Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Validation of Photoplethysmography Using a Mobile Phone Application for the Assessment of Heart Rate Variability in the Context of Heart Rate Variability-Biofeedback.

OBJECTIVE: Heart rate variability-biofeedback (HRV-BF) is an effective intervention to reduce stress and anxiety and requires accurate measures of real-time HRV. HRV can be measured through photoplethysmography (PPG) using the camera of a mobile phone. No studies have directly compared HRV-BF supported through PPG against classical electrocardiogram (ECG). The current study aimed to validate PPG HRV measurements during HRV-BF against ECG. METHODS: Fifty-seven healthy participants (70% women) with a mean (standard deviation) age of 26.70 (9.86) years received HRV-BF in the laboratory. Participants filled out questionnaires and performed five times a 5-minute diaphragmatic breathing exercise at different paces (range, ~6.5 to ~4.5 breaths/min). Four HRV indices obtained through PPG, using the Happitech software development kit, and ECG, using the validated NeXus apparatus, were calculated and compared: RMSSD, pNN50, LFpower, and HFpower. Resonance frequency (i.e., optimal breathing pace) was also compared between methods. RESULTS: All intraclass correlation coefficient values of the five different breathing paces were "near perfect" (>0.90) for all HRV indices: lnRMSSD, lnpNN50, lnLFpower, and lnHFpower. All Bland-Altman analyses (with just three incidental exceptions) showed good interchangeability of PPG- and ECG-derived HRV indices. No systematic evidence for proportional bias was found for any of the HRV indices. In addition, correspondence in resonance frequency detection was good with 76.6% agreement between PPG and ECG. CONCLUSIONS: PPG is a potentially reliable and valid method for the assessment of HRV. PPG is a promising replacement of ECG assessment to measure resonance frequency during HRV-BF.

A Few Close Friends? Adolescent Friendships' Effect on Internalizing Symptoms Is Serially Mediated by Desire for More Friends and Social Goal Orientation.

Interpersonal connection is a fundamental human motivation, and the extent to which it is fulfilled is a strong predictor of symptoms of internalizing disorders such as social anxiety and depression, perhaps especially during the "social reorienting" period of adolescence. However, little is known about the contribution to this effect of the individual's social motivations, which are intensified during adolescence. Furthermore, social goal orientation - an individual's priorities and intentions in social interactions - is an important predictor of vulnerability to internalizing symptoms. Adolescents spend most of their waking lives in classrooms, bounded social networks with a limited pool of candidates for befriending. This study investigated whether friendships within one's class protects against internalizing symptoms in part by reducing the desire for more classmate friendships, which may tend to promote maladaptive social goals. Participants were 423 young adolescents (M age = 13.2, sd = 0.52 years; 49.4% girls). As predicted, adolescents' number of reciprocated classroom friendships had a protective effect on internalizing symptoms which was serially mediated by desire for more such friendships, and social goal orientation. However, only demonstration-avoidance goals significantly predicted internalizing symptoms. Unreciprocated friendship nominations were unexpectedly associated with stronger desire and more social anxiety symptoms. The results suggest that the effect of number of friends is mediated by the individual's thoughts and feelings about their number of friendships, such that a strong desire for more friendships promotes maladaptive goals, oriented toward social status and consequently less oriented toward the cultivation of interpersonal intimacy with the friends they already have.

Exploring the association between social behaviour, trust, and its neural correlates in first episode psychosis patients and in individuals at clinical high risk for psychosis.

