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The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies. Using an immature rat model of FSE [experimental FSE (eFSE)], we administered dexamethasone (DEX), a broad anti-inflammatory agent, over 3 d following eFSE. We assessed eFSE-provoked hippocampal network hyperexcitability by quantifying the presence, frequency, and duration of hippocampal spike series, as these precede and herald the development of TLE-like epilepsy. We tested whether eFSE provoked hippocampal microgliosis, astrocytosis, and proinflammatory cytokine production in male and female rats and investigated blood-brain barrier (BBB) breaches as a potential contributor. We then evaluated whether DEX attenuated these eFSE sequelae. Spike series were not observed in control rats given vehicle or DEX, but occurred in 41.6% of eFSE-vehicle rats, associated with BBB leakage and elevated hippocampal cytokines. eFSE did not induce astrocytosis or microgliosis but provoked BBB disruption in 60% of animals. DEX significantly reduced spike series prevalence (to 7.6%) and frequency, and abrogated eFSE-induced cytokine production and BBB leakage (to 20%). These findings suggest that a short, postinsult intervention with a clinically available anti-inflammatory agent potently attenuates epilepsy-predicting hippocampal hyperexcitability, potentially by minimizing BBB disruption and related neuroinflammation.

Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'.

Corticotropin-releasing hormone (CRH) is an essential, evolutionarily-conserved stress neuropeptide. In addition to hypothalamus, CRH is expressed in brain regions including amygdala and hippocampus where it plays crucial roles in modulating the function of circuits underlying emotion and cognition. CRH+ fibers are found in nucleus accumbens (NAc), where CRH modulates reward/motivation behaviors. CRH actions in NAc may vary by the individual's stress history, suggesting roles for CRH in neuroplasticity and adaptation of the reward circuitry. However, the origin and extent of CRH+ inputs to NAc are incompletely understood. We employed viral genetic approaches to map both global and CRH+ projection sources to NAc in mice. We injected into NAc variants of a new designer adeno-associated virus that permits robust retrograde access to NAc-afferent projection neurons. Cre-dependent viruses injected into CRH-Cre mice enabled selective mapping of CRH+ afferents. We employed anterograde AAV1-directed axonal tracing to verify NAc CRH+ fiber projections and established the identity of genetic reporter-labeled cells via validated antisera against native CRH. We quantified the relative contribution of CRH+ neurons to total NAc-directed projections. Combined retrograde and anterograde tracing identified the paraventricular nucleus of the thalamus, bed nucleus of stria terminalis, basolateral amygdala, and medial prefrontal cortex as principal sources of CRH+ projections to NAc. CRH+ NAc afferents were selectively enriched in NAc-projecting brain regions involved in diverse aspects of the sensing, processing and memory of emotionally salient events. These findings suggest multiple, complex potential roles for the molecularly-defined, CRH-dependent circuit in modulation of reward and motivation behaviors.

BackgroundEarly life experiences have persisting influence on brain function throughout life. Maternal signals constitute a primary source of early life experiences, and their quantity and quality during sensitive developmental periods exert enduring effects on cognitive function and emotional and social behaviors. Here we examined if, in addition to established qualitative dimensions of maternal behavior during her interactions with her infant and child, patterns of maternal signals may contribute to the maturation of children's executive functions. We focused primarily on effortful control, a potent predictor of mental health outcomes later in life.MethodsIn two independent prospective cohorts in Turku, Finland (N = 135), and Irvine, CA, USA (N = 192) that differed significantly in race/ethnicity and sociodemographic parameters, we assessed whether infant exposure to unpredictable patterns of maternal-derived sensory signals portended poor effortful control.OutcomesIn both the Irvine and Turku cohorts, unpredictable sequences of maternal behavior during infancy were associated with worse effortful control at one year of age. Longitudinal analyses demonstrated that this association persisted for as long as each cohort was assessed-until two years of age in the Turku cohort and to 9.5 years in the Irvine cohort. The relation of unpredictable maternal signals during infancy and the measures of executive function persisted after adjusting for covariates.InterpretationsThe consistency of our findings across two cohorts from different demographic backgrounds substantiated the finding that patterns, and specifically unpredictable sequences, of maternal behaviors may influence the development of executive functions which may be associated with vulnerability to subsequent psychopathology. FUND: This research was supported by the National Institutes of Health (NIH) awards P50MH096889, HD051852, NS041298, HD02413, HD050662, HD065823, and by the FinnBrain funders: Academy of Finland (129839, 134950, 253270, 286829, 287908, 308176, 308252), Jane and Aatos Erkko Foundation, Signe and Ane Gyllenberg Foundation, Yrjö Jahnsson Foundation, and State Research Grants (P3498, P3654).

