interaction remained significant after addition of the above covariates. Change in worry was the only covariate associated with change in suicidal ideation, causing a moderate reduction in the interaction effect size. CONCLUSIONS: The results suggest that MBCT may affect suicidal ideation in patients with residual depressive symptoms and that this effect may be mediated, in part, by participants' enhanced capacity to distance themselves from worrying thoughts.

FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma.

BACKGROUND: FK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma. AIMS: To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype. METHOD: In 401 general population twins, four functional polymorphisms were examined in models of psychosis and cortisol, and followed up in models of psychosis in three samples at different familial liability (175 controls, 200 unaffected siblings and 195 patients with a psychotic disorder). RESULTS: The most consistent finding was an interaction between childhood trauma and rs9296158/rs4713916 on psychotic symptoms and cortisol in the twin sample, combined with a directionally similar interaction in siblings (rs4713916) and patients (rs9296158), A-allele carriers at both polymorphisms being most vulnerable to trauma. CONCLUSIONS: Trauma may increase the risk of psychosis through enduring changes in the cortisol feedback loop, similar to that for PTSD, suggesting comparable biological mechanisms for psychosis across diagnostic boundaries.

Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [¹8F]fallypride.

Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D2/3 PET radioligand [¹8F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹8F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹8F]fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

Recovery from daily-life stressors in early and chronic psychosis.

Initial affective and psychotic reactivity to daily stressors is altered in psychosis, and most notably in early psychosis. In addition to altered initial stress reactivity, results from studies using Experience Sampling Methodology (ESM) and psychophysiological measures indicate that impaired recovery from mild stressors may also be a risk factor for mental illness. The current ESM study investigated affective recovery from daily stressors in chronic psychosis patients (CP; n = 162), individuals at early stages of psychosis (EP; n = 127), and healthy volunteers (HV; n = 220) assessing fluctuations in negative affect (NA), tension, and suspiciousness ten times a day on six consecutive days. Recovery was operationalized for all three variables as the return to baseline (i.e., level at t-1) following the first stressful event of a day (i.e., t0). The EP group showed a delayed recovery of NA (t1-t3: B = 0.185; p = .007 and B = 0.228; p = .002) and suspiciousness (t1: B = 0.223; p = .010 and B = 0.291; p = .002) compared to HV and CP, respectively. Delayed recovery was detected for tension as well (t1-t2: EP > HV: B = 0.242; p = .040 and EP > CP: B = 0.284; p = .023), but contrary to both other momentary states, this effect disappeared when controlling for subsequent stressful events. There were no significant differences in recovery between HV and CP. These results suggest that in EP, stressful daily events have longer-lasting effects on overall negative affect and subclinical psychotic-like experiences. Future studies should incorporate physiological and endocrine measures in order to integrate recovery patterns of the different stress systems.

Does the concept of "sensitization" provide a plausible mechanism for the putative link between the environment and schizophrenia?

Previous evidence reviewed in Schizophrenia Bulletin suggests the importance of a range of different environmental factors in the development of psychotic illness. It is unlikely, however, that the diversity of environmental influences associated with schizophrenia can be linked to as many different underlying mechanisms. There is evidence that environmental exposures may induce, in interaction with (epi)genetic factors, psychological or physiological alterations that can be traced to a final common pathway of cognitive biases and/or altered dopamine neurotransmission, broadly referred to as "sensitization," facilitating the onset and persistence of psychotic symptoms. At the population level, the behavioral phenotype for sensitization may be examined by quantifying, in populations exposed to environmental risk factors associated with stress or dopamine-agonist drugs, (1) the increased rate of persistence (indicating lasting sensitization) of normally transient developmental expressions of subclinical psychotic experiences and (2) the subsequent increased rate of transition to clinical psychotic disorder.

Overall cortisol, diurnal slope, and stress reactivity in psychosis: An experience sampling approach.

OBJECTIVE: Results from experimental studies suggest that psychosis and psychosis liability are associated with increased cortisol levels and blunted cortisol reactivity, and that use of antipsychotics may reduce these aberrations. Here, we report on overall cortisol, diurnal slope, and cortisol stress reactivity in everyday life in psychosis and psychosis liability using the experience sampling method (ESM). METHODS: Our sample consisted of individuals diagnosed with psychotic disorder currently on (MPD; n = 53) or off antipsychotic medication (NMPD; n = 20), first-degree relatives of psychotic patients (REL; n = 47), and healthy volunteers (HV; n = 67). Saliva samples were collected throughout the day on six consecutive days and analyzed for cortisol levels. Simultaneously, stressfulness of the current activity was assessed with ESM questionnaires. RESULTS: We found no group differences in overall cortisol level between groups, but REL had a steeper diurnal slope than HV; in MPD a trend was found in the same direction. Regarding reactivity to stressful activities, results indicated attenuation of the cortisol response in both patient groups compared to HV. CONCLUSION: These results do not confirm reports of increased cortisol levels in psychosis, but provide evidence of stress-related cortisol alterations in everyday life.

