Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction.

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.

Impact of maternal adverse childhood experiences on child socioemotional function in rural Kenya: Mediating role of maternal mental health.

Mothers in low- and middle-income countries (LMIC) suffer heightened vulnerability for adverse childhood experiences (ACEs), which is exacerbated by the multitude of risk factors associated with poverty and may lead to increased risk of psychiatric disorder. The constellation of complex, co-occurring biological, environmental, social, economic and psychological risk factors are in turn transmitted to her child, conferring vulnerability for adverse development. This study examines the association between maternal intra- and extra-familial ACEs, maternal education and the mental health of her child, mediated by maternal mental health. Mother-child dyads (n = 121) in Machakos, Kenya were examined cross-sectionally using self-report measures of ACEs, maternal mental health and child internalizing and externalizing mental health problems. The four models proposed to examine the relationship between intra- and extra-familial maternal ACEs and child internalizing and externalizing problems demonstrated indirect pathways through maternal mental health. These effects were found to be conditional on levels of maternal education, which served as a protective factor at lower levels of maternal ACEs. These models demonstrate how the impact of ACEs persists across the lifespan resulting in a negative impact on maternal mental health and conferring further risk to subsequent generations. Elucidating the association between ACEs and subsequent intergenerational sequelae, especially in LMIC where risk is heightened, may improve targeted caregiver mental health programs for prevention and intervention.

A Brainwide Risk Score for Psychiatric Disorder Evaluated in a Large Adolescent Population Reveals Increased Divergence Among Higher-Risk Groups Relative to Control Participants.

BACKGROUND: Accurate psychiatric risk assessment requires biomarkers that are both stable and adaptable to development. Functional network connectivity (FNC), which steadily reconfigures over time, potentially contains abundant information to assess psychiatric risks. However, the absence of suitable analytical methodologies has constrained this area of investigation. METHODS: We investigated the brainwide risk score (BRS), a novel FNC-based metric that contrasts the relative distances of an individual's FNC to that of psychiatric disorders versus healthy control references. To generate group-level disorder and healthy control references, we utilized a large brain imaging dataset containing 5231 total individuals diagnosed with schizophrenia, autism spectrum disorder, major depressive disorder, and bipolar disorder and their corresponding healthy control individuals. The BRS metric was employed to assess the psychiatric risk in 2 new datasets: Adolescent Brain Cognitive Development (ABCD) Study (n = 8191) and Human Connectome Project Early Psychosis (n = 170). RESULTS: The BRS revealed a clear, reproducible gradient of FNC patterns from low to high risk for each psychiatric disorder in unaffected adolescents. We found that low-risk ABCD Study adolescent FNC patterns for each disorder were strongly present in over 25% of the ABCD Study participants and homogeneous, whereas high-risk patterns of each psychiatric disorder were strongly present in about 1% of ABCD Study participants and heterogeneous. The BRS also showed its effectiveness in predicting psychosis scores and distinguishing individuals with early psychosis from healthy control individuals. CONCLUSIONS: The BRS could be a new image-based tool for assessing psychiatric vulnerability over time and in unaffected individuals, and it could also serve as a potential biomarker, facilitating early screening and monitoring interventions.

College student mental health: Psychiatric risk and psychological wellbeing.

OBJECTIVE: To examine both psychiatric risk and psychological wellbeing in a college student sample drawn from a majority-minority university. PARTICIPANTS: 100 participants (42% White; 70 females), mean age, 21.22 years. METHODS: Univariate and multivariate analyses examined the relationship of psychiatric risk (Brief Symptom Inventory; BSI) and psychological wellbeing (Mental Health Continuum-Short Form; MHC-SF) with student stress, cognition, Adverse Childhood Experiences (ACEs) and a new Positive Childhood Experiences (PCEs) scale. RESULTS: Risk correlated with increased student stress, higher ACEs and lower PCEs, whereas wellbeing correlated with lower student stress, better neuropsychological functioning, lower ACE and increased PCEs. PCEs predicted enhanced MHC-SF wellbeing and reduced BSI risk, accounting for 22.4% and 13.7% of variance in these measures, respectively. ACEs predicted elevated BSI risk and diminished MHC-SF wellbeing accounting for 8.6% and 5.9% of variance in these measures, respectively. CONCLUSION: College student mental health may benefit from practices aim specifically to enhance wellbeing, stress-resistance, and cognition.

Psychiatric risks for worsened mental health after psychedelic use.

BACKGROUND: Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. METHODS: A "bottom margin analysis" approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. RESULTS: We find that 16% of the cohort falls into the "negative responder" subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality disorder subsample (b = 1.425, p < 0.05). CONCLUSION: We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.