Abstract: The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early-life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function and cause opioid addiction vulnerability is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

Spatial memory, the aspect of memory involving encoding and retrieval of information regarding one's environment and spatial orientation, is a complex biological function incorporating multiple neuronal networks. Hippocampus-dependent spatial memory is not innate and emerges during development in both humans and rodents. In children, nonhippocampal dependent egocentric (self-to-object) memory develops before hippocampal-dependent allocentric (object-to-object) memory. The onset of allocentric spatial memory abilities in children around 22 mo of age occurs at an age-equivalent time in rodents when spatially tuned grid and place cells arise from patterned activity propagating through the entorhinal-hippocampal circuit. Neuronal activity, often driven by specific sensory signals, is critical for the normal maturation of brain circuits This patterned activity fine-tunes synaptic connectivity of the network and drives the emergence of specific firing necessary for spatial memory. Whereas normal activity patterns are required for circuit maturation, aberrant neuronal activity during development can have major adverse consequences, disrupting the development of spatial memory. Seizures during infancy, involving massive bursts of synchronized network activity, result in impaired spatial memory when animals are tested as adolescents or adults. This impaired spatial memory is accompanied by alterations in spatial and temporal coding of place cells. The molecular mechanisms by which early-life seizures lead to disruptions at the cellular and network levels are now becoming better understood, and provide a target for intervention, potentially leading to improved cognitive outcome in individuals experiencing early-life seizures.

Predictability of behavior is an important characteristic in many fields including biology, medicine, marketing, and education. When a sequence of actions performed by an individual can be modeled as a stationary time-homogeneous Markov chain the predictability of the individual’s behavior can be quantified by the entropy rate of the process. This article compares three estimators of the entropy rate of finite Markov processes. The first two methods directly estimate the entropy rate through estimates of the transition matrix and stationary distribution of the process. The third method is related to the sliding-window Lempel–Ziv compression algorithm. The methods are compared via a simulation study and in the context of a study of interactions between mothers and their children.

Mental illnesses originate early in life, governed by environmental and genetic factors. Because parents are a dominant source of signals to the developing child, parental signals - beginning with maternal signals in utero - are primary contributors to children's mental health. Existing literature on maternal signals has focused almost exclusively on their quality and valence (e.g. maternal depression, sensitivity). Here we identify a novel dimension of maternal signals: their patterns and especially their predictability/unpredictability, as an important determinant of children's neurodevelopment. We find that unpredictable maternal mood and behavior presage risk for child and adolescent psychopathology. In experimental models, fragmented/unpredictable maternal care patterns directly induce aberrant synaptic connectivity and disturbed maturation of cognitive and emotional brain circuits, with commensurate memory problems and anhedonia-like behaviors. Together, our findings across species demonstrate that patterns of maternal signals influence brain circuit maturation, promoting resilience or vulnerability to mental illness.

