Future Directions in the Mental Health of Transgender Youth: Towards a Social-Affective Developmental Model of Health Disparity.

Mental health disparities in transgender and gender diverse (TGD) youth are well-documented. These disparities are often studied in the context of minority stress theory, and most of this research focuses on experiences of trauma and discrimination TGD youth experience after coming out. However, TGD youth may be targets of violence and victimization due to perceived gender nonconformity before coming out. In this Future Directions, we integrate research on attachment, developmental trauma, and effects of racism and homophobia on mental health to propose a social-affective developmental framework for TGD youth. We provide a clinical vignette to highlight limitations in current approaches to mental health assessment in TGD youth and to illustrate how using a social-affective developmental framework can improve clinical assessment and treatment approaches and deepen our understanding of mental health disparities in TGD people.

Enhanced visual cortical activation for emotional stimuli is preserved in patients with unilateral amygdala resection.

Emotionally arousing pictures induce increased activation of visual pathways relative to emotionally neutral images. A predominant model for the preferential processing and attention to emotional stimuli posits that the amygdala modulates sensory pathways through its projections to visual cortices. However, recent behavioral studies have found intact perceptual facilitation of emotional stimuli in individuals with amygdala damage. To determine the importance of the amygdala to modulations in visual processing, we used functional magnetic resonance imaging to examine visual cortical blood oxygenation level-dependent (BOLD) signal in response to emotionally salient and neutral images in a sample of human patients with unilateral medial temporal lobe resection that included the amygdala. Adults with right (n = 13) or left (n = 5) medial temporal lobe resections were compared with demographically matched healthy control participants (n = 16). In the control participants, both aversive and erotic images produced robust BOLD signal increases in bilateral primary and secondary visual cortices relative to neutral images. Similarly, all patients with amygdala resections showed enhanced visual cortical activations to erotic images both ipsilateral and contralateral to the lesion site. All but one of the amygdala resection patients showed similar enhancements to aversive stimuli and there were no significant group differences in visual cortex BOLD responses in patients compared with controls for either aversive or erotic images. Our results indicate that neither the right nor left amygdala is necessary for the heightened visual cortex BOLD responses observed during emotional stimulus presentation. These data challenge an amygdalo-centric model of emotional modulation and suggest that non-amygdalar processes contribute to the emotional modulation of sensory pathways.

Adolescent neurocognitive development and decision-making abilities regarding gender-affirming care.

Recently, politicians and legislative bodies have cited neurodevelopmental literature to argue that brain immaturity undermines decision-making regarding gender-affirming care (GAC) in youth. Here, we review this literature as it applies to adolescents' ability to make decisions regarding GAC. The research shows that while adolescence is a time of peak risk-taking behavior that may lead to impulsive decisions, neurocognitive systems supporting adult-level decisions are available given deliberative processes that minimize influence of short-term rewards and peers. Since GAC decisions occur over an extended period and with support from adult caregivers and clinicians, adolescents can engage adult-level decision-making in this context. We also weigh the benefits of providing GAC access during adolescence and consider the significant costs of blocking or delaying GAC. Transgender and non-binary (TNB) adolescents face significant mental health challenges, many of which are mitigated by GAC access. Further, initiating the GAC process during adolescence, which we define as beginning at pubertal onset, leads to better long-term mental health outcomes than waiting until adulthood. Taken together, existing research indicates that many adolescents can make informed decisions regarding gender-affirming care, and that this care is critical for the well-being of TNB youth. We highlight relevant considerations for policy makers, researchers, and clinicians.

Gender diversity in autistic and neurotypical youth over adolescence and puberty: A longitudinal study.

