Acceptability of an Intervention to Promote Viral Suppression and Serostatus Disclosure for Men Living with HIV in South Africa: Qualitative Findings.

Men living with HIV (MLWH) often have reproductive goals that can increase HIV-transmission risks to their pregnancy partners. We developed a safer conception intervention for MLWH in South Africa employing cognitive behavioral skills to promote serostatus disclosure, ART uptake, and viral suppression. MLWH were recruited from an HIV clinic near Durban, South Africa, and encouraged to include partners in follow-up visits. Exit in-depth interviews were conducted with eleven men and one female partner. The emerging over-arching theme is that safer conception care mitigates internalized and community-level HIV-stigma among MLWH. Additional related sub-themes include: (1) safer conception care acceptability is high but structural barriers challenge participation; (2) communication skills trainings helped overcome barriers to disclose serostatus; (3) feasibility and perceived effectiveness of strategies informed safer conception method selection. Our findings suggest that offering safer conception care to MLWH is a novel stigma-reducing strategy for motivating HIV prevention and treatment and serostatus disclosure to partners.

Overcoming Ethical Challenges to Engaging Men Who Have Sex with Women in HIV Research.

Men who have sex with women are understudied in HIV research despite the extent to which they experience HIV-related mortality and contribute to the epidemic among women. During our experience of developing and piloting an HIV prevention intervention for men living with HIV in South Africa, and planning to have a child with an HIV-negative woman, ethical questions were posed regarding implementation of a male-centered intervention that did not require female partner participation. Two overarching ethical issues were the potential for (1) compromising women's reproductive and sexual autonomy and (2) increasing HIV-acquisition risks for the woman because the intervention efficacy was unknown. We describe here how these concerns were addressed to facilitate development of a male-centered HIV-prevention intervention. We hope this process manuscript will support researchers, clinicians, and reviewers to engage men who have sex with women in HIV prevention and care.

Sexually Transmitted Infection Prevalence Among Women at Risk for HIV Exposure Initiating Safer Conception Care in Rural, Southwestern Uganda.

BACKGROUND: Knowledge of sexually transmitted infection (STI) prevalence and risk factors is important to the development of tenofovir-based preexposure prophylaxis (PrEP) and safer conception programming. We introduced STI screening among women at risk for HIV exposure who were participating in a safer conception study in southwestern Uganda. METHODS: We enrolled 131 HIV-uninfected women, planning for pregnancy with a partner living with HIV or of unknown HIV serostatus (2018-2019). Women were offered comprehensive safer conception counseling, including PrEP. Participants completed interviewer-administered questionnaires detailing sociodemographics and sexual history. We integrated laboratory screening for chlamydia, gonorrhea, trichomoniasis, and syphilis as a substudy to assess STI prevalence. Multivariable logistic regression was used to determine correlates. RESULTS: Ninety-four women completed STI screening (72% of enrolled). Median age was 30 (interquartile range, 26-34) years, and 94% chose PrEP as part of safer conception care. Overall, 24% had STIs: 13% chlamydia, 2% gonorrhea, 6% trichomoniasis, 6% syphilis, and 3% ≥2 STI. Sexually transmitted infection prevalence was associated with younger age (adjusted odds ratio [AOR], 0.87; 95% confidence interval [CI], 0.77-0.99), prior stillbirth (AOR, 5.04; 95% CI, 1.12-22.54), and not feeling vulnerable to HIV (AOR, 16.33; 95% CI, 1.12-237.94). CONCLUSIONS: We describe a 24% curable STI prevalence among women at risk for HIV exposure who were planning for pregnancy. These data highlight the importance of integrating laboratory-based STI screening into safer conception programs to maximize the health of HIV-affected women, children, and families.

Developing a Safer Conception Intervention for Men Living with HIV in South Africa.