OBJECTIVES: Psychosis is characterized by paranoid delusions, social withdrawal, and distrust towards others. Trust is essential for successful social interactions. It remains unknown which aspects of social functioning are associated with reduced trust in psychosis. Therefore, we investigated the association between social behaviour, trust, and its neural correlates in a group of individuals with psychotic symptoms (PS-group), consisting of first episode psychosis patients combined with individuals at clinical high risk. METHODS: We compared 24 PS individuals and 25 healthy controls. Affect and social withdrawal were assessed using the Experience Sampling Method. Trust was measured during functional magnetic resonance imaging (fMRI) scanning, using a trust game with a cooperative and unfair counterpart. RESULTS: The PS-group showed lower baseline trust compared to controls and reported less positive and more negative general affect. Social withdrawal did not differ between the groups. Social withdrawal and social reactivity in affect (i.e., changes in affect when with others compared to when alone) were not associated with trust. On the neural level, in controls but not in the PS-group, social withdrawal was associated with caudate activation during interactions with an unfair partner. An increase in positive social reactivity, was associated with reduced insula activation in the whole sample. CONCLUSIONS: Social withdrawal and social reactivity were not associated with reduced initial trust in the PS-group. Like controls, the PS-group showed a positive response in affect when with others, suggesting a decrease in emotional distress. Supporting patients to keep engaging in social interactions, may alleviate their emotional distress. PRACTITIONER POINTS: Individuals with psychotic symptoms show reduced initial trust towards unknown others. Trust in others is not associated with social withdrawal and reported affect when with others, nor when alone. Like controls, individuals with psychotic symptoms showed reduced negative affect and increased positive affect when with others compared to when alone. We emphasize to support individuals with psychotic symptoms to keep engaging in social interactions, given it may reduce social withdrawal and alleviate their emotional distress.

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Benefits of Social Contact in Individuals With Psychotic Symptoms: Do Closeness of the Contact and Empathic Skills Make the Difference?

Objectives: Social contact is known to be beneficial for humans' mental health. Individuals with psychotic symptoms (PS) tend to show poorer social and interpersonal functioning. However, in this patient population, social contact may be crucial for their mental wellbeing and treatment success. Additionally, closeness of social contact (familiar versus less familiar others), rather than only the presence or absence of social contacts, may play an important role. Empathy may heighten the beneficial effects of social/close contact on mental health, facilitating interactions. We investigated the association between social contact and closeness of contact on mental health, defined as positive symptoms, positive affect and negative affect in PS and control participants, with empathy as a moderator. Methods: Participants were 16-30 years old. Information regarding social/close contact and mental health was obtained using the experience sampling method in individuals with PS (n = 29) and healthy controls (n = 28). Empathy was measured using a self-report questionnaire. Results: Social contact was associated with higher positive affect in the total sample. Contact with close as opposed to less close others was related to better mental health: It was associated with lower positive symptoms in the PS group, and with more positive affect in the total sample. Empathy moderated the association between closeness of contact and positive affect in the total sample, in which the combination of higher levels of empathy combined with the presence of close contact was associated with higher positive affect in the total sample. However, the direct association between empathy and positive affect was not significant per group of contact. Conclusion: The results suggest that social contact, but especially contact with a close other is important for mental health outcomes: Contact with close others is beneficial for positive affect in the total sample and for positive symptoms in individuals with PS.

Girls-Boys: An Investigation of Gender Differences in the Behavioral and Neural Mechanisms of Trust and Reciprocity in Adolescence.