Recent research in autism spectrum disorder (ASD) has suggested a higher prevalence of gender diversity in individuals diagnosed with ASD. Adolescence is a critical period for the consolidation of gender identity, yet the extent to which the experience of gender diversity is stable over adolescence and puberty in autistic youth is poorly understood. The aim of the study was to examine the consistency of gender diversity using the gender diversity screening questionnaire for self- and parent-report of youth (GDSQ-S, GDSQ-P) over a four-year longitudinal study of pubertal development in youth with ASD (N = 140, 36 assigned-female-at birth (AFAB)) and typical development (TD, N = 104, 58 assigned-male-at-birth [AMAB]) and their parents. The extent to which diagnosis (ASD vs. TD), assigned sex (AFAB vs. AMAB) and developmental level (age, puberty) predict GDSQ trajectory over time was explored. There was a significant diagnosis by sex-assigned-at-birth by age interaction for GDSQ-S Gender Diversity, p = 0.002, showing higher scores in autistic AFAB youth over adolescence, and TD AFAB showing initially lower, then increasing levels over adolescence. For GDSQ-P, Gender Incongruence was significantly different between the groups, p = 0.032, showing higher incongruence for autistic AFAB around age 10, decreasing between age 12-14 before increasing again, while TD AFAB evidence the inverse trend. AMAB trends were stable. The significant diagnostic, developmental and sex-based differences indicate AFAB youth experience greater gender diversity that evolves over development. Findings suggest gender identity formation is nuanced and may be influenced by pubertal progression, hormonal patterns, and psychosocial factors. Results underscore the need for enhanced understanding of the unique, dynamic profiles of females-assigned-at-birth.

Gender-related association among childhood maltreatment, brain structure and clinical features in bipolar disorder.

Bipolar disorder (BD) and exposure to childhood maltreatment (CM), which is present at high rates in BD, are both associated with hippocampus and prefrontal cortex structural alterations thought to contribute to clinical features. Gender-related differences are implicated in BD for CM exposure, brain structure and clinical features. However, relationships among these factors in BD are understudied. This study aimed to investigate associations among gender, CM, hippocampus and prefrontal gray matter structure and clinical features in BD. Childhood trauma questionnaire, structured clinical assessments and 3 Tesla structural magnetic resonance imaging were obtained for 236 adults (18-63 years, 32.0 ± 12.6): 119 with BD (58.8% women) and 117 healthy controls (HCs, 50.4% women). Women with BD reported higher CM severity than men with BD and HCs (B=-14.34, 95% confidence intervals (CI)[-22.71,-5.97], p<.001). CM and gender showed a significant interaction for left hippocampus (B=-7.41, 95% CI[-14.10,-0.71], p<.05); CM severity was negatively associated with left hippocampus only in women with BD. In women with BD, CM was associated with post-traumatic stress disorder comorbidity (B = 25.68, 95% CI[15.11,36.25], p<.001). In men with BD, CM severity was associated with lower left frontal pole (B=-0.71, 95% CI[-1.14,-0.28], p<.05) and right superior frontal (B=-17.78, 95% CI[-30.66,-4.90], p<.05) surface area; the latter related to earlier age of first mood symptoms (B = 33.97, 95% CI[7.61, 60.33], p<.05). Findings support gender-related effects of CM on frontotemporal structure and clinical features of BD. The findings bring novel perspectives for gendered pathophysiological models of effects of CM in BD.

A Model for Improving Health Care Quality for Transgender and Gender Nonconforming Patients.

PROBLEM DEFINITION: Transgender and gender nonconforming (TGNC) populations are disproportionately affected by limited health care access and poor health outcomes and commonly report discrimination and mistreatment in health care settings. Despite these disparities, comprehensive approaches to improve the quality of health care of TGNC patient populations are currently lacking. INITIAL APPROACH: The Vanderbilt Program for LGBTQ Health has developed a multifaceted, community-engaged approach to improve the quality of health care of TGNC patients, which includes the creation of a transgender patient advocacy program, a community advisory board, and a transgender health clinic. To support the continuous quality improvement of transgender health care, the program is currently piloting a novel multilevel monitoring and evaluation (M&E) system to collect information at the individual patient visit and health systems levels. NEXT STEPS: The next steps for Vanderbilt's community-engaged M&E system are to identify the clinics and health services most used by TGNC patients and assess the level of patient satisfaction in each area. This process will support the identification of high- and low-performing clinics and health services and allow for targeted delivery of trainings to improve the quality of culturally competent health care TGNC patients receive systemwide. CONCLUSION: In collaboration with TGNC patient populations and community stakeholders, Vanderbilt has created a model to improve the quality of both transition- and non-transition-related health care at the systems level that can be adopted by other health care systems nationally.