Increasing evidence indicates that, in addition to poverty, maternal depression, and other well-established factors, unpredictability of maternal and environmental signals early in life influences trajectories of brain development, determining risk for subsequent mental illness. However, whereas most risk factors for later vulnerability to mental illness are readily measured using existing, clinically available tools, there are no similar measures for assessing early-life unpredictability. Here we validate the Questionnaire of Unpredictability in Childhood (QUIC) and examine its associations with mental health in the context of other indicators of childhood adversity (e.g., traumatic life events, socioeconomic status, and parenting quality). The QUIC was initially validated through administration to a cohort of adult females (N = 116) and then further refined in two additional independent cohorts (male Veterans, N = 95, and male and female adolescents, N = 175). The QUIC demonstrated excellent internal (α = 0.89) and test-retest reliability (r = 92). Scores on the QUIC were positively correlated with other prospective indicators of exposures to unpredictable maternal inputs in infancy and childhood (unpredictable maternal mood and sensory signals), and accuracy of recall also was confirmed with prospective data. Importantly, the QUIC predicted symptoms of anxiety, depression, and anhedonia in the three study cohorts, and these effects persisted after adjusting for other previously established risk factors. The QUIC, a reliable and valid self-report assessment of exposure to unpredictability in the social, emotional, and physical domains during early life, is a brief, comprehensive, and promising instrument for predicting risk for mental illness.

Genetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an "epigenetic signature" of early-life experiences. Here, we used a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular metabolic enzymes, ion channels, and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate-related transcription factors, indicating their potential up-regulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth, and function.

Hippocampal inhibitory interneurons comprise an anatomically, neurochemically and electrophysiologically diverse population of cells that are essential for the generation of the oscillatory activity underlying hippocampal spatial and episodic memory processes. Here, we aimed to characterize a population of interneurons that express the stress-related neuropeptide corticotropin-releasing hormone (CRH) within existing interneuronal categories through the use of combined electrophysiological and immunocytochemical approaches. Focusing on CA1 strata pyramidale and radiatum of mouse hippocampus, CRH interneurons were found to exhibit a heterogeneous neurochemical phenotype with parvalbumin, cholecystokinin and calretinin co-expression observed to varying degrees. In contrast, CRH and somatostatin were never co-expressed. Electrophysiological categorization identified heterogeneous firing pattern of CRH neurons, with two distinct subtypes within stratum pyramidale and stratum radiatum. Together, these findings indicate that CRH-expressing interneurons do not segregate into any single distinct subtype of interneuron using conventional criteria. Rather our findings suggest that CRH is likely co-expressed in subpopulations of previously described hippocampal interneurons. In addition, the observed heterogeneity suggests that distinct CRH interneuron subtypes may have specific functional roles in the both physiological and pathophysiological hippocampal processes.

The genotype of the SARS-CoV-2 virus pathogen plays an important role in the epidemiological and clinical characteristics of a new coronovirus infection. There are no published data on the morphological features of lesions caused by different virus genotypes.The aim of the study was to evaluate clinical, laboratory and morphological changes depending on the genotype of the SARS-CoV-2 virus.Materials and methods. A retrospective analysis of the medical records of 39 patients with COVID-19 with a severe course of the disease, which ended in death, who were hospitalized at the St. Petersburg State Budgetary Infectious Diseases Clinical Hospital named after S.P. Botkin” in 20202022. Clinical and laboratory characteristics were assessed, including determination of the virus genotype, levels of leukocytes, lymphocytes, alanine aminotransferase, creatinine, ferritin, C-reactive protein, D-dimer, interleukin-6. Macro- and microscopic changes were assessed, including immunohistochemical examination of the lungs and other organs using sera to CD14 68, 163, type 1 and 3 collagen. The preparations were digitized on a Panoramic scanner, morphometric studies were carried out using the SlideViewer program, including the quantitative determination of the content of CD68+ macrophages in 12 cases.Results. In all patients, the disease was complicated by the development of pneumonia, the majority had concomitant diseases (94.6%). The average time of hospitalization was 19.0±1.6 days, the average time of stay in the intensive care unit was 7.7±1.2 days. The analysis, depending on the genotype of the SARS-CoV-2 virus, showed a statistical difference between the age of patients, the length of stay in the intensive care unit and the level of lymphocytes. Differences in the average duration of hospitalization, the level of laboratory parameters were not revealed. Histopathological picture in all examined was approximately the same. The content of CD68+ macrophages per unit area in different genotypes did not differ, but varied significantly within the same genotype.Conclusion. Thus, it was not possible to identify significant differences between the changes caused by different genotypes of the new coronavirus, which can probably be explained by the fact that mutations do not include genome regions that are relevant to virulence factors, although further research is needed.