Elevated risk for psychiatric outcomes in pediatric patients with Multisystem Inflammatory Syndrome (MIS-C): A review of neuroinflammatory and psychosocial stressors.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a secondary immune manifestation of COVID-19 involving multiple organ systems in the body, resulting in fever, skin rash, abdominal pain, nausea, shock, and cardiac dysfunction that often lead to hospitalization. Although many of these symptoms resolve following anti-inflammatory treatment, the long-term neurological and psychiatric sequelae of MIS-C are unknown. In this review, we will summarize two domains of the MIS-C disease course, 1) Neuroinflammation in the MIS-C brain and 2) Psychosocial disruptions resulting from stress and hospitalization. In both domains, we present existing clinical findings and hypothesize potential connections to psychiatric outcomes. This is the first review to conceptualize a holistic framework of psychiatric risk in MIS-C patients that includes neuroinflammatory and psychosocial risk factors. As cases of severe COVID-19 and MIS-C subside, it is important for clinicians to monitor outcomes in this vulnerable patient population.

The Impact of Stopping Risk Assessment Checklists at a Specialist Personality Disorder Unit.

Aim This study was conducted in Springbank Ward, a specialist ward for patients with emotionally unstable personality disorder, based in Cambridge, United Kingdom. We aimed to assess any change in incident frequency following the introduction of a new protocol for leaving the ward, in which patients are offered an optional conversation with staff in place of a formal risk assessment checklist. We also aimed to assess patient and staff perceptions of the change. Methods We used data routinely collected by Springbank Ward to compare incident frequency in the year before and after the change in protocol. We conducted structured interviews with patients and staff to obtain qualitative data on the new protocol and used thematic analysis to interpret the interview data. Results There were 466 incidents during the period before the change in protocol and 408 incidents in the period after. Adjusted for occupancy rate, there was no statistically significant difference in the frequency of incidents. Patients and staff were generally satisfied with the new protocol, with an average satisfaction rating of 4.1 out of 5. Thematic analysis generated five main themes: 'taking ownership', 'autonomy versus restriction', 'staff-patient interaction', 'staff expertise' and 'protocol efficiency'. Conclusions Our study reveals high satisfaction with the new way risk is assessed and managed for patients leaving Springbank Ward, with an appreciation for its holistic and minimally restrictive approach. This was achieved without significantly increasing incident frequency.

Early evidence on the mental health of Ukrainian civilian and professional combatants during the Russian invasion.

BACKGROUND: The ongoing Russian invasion of Ukraine has led many Ukrainians to fight for their country, either in the regular army or as civilian members of voluntary territorial defense forces. There is, however, a dearth of knowledge on the mental health of combatants in this conflict. Prior research on the mental health of combatants is unlikely to translate to the situation at hand because such research is focused on combatants fighting abroad and neglects civilian combatants. METHODS: This study provides the first attempt to investigate the mental health of Ukrainian combatants in the regular army and voluntary territorial defense forces by analyzing the prevalence rates of common mental health issues, as well as their demographic and socioeconomic predictors. RESULTS: Between March 19 and 31, 2022, the initial period of Russia's invasion of Ukraine, a sample of 178 Ukrainian combatants (104 in the regular army and 74 civilian combatants) participated in a survey on symptoms of anxiety (GAD-2), depression (PHQ-2), and insomnia (ISI). CONCLUSIONS: A sizable portion of Ukrainian combatants reached cut-off levels for clinical symptoms of anxiety (44·4%), depression (43·3%), and insomnia (12·4%). Importantly, the mental health of Ukrainian combatants varied between professional soldiers and civilian combatants, as well as by gender, marital status, by whether or not they were located in Russian-occupied/active-combat areas, and dependent on whether they were personally involved in combat. This study provides early evidence on the mental health of Ukrainian combatants, pointing to their urgent need for mental health assistance in the ongoing war.

Attenuated and delayed niacin skin flushing in schizophrenia and affective disorders: A potential clinical auxiliary diagnostic marker.

AIM: Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker. METHODS: In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off. RESULTS: Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%. CONCLUSIONS: The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.

Suicide Risk Assessment and Prevention: Challenges and Opportunities.