Hippocampal Resting State Functional Connectivity in Patients With Schizophrenia and Unaffected Family Members.

The hippocampus is an important candidate region in the study of functional connectivity alterations in schizophrenia (SZ) given its role as a functional hub for multiple brain networks. Although studies have implicated the hippocampus in SZ, no studies have compared hippocampal functional connectivity in healthy participants, patients with SZ, and unaffected family members (UAFMs). Patients and UAFM likely share biomarkers associated with susceptibility to SZ; the study of UAFM may also reveal compensatory markers. Patients with SZ, UAFM, and healthy control (HC) participants underwent resting state magnetic resonance imagingty and completed the Wisconsin Card Sort Task (WCST) as a measure of general cognitive function. We compared functional coupling with a hippocampus seed across the three groups. SZ and UAFM groups shared reductions in connectivity between the hippocampus and the striatum relative to HC. We also identified a significant positive correlation between WCST errors and hippocampal-striatal connectivity in the UAFM group. Hippocampal-striatal rsFC may be associated with familial susceptibility to SZ and with subtle cognitive deficits in the UAFM of individuals with SZ.

Assessing Relationships Among Impulsive Sensation Seeking, Reward Circuitry Activity, and Risk for Psychopathology: A Functional Magnetic Resonance Imaging Replication and Extension Study.

BACKGROUND: High trait impulsive sensation seeking (ISS), the tendency to engage in behavior without forethought and to seek out new or extreme experiences, is a transdiagnostic risk factor for externalizing and mood disorders, particularly bipolar disorder. We published a positive association between trait ISS and reward expectancy-related activity in the left ventrolateral prefrontal cortex (L vlPFC) and the ventral striatum. We aimed to replicate this finding and extend it by testing for mediation effects of ISS on relationships between reward expectancy-related activity and measures denoting hypomania. METHODS: A transdiagnostic sample of 127 adults, 18 to 25 years of age, completed a card-guessing functional magnetic resonance imaging task as well as measures of ISS (inattention, motor impulsivity, fun seeking, positive and negative urgency) and the Moods Spectrum as a measure of hypomania. An original sample of 98 was included for confirmatory and mediation analyses. RESULTS: We replicated a positive relationship between reward expectancy-related L vlPFC activity and negative urgency, an ISS component (ß = .28, t = 2.44, p = .0169). We combined these data with the original sample, confirming this finding (ß = .27, t = 2.41, p = .0184). Negative urgency statistically mediated the relationship between reward expectancy-related L vlPFC activity and Moods Spectrum factors associated with hypomania. No other associations between ISS measures and reward expectancy-related activity were replicated. CONCLUSIONS: We replicated findings showing that reward expectancy-related L vlPFC activity is a biomarker for negative urgency, the tendency to react with frustration during distressing conditions. Negative urgency also statistically mediated the relationship between L vlPFC activity and measures indicative of hypomanic symptoms.

Altered structural connectivity and cytokine levels in Schizophrenia and Genetic high-risk individuals: Associations with disease states and vulnerability.

BACKGROUND: Alterations of white matter (WM) integrity have been observed in both schizophrenia (SZ) and individuals at genetic high risk for SZ (GHR-SZ); however, the molecular mechanisms underlying WM disruption remain unclear. Cytokines are chemical messengers of the immune system that are closely related to inflammation and neurogenesis in the brain. This study aimed to identify abnormalities in WM integrity, cytokine levels, and their association in SZ and GHR-SZ. METHODS: A total of 355 participants (126 with SZ, 99 GHR-SZ, and 130 healthy controls [HCs]) were recruited. All participants underwent diffusion tensor imaging and blood samples were obtained from 113 participants within 24 h of imaging. RESULTS: In SZ, there was decreased fractional anisotropy(FA) in the genu and body of the corpus callosum (GCC/BCC), anterior corona radiata, anterior and posterior limbs of the internal capsule (ALIC/PLIC), superior fronto-occipital fasciculus, external capsule, and fornix, and elevated IL-6 levels. In both SZ and GHR-SZ, decreased FA in the splenium of the corpus callosum (SCC), posterior corona radiate (PCR), and posterior thalamic radiation (PTR) was observed, and elevated leptin levels were present. Additionally, the IL-6 levels were negatively correlated with FA in the GCC and ALIC in SZ, and leptin levels were negatively correlated with the SCC, PCR, and PTR in SZ and GHR-SZ. CONCLUSIONS: Abnormal WM integrity in SZ may reflect the state of disease and is associated with increased IL-6 levels. In addition, these leptin-associated WM integrity abnormalities in both SZ and GHR-SZ may reflect a genetic vulnerability to SZ.