Numerous studies have explored internal factors such as cultural values and acquired knowledge accounting for how people engage with science. However, it remains unclear how external factors embedded in science texts relate to audience engagement. A content analysis of 298 text-based popular science news articles and their following 5852 reader comments was conducted in two Israeli audiences, science-minded and general readers, to explore how the accessibility strategies embedded in these articles relate to cognitive, affective, and behavioral engagement. Findings indicated similar patterns of relationship between accessibility strategies and engagement expressions for both audiences; however, the relationships were more pronounced for general readers compared to science-minded readers. Using jargon and a narrative writing style increased the odds of positive emotions in reader comments, whereas addressing socio-scientific issues increased the odds of cognitive expressions. These results may contribute to a fuller understanding of ways to drive meaningful public engagement. [ABSTRACT FROM AUTHOR]

In this response, we summarize the affirmations, extensions, and critiques of the framework for science communication training that we presented in Lewenstein and Baram-Tsabari (2022. How should we organize science communication trainings to achieve competencies? International Journal of Science Education – Part B: Communication and Public Engagement, 12(4), 289–308. https://doi.org/10.1080/21548455.2022.2136985). We ask how the comments collected in this special issue can, at a practical level, help push our field forward, increasing long-term promise for science communication. To address this question, we have posted online a version of our original framework, and we invite the community to co-create a refined version of the document. [ABSTRACT FROM AUTHOR]

Background: Congenital craniovertebral junction anomalies (CCVJAs) encompass a diverse range of conditions characterized by distorted anatomy and significant variation in the pathways of neurovascular structures. This study aims to assess the safety and feasibility of tailoring posterior fixation for CCVJAs through intraoperative CT-based navigation. Methods: An in-depth retrospective analysis was conducted on eight patients diagnosed with CCVJAs (excluding Arnold–Chiari malformation). These patients underwent posterior fixation/arthrodesis facilitated by intraoperative CT-based navigation. The analysis included an examination of the fixation strategies, complication rates, length of stay, post-operative complications, and success of arthrodesis. Additionally, a comprehensive literature review was undertaken to contextualize and compare our findings. Results: Patients undergoing CVJ posterior fixation with intraoperative CT-based navigation exhibited a flawless record, devoid of complications related to the damage to neurovascular structures, as well as any instances of screw misposition, pullout, or breakage (0 out of 36 total screws). Furthermore, the entire cohort demonstrated a 100% arthrodesis rate. None of the patients required treatment with an occipital plate. Conclusions: The incorporation of intraoperative CT-based navigation proves to be an invaluable asset in executing CVJ posterior fixation within the context of CCVJAs. This technology facilitates the customization of posterior constructs, a crucial adaptation required to navigate the anatomical challenges posed by these anomalies. The secure placement of screws into the occipital condyles, made possible by navigation, has proven highly effective in achieving CVJ fixation, obviating the need for an occipital plate. This technological leap represents a significant advancement, enhancing the safety, precision, and overall outcomes for patients undergoing this surgical procedure, while concurrently reducing the necessity for more invasive and morbid interventions. [ABSTRACT FROM AUTHOR]

