Storm Clouds and Silver Linings: Day-to-Day Life in COVID-19 Lockdown and Emotional Health in Adolescent Girls.

OBJECTIVE: We examined risk and protective factors for emotional health problems in adolescent girls during the COVID-19 pandemic. We investigated pre- to early-pandemic changes in symptoms of anxiety and depression, documented daily activities and perceived positive and negative impacts of the pandemic, and linked perceived positive and negative impacts of the pandemic to real-time changes in emotional health. METHODS: The study was a 10-day daily diary study with 93 U.S. adolescent girls (aged 12-17; 68% White non-Hispanic) at temperamental risk for anxiety and depression, conducted in April/May 2020 when all participants were under state-issued stay-at-home orders. Girls provided daily reports of positive and negative affect, depressive and anxious symptoms, activities, and positive and negative impacts resulting from the pandemic. RESULTS: Girls reported engaging in many activities that may contribute to well-being. Mixed effects analyses revealed positive impacts associated with improved same-day emotional health such as more time for family and relaxation and reduced pressure from school/activities. Negative impacts associated with poorer same-day emotional health included problems with online schooling, lack of space/privacy, lack of a regular schedule, and family conflict. CONCLUSION: Findings highlight the importance of providing in-person or quality online schooling, resources and space for learning, promoting daily routines, and spending time with teens while reducing family conflict. The pandemic also appears to have offered many girls a respite from the chronic stress of modern teen life, with time to relax and engage in creative and healthy pursuits showing benefits for daily emotional health, which should be considered following the return to normal life.

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy⋅s-1). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy⋅s-1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

Cytokines IL-1ß and IL-10 are required for Müller glia proliferation following light damage in the adult zebrafish retina.

Zebrafish possess the ability to regenerate dying neurons in response to retinal injury, with both Müller glia and microglia playing integral roles in this response. Resident Müller glia respond to damage by reprogramming and undergoing an asymmetric cell division to generate a neuronal progenitor cell, which continues to proliferate and differentiate into the lost neurons. In contrast, microglia become reactive, phagocytose dying cells, and release inflammatory signals into the surrounding tissue following damage. In recent years, there has been increased attention on elucidating the role that microglia play in regulating retinal regeneration. Here we demonstrate that inflammatory cytokines are differentially expressed during retinal regeneration, with the expression of a subset of pro-inflammatory cytokine genes upregulated shortly after light damage and the expression of a different subset of cytokine genes subsequently increasing. We demonstrate that both cytokine IL-1ß and IL-10 are essential for Müller glia proliferation in the light-damaged retina. While IL-1ß is sufficient to induce Müller glia proliferation in an undamaged retina, expression of IL-10 in undamaged retinas only induces Müller glia to express gliotic markers. Together, these findings demonstrate the essential role of inflammatory cytokines IL-1ß and IL-10 on Müller glia proliferation following light damage in adult zebrafish.

An Exposure-Based Video Game (Dr. Zoo) to Reduce Needle Phobia in Children Aged 3 to 6 Years: Development and Mixed Methods Pilot Study.

BACKGROUND: Needle phobia, which affects 19% of children aged 4 to 6 years, prevents many children from receiving necessary or preventive medical treatments. Digital interventions have been made to target needle phobia but currently rely on distraction rather than evidence-based exposure. OBJECTIVE: We designed and evaluated a serious exposure-based mobile game called Dr. Zoo to reduce the fear of needles in children aged 3 to 6 years, where players administered shots to cartoon animals. METHODS: We conducted a mixed methods study with 30 parents (mean age 35.87, SD 4.39 years) and their 36 children (mean age 4.44, SD 1.11 years) who played the game for 5 days leading to a scheduled appointment that included an injection (eg, influenza vaccination). After the study, parents completed exit surveys and participated in semistructured interviews to evaluate ease of use, acceptability, and preliminary effectiveness of the game and to provide insights on their experience with the game to inform future developments. Interview transcripts were analyzed by 3 independent coders following an open coding process and subsequently coded and discussed to reach consensus. RESULTS: Parents rated their child's difficulty in completing the game as very low on average (scale 1-5; mean 1.76, SD 0.82) and were highly likely to recommend Dr. Zoo to other parents (scale 1-5; mean 4.41, SD 0.87), suggesting Dr. Zoo's strong ease of use and high acceptability. In the exit survey, parents rated their child's fear as significantly lower after participating in the study (scale 1-5; mean 3.09, SD 1.17) compared with that before participating (scale 1-5; mean 4.37, SD 0.81; z score=-4.638; P<.001). Furthermore, 74% (26/35) of the parents reported that the game had a positive impact on their child's fear or perception of needles (only 2 parents reported a negative impact). Qualitative analysis of the interview transcripts revealed potentially important features of the game in this positive impact, such as the game's interactive design, as observed in 69% (24/35) of our participants. CONCLUSIONS: The results suggest that an evidence-based serious mobile game can be an easy-to-use, acceptable, and potentially effective intervention for changing young children's fear and perceptions of needles. Leveraging digital interventions may be a potential solution to needle anxiety as a public health concern.

Peer Connectedness and Social Technology Use During COVID-19 Lockdown.