Antipsychotic Effects on Cortical Morphology in Schizophrenia and Bipolar Disorders.

Background: Previous studies of atypical antipsychotic effects on cortical structures in schizophrenia (SZ) and bipolar disorder (BD) have findings that vary between the short and long term. In particular, there has not been a study exploring the effects of atypical antipsychotics on age-related cortical structural changes in SZ and BD. This study aimed to determine whether mid- to long-term atypical antipsychotic treatment (mean duration = 20 months) is associated with cortical structural changes and whether age-related cortical structural changes are affected by atypical antipsychotics. Methods: Structural magnetic resonance imaging images were obtained from 445 participants consisting of 88 medicated patients (67 with SZ, 21 with BD), 84 unmedicated patients (50 with SZ, 34 with BD), and 273 healthy controls (HC). Surface-based analyses were employed to detect differences in thickness and area among the three groups. We examined the age-related effects of atypical antipsychotics after excluding the potential effects of illness duration. Results: Significant differences in cortical thickness were observed in the frontal, temporal, parietal, and insular areas and the isthmus of the cingulate gyrus. The medicated group showed greater cortical thinning in these regions than the unmediated group and HC; furthermore, there were age-related differences in the effects of atypical antipsychotics, and these effects did not relate to illness duration. Moreover, cortical thinning was significantly correlated with lower symptom scores and Wisconsin Card Sorting Test (WCST) deficits in patients. After false discovery rate correction, cortical thinning in the right middle temporal gyrus in patients was significantly positively correlated with lower HAMD scores. The unmedicated group showed only greater frontotemporal thickness than the HC group. Conclusion: Mid- to long-term atypical antipsychotic use may adversely affect cortical thickness over the course of treatment and ageing and may also result in worsening cognitive function.

Functional disruption in prefrontal-striatal network in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. While a cortico-striatal-limbic network has been implicated in the pathophysiology of OCD, the neural correlates of this network in OCD are not well understood. In this study, we examined resting state functional connectivity among regions within the cortico-striatal-limbic OCD neural network, including the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus and caudate, in 44 OCD and 43 healthy participants. We then examined relationships between OCD neural network connectivity and OCD symptom severity in OCD participants. OCD relative to healthy participants showed significantly greater connectivity between the left caudate and bilateral dorsolateral prefrontal cortex. We also found a positive correlation between left caudate-bilateral dorsolateral prefrontal cortex connectivity and depression scores in OCD participants, such that greater positive connectivity was associated with more severe symptoms. This study makes a significant contribution to our understanding of functional networks and their relationship with depression in OCD.

Functional Disruption of Cerebello-thalamo-cortical Networks in Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. Neuroimaging studies have implicated altered connectivity among the functional networks of the cerebral cortex in the pathophysiology of OCD. However, there has been no comprehensive investigation of the cross-talk between the cerebellum and functional networks in the cerebral cortex. METHODS: This functional neuroimaging study was completed by 44 adult participants with OCD and 43 healthy control participants. We performed large-scale data-driven brain network analysis to identify functional connectivity patterns using resting-state functional magnetic resonance imaging data. RESULTS: Participants with OCD showed lower functional connectivity within the somatomotor network and greater functional connectivity among the somatomotor network, cerebellum, and subcortical network (e.g., thalamus and pallidum; all p < .005). Network-based statistics analyses demonstrated one component comprising connectivity within the somatomotor network that showed lower connectivity and a second component comprising connectivity among the somatomotor network, and motor regions in particular, and the cerebellum that showed greater connectivity in participants with OCD relative to healthy control participants. In participants with OCD, abnormal connectivity across both network-based statistics-derived components positively correlated with OCD symptom severity (p = .006). CONCLUSIONS: To our knowledge, this study is the first comprehensive investigation of large-scale network alteration across the cerebral cortex, subcortical regions, and cerebellum in OCD. Our findings highlight a critical role of the cerebellum in the pathophysiology of OCD.