Within sexual partnerships, men make many decisions about sexual behavior, reproductive goals, and HIV prevention. There are increasing calls to involve men in reproductive health and HIV prevention. This paper describes the process of creating and evaluating the acceptability of a safer conception intervention for men living with HIV who want to have children with partners at risk for acquiring HIV in KwaZulu-Natal, South Africa. Based on formative work conducted with men and women living with HIV, their partners, and providers, we developed an intervention based on principles of cognitive-behavioral therapy to support men in the adoption of HIV risk-reduction behaviors such as HIV-serostatus disclosure and uptake of and adherence to antiretroviral therapy. Structured group discussions were used to explore intervention acceptability and feasibility. Our work demonstrates that men are eager for reproductive health services, but face unique barriers to accessing them.

"I beg you breastfeed the baby, things changed": infant feeding experiences among Ugandan mothers living with HIV in the context of evolving guidelines to prevent postnatal transmission.

BACKGROUND: For women living with HIV (WLWH) in low- and middle-income countries, World Health Organization (WHO) infant feeding guidelines now recommend exclusive breastfeeding until six months followed by mixed feeding until 24 months, alongside lifelong maternal antiretroviral therapy (ART). These recommendations represent the sixth major revision to WHO infant feeding guidelines since 1992. We explored how WLWH in rural Uganda make infant feeding decisions in light of evolving recommendations. METHODS: We conducted semi-structured interviews with 20 postpartum Ugandan WLWH accessing ART, who reported pregnancy < 2 years prior to recruitment. Interviews were conducted between February-August 2014 with babies born between March 2012-October 2013, over which time, the regional HIV treatment clinic recommended lifelong ART for all pregnant and breastfeeding women (Option B+). Content analysis was used to identify major themes. Infant feeding experiences was an emergent theme. NVivo 10 software was used to organize analyses. RESULTS: Among 20 women, median age was 33 years [IQR: 28-35], number of livebirths was 3 [IQR: 2-5], years on ART was 2.3 [IQR: 1.5-5.1], and 95% were virally suppressed. Data revealed that women valued opportunities to reduce postnatal transmission. However, women made infant feeding choices that differed from recommendations due to: (1) perception of conflicting recommendations regarding infant feeding; (2) fear of prolonged infant HIV exposure through breastfeeding; and (3) social and structural constraints shaping infant feeding decision-making. CONCLUSIONS: WLWH face layered challenges navigating evolving infant feeding recommendations. Further research is needed to examine guidance and decision-making on infant feeding choices to improve postpartum experiences and outcomes. Improved communication about changes to recommendations is needed for WLWH, their partners, community members, and healthcare providers.

Understanding coping strategies during pregnancy and the postpartum period: a qualitative study of women living with HIV in rural Uganda.

BACKGROUND: In sub-Saharan Africa, 58% of adults living with HIV are women. In Uganda, HIV prevalence is 8.3% for women compared to 6.1% for men. Access to antiretroviral therapy (ART) and prevention of mother to child transmission (PMTCT) programs have enabled women living with HIV (WLWH) to have children with minimal risk of perinatal transmission. Nevertheless, pregnant WLWH face many challenges. We explored women's perceptions of how they cope with the challenges of pregnancy and the postpartum period as HIV-infected women. METHODS: We conducted semi-structured interviews with postpartum WLWH accessing ART who had a pregnancy within 2 years prior to recruitment between February-August, 2014. Childbearing associated stressors and coping strategies were discussed. We used content analysis to identify major themes and NVivo 10 software facilitated data analysis. RESULTS: Twenty women were interviewed with median age 33 (IQR: 28-35) years, CD4 cell count 677 cells/mm3 (IQR: 440-767), number of live births 4 (IQR: 2-6), and number of living children 3 (IQR: 2-4.3). We summarize five identified coping strategies within a socio-ecological framework according to Bronfenbrenner's Ecological Model. Coping strategies on the individual level included acceptance of self and HIV status, and self-reliance. On the interpersonal level, participants reported coping through support from partners, family, and friends. On the organizational level, participants reported coping through HIV-related healthcare delivery and system supports. At the community level, women reported coping through support from church and spirituality. CONCLUSIONS: The results highlight coping strategies used by WLWH to manage the myriad challenges faced during pregnancy and the postpartum period. Intervention programs for WLWH must emphasize psychosocial care and incorporate strategies that address psychosocial challenges in the HIV care package in order to optimize well-being. Additionally policies that support networks of WLWH should be put in place and funding support should be provided through existing funding mechanisms in order to respond to the needs and challenges of WLWH. Programmes that support WLWH for economic empowerment and improved livelihoods should be strengthened across all regions in the country.

