Disproportionate neuroanatomical effects of DCC haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice.

BACKGROUND: Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced DCC on neuroanatomy in the adolescent and adult mouse brain. METHODS: We examined neuronal connectivity, structural covariance, and molecular processes in a DCC-haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute. RESULTS: We included 11 DCC-haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of DCC haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that DCC haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of DCC, UNC5C (encoding DCC's co-receptor), and NTN1 (encoding its ligand, netrin-1) as underlying our structural findings. LIMITATIONS: Our study involved a single sex (males) at only 2 ages. CONCLUSION: The neuroanatomical phenotype of DCC haploinsufficiency described in mice parallels that observed in DCC-haploinsufficient humans. It is critical to understand the DCC-haploinsufficient mouse as a clinically relevant model system.

MicroRNA regulation of prefrontal cortex development and psychiatric risk in adolescence.

In this review, we examine the role of microRNAs in the development of the prefrontal cortex (PFC) in adolescence and in individual differences in vulnerability to mental illness. We describe results from clinical and preclinical research indicating that adolescence coincides with drastic changes in local microRNA expression, including microRNAs that control gene networks involved in PFC and cognitive refinement. We highlight that altered levels of microRNAs in the PFC are associated with psychopathologies of adolescent onset, notably depression and schizophrenia. We show that microRNAs can be measured non-invasively in peripheral samples and could serve as longitudinal physiological readouts of brain expression and psychiatric risk in youth.

Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children.

Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.

Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth.

Adolescence is a period of increased exploration and novelty-seeking, which includes new social behaviors, as well as drug experimentation, often spurred on by peer pressure. This is unfortunate, as the immature state of the adolescent brain makes it particularly susceptible to the negative developmental impact of drug use. During adolescence, dopamine terminals, which have migrated from the ventral tegmental area, pause in the nucleus accumbens, before segregating by either forming local connections or growing towards the prefrontal cortex (PFC). This developmentally late and lengthy process renders adolescent dopamine axon pathfinding vulnerable to disruption by substance use. Indeed, exposure to stimulant drugs in adolescent male mice, but not females, triggers dopamine axons to mistarget the nucleus accumbens and to grow ectopically to the PFC. Some evidence suggests that at this novel site, the functional organization of the ectopic dopamine axons mirrors that of the intended target. The structural rewiring dysregulates local synaptic connectivity, leading to poor impulse control ability, deficits of which are a core symptom of substance-use disorders. In the present commentary, we argue that different substances of abuse induce dopamine mistargeting events with the off-target trajectory prescribed by the type of drug, leading to psychiatric outcomes later in life.

Skin Tone, Discrimination, and Allostatic Load in Middle-Aged and Older Puerto Ricans.

OBJECTIVE: A growing body of research suggests that skin tone may be a health risk indicator for Hispanics. Black and darker-skinned Hispanics have worse mental and physical outcomes than White and lighter-skinned Hispanics. Discrimination exposure has been implicated as a risk factor that may explain the association between skin tone and health. However, there is scant research examining the interrelationship between skin tone, discrimination, and health, particularly among Puerto Ricans. We examine the interrelationships between two measures of skin tone, two measures of discrimination, and allostatic load (AL) among Puerto Rican adults. METHODS: Using cross-sectional data from wave 3 of the Boston Puerto Rican Health Study (n = 882), we examined the indirect association (IA) of skin tone on physiological dysregulated systems, also known as AL, through major discrimination and everyday discrimination. We tested these associations using two distinct measures of skin tone: interviewer-ascribed skin tone and spectrophotometer-measured skin tone. RESULTS: Interviewer-ascribed skin tone was indirectly associated with AL through major discrimination (IA = 0.03, 95% confidence interval = 0.004 to 0.06). However, there was no evidence of an IA of interviewer-ascribed skin tone on AL through everyday discrimination (IA = -0.01, 95% confidence interval = -0.03 to 0.01). In addition, there was no evidence that spectrophotometer-measured skin tone was indirectly associated with AL through major discrimination or everyday discrimination. CONCLUSIONS: The sociocultural significance of skin tone may affect how Puerto Ricans are perceived and treated by others, which can, in turn, have physiological health consequences. Future research is needed to replicate these findings and examine the interrelationship between skin tone, discrimination, and other health outcomes.

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence.

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

MiR-218: a molecular switch and potential biomarker of susceptibility to stress.

Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in blood, as compared with control or resilient groups. We show further that upregulation and downregulation of miR-218 levels specifically in the mPFC correlate with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility vs. resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.

White Matter Abnormalities in Late Onset First Episode Mania: A Diffusion Tensor Imaging Study.