During the COVID-19 pandemic lockdown, adolescents relied on social technology for social connection. Although some research suggests small, negative effects for quantity of social technology use on adolescent mental health, the quality of the interaction may be more important. We conducted a daily diary study in a risk-enriched sample of girls under COVID-19 lockdown to investigate associations between daily social technology use, peer closeness, and emotional health. For 10 days, 93 girls (ages 12-17) completed an online daily diary (88% compliance) assessing positive affect, symptoms of anxiety and depression, peer closeness, and daily time texting, video-chatting and using social media. Multilevel fixed effects models with Bayesian estimation were conducted. At the within-person level, more daily time texting or video-chatting with peers was associated with feeling closer to peers that day, which was associated with more positive affect and fewer depressive and anxiety symptoms that day. At the between-person level, more time video-chatting with peers across the 10 days was indirectly associated with higher average positive affect during lockdown and less depression seven-months later, via higher mean closeness with peers. Social media use was not associated with emotional health at the within- or between-person levels. Messaging and video-chatting technologies are important tools for maintaining peer connectedness during social isolation, with beneficial effects on emotional health.

Picture Perfect During a Pandemic? Body Image Concerns and Depressive Symptoms in U.S. Adolescent Girls During the COVID-19 Lockdown.

The stay-at-home orders of the COVID-19 pandemic disrupted U.S. adolescents' lives in numerous ways during the spring of 2020, including substantial changes to in-person routines and increased reliance on digital media. For adolescent girls, stay-at-home practices may have implications for body image concerns. In this research brief, we examine adolescent girls' pandemic-related body image concerns and longitudinal associations with depressive symptoms. The sample included 93 U.S. adolescent girls (M age = 15.01; 68.8% White), with approximately 2/3 at temperamental risk for depression. Participants self-reported their depressive symptoms and pandemic-related body image concerns via online surveys at three assessments: Time 1 occurred in April/May 2020, approximately one month into stay-at-home orders, followed by two-week and seven-month follow-up assessments. Two pandemic-related body image concerns were assessed: (1) concerns about disrupted appearance-management routines and (2) evaluating one's appearance on video-chat. Both forms of pandemic-related body image concerns predicted depressive symptoms two weeks later, and concerns about disrupted routines also predicted depressive symptoms seven months later. In an era of social distancing, frequent technology-based interactions, and disrupted routines, future work should continue to investigate adolescents' body image concerns and the implications for longer-term mental health outcomes.

Sex-Specific Effects of a Wartime-Like Radiation Exposure on Cognitive Function.

Evaluating the risk for central nervous system (CNS) effects after whole-body or partial-body irradiation presents challenges due in part to the varied exposure scenarios in the context of occupational, accidental or wartime releases. Risk estimations are further complicated by the fact that robust changes in brain function are unlikely to manifest until significantly late post exposure times. Collectively, the current data regarding CNS radiation risk are conflicting in humans and a survey of the animal model data shows that it is similarly inconsistent. Due to the sparseness of such data, the current study was conducted using male and female mice to evaluate the brain for the delayed effects of a 2 Gy whole-body exposure to c rays starting six months postirradiation. Behavioral testing indicated sex-specific differences in the induction of anxiety-like behaviors and in the ability to abolish fear memories. Molecular analyses showed alterations in post-synaptic protein levels that might affect synaptic plasticity and increased levels of global DNA methylation, suggesting a potential epigenetic mechanism that might contribute to radiation-induced cognitive dysfunction. These data add to the understanding of the CNS response to whole-body irradiation and may lead to improved risk assessment and provide guidance in the development of effective radiation countermeasures to protect military personnel and civilians alike.

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain.

Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation.

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments.

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189.

Clinical management of primary and secondary central nervous system (CNS) malignancies frequently includes radiotherapy to forestall tumor growth and recurrence after surgical resection. While cranial radiotherapy remains beneficial, adult and pediatric brain tumor survivors suffer from a wide range of debilitating and progressive cognitive deficits. Although this has been recognized as a significant problem for decades, there remains no clinical recourse for the unintended neurocognitive sequelae associated with these types of cancer treatments. In previous work, multiple mechanisms have been identified that contribute to radiation-induced cognitive dysfunction, including the inhibition of neurogenesis caused by the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. To explore the potential neuroprotective properties of a pro-neurogenic compound NSI-189, Long-Evans rats were subjected to a clinically relevant fractionated irradiation protocol followed by four weeks of NSI-189 administered daily by oral gavage. Animals were then subjected to five different behavioral tasks followed by an analysis of neurogenesis, hippocampal volume and neuroinflammation. Irradiated cohorts manifested significant behavioral decrements on all four spontaneous exploration tasks. Importantly, NSI-189 treatment resulted in significantly improved performance in four of these tasks: novel place recognition, novel object recognition, object in place and temporal order. In addition, there was a trend of improved performance in the contextual phase of the fear conditioning task. Importantly, enhanced cognition in the NSI-189-treated cohort was found to persist one month after the cessation of drug treatment. These neurocognitive benefits of NSI-189 coincided with a significant increase in neurogenesis and a significant decrease in the numbers of activated microglia compared to the irradiated cohort that was given vehicle alone. The foregoing changes were not accompanied by major changes in hippocampal volume. These data demonstrate that oral administration of a pro-neurogenic compound exhibiting anti-inflammatory indications could impart long-term neurocognitive benefits in the irradiated brain.