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia.

The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.

STI prevalence, incidence, and partner notification among women in a periconception HIV prevention program in Uganda.

BACKGROUND: We provided sexually transmitted infection (STI) screening and facilitated partner notification and treatment among women participating in a periconception HIV prevention program in southwestern Uganda to understand follow-up STI incidence. METHODS: Women at-risk for HIV exposure while planning for pregnancy completed laboratory screening for chlamydia, gonorrhea, trichomoniasis, and syphilis at enrollment and 6 months of follow-up and/or incident pregnancy; facilitated partner notification and treatment were offered for those with positive tests. We performed a logistic regression to determine correlates of follow-up STI. RESULTS: Ninety-four participants completed enrollment STI screening with a median age of 29 (IQR 26-34); 23 (24%) had ≥1 STI. Of the 23 participants with enrollment STI(s), all completed treatment and 19 (83%) returned for follow-up; 18 (78%) reported delivering partner notification cards and discussing STIs with partner(s), and 14 (61%) reported all partners received STI treatment. Of the 81 (86%) who successfully completed follow-up STI screening, 17 (21%) had ≥1 STI. The STI incidence rate was 29.0 per 100 person-years. In univariable regression analysis, enrollment STI, younger age, less education, and alcohol consumption were all significantly associated with follow-up STI. CONCLUSIONS: We demonstrated high enrollment and follow-up STI rates and moderate participant-reported partner treatment among women planning for pregnancy in Uganda despite partner notification and treatment. Novel STI partner notification and treatment interventions are needed to decrease the STI burden, especially among women planning for and with pregnancy.

"It really proves to us that we are still valuable": Qualitative research to inform a safer conception intervention for men living with HIV in South Africa.

OBJECTIVE: Many men living with HIV want to have children. Opportunities to reduce periconception HIV transmission include antiretroviral therapy as prevention, pre-exposure prophylaxis, limiting condomless sex to peak fertility, and sperm processing. Whether men have knowledge of or want to adopt these strategies remains unknown. METHODS: We conducted focus group discussions (FGDs) with men accessing HIV care in South Africa in 2014 to inform a safer conception intervention for men. Eligible men were 25-45 years old, living with HIV, not yet accessing treatment, and wanting to have a child with an HIV-negative or unknown serostatus female partner (referred to as the "desired pregnancy partner"). FGDs explored motivations for having a healthy baby, feasibility of a clinic-based safer conception intervention, and acceptability of safer conception strategies. Data were analyzed using thematic analysis. RESULTS: Twelve participants from three FGDs had a median age of 37 (range 23-45) years, reported a median of 2 (range 1-4) sexual partners, and 1 (range 1-3) desired pregnancy partner(s). A third (N = 4) had disclosed HIV-serostatus to the pregnancy partner. Emergent themes included opportunities for and challenges to engaging men in safer conception services. Opportunities included enthusiasm for a clinic-based safer conception intervention and acceptance of some safer conception strategies. Challenges included poor understanding of safer conception strategies, unfamiliarity with risk reduction [versus "safe" (condoms) and "unsafe" (condomless) sex], mixed acceptability of safer conception strategies, and concerns about disclosing HIV-serostatus to a partner. CONCLUSIONS: Men living with HIV expressed interest in safer conception and willingness to attend clinic programs. Imprecise prevention counseling messages make it difficult for men to conceptualize risk reduction. Effective safer conception programs should embrace clear language, e.g. undetectable = untransmittable (U = U), and support multiple approaches to serostatus disclosure to pregnancy partners.