INTRODUCTION: A first manic episode after 50 years of age is uncommon. Late Onset Mania might be indicative of abnormalities in white matter, probably related to vascular, degenerative, or inflammatory processes. OBJECTIVE: To determine if patients with late onset mania have reduced white matter integrity according to Magnetic Resonance Diffusion Tensor Imaging (DTI) and structural MRI. METHODS: Twenty-two patients with late onset mania (>50 years old) and 22 age-paired healthy subjects were included in the study. Fractional anisotropy (FA) was used as a quantitative measure of white matter integrity. Fazekas scale was assessed also to measure white matter abnormalities in the FLAIR sequence. The Frontal Assessment Battery, COGNISTAT and Trail making test A and B were used as cognitive measurements. RESULTS: According to DTI, commissural connections (left corpus callosum), and limbic connections (right and left uncinate fasciculus) were different between the patients and the comparison group. Fractional anisotropy values in the left corpus callosum showed significant correlations with neuropsychological measures, and with the Fazekas scale score. According to Fazekas scale, a pathological score in the FLAIR sequence was significantly more frequent in the patients as compared to the comparison group. CONCLUSIONS: Patients with first episode mania in late life have relevant white matter abnormalities not explained by age, affecting interhemispheric and fronto-limbic networks probably related to executive functioning and emotional processing, at the level of the corpus callosum and the uncinate fasciculus. The etiology of this white matter loss of integrity in patients with late-onset mania is yet to be explored.

Neural function in DCC mutation carriers with and without mirror movements.

OBJECTIVE: Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. METHODS: The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. RESULTS: Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. INTERPRETATION: Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Early Adolescence is a Critical Period for the Maturation of Inhibitory Behavior.

Psychiatric conditions marked by impairments in cognitive control often emerge during adolescence, when the prefrontal cortex (PFC) and its inputs undergo structural and functional maturation and are vulnerable to disruption by external events. It is not known, however, whether there exists a specific temporal window within the broad range of adolescence when the development of PFC circuitry and its related behaviors are sensitive to disruption. Here we show, in male mice, that repeated exposure to amphetamine during early adolescence leads to impaired behavioral inhibition, aberrant PFC dopamine connectivity, and reduced PFC dopamine function in adulthood. Remarkably, these deficits are not observed following exposure to the exact same amphetamine regimen at later times. These findings demonstrate that there is a critical period for the disruption of the adolescent maturation of cognitive control and PFC dopamine function and suggest that early adolescence is particularly relevant to the emergence of psychopathology in humans.

DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence.

The guidance cue receptor DCC controls mesocortical dopamine development in adolescence. Repeated exposure to an amphetamine regimen of 4 mg/kg during early adolescence induces, in male mice, downregulation of DCC expression in dopamine neurons by recruiting the Dcc microRNA repressor, microRNA-218 (miR-218). This adolescent amphetamine regimen also disrupts mesocortical dopamine connectivity and behavioral control in adulthood. Whether low doses of amphetamine in adolescence induce similar molecular and developmental effects needs to be established. Here, we quantified plasma amphetamine concentrations in early adolescent mice following a 4 or 0.5 mg/kg dose and found peak levels corresponding to those seen in humans following recreational and therapeutic settings, respectively. In contrast to the high doses, the low amphetamine regimen does not alter Dcc mRNA or miR-218 expression; instead, it upregulates DCC protein levels. Furthermore, high, but not low, drug doses downregulate the expression of the DCC receptor ligand, Netrin-1, in the nucleus accumbens and prefrontal cortex. Exposure to the low-dose regimen did not alter the expanse of mesocortical dopamine axons or their number/density of presynaptic sites in adulthood. Strikingly, adolescent exposure to the low-dose drug regimen does not impair behavioral inhibition in adulthood; instead, it induces an overall increase in performance in a go/no-go task. These results show that developmental consequences of exposure to therapeutic- versus abused-like doses of amphetamine in adolescence have dissimilar molecular signatures and opposite behavioral effects. These findings have important clinical relevance since amphetamines are widely used for therapeutic purposes in youth.

Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

Adolescence and Reward: Making Sense of Neural and Behavioral Changes Amid the Chaos.

Adolescence is a time of significant neural and behavioral change with remarkable development in social, emotional, and cognitive skills. It is also a time of increased exploration and risk-taking (e.g., drug use). Many of these changes are thought to be the result of increased reward-value coupled with an underdeveloped inhibitory control, and thus a hypersensitivity to reward. Perturbations during adolescence can alter the developmental trajectory of the brain, resulting in long-term alterations in reward-associated behaviors. This review highlights recent developments in our understanding of how neural circuits, pubertal hormones, and environmental factors contribute to adolescent-typical reward-associated behaviors with a particular focus on sex differences, the medial prefrontal cortex, social reward, social isolation, and drug use. We then introduce a new approach that makes use of natural adaptations of seasonally breeding species to investigate the role of pubertal hormones in adolescent development. This research has only begun to parse out contributions of the many neural, endocrine, and environmental changes to the heightened reward sensitivity and increased vulnerability to mental health disorders that characterize this life stage.

A computational application for multi-skill nurse staffing in hospital units.