Neurobiological Commonalities and Distinctions Among Three Major Psychiatric Diagnostic Categories: A Structural MRI Study.

BACKGROUND: Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are distinct diagnostic categories in current psychiatric nosology, yet there is increasing evidence for shared clinical and biological features in these disorders. No previous studies have examined brain structural features concurrently in these 3 disorders. The aim of this study was to identify the extent of shared and distinct brain alterations in SZ, BD, and MDD. We examined gray matter (GM) volume and white matter (WM) integrity in a total of 485 individuals (135 with SZ, 86 with BD, 108 with MDD, and 156 healthy controls [HC]) who underwent high-resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at a single site. RESULTS: Significant 4-group (SZ, BD, MDD, and HC groups) differences (P < .05, corrected) in GM volumes were found primarily in the paralimbic and heteromodal corticies. Post hoc analyses showed that the SZ, BD, and MDD groups shared GM volume decreases in 87.9% of the total regional volume with significant 4-group differences. Significant 4-group differences in WM integrity (P < .05 corrected) were found in callosal, limbic-paralimbic-hetermodal, cortico-cortical, thalamocortical and cerebellar WM. Post hoc analyses revealed that the SZ and BD groups shared WM alterations in all regions, while WM alterations were not observed with MDD. CONCLUSIONS: Our findings of common alterations in SZ, BD, and MDD support the presence of core neurobiological disruptions in these disorders and suggest that neural structural distinctions between these disorders may be less prominent than initially postulated, particularly between SZ and BD.

Altered Pre-Ejection Period Response to Social Evaluative Threat in Adolescents with Autism Spectrum Disorder.

INTRODUCTION: The autonomic nervous system (ANS) is involved in regulating social behavior; Autism Spectrum Disorder (ASD) is characterized by alterations in social behavior and reduced physiological response to threat. We hypothesized that adolescents with ASD would show reduced ANS response to social threat. METHODS: Eighteen males with ASD and thirteen males with typical development (TD), ages 12 to 17, completed a social threat paradigm while wearing an impedance cardiography apparatus. We calculated pre-ejection period (PEP) and tested for between-group differences in PEP response to social threat. We also conducted correlation analyses between PEP change scores and clinical symptom scales. RESULTS: There was an effect of diagnosis on change in PEP from baseline to the onset of social threat (F=7.60, p=0.01), with greater changes in PEP in TD compared to ASD. PEP change score and the Social Communication Questionnaire (r=0.634, p=0.005) and the ADHD Problems Subscale of the Child Behavior Checklist (r=0.568, p=0.014) were correlated. CONCLUSIONS: These findings suggest reduced arousal in response to social threat in ASD, with preliminary evidence that reduced sympathetic activation is associated with increased social behavior symptoms.

Salivary cortisol and behavioral response to social evaluative threat in adolescents with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social behavior. One possible explanation for social communication deficits in ASD could be differences in biological systems that support responses to environmental stimuli. If so, it is unclear if differences in the arousal response to social stimuli in ASD are due to reduced interest in social information, or to an increased stress response. The hypothalamic pituitary adrenal axis facilitates arousal and the stress response to sensory input, including social stimuli. Previous research shows blunted cortisol response to social evaluative threat in children with ASD. The majority of prior work has focused on children with ASD, but adolescents with ASD are understudied. The adolescent period is of interest, as this developmental epoch is associated with increased salience of social evaluative threat in typically developing (TD) populations. In this study, we employed the Trier Social Stress Test (TSST), a laboratory paradigm that involves exposure to social evaluative threat, to study the cortisol and behavioral response to social evaluative threat in ASD and TD adolescents. Salivary cortisol data were collected at six time points before and after the TSST. Behavioral data were collected using video recordings of the TSST, which were then operationalized and coded. Paired sample t-tests were used to calculate within-group cortisol response to the TSST. Cortisol significantly increased in response to the TSST in the TD group but not the ASD group. The TD group showed a trend for more self-soothing behaviors during the stressor than the ASD group. The lack of a cortisol response to the TSST in the ASD group suggests that the TSST is not interpreted as stressful or salient for ASD adolescents. Autism Res 2017, 10: 346-358. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Physiological Response to Social Evaluative Threat in Adolescents with Autism Spectrum Disorder.