Stress reactivity links childhood trauma exposure to an admixture of depressive, anxiety, and psychosis symptoms.

Childhood trauma exposure has been associated with a clinically relevant mixed phenotype of psychopathology composed of depressive, anxiety, and psychosis symptoms, across healthy and clinical samples. Altered stress-reactivity after exposure to childhood trauma may be a plausible underlying mechanism explaining this association. In a general population sample of female twins (T0 = 564; T1 = 483), associations between childhood trauma exposure and symptom profile (no symptoms, isolated symptoms, or a mixed phenotype) on the one hand, and daily life stress reactivity on the other were investigated. Daily life stress reactivity was measured using the Experience Sampling Method (ESM), and was defined as negative affect reactivity to minor daily life stressors. Individuals exposed to childhood trauma who reported a mixed phenotype of psychopathology showed a significant increase in emotional reactivity to daily life stress (activity and social stress), compared with trauma-exposed individuals without a mixed phenotype. In the trauma-exposed mixed phenotype group, increased emotional reactivity to event-stress predicted more severe symptoms at ± 14 month follow-up. This study found evidence that may link heightened emotional reactivity to stress in individuals with a trauma history to the risk for later comorbid psychopathology.

Unraveling the Role of Loneliness in Depression: The Relationship Between Daily Life Experience and Behavior.

OBJECTIVE: Focusing on temporal associations between momentary (or state) loneliness, appraisal of social company, and being alone in daily life may help elucidate mechanisms that contribute to the development of prolonged (or trait) loneliness and major depressive disorder (MDD). We aim to examine if (a) a self-reinforcing loop between loneliness, negative appraisals of social company, and being alone in daily life may contribute to trait loneliness; (b) this possible self-reinforcing loop may also contribute to the development of MDD, by testing differences in temporal relationships between these social elements in participants who did or did not develop MDD during follow-up; and (c) any of these social elements at baseline predicted a MDD at follow-up. METHODS: A female general population sample (n = 417) participated in an experience sampling method (ESM) study. Time-lagged analyses between loneliness, appraisal of social company, and being alone were examined at baseline, and their associations with the development of MDD during 20 months follow-up were investigated. RESULTS: State loneliness was followed by an increase in negative appraisals of social company and a higher frequency of being alone. Further, negative appraisals of social company were associated with a higher frequency of being alone afterward. Only the latter was significant in the transition to MDD group. Trait loneliness predicted MDD during follow-up. CONCLUSIONS: Avoiding social contact after appraising company more negatively may contribute to the development of MDD.

Psychological and Biological Validation of a Novel Digital Social Peer Evaluation Experiment (digi-SPEE).

INTRODUCTION: Negative social evaluation is associated with psychopathology. Given the frequency of evaluation through increasingly prevalent virtual social networks, increased understanding of the effects of this social evaluation is urgently required. METHODS: A new digital social peer evaluation experiment (digi-SPEE) was developed to mimic everyday online social interactions between peers. Participants received mildly negative feedback on their appearance, intelligence, and congeniality. Two hundred and forty-one young people [58.9% female, aged 18.9 years (15 to 34)] from an ongoing novel general population twin study participated in this study. Positive affect (PA), negative affect (NA), implicit self-esteem, and cortisol were assessed before and after exposure to the social evaluation experiment. RESULTS: The social evaluation experiment decreased PA (B=-5.25, p<.001) and implicit self-esteem (B=-.19; p<.001), whereas it increased NA (B=5.99; p<.001) and cortisol levels (B=.07; p<.001). Females (PA: B=-7.62; p<.001; NA: B=8.28; p<.001) and participants with higher levels of general psychological distress (PA: B=-.04, p=.035; NA: B=.06; p=.028) showed stronger affective responses. Stressor-induced cortisol increase was stronger in adolescents under the age of 18 than in participants 18 years and older (B=-.06, p=.002). CONCLUSION: The digi-SPEE represents a social evaluation stressor that elicits biological and implicit and explicit mental changes that are relevant to mechanisms of psychopathology.

Network Approach to Understanding Emotion Dynamics in Relation to Childhood Trauma and Genetic Liability to Psychopathology: Replication of a Prospective Experience Sampling Analysis.