Protocol for a longitudinal study to evaluate the use of tenofovir-based PrEP for safer conception and pregnancy among women in South Africa.

INTRODUCTION: Women who choose to conceive a baby with a partner living with HIV or a partner whose HIV serostatus is unknown in HIV-endemic settings need prevention strategies to mitigate HIV acquisition during conception and pregnancy. METHODS AND ANALYSIS: We are conducting a single-arm longitudinal study offering oral tenofovirdisoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis (PrEP) for periconception use to 350 HIV-uninfected women in KwaZulu-Natal, South Africa. PrEP is offered as part of woman-centred safer conception programme that promotes couples-based HIV counselling and testing, antiretroviral therapy for partners who are HIV-infected, treatment for sexually transmitted infections and safer conception strategies, such as limiting condomless sex to peak fertility. We enrol HIV-uninfected women who are not currently pregnant, in a stable relationship (≥6 months) with a partner living with HIV or of unknown serostatus, and personal or partner plans for pregnancy in the next 12 months. We follow enrolled women for 12 months. Women who become pregnant are followed through pregnancy outcome, independent of their decisions regarding PrEP use. The primary objective of the study is to evaluate the uptake of and adherence to PrEP during the periconception period and pregnancy. Secondary outcomes include the uptake of other safer conception strategies. We also measure clinical outcomes including HIV seroconversion rates and pregnancy and infant outcomes. Finally, we will explore conduct and evaluate qualitative interviews in 25 participants to further inform our conceptual framework for periconception PrEP uptake and adherence among HIV-exposed women in South Africa. ETHICS AND DISSEMINATION: The protocol has been approved by the Human Research Ethics Committee at the University of the Witwatersrand (Johannesburg, South Africa) and the Institutional Review Board of Partners Healthcare (Boston, Massachusetts, USA). Study findings will be made available to interested participants. Results will be presented to local health officials and stakeholders at meetings. Investigators will share the results at meetings and in manuscripts. De-identified quantitative data will be made available. TRIAL REGISTRATION NUMBER: The protocol is registered with the South African Health Products Regulatory Agency (SAHPRA, formerly known as the Medicine Controls Council, MCC#20170131) and ClinicalTrials.gov (NCT03194308); Pre-results.

Psychosocial challenges facing women living with HIV during the perinatal period in rural Uganda.

The complexities of navigating pregnancy while living with HIV predispose women to additional stress. Finding ways to minimize psychosocial challenges during the perinatal period may maximize the well-being of mothers living with HIV and their children. The goal of this study was to explore psychosocial challenges experienced by women living with HIV (WLWH) during pregnancy and the postpartum. We conducted individual in-depth interviews with 20 WLWH recruited from an HIV treatment cohort study in Mbarara, Uganda as part of a larger study exploring perinatal depression. We conducted content analyses to identify themes related to challenges of WLWH during pregnancy and the postpartum. Participants had a median age of 33 years [IQR: 28-35], a median of 3 living children [IQR: 2-5], and 95% had achieved HIV-RNA suppression. Challenges were organized around the following themes: HIV -related stigma from health professionals, HIV status disclosure dilemma, unintended pregnancy and intimate partner violence, HIV and environmental structural barriers and distress and fear related to maternal and child health. Stigma centered on discrimination by health care professionals and personal shame associated with being pregnant as a WLWH. This led to difficulty engaging in HIV care, particularly when coupled with structural barriers, such as lack of transportation to clinic. Participants experienced intimate partner violence and lacked support from their partners and family members. Distress and fear about the health and uncertainty about the future of the unborn baby due to maternal deteriorating physical health was common. The perinatal period is a time of stress for WLWH. Challenges experienced by WLWH may compromise successful engagement in HIV care and may reduce quality of life for women and their children. Strategies aimed at alleviating the challenges of WLWH should involve the larger structural environment including partners, family and community member as well as policy makers, funders and program implementers to work together for the common cause. These consolidated efforts may not only lower the risk of psychological distress but has potential to create long lasting solutions to benefit the wider community.

Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study.

OBJECTIVE: Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis. METHOD: The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools. RESULTS: Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis. CONCLUSIONS: This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.

Resting state electroencephalogram oscillatory abnormalities in schizophrenia and psychotic bipolar patients and their relatives from the bipolar and schizophrenia network on intermediate phenotypes study.

BACKGROUND: Abnormal resting state electroencephalogram (EEG) oscillations are reported in schizophrenia (SZ) and bipolar disorder, illnesses with overlapping symptoms and genetic risk. However, less evidence exists on whether similar EEG spectral abnormalities are present in individuals with both disorders or whether these abnormalities are present in first-degree relatives, possibly representing genetic predisposition for these disorders. METHODS: Investigators examined 64-channel resting state EEGs of 225 SZ probands and 201 first-degree relatives (SZR), 234 psychotic bipolar (PBP) probands and 231 first-degree relatives (PBPR), and 200 healthy control subjects. Eight independent resting state EEG spectral components and associated spatial weights were derived using group independent component analysis. Analysis of covariance was conducted on spatial weights to evaluate group differences. Relative risk estimates and familiality were evaluated on abnormal spectral profiles in probands and relatives. RESULTS: Both SZ and PBP probands exhibited increased delta, theta, and slow and fast alpha activity. Post-hoc pair-wise comparison revealed increased frontocentral slow beta activity in SZ and PBP probands as well as SZR and PBPR. Augmented frontal delta activity was exhibited by SZ probands and SZR, whereas PBP probands and PBPR showed augmented fast alpha activity. CONCLUSIONS: Both SZ and PBP probands demonstrated aberrant low-frequency activity. Slow beta activity was abnormal in SZ and PBP probands as well as SZR and PBPR perhaps indicating a common endophenotype for both disorders. Delta and fast alpha activity were unique endophenotypes for SZ and PBP probands, respectively. The EEG spectral activity exhibited moderate relative risk and heritability estimates, serving as intermediate phenotypes in future genetic studies for examining biological mechanisms underlying the pathogenesis of the two disorders.

Semantic association fMRI impairments represent a potential schizophrenia biomarker.

Semantic association retrieval task (SORT) requires participants to indicate whether word pairs recall a third object, e.g. 'honey' and 'stings' activates 'bees'. We have previously shown that individuals with schizophrenia with more severe positive symptoms tend to report associations between unrelated word pairs than healthy controls; schizophrenia individuals with more severe negative symptoms tend to fail to report associations between related word pairs. This over-retrieval and under-retrieval on SORT correlates with functional magnetic resonance imaging (fMRI) activity in inferior parietal lobule (IPL). To examine the suitability of SORT as an endophenotype for schizophrenia, we examined SORT performance and activity across multiple stages of the illness: chronic, relapse, and first episode. We also examine SORT performance and activity in unaffected relatives. SORT performance and fMRI activity in schizophrenia-first episode, schizophrenia-chronic and schizophrenia-relapse were significantly impaired relative to healthy controls and unaffected relatives. Schizophrenia-chronic and schizophrenia-relapse participants showing more severe PANSS-positive and -general symptoms showed larger SORT impairments. For schizophrenia-first episode more severe negative symptoms were related to lower IPL activation, consistent with previous results showing that negative symptoms are among the first to emerge in the schizophrenia prodrome and that more severe symptoms in the first episode predict worse future outcomes. Unaffected relatives showed no impairments on SORT performance or fMRI activity relative to healthy controls, which is incompatible with the concept of SORT as an endophenotype for schizophrenia, but is consistent with the concept of SORT as a potential schizophrenia biomarker.

Impairment in semantic retrieval is associated with symptoms in schizophrenia but not bipolar disorder.