The Trier Social Stress Test (TSST) was employed to study response to social evaluative threat in male adolescents with Autism Spectrum Disorder (ASD, n = 21) and typical development (n = 13). Participants wore a mobile electrocardiogram to collect heart rate data. There were significant group effects on respiratory sinus arrhythmia (RSA), a measure of parasympathetic nervous system function, with lower values in ASD (F = 4.97). Bivariate correlations also showed a significant relationship between parent reports of social problems and RSA response to the TSST (r = -0.586). These findings suggest that autonomic dysregulation may contribute to social deficits in adolescents with ASD.

Opportunities and Gaps in Primary Care Preventative Health Services for Transgender Patients: A Systemic Review.

Purpose: Transgender people face barriers to accessing healthcare, resulting in population-level disparities in health outcomes. Little research is available to better understand the receipt of primary healthcare among transgender patients or how the rate of receipt of preventive care may differ among transgender populations. Methods: The medical literature regarding U.S. adult transgender primary healthcare was reviewed using a keyword search strategy: transgender OR transsexual OR transvestite OR gender nonconforming for articles published between January 1, 2001 and June 15, 2015. Studies addressing the following topics as assessed by the Behavioral Risk Factor Surveillance System were extracted for qualitative review: colorectal cancer screenings, mammography or chest/breast tissue examinations, cholesterol and blood pressure screenings, tobacco use and smoking cessation, cervical cancer or human papillomavirus (HPV) screenings, human immunodeficiency virus (HIV), annual flu shot, and insurance coverage. Results: The search identified 1304 eligible records, of which 41 discussed transgender primary or preventive care. The majority of studies discussed HIV rates or risk behaviors, while fewer articles addressed pelvic examinations, tobacco use, insurance coverage, and cholesterol screenings. No studies addressed mammography or chest/breast tissue examinations, colorectal screenings, or flu shots. Conclusions: Findings from articles addressing five topics are discussed: HIV, cholesterol screenings, tobacco use, pelvic health, and insurance coverage. Gaps in the extant literature, including the lack of studies of nonbinary people, transgender men of color, and transgender people living outside of large coastal urban centers, are discussed. This review, coincident with other health disparity findings, suggests an urgent need for research that addresses the primary care needs of all transgender and gender nonconforming people.

Neural activity changes in unaffected children of patients with schizophrenia: A resting-state fMRI study.

Previous neuroimaging studies have suggested that individuals at risk for schizophrenia exhibit structural and functional brain abnormalities. However, few studies focus on resting state baseline activity in individuals with genetic high-risk for schizophrenia (HR). We examined cerebral spontaneous neural activity in HR by measuring the amplitude of low frequency fluctuations (ALFF) in the blood oxygen level-dependent (BOLD) functional magnetic resonance signal during resting state. Using a 3T MRI scanner, 28 non-psychotic young adult participants with at least one parent with schizophrenia and 44 matched unrelated healthy comparison subjects (HC) were scanned during the resting-state. The ALFF of the BOLD signal for each participant was calculated, and these values were then compared between-groups using voxel-based analysis of the ALFF maps. The HR group showed significantly increased ALFF compared to the HC group in the striatum, including the left caudate nucleus extending to the putamen and the right caudate nucleus. There was also increased ALFF in HR relative to controls in the left medial temporal region including hippocampus, parahippocampal gyrus and the fusiform gyrus, as well as regions including the left lateral thalamus, bilateral ventral and dorsal anterior cingulate cortex, bilateral calcarine sulcus and precuneus. There was significantly decreased ALFF in the HR group relative to controls in the left inferior parietal lobule/postcentral gyrus. Our findings suggest that altered intrinsic neuronal activity in cortico-striato-thalamic networks may represent genetic vulnerability for the development of schizophrenia.