Background/Objectives: Postoperative cerebrospinal fluid (CSF) fistulas remain a significant concern in spinal neurosurgery, particularly following dural closure. The incidence of dural tears during spinal surgery is estimated between 1.6% and 10%. While direct suturing remains the gold standard, it has a failure rate of 5–10%. Various materials and techniques have been used to enhance dural closure. This study aims to assess the effectiveness of non-penetrating titanium clips (AnastoClip®) for dural closure in intradural spinal lesion surgeries. Methods: A prospective analysis was conducted on 272 patients who were operated on for intradural spinal lesions from August 2017 to December 2023. Dural closure was performed using non-penetrating titanium clips with sealant, and, in select cases, autologous grafts. Postoperative care included early mobilization and routine MRI to assess outcomes. A comparative analysis was performed with a cohort of 81 patients treated with traditional sutures. Results: Among the 272 patients, postoperative CSF leaks occurred in 32 cases (11.76%), requiring various management approaches. Thirteen cases required surgical revision, while others resolved with external lumbar drainage or fluid aspiration. Compared to the suture group, which had a fistula rate of 23.46%, the titanium clip group had a significantly lower fistula rate. Logistic regression analysis did not find statistically significant associations between fistula risk and clinical factors. Conclusions: Non-penetrating titanium clips provide an effective alternative to sutures for dural closure, reducing CSF leak rates. They preserve dural integrity, reduce operative time, and avoid imaging artifacts, making them a viable advancement in spinal surgery with outcomes comparable to, or better than, traditional techniques. [ABSTRACT FROM AUTHOR]

This theoretical paper focuses on the social processes of public engagement with science and their implications for science education. The core of our argument is that science education should help people become better at evaluating, using, and curating their epistemic networks to make personal and civic decisions and to understand the natural world. In this context, an epistemic network is a set of people who support sensemaking by providing new information and aiding in the interpretation and reconstruction of scientific knowledge in context. We believe epistemic networks are an important consideration for science education, particularly when misinformation plays an outsized role in the cultural landscape. Understanding when epistemic networks are useful and how science education should incorporate them requires a clear sense of how they work in different contexts. We start by contrasting the inevitably social nature of all public engagement with science with the particularly social or interpersonal nature of some public engagement with science. We draw on research from education, communication, and science and technology studies to develop the idea of an epistemic network and to describe two basic types: the individual resource network and the collective action network. We illustrate each type with an extended example that is hypothetical but informed by both research and experience. Finally, we discuss how science education can incorporate epistemic networks, as well as the challenges inherent in that educational strategy. [ABSTRACT FROM AUTHOR]

Recent conceptualizations of science literacy, a key aim of contemporary science education, suggest defining it as a function of actual uses of science in daily life. We characterize expressions of science literacy in online authentic public discourse, using content analysis of a year's worth of widely-read Israeli online news site coverage of animal experimentation and its reader comments, we explore how expressions of science literacy interact with coverage. The national Israeli science-curricula were used as an analytical framework, including scientific knowledge, nature of science (NOS), and inquiry skills. The findings indicate that over half of the scientific concepts used by the commentators are at the high school or academic level, in which science is elective. There were strong correlations (r = 0.96) between the level of overall science concepts used in the articles and reader comments. Comments supporting animal experimentation employed more and higher level of scientific concepts. Contrasting positions were supported by different types of NOS content: opponents of animal experimentation referred more to the social aspects of NOS, echoing differences in worldviews and lack of trust in scientists. We suggest that enabling informed public engagement with science requires explicit integration of investigative and social aspects of the nature of science.

Certain science-related topics elicit persistent public controversy, such as routine childhood vaccinations and anthropogenic climate change. Many people are misinformed about the scientific facts underlying these issues. In response, science educators have called for improvements in the public's science literacy, but it is not clear which components of science literacy would help individuals identify misinformation. In this position paper, we examine this issue and make two arguments. First, we unpack the construct of science literacy to the seven components identified by the National Academies, and argue that four of these components are most likely to help individuals identify misinformation in everyday life: (a) Understanding of scientific practices; (b) Identifying and judging appropriate scientific expertise, (c) Epistemic knowledge, and (d) Dispositions and habits of mind, for example, inquisitiveness and open-mindedness. We also show that three of these four components are not commonly used in definitions of science literacy. Second, we posit that two opposite reasons explain why misinformation is so intractable: on the one hand, that individuals uncritically accept most information, even if it is false, and on the other hand, that they reject information that contradicts their worldview, even if it is true. Consequently, we argue that inculcating intellectual virtues, such as open-mindedness, should be central to imparting science literacy and propose some implications for educational practice. Lastly, we point out some limitations of our arguments and offer recommendations for further research.