Background: The network analysis of intensive time series data collected using the Experience Sampling Method (ESM) may provide vital information in gaining insight into the link between emotion regulation and vulnerability to psychopathology. The aim of this study was to apply the network approach to investigate whether genetic liability (GL) to psychopathology and childhood trauma (CT) are associated with the network structure of the emotions "cheerful," "insecure," "relaxed," "anxious," "irritated," and "down"-collected using the ESM method. Methods: Using data from a population-based sample of twin pairs and siblings (704 individuals), we examined whether momentary emotion network structures differed across strata of CT and GL. GL was determined empirically using the level of psychopathology in monozygotic and dizygotic co-twins. Network models were generated using multilevel time-lagged regression analysis and were compared across three strata (low, medium, and high) of CT and GL, respectively. Permutations were utilized to calculate p values and compare regressions coefficients, density, and centrality indices. Regression coefficients were presented as connections, while variables represented the nodes in the network. Results: In comparison to the low GL stratum, the high GL stratum had significantly denser overall (p = 0.018) and negative affect network density (p < 0.001). The medium GL stratum also showed a directionally similar (in-between high and low GL strata) but statistically inconclusive association with network density. In contrast to GL, the results of the CT analysis were less conclusive, with increased positive affect density (p = 0.021) and overall density (p = 0.042) in the high CT stratum compared to the medium CT stratum but not to the low CT stratum. The individual node comparisons across strata of GL and CT yielded only very few significant results, after adjusting for multiple testing. Conclusions: The present findings demonstrate that the network approach may have some value in understanding the relation between established risk factors for mental disorders (particularly GL) and the dynamic interplay between emotions. The present finding partially replicates an earlier analysis, suggesting it may be instructive to model negative emotional dynamics as a function of genetic influence.

White noise speech illusion and psychosis expression: An experimental investigation of psychosis liability.

BACKGROUND: An association between white noise speech illusion and psychotic symptoms has been reported in patients and their relatives. This supports the theory that bottom-up and top-down perceptual processes are involved in the mechanisms underlying perceptual abnormalities. However, findings in nonclinical populations have been conflicting. OBJECTIVES: The aim of this study was to examine the association between white noise speech illusion and subclinical expression of psychotic symptoms in a nonclinical sample. Findings were compared to previous results to investigate potential methodology dependent differences. METHODS: In a general population adolescent and young adult twin sample (n = 704), the association between white noise speech illusion and subclinical psychotic experiences, using the Structured Interview for Schizotypy-Revised (SIS-R) and the Community Assessment of Psychic Experiences (CAPE), was analyzed using multilevel logistic regression analyses. RESULTS: Perception of any white noise speech illusion was not associated with either positive or negative schizotypy in the general population twin sample, using the method by Galdos et al. (2011) (positive: ORadjusted: 0.82, 95% CI: 0.6-1.12, p = 0.217; negative: ORadjusted: 0.75, 95% CI: 0.56-1.02, p = 0.065) and the method by Catalan et al. (2014) (positive: ORadjusted: 1.11, 95% CI: 0.79-1.57, p = 0.557). No association was found between CAPE scores and speech illusion (ORadjusted: 1.25, 95% CI: 0.88-1.79, p = 0.220). For the Catalan et al. (2014) but not the Galdos et al. (2011) method, a negative association was apparent between positive schizotypy and speech illusion with positive or negative affective valence (ORadjusted: 0.44, 95% CI: 0.24-0.81, p = 0.008). CONCLUSION: Contrary to findings in clinical populations, white noise speech illusion may not be associated with psychosis proneness in nonclinical populations.

Acceptance and Commitment Therapy in Daily Life Training: A Feasibility Study of an mHealth Intervention.

BACKGROUND: With the development of mHealth, it is possible to treat patients in their natural environment. Mobile technology helps to bridge the gap between the therapist's office and the "real world." The ACT in Daily Life training (ACT-DL) was designed as an add-on intervention to help patients practice with acceptance and commitment therapy in their daily lives. The ACT-DL consists of two main components: daily monitoring using experience sampling and ACT training in daily life. OBJECTIVES: To assess the acceptability and feasibility of the ACT-DL in a general outpatient population. A secondary objective was to conduct a preliminary examination of the effectiveness of the ACT-DL. METHODS: An observational comparative study was conducted. The experimental group consisted of 49 patients who volunteered for ACT-DL, and the control group consisted of 112 patients who did not volunteer. As part of an inpatient treatment program, both groups received a 6-week ACT training. Participants went home to continue their treatment on an outpatient basis, during which time the experimental group received the 4-week add-on ACT-DL. Acceptability and feasibility of the ACT-DL was assessed weekly by telephone survey. Effectiveness of the ACT-DL was evaluated with several self-report questionnaires ( Flexibility Index Test (FIT-60): psychological flexibility, Brief Symptom Inventory: symptoms, Utrechtse Coping List: coping, and Quality of life visual analog scale (QoL-VAS): quality of life). RESULTS: More than three-quarters of the participants (76%) completed the full 4-week training. User evaluations showed that ACT-DL stimulated the use of ACT in daily life: participants practiced over an hour a week (mean 78.8 minutes, standard deviation 54.4), doing 10.4 exercises (standard deviation 6.0) on average. Both ACT exercises and metaphors were experienced as useful components of the training (rated 5 out of 7). Repeated measures ANCOVA did not show significant effects of the ACT-DL on psychological flexibility (P=.88), symptoms (P=.39), avoidant coping (P=.28), or quality of life (P=.15). CONCLUSIONS: This is the first study that uses experience sampling to foster awareness in daily life in combination with acceptance and commitment therapy to foster skill building. Adherence to the ACT-DL was high for an intensive mHealth intervention. ACT-DL appears to be an acceptable and feasible mHealth intervention, suitable for a broad range of mental health problems. However, short-term effectiveness could not be demonstrated. Additional clinical trials are needed to examine both short-term and long-term effects.