BACKGROUND: Trust and reciprocity toward others have often been found to increase from childhood to adulthood. Gender differences in these social behaviors have been reported in adults. While adolescence is a key-period of change in social behavior, gender differences in trust and reciprocity during this developmental stage have rarely been investigated. METHODS: Here we investigate age-related gender differences in trust and reciprocity (n = 100, 51 female) and associated neural mechanisms (n = 44, 20 female) in adolescents between 13 and 19 years of age. Participants played two multi-round trust games with a pre-programmed cooperative and an unfair partner. Forty-four of 100 participants completed the trust game while undergoing functional brain imaging. RESULTS: Participants' investments were greater toward a cooperative than unfair game partner (p < 0.01), showing sensitivity to the degree of trustworthiness. There were no gender or age or related differences in baseline trust. In repeated cooperative interactions no gender differences were found, but younger adolescents showed slightly steeper increase of investments than older adolescents. In unfair interactions, younger males reacted with stronger decrease of investments than older males. Region of interest analysis of brain areas associated with in mentalizing, reward learning, conflict processing, and cognitive control revealed gender-by-age interactions on trusting behavior in the temporo-parietal junction (TPJ) and the caudate, showing stronger influence of age in males than in females during cooperation, and the reverse in unfair interactions. Additionally, main effects of gender were found in the TPJ, with higher activation in males, and in the caudate, with females showing greater activation. CONCLUSION: In first interactions and during repeated cooperative interactions, adolescent males and females showed similar trusting behavior. Younger males showed stronger responses to unfairness by others. Gender-by-age interactions in specific ROIs suggest differential development in mentalizing and reward related cognitive processes. In conjunction with previous research, our findings suggest the presence of subtle gender and age-related changes in trust and cooperation that are only detectable using larger age windows.

Social Mindfulness and Psychosis: Neural Response to Socially Mindful Behavior in First-Episode Psychosis and Patients at Clinical High-Risk.

Background: Psychosis is characterized by problems in social functioning and trust, the assumed glue to positive social relations. But what helps building trust? A prime candidate could be social mindfulness: the ability and willingness to see and consider another person's needs and wishes during social decision making. We investigated whether first-episode psychosis patients (FEP) and patients at clinical high-risk (CHR) show reduced social mindfulness, and examined the underlying neural mechanisms. Methods: Twenty FEP, 17 CHR and 46 healthy controls, aged 16-31, performed the social mindfulness task (SoMi) during fMRI scanning, spontaneously and after the instruction "to keep the other's best interest in mind." As first of two people, participants had to choose one out of four products, of which three were identical and one was unique, differing in a single aspect (e.g., color). Results: FEP tended to choose the unique item (unmindful choice) more often than controls. After instruction, all groups significantly increased the number of mindful choices compared to the spontaneous condition. FEP showed reduced activation of the caudate and medial prefrontal cortex (mPFC) during mindful, and of the anterior cingulate cortex (ACC), mPFC, and left dorsolateral prefrontal cortex (dlPFC) during unmindful decisions. CHR showed reduced activation of the ACC compared to controls. Discussion: FEP showed a trend toward more unmindful choices. A similar increase of mindful choices after instruction indicated the ability for social mindfulness when prompted. Results suggested reduced sensitivity to the rewarding aspects of social mindfulness in FEP, and reduced consideration for the other player. FEP (and CHR to a lesser extent) might perceive unmindful choices as less incongruent with the automatic mindful responses than controls. Reduced socially mindful behavior in FEP may hinder the building of trust and cooperative interactions.

Psychosis and urbanicity: a review of the recent literature from epidemiology to neurourbanism.

PURPOSE OF REVIEW: Epidemiological studies associate city living with an elevated psychosis risk. Urban (social/economic) stress and exposure to environmental toxins, pollution or disease agents have been proposed to underlie this association. This review provides an update on the recent evidence (May 2017 - November 2018). RECENT FINDINGS: Of 647 screened studies, 17 on: urbanicity-psychosis associations in worldwide high, middle and low-income countries; explanatory mechanisms, including nature exposure, social and economic stressors and genetic risk; urbanicity effects on the brain and coping; and urbanicity and resources, were included. The reviewed evidence revealed complex patterns of urbanicity-psychosis associations with considerable international variation within Europe and between low, middle and high-income countries worldwide. Social and economic stressors (e.g. migration, ethnic density and economic deprivation), nature exposure and access to resources could only explain part of the urbanicity effects. Risk factors differed between countries and between affective and non-affective psychosis. SUMMARY: Urbanicity-psychosis associations are heterogeneous and driven by multiple risk and protective factors that seem to act differently in different ethnic groups and countries. Interdisciplinary research combining approaches, for example from experimental neuroscience and epidemiology, are needed to unravel specific urban mechanisms that increase or decrease psychosis risk.