Early-life experiences influence brain structure and function long-term, contributing to resilience or vulnerability to stress and stress-related disorders. Therefore, understanding the mechanisms by which early-life experiences program specific brain cells and circuits to shape life-long cognitive and emotional functions is crucial. We identify the population of corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) as a key, early target of early-life experiences. Adverse experiences increase excitatory neurotransmission onto PVN CRH cells, whereas optimal experiences, such as augmented and predictable maternal care, reduce the number and function of glutamatergic inputs onto this cell population. Altered synaptic neurotransmission is sufficient to initiate large-scale, enduring epigenetic re-programming within CRH-expressing neurons, associated with stress resilience and additional cognitive and emotional outcomes. Thus, the mechanisms by which early-life experiences influence the brain provide tractable targets for intervention.

ObjectiveA subset of children with febrile status epilepticus (FSE) are at risk for development of temporal lobe epilepsy later in life. We sought a noninvasive predictive marker of those at risk that can be identified soon after FSE, within a clinically realistic timeframe.MethodsLongitudinal T2 -weighted magnetic resonance imaging (T2 WI MRI) of rat pups at several time points after experimental FSE (eFSE) was performed on a high-field scanner followed by long-term continuous electroencephalography. In parallel, T2 WI MRI scans were performed on a 3.0-T clinical scanner. Finally, chronic T2 WI MRI signal changes were examined in rats that experienced eFSE and were imaged months later in adulthood.ResultsEpilepsy-predicting T2 changes, previously observed at 2 hours after eFSE, persisted for at least 6 hours, enabling translation to the clinic. Repeated scans, creating MRI trajectories of T2 relaxation times following eFSE, provided improved prediction of epileptogenesis compared with a single MRI scan. Predictive signal changes centered on limbic structures, such as the basolateral and medial amygdala. T2 WI MRI changes, originally described on high-field scanners, can also be measured on clinical MRI scanners. Chronically elevated T2 relaxation times in hippocampus were observed months after eFSE in rats, as noted for post-FSE changes in children.SignificanceEarly T2 WI MRI changes after eFSE provide a strong predictive measure of epileptogenesis following eFSE, on both high-field and clinical MRI scanners. Importantly, the extension of the acute signal changes to at least 6 hours after the FSE enables its inclusion in clinical studies. Chronic elevations of T2 relaxation times within the hippocampal formation and related structures are common to human and rodent FSE, suggesting that similar processes are involved across species.

Increasing evidence indicates that, in addition to poverty, maternal depression and other well-established factors, unpredictability of maternal and environmental signals early in life influences trajectories of brain development, determining risk for subsequent mental illness. However, whereas most risk factors for later vulnerability to mental illness are readily measured using existing, clinically available tools, there are no similar measures for assessing early-life unpredictability. Here we validate the Questionnaire of Unpredictability in Childhood (QUIC) and examine its associations with mental health in the context of other indicators of childhood adversity (e.g. traumatic life events, socioeconomic status and parenting quality). The QUIC was initially validated through administration to a cohort of adult females (N = 116) and then further refined in two additional independent cohorts (male Veterans, N = 95, and male and female adolescents, N = 175). The QUIC demonstrated excellent internal (α = .89) and test-retest reliability (r = 92). Scores on the QUIC were positively correlated with other prospective indicators of exposures to unpredictable maternal inputs in infancy and childhood (unpredictable maternal mood and sensory signals), and accuracy of recall also was confirmed with prospective data. Importantly, the QUIC predicted symptoms of anxiety, depression and anhedonia in the three study cohorts, and these effects persisted after adjusting for other previously established risk factors. The QUIC, a reliable and valid self-report assessment of exposure to unpredictability in the social, emotional and physical domains during early life, is a brief, comprehensive and promising instrument for predicting risk for mental illness.

Adolescence is a complex period of concurrent mental and physical development that facilitates adult functioning at multiple levels. Despite the growing number of neuroimaging studies of cognitive development in adolescence focusing on regional activation patterns, there remains a paucity of information about the functional interactions across these participating regions that are critical for cognitive functioning, including memory. The current study used structural equation modeling (SEM) to determine how interactions among brain regions critical for memory change over the course of adolescence. We obtained functional MRI in 77 individuals aged 8-16 years old, divided into younger (ages 8-10) and older (ages > 11) cohorts, using an incidental encoding memory task to activate hippocampus formation and associated brain networks, as well as behavioral data on memory function. SEM was performed on the imaging data for four groups (younger girls, younger boys, older girls, and older boys) that were subsequently compared using a stacked model approach. Significant differences were seen between the models for these groups. Younger boys had a predominantly posterior distribution of connections originating in primary visual regions and terminating on multi-modal processing regions. In older boys, there was a relatively greater anterior connection distribution, with increased effective connectivity within association and multi-modal processing regions. Connection patterns in younger girls were similar to those of older boys, with a generally anterior-posterior distributed network among sensory, multi-modal, and limbic regions. In contrast, connections in older girls were widely distributed but relatively weaker. Memory performance increased with age, without a significant difference between the sexes. These findings suggest a progressive reorganization among brain regions, with a commensurate increase in efficiency of cognitive functioning, from younger to older individuals in both girls and boys, providing insight into the age- and gender-specific processes at play during this critical transition period.

OBJECTIVE:The authors sought to assess associations among early-life exposure to adversity, the development and maturation of neurons and brain circuits, and neurodevelopmental outcomes. Specifically, they examined whether fetal exposure to placental corticotropin-releasing hormone (CRH), a molecule conveying maternal signals to the fetus, predicts brain growth and neuropsychiatric outcomes in school-age children. METHOD:In a large, well-characterized prospective cohort, concentrations of placental CRH (pCRH) in maternal plasma were determined during five intervals during gestation. When the children reached school age, their brain structures were examined using MRI, and emotional and cognitive tests assessing internalizing and externalizing behaviors and attention were administered (N=97, 49 of them girls). RESULTS:Levels of pCRH during gestation predicted structural and functional brain outcomes in children. Specifically, fetal exposure to elevated pCRH levels was associated with thinning of selective cortical regions and with commensurate cognitive and emotional deficits. The relations among fetal exposure to pCRH, cortical thinning, and childhood function were sex specific. CONCLUSIONS:In view of the established effects of CRH on maturation and arborization of cortical neurons, and the major contribution of dendrites to cortical volume, these findings position pCRH as an important mediator of the consequences of early-life adversity on neuropsychiatric outcomes.

Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain.

BackgroundThis study quantifies the dynamics of maternal mood focusing on unpredictability, and to assess ifgreater unpredictability of prenatal maternal mood predicts child temperament and internalizingsymptoms through early adolescence.MethodsThe association between prenatal mood predictability and child internalizing symptoms were assessedin two longitudinal cohorts (N’s = 227 and 180). Maternal mood was assessed repeatedly duringpregnancy as early as 15 weeks’ gestation. Predictability of maternal mood was calculated by applyingShannon’s entropy to the distribution of responses on mood questionnaires. Maternal reports of childnegative affectivity (a predictor of later internalizing) were collected at 6, 12, 24 months and 7 years ofage. Child self-reports of anxiety symptoms were collected at 10 years and reports of depressionsymptoms at 13 years.ResultsFetal exposure to more elevated maternal mood entropy predicted higher levels of child negativeaffectivity at 12 months (r = .36; p < 01), 24 months (r = .31; p < 01) and 7 years (r = .32; p < 01) of age.In addition, children exposed to higher prenatal maternal mood entropy, reported higher levels ofanxiety symptoms at 10 years (r = .24; p < 01) and elevated depressive symptoms at 13 years (r = .29; p< .01). These associations persisted after adjusting for maternal pre and postnatal mood valence (e.g.depression levels) and for other relevant demographic characteristics.ConclusionsOur findings provide strong support for the notion that patterns of maternal mood influence thedeveloping brain. More specifically, they suggest that prenatal maternal mood predictability may be acritical predictor of developmental mental health trajectories and should be considered whenassessing early life influences on lifespan mental health.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