Despite increased access to mental health care for the previously uninsured and expanding evidence-based treatments for mood, anxiety, psychotic, and substance use disorders, suicide is on the rise in the United States. Since 1999, the age-adjusted suicide rate in the United States has increased 33%, from 10.5 per 100,000 standard population to 14.0. As of yet, there are no clinically available biomarkers, laboratory tests, or imaging to assist in diagnosis or the identification of the suicidal individual. Suicide risk assessment remains a high-stakes component of the psychiatric evaluation and can lead to overly restrictive management in the name of prevention or to inadequate intervention because of poor appreciation of the severity of risk. This article focuses primarily on suicide risk assessment and management as a critical first step to prevention, given the fact that more research is needed to identify precision treatments and effective suicide prevention strategies. Suicide risk assessment provides the clinical psychiatrist with an opportunity for therapeutic engagement with the ultimate goals of relieving suffering and preventing suicide.

Natural surroundings in childhood are associated with lower schizophrenia rates.

High exposure to green space and natural environments has previously been associated with lower schizophrenia rates possibly through low air pollution and improved psychological restoration. Exposure to natural environments could explain the negative urban-rural gradient of schizophrenia, but it is unclear if all natural environments are associated with schizophrenia rates. We investigated the association between schizophrenia and growing up surrounded by environments classified as mainly urban, agricultural, near-natural green space, and blue space. Vegetation density and air pollution were assessed as potential pathways. We used the Danish population (943 027 people) and remotely-sensed environmental data to determine land cover exposure and vegetation density around each individual's residence. Effect sizes were estimated using Cox regression and adjusted for air pollution, socioeconomic status, and urbanization. Our results show that growing up surrounded by non-urban environments is associated with lower schizophrenia rates. Firstly, growing up surrounded by non-built-up areas (agricultural areas, near-natural green and blue space) is associated with lower schizophrenia rates compared to urban areas. Secondly, rates decrease with vegetation density in a dose-response relationship for urban and agricultural areas. Air pollution mitigation more strongly explained the protective association in near-natural green spaces, implying that restorative pathways together with air pollution mitigation may explain lower rates in natural environments. This study suggests that ensuring access to natural environments during childhood may be important for schizophrenia prevention, whilst being the first study to show that natural environments may influence schizophrenia rates through multiple pathways.

White Matter Connectivity in Youth at Risk for Serious Mental Illness: A Longitudinal Analysis.

Longitudinal changes in white matter connectivity were assessed in a sample of youth at-risk for serious mental illness (n=183; age 12-25). Diffusion tensor imaging (DTI) was acquired at baseline and 12 months from youth recruited across two sites and classified as healthy controls (n=36), familial risk (n=30), mild-symptoms (n=41), attenuated syndromes (n=70), or transition (n=9) based on clinical assessments. Fractional anisotropy (FA) and mean diffusivity (MD) values were derived for the whole brain white matter, forceps minor, anterior cingulate, anterior thalamic radiations, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and uncinate fasciculus. MANCOVA analysis controlling for site, sex, and age showed no significant group differences in FA and MD at baseline or at 12 months. Linear mixed effects analysis showed a significant effect for time for most white matter tracts, but no effect for group, or group by time interaction. Transdiagnostic risk groups have similar profiles of WM connectivity and similar rates of change over time.

The beneficial effects of a positive attention bias amongst children with a history of psychosocial deprivation.

Children raised in institutions experience psychosocial deprivation that has detrimental influences on attention and mental health. The current study examined patterns of attention biases in children from institutions who were randomized at approximately 21.6 months to receive either a high-quality foster care intervention or care-as-usual. At age 12, children performed a dot-probe task and indices of attention bias were calculated. Additionally, children completed a social stress paradigm and cortisol reactivity was computed. Children randomized into foster care (N=40) exhibited an attention bias toward positive stimuli but not threat, whereas children who received care-as-usual (N=40) and a never-institutionalized comparison group (N=47) showed no bias. Stability of foster care placement was related to positive bias, while instability of foster care placement was related to threat bias. The magnitude of the positive bias was associated with fewer internalizing problems and better coping mechanisms. Within the foster care group, positive attention bias was related to less blunted cortisol reactivity.

Broken heart syndrome -- is it a psychosomatic disorder?

OBJECTIVE: The development of somatoform illnesses is often associated with prior psychiatric illness and life stress. Broken heart syndrome has been associated with a range of stressors and we aimed to investigate if psychiatric illnesses are risk factors for developing broken heart syndrome. METHODS: We systematically assessed for antecedent psychiatric risk factors in two groups of cases (people who developed sporadic and earthquake-related broken heart syndrome) and compared them to a control group of healthy volunteers. RESULTS: We found that of the ten psychiatric risk factors examined, only 'neuroticism' significantly differed between participants with broken heart syndrome and healthy volunteers. CONCLUSION: There was no association between previous psychiatric illness and development of broken heart syndrome in this study. Clinical assessment of psychiatric risk factors may not identify patients at increased risk of broken heart syndrome.