Learning to trust: social feedback normalizes trust behavior in first-episode psychosis and clinical high risk.

BACKGROUND: Psychosis is characterized by problems in social functioning that exist well before illness onset, and in individuals at clinical high risk (CHR) for psychosis. Trust is an essential element for social interactions that is impaired in psychosis. In the trust game, chronic patients showed reduced baseline trust, impaired response to positive social feedback, and attenuated brain activation in reward and mentalizing areas. We investigated whether first-episode psychosis patients (FEP) and CHR show similar abnormalities in the neural and behavioral mechanisms underlying trust. METHODS: Twenty-two FEP, 17 CHR, and 43 healthy controls performed two trust games, with a cooperative and an unfair partner in the fMRI scanner. Region of interest analyses were performed on mentalizing and reward processing areas, during the investment and outcome phases of the games. RESULTS: Compared with healthy controls, FEP and CHR showed reduced baseline trust, but like controls, learned to trust in response to cooperative and unfair feedback. Symptom severity was not associated with baseline trust, however in FEP associated with reduced response to feedback. The only group differences in brain activation were that CHR recruited the temporo-parietal junction (TPJ) more than FEP and controls during investment in the unfair condition. This hyper-activation in CHR was associated with greater symptom severity. CONCLUSIONS: Reduced baseline trust may be associated with risk for psychotic illness, or generally with poor mental health. Feedback learning is still intact in CHR and FEP, as opposed to chronic patients. CHR however show distinct neural activation patterns of hyper-activation of the TPJ.

Giving others the option of choice: An fMRI study on low-cost cooperation.

Successful social relationships require a consideration of a partner's thoughts and intentions. This aspect of social life is captured in the social mindfulness paradigm (SoMi task), in which participants make decisions that either limit or preserve options for their interaction partner's subsequent choice. Here we investigated the neural correlates of spontaneous socially mindful and unmindful behaviours. Functional magnetic resonance data were acquired from 47 healthy adolescents and young adults (age 16-27) as they completed the SoMi task. Being faced with socially relevant choices was associated with activity in the medial prefrontal cortex, anterior cingulate, caudate, and insula, which is consistent with prior neuroeconomical research. Importantly, socially mindful choices were associated with activity in the right parietal cortex and the caudate, whereas unmindful choices were associated with activity in the left prefrontal cortex. These neural findings were consistent with the behavioural preference for mindful choices, suggesting that socially mindful decisions are the basic inclination, whereas socially unmindful responses may require greater effort and control. Together, these results begin to uncover the neural correlates of socially mindful and unmindful choices, and illuminate the psychological processes involved in cooperative social behaviour.

Boys vs. girls: Gender differences in the neural development of trust and reciprocity depend on social context.

Trust and cooperation increase from adolescence to adulthood, but studies on gender differences in this development are rare. We investigated gender and age-related differences in trust and reciprocity and associated neural mechanisms in 43 individuals (16-27 years, 22 male). Participants played two multi-round trust games with a cooperative and an unfair partner. Males showed more basic trust towards unknown others than females. Both genders increased trust during cooperative interactions, with no differences in average trust. Age was unrelated to trust during cooperation. During unfair interactions males decreased their trust more with age than females. ROI analysis showed age-related increases in activation in the temporo-parietal junction (TPJ) and dorsolateral prefrontal cortex (dlPFC) during cooperative investments, and increased age-related caudate activation during both cooperative and unfair repayments. Gender differences in brain activation were only observed during cooperative repayments, with males activating the TPJ more than females, and females activating the caudate more. The findings suggest relatively mature processes of trust and reciprocity in the investigated age range. Gender differences only occur in unfair contexts, becoming more pronounced with age. Largely similar neural activation in males and females and few age effects suggest that similar, mature cognitive strategies are employed.