Early-Life Stress Affects Stress-Related Prefrontal Dopamine Activity in Healthy Adults, but Not in Individuals with Psychotic Disorder.

Early life stress may have a lasting impact on the developmental programming of the dopamine (DA) system implicated in psychosis. Early adversity could promote resilience by calibrating the prefrontal stress-regulatory dopaminergic neurotransmission to improve the individual's fit with the predicted stressful environment. Aberrant reactivity to such match between proximal and distal environments may, however, enhance psychosis disease risk. We explored the combined effects of childhood adversity and adult stress by exposing 12 unmedicated individuals with a diagnosis of non-affective psychotic disorder (NAPD) and 12 healthy controls (HC) to psychosocial stress during an [18F]fallypride positron emission tomography. Childhood trauma divided into early (ages 0-11 years) and late (12-18 years) was assessed retrospectively using a questionnaire. A significant group x childhood trauma interaction on the spatial extent of stress-related [18F]fallypride displacement was observed in the mPFC for early (b = -8.45, t(1,23) = -3.35, p = .004) and late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). In healthy individuals, the spatial extent of mPFC DA activity under acute psychosocial stress was positively associated with the severity of early (b = 7.23, t(11) = 3.06, p = .016) as well as late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). Additionally, a trend-level main effect of early childhood trauma on subjective stress response emerged within this group (b = -.7, t(11) = -2, p = .07), where higher early trauma correlated with lower subjective stress response to the task. In the NAPD group, childhood trauma was not associated with the spatial extent of the tracer displacement in mPFC (b = -1.22, t(11) = -0.67), nor was there a main effect of trauma on the subjective perception of stress within this group (b = .004, t(11) = .01, p = .99). These findings reveal a potential mechanism of neuroadaptation of prefrontal DA transmission to early life stress and suggest its role in resilience and vulnerability to psychosis.

Psychotic reactivity to daily life stress and the dopamine system: a study combining experience sampling and [18F]fallypride positron emission tomography.

Stressful life events increase the risk for psychosis, and the subjective experience of stress related to daily life activities drives moment-to-moment variation in psychotic intensity. Positron emission tomography (PET) studies suggest that dopaminergic (DAergic) activity mediates the behavioral response to an experimental stressor. However, it is not known how alterations in this DAergic stress response relate to the subjective experience of stress in real life situations assessed in momentary assessment studies. This study combined [18F]fallypride PET with an Experience Sampling ambulatory assessment approach to examine the association between the prefrontal DAergic response to experimentally induced stress and real life psychotic reactivity to the subjective experience of stress in daily life. Healthy first-degree relatives of individuals with a psychotic disorder (N = 14) and healthy controls (N = 11) participated in (a) a psychosocial [18F]fallypride PET stress paradigm and (b) an experience sampling study, using a structured diary approach. Mixed multilevel random intercept models revealed that stress-induced [18F]fallypride displacement, indicative of DAergic activity, in ventromedial prefrontal cortex (VMPFC) was associated with psychotic reactivity to daily life stress in the entire sample. Lower levels of [18F]fallypride displacement to stress predicted increased psychotic reactivity to daily life stress. This study combined PET neuroimaging with real life behavioral assessments in the investigation of psychotic symptoms; we showed decreased [18F]fallypride displacement to stress in VMPFC to be associated with increased psychotic reactivity to daily life stress. The preliminary evidence in this study demonstrates that it is possible to acquire a grasp on how brain function is associated with contextualized experience, which has relevance for neuroimaging studies in general.

Familial liability to psychosis is associated with attenuated dopamine stress signaling in ventromedial prefrontal cortex.

OBJECTIVE: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. METHOD: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. RESULTS: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. CONCLUSION: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.