BACKGROUND: The Semantic Object Retrieval Task (SORT) requires participants to indicate whether word pairs recall a third object. Schizophrenia individuals (SZ) tend to report associations between nonassociated word pairs; this overretrieval is related to formal thought disorder (FTD). Since semantic memory impairments and psychosis are also found in bipolar disorder (BP), we examined whether SORT impairments and their relationship to symptoms are also present in BP. METHODS: Participants (n = 239; healthy control subjects [HC] = 133; BP = 32; SZ = 74) completed SORT while undergoing functional magnetic resonance imaging (fMRI) scanning. RESULTS: Retrieval accuracy negatively correlated with negative symptoms and no-retrieval accuracy negatively correlated with FTD severity in SZ but not BP. Retrieval versus no-retrieval trials activated a distributed fronto-parieto-temporal network; bilateral inferior parietal lobule (IPL) activity was larger in HC versus SZ and HC versus BP, with no difference in SZ versus BP. Right IPL activity positively correlated with positive and general psychosis symptoms in SZ but not BP. CONCLUSIONS: SZ reported more associations between unrelated word pairs than HC; this overretrieval increased with FTD severity. Schizophrenia individuals were also more likely to fail to find associations between related word pairs; this underretrieval increased with negative symptom severity. fMRI symptom correlations in IPL in SZ are consistent with arguments that IPL abnormality relates to loosening of associations in SZ. By comparison, BP showed intermediate impairments on SORT, uncorrelated with symptoms, suggesting that the relationship between SORT performance, fMRI activity, and psychotic symptoms is schizophrenia-specific.

Diffusion tensor imaging white matter endophenotypes in patients with schizophrenia or psychotic bipolar disorder and their relatives.

OBJECTIVE Both schizophrenia and bipolar disorder are hypothesized to involve disordered brain connectivity. Prior studies show low white matter integrity, measured with diffusion tensor imaging, for both disorders. The authors studied disease specificity and endophenotypic status of these abnormalities by examining patients and their unaffected relatives. METHOD The 513 participants included probands with schizophrenia, probands with psychotic bipolar disorder, their first-degree relatives, and healthy comparison subjects. Fractional anisotropy measures of white matter integrity were collected at two sites as a part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes project. Relatives with cluster A or B personality characteristics were further examined. RESULTS Both the probands with schizophrenia and those with psychotic bipolar disorder showed lower fractional anisotropy than the comparison subjects in multiple white matter regions; differences were more marked in schizophrenia. No significant differences existed between proband groups, but in some brain regions scores on a measure of the dimensional continuum between schizophrenia and bipolar disorder, the Schizo-Bipolar Scale, showed correlations with fractional anisotropy. Many regions affected in schizophrenia probands showed similar but smaller effects in relatives, with a continuous fractional anisotropy decrease from healthy subjects to relatives to cluster A/B relatives to probands. The pattern for psychotic bipolar disorder was similar but involved fewer brain regions. Effects in bipolar relatives were limited to younger subjects. Fractional anisotropy decreased with age in all groups; this decrease was exaggerated in schizophrenia but not psychotic bipolar disorder. CONCLUSIONS Fractional anisotropy was highly heritable, supporting its value as a potential endophenotype.

Is aberrant functional connectivity a psychosis endophenotype? A resting state functional magnetic resonance imaging study.

BACKGROUND: Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives. METHODS: We investigated resting state functional magnetic resonance imaging in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (n = 70 and 52), and 118 healthy subjects. We used independent component analysis to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post hoc t tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships. RESULTS: Seven networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < .05): A) fronto-occipital, B) midbrain/cerebellum, C) frontal/thalamic/basal ganglia, D) meso/paralimbic, E) posterior default mode network, F) fronto-temporal/paralimbic and G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C, and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale negative and positive scores were found in regions within network C and F respectively, and positive correlation with Positive and Negative Syndrome Scale negative scores was found in regions in network D among schizophrenia probands only. CONCLUSIONS: Schizophrenia, psychotic bipolar probands, and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes.