Department of Psychiatry, UCSD

BACKGROUND:Higher cumulative burden of depression among people with HIV (PWH) is associated with poorer health outcomes; however, longitudinal relationships with neurocognition are unclear. This study examined hypotheses that among PWH, (1) higher cumulative burden of depression would relate to steeper declines in neurocognition, and (2) visit-to-visit depression severity would relate to fluctuations in neurocognition within persons. SETTING:Data were collected at a university-based research center from 2002 to 2016. METHODS:Participants included 448 PWH followed longitudinally. All participants had >1 visit (M = 4.97; SD = 3.53) capturing depression severity (Beck Depression Inventory-II) and neurocognition (comprehensive test battery). Cumulative burden of depression was calculated using an established method that derives weighted depression severity scores by time between visits and total time on study. Participants were categorized into low (67%), medium (15%), and high (18%) depression burden. Multilevel modeling examined between- and within-person associations between cumulative depression burden and neurocognition over time. RESULTS:The high depression burden group demonstrated steeper global neurocognitive decline compared with the low depression burden group (b = -0.100, P = 0.001); this was driven by declines in executive functioning, delayed recall, and verbal fluency. Within-person results showed that compared with visits when participants reported minimal depressive symptoms, their neurocognition was worse when they reported mild (b = -0.12, P = 0.04) or moderate-to-severe (b = -0.15, P = 0.03) symptoms; this was driven by worsened motor skills and processing speed. CONCLUSIONS:High cumulative burden of depression is associated with worsening neurocognition among PWH, which may relate to poor HIV-related treatment outcomes. Intensive interventions among severely depressed PWH may benefit physical, mental, and cognitive health.

OBJECTIVE:The hippocampus is a key structure in feeding behaviors and weight regulation. Obesity may lead to disruptions in hippocampal structure. In animals, obesity-related factors (e.g., high-fat/sugar foods) are associated with hippocampal insult (e.g., alterations in the blood brain barrier). In humans, individuals with obesity, relative to healthy weight, have smaller hippocampal volumes. Few studies have examined the association between body weight and the hippocampus during adolescence, a critical brain development period. This study examined hippocampal volume and tissue signal intensity in adolescents across the weight spectrum. METHODS:Structural magnetic resonance imaging and anthropomorphic data were available for 102 12- to 18-year-old adolescents (53% female; 15.07 [SD 1.84] years; standardized BMI [BMIz] scores using the Centers for Disease Control and Prevention growth charts: 0.54 [SD 1.17]) from the Pediatric Imaging, Neurocognition, and Genetics database. Linear regression models controlling for age, sex, genetic ancestry, scanner, and household income examined the relationship between BMIz, hippocampal volume, and T2-weighted hippocampal signal intensity. RESULTS:BMIz was negatively associated with T2-weighted hippocampal signal intensity in the left (t = -3.05; P = 0.003; r = -0.21) and right (t = -2.50; P = 0.01; r = -0.36) hippocampi. BMIz was not significantly associated with hippocampal volume. CONCLUSIONS:BMIz is associated with hippocampal tissue characteristics during adolescence, which could impact later brain development.

Information about genetic engineering (GE) for vector control in the United States is disseminated primarily in English, though non-English speakers are equally, and in some geographic regions even more affected by such technologies. Non-English-speaking publics should have equal access to such information, which is especially critical when the technology in question may impact whole communities. We convened an interdisciplinary workgroup to translate previously developed narrated slideshows on gene drive mosquitoes from English into Spanish, reviewing each iteration for scientific accuracy and accessibility to laypeople. Using the finalised stimuli, we conducted five online, chat-based focus groups with Spanish-speaking adults from California. Overall, participants expressed interest in the topic and were able to summarise the information presented in their own words. Importantly, participants asked for clarification and expressed scepticism about the information presented, indicating critical engagement with the material. Through collaboration with Spanish-speaking scientists engaged in the development of GE methods of vector control, we translated highly technical scientific information into Spanish that successfully engaged Spanish-speaking participants in conversations about this topic. In this manuscript, we document the feasibility of consulting Spanish-speaking publics about a complex emerging technology by drawing on the linguistic diversity of the scientific teams developing the technology.

For people living with HIV (PLWH) and sexual minorities (SM), the intersection of identities can compound experiences like stigma and discrimination resulting in poor emotional health. We investigated the separate and interactive associations of HIV serostatus and sexual identity with emotional health. Our dataset included 371 participants. Emotional health was assessed by the NIH Toolbox emotion battery which yields negative affect, social satisfaction, and psychological well-being. Regressions were conducted for each composite, with HIV serostatus, sexual identity, and their interaction as independent variables along with covariates. The HIV serostatus x SM identity interaction was statistically significant in the regression of Negative Affect (p = .01): heterosexuals living with HIV had worse Negative Affect compared to heterosexual HIV-persons (p = .01). The interaction terms were for social satisfaction and psychological well-being were not significant. However, among PLWH, sexual minorities reported better Social Satisfaction (p = .03) and marginally better psychological well-being (p = .07) compared to heterosexuals.

BACKGROUND:The ultimate goal of artificial intelligence (AI) is to develop technologies that are best able to serve humanity. This will require advancements that go beyond the basic components of general intelligence. The term "intelligence" does not best represent the technological needs of advancing society, because it is "wisdom", rather than intelligence, that is associated with greater well-being, happiness, health, and perhaps even longevity of the individual and the society. Thus, the future need in technology is for artificial wisdom (AW). METHODS:We examine the constructs of human intelligence and human wisdom in terms of their basic components, neurobiology, and relationship to aging, based on published empirical literature. We review the development of AI as inspired and driven by the model of human intelligence, and consider possible governing principles for AW that would enable humans to develop computers which can operationally utilize wise principles and result in wise acts. We review relevant examples of current efforts to develop such wise technologies. RESULTS:AW systems will be based on developmental models of the neurobiology of human wisdom. These AW systems need to be able to a) learn from experience and self-correct; b) exhibit compassionate, unbiased, and ethical behaviors; and c) discern human emotions and help the human users to regulate their emotions and make wise decisions. CONCLUSIONS:A close collaboration among computer scientists, neuroscientists, mental health experts, and ethicists is necessary for developing AW technologies, which will emulate the qualities of wise humans and thus serve the greatest benefit to humanity. Just as human intelligence and AI have helped further the understanding and usefulness of each other, human wisdom and AW can aid in promoting each other's growth.

BACKGROUND:Methamphetamine use poses a barrier to antiretroviral therapy (ART) adherence. Black and Hispanic men who have sex with men living with HIV (PLWH) shoulder much of the health burden resulting from the methamphetamine and HIV syndemic. Smartphones are nearly ubiquitous in the USA and may be promising vehicles for delivering interventions for ART adherence and drug use cessation. However, the acceptability of using applications to collect sensitive information and deliver feedback in this population has not been adequately explored. OBJECTIVE:This study examined minority PLWH's appraisals of the risks of participating in smartphone-based research to promote ART adherence in the context of methamphetamine use and explored their views on appropriate steps to mitigate perceived risks of participation. METHODS:Three focus groups were conducted among Black and Hispanic PLWH who use methamphetamine. Of the 13 participants, 5 had previously participated in a smartphone-based observational study of ART adherence and substance use. Discussants provided feedback on smartphone-based research, including receiving probes for HIV medication adherence, mood, and substance use as well as feedback on passive location-tracking for personalized messages. Transcribed audio-recordings were thematically coded and analyzed using the qualitative software MAXQDA. RESULTS:Participants expressed confidentiality concerns related to potential unintentional disclosure of their HIV status and methamphetamine use and to possible legal consequences. They additionally expressed concerns around the invasiveness of daily assessments and the potential of methamphetamine use questions to trigger cravings. To mitigate these concerns, they suggested maintaining participant privacy by indirectly asking sensitive questions, focusing on positive behaviors (e.g., number of days sober), allowing user-initiated reporting of location to tailor messages, and ensuring adequate data protections. In addition to financial compensation, participants cited altruism (specifically, continuing a tradition of volunteerism in HIV research) as a motivator for potentially engaging in such research. CONCLUSIONS:Minority PLWH have concerns regarding the use of smartphones for ART adherence and methamphetamine sobriety intervention research. However, minority PLWH are likely to participate if studies include appropriate protections against risks to confidentiality and experimental harm and are designed to offer future benefit to themselves and other PLWH.

The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN-specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.

Early weight loss (rapid response [RR]) is associated with better outcomes in adults. Less is known about RR in children enrolled in weight-loss treatment. The aim of the current study was to establish an RR weight-loss threshold following 4 weeks of pediatric obesity treatment and identify characteristics associated with achieving RR. One hundred thirty-seven children aged 8 to 12 with overweight/obesity and parents participated in 6 months of family-based or parent-based treatment. Receiver operating characteristic curves evaluated how weight loss at week 4 related to decreases of 5% at posttreatment and 10% at 6- and 18-month follow-ups of standardized body mass index (BMIz), percentage distance of a child's BMI from the median BMI for sex and age, and percentage above the 95th percentile. Weight loss of 2.4% to 3.4% at week 4 predicted 5% change at posttreatment (AUC's = .68-.75; P's ≤ .002) and 10% change at 6-month follow-up (AUC's = .63-.70; P's ≤ .02). No model was significant at 18-month follow-up. Amount of parent weight (lbs) change at week 4 was associated with child achieving RR. Males and Non-Hispanic Whites were more likely to achieve RR. This threshold could be used to mark early significant progress and guide clinical evaluations of treatment response to paediatric obesity treatment.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.

INTRODUCTION:Anorexia nervosa is a severe psychiatric illness and no medication has been approved for its treatment. This lack of biological treatments requires the development of new directions for pharmacological research. AREAS COVERED:There is modest but emerging evidence that dopamine D2 and serotonin 1A and 2A receptor agonistic and antagonist medication might be beneficial for weight gain, although the underlying mechanisms are uncertain. Improving quality of life including treating comorbid conditions is an additional important outcome measure, but this has not been well researched. Biological and psychological risk factors together with neurobiological alterations during the illness maintain the disorder 's pathophysiology. Neuroscience research can be used to understand those interactions and advance the research agenda. The authors discuss the above as well as give perspectives on future research. EXPERT OPINION:If a multidisciplinary approach that includes evidence-based psychotherapy shows unsatisfactory success in weight normalization and cognitive-emotional recovery, then more experimental treatments that are safe and have indicated treatment effectiveness should be tried to augment treatment. Identification and treatment of comorbid conditions to improve quality of life of the patient should also be part of the treatment regimen, even if the effect on weight gain is uncertain.