BackgroundSleeve gastrectomy is a relatively new procedure that developed as a result of rapid innovation in the field of bariatric surgery. As with any newly developed operation, there is a learning curve that potentially can be associated with higher morbidity. Real-time surgical mentoring reduces the learning curve effect but can be time intensive for the mentor. The aim of this initiative was to evaluate the feasibility, effectiveness, and satisfaction of surgical telementoring for laparoscopic sleeve gastrectomy. This is the first national specialty society effort to determine if the "remote presence" of an expert surgeon (mentor) can help practicing surgeons improve skills.MethodsThe experience of 15 surgical trainees (mentees) who performed laparoscopic sleeve gastrectomy under real-time telementoring by 7 mentors was reviewed. Telementoring was implemented using the Visitor1® remote presence system with two-way live audio and video communication. The receiving platform utilized a conventional laptop, iPad, or iPhone. The mentee followed a structured telementoring program including didactic learning, live case teleobservation, and telementoring of 2-3 cases. A survey on the quality of the telecommunication and effectiveness of the mentoring was performed by the mentor and mentee on a scale of "exceeded," "met," "almost met," or "failed to meet" expectations. The overall telementoring experience was rated on a scale of 1 for "poor" to 5 for "excellent."ResultsBased on the mentees' survey, the overall telementoring experience was rated as 4.8. Despite the mentees having experience with laparoscopic sleeve gastrectomy, most commented that the telementoring experience was an excellent educational tool and they learned some new techniques they plan to apply it in their practice. Based on the mentors' survey, the overall telementoring experience was rated as 4.7. All mentors stated that they were satisfied with the telementoring sessions and there were no unexpected intraoperative occurrences. There were some logistical limitations including difficulties in scheduling of cases or the delay of cases.ConclusionsSurgical instruction by telementoring was shown to be feasible, practical, and successful, and was highly rated in this study by both the mentors and mentees. The currently utilized telementoring platform is thus an effective educational tool that can facilitate acquisition of surgical skills and assist with the conventional on-site surgical mentoring model.

Early-life adversity increases the risk for emotional disorders such as depression and schizophrenia. Anhedonia, thought to be a core feature of these disorders, is provoked by our naturalistic rodent model of childhood adversity (i.e., rearing pups for one week in cages with limited bedding and nesting, LBN). Drug use and addiction are highly comorbid with psychiatric disorders featuring anhedonia, yet effects of LBN on drug-seeking behavior and the reward and stress-related circuits that underlie it remain unknown. Here we examined the effects of LBN on cocaine intake and seeking, using a battery of behavioral tests measuring distinct aspects of cocaine reward, and for comparison, chocolate intake. We also examined activation of neurons within the pleasure/reward and stress circuits following cocaine in LBN and control rats. Early-life adversity reduced spontaneous intake of palatable chocolate, extending prior reports of sucrose and social-play anhedonia. In a within-session cocaine behavioral economic test, LBN rats self-administered lower dosages of cocaine under low-effort conditions, consistent with a reduced hedonic set-point for cocaine, and potentially anhedonia. In contrast, cocaine demand elasticity was not consistently affected, indicating no major changes in motivation to maintain preferred cocaine blood levels. These changes were selective, as LBN did not cause an overt anxiety-like phenotype, nor did it affect sensitivity to self-administered cocaine dose, responding for cocaine under extinction conditions, cocaine- or cue-induced reinstatement of cocaine seeking, or locomotor response to acute cocaine. However, high Fos expression was seen after cocaine in both reward- and stress-related brain regions of LBN rats, including nucleus accumbens core, central amygdala, and lateral habenula. In contrast, hypothalamic orexin neuron activation after cocaine was significantly attenuated in LBN rats. Together, these findings demonstrate enduring effects of early-life adversity on both reward- and fear/anxiety-related neural circuits, as well as anhedonia-like reductions in consumption of natural and drug rewards.