BACKGROUND: Approaches to nurse staffing are commonly concerned with determining the minimum number of care hours according to the illness severity of patients. However, there is a gap in the literature considering multi-skill and multi-shift nurse staffing. This study addresses nurse staffing per skill category, at a strategical decision level, by considering the organization of work in shifts and coping with variability in demand. METHODS: We developed a method to determine the nursing staff levels in a hospital, given the required patient assistance. This method relies on a new mathematical model for complying with the legislation and guidelines while minimizing salary costs. A spreadsheet-based tool was developed to embed the model and to allow simulating different scenarios and evaluating the impact of demand fluctuations, thus supporting decision-making on staff dimensioning. RESULTS: Experiments were carried out considering real data from a Brazilian hospital unit. The results obtained by the model support the current total staff level in the unit under study. However, the distribution of staff among different skill categories revealed that the current real situation can be improved. CONCLUSIONS: The method allows the determining of staff level per shift and skill depending on the mix of patients' illness severity. Hospital management is offered the possibility of optimizing the staff level using a spreadsheet, a tool most managers are familiar with. In addition, it is possible to evaluate the implications of decisions on workforce dimensioning by simulating different demand scenarios. This tool can be easily adapted to other hospitals, using local rules and legislation.

Role of the Nurse Navigator: integrative review. / Atuação do Nurse Navigator: revisão integrativa.

OBJECTIVE: To identify scientific literature on oncology nurses who provide patient navigation services as nurse navigators. METHODS: Integrative review of literature searches in the databases LILACS, MEDLINE/PubMed, SCOPUS, SciELO, Web of Science and Science Direct based on the descriptors patient; navigation; nurse; professional; cancer; oncology; navigator; and navigators. RESULTS: Seventeen articles were identified and grouped according to the following thematic approach: Care Processes; Patients; and Health Workers. It was observed that scientific literature on nurse navigators mostly comes from the United States, Australia, Canada, Sweden, and Demark, where the first nurse navigator programmes were introduced. No studies were found in local journals or populations. CONCLUSIONS: The nurse navigator offer a unique service for the provision of quality care. Although international research is recent, further studies on the role of these professionals are clearly needed.

Impact of video game genre on surgical skills development: a feasibility study.

BACKGROUND: The playing of video games (VGs) was previously shown to improve surgical skills. This is the first randomized, controlled study to assess the impact of VG genre on the development of basic surgical skills. MATERIALS AND METHODS: Twenty first-year, surgically inexperienced medical students attended a practical course on surgical knots, suturing, and skin-flap technique. Later, they were randomized into four groups: control and/or nongaming (ContG), first-person-shooter game (ShotG), racing game (RaceG), and surgery game (SurgG). All participants had 3 wk of Nintendo Wii training. Surgical and VG performances were assessed by two independent, blinded surgeons who evaluated basal performance (time 0) and performance after 1 wk (time 1) and 3 wk (time 2) of training. RESULTS: The training time of RaceG was longer than that of ShotG and SurgG (P = 0.045). Compared to SurgG and RaceG, VG scores for ShotG improved less between times 0 and 1 (P = 0.010) but more between times 1 and 2 (P = 0.004). Improvement in mean surgical performance scores versus time differed in each VG group (P = 0.011). At time 2, surgical performance scores were significantly higher in ShotG (P = 0.002) and SurgG (P = 0.022) than in ContG. The surgical performance scores of RaceG were not significantly different from the score achieved by ContG (P = 0.279). CONCLUSIONS: Different VG genres may differentially impact the development of surgical skills by medical students. More complex games seem to improve performance even if played less. Although further studies are needed, surgery-related VGs with sufficient complexity and playability could be a feasible adjuvant to improving surgical skills.

Placebo-controlled study of rTMS combined with Lokomat® gait training for treatment in subjects with motor incomplete spinal cord injury.

High-frequency rTMS combined with gait training improves lower extremity motor score (LEMS) and gait velocity in SCI subjects who are able to walk over ground. The aim of this study was to optimize the functional outcome in early phases of gait rehabilitation in SCI using rTMS as an additional treatment to physical therapy. The present study included 31 motor incomplete SCI subjects randomized to receive real or sham rTMS, just before Lokomat gait training (15 subjects for real, 16 for sham rTMS). rTMS consisted of one daily session for 20 days over vertex (at 20 Hz). The subjects were evaluated using modified Ashworth scale (MAS) for spasticity, upper and lower extremity motor score (UEMS and LEMS, respectively), ten meters walking test (10MWT) and Walking Index for SCI (WISCI-II) for gait at baseline, after last rTMS session, and during follow-up. UEMS and LEMS improved significantly after last session in both groups and during follow-up period. The improvement was greater in real than in sham rTMS group. At follow-up, 71.4 % of the subjects after real rTMS and 40 % of the subjects after sham rTMS could perform 10MWT without significant differences in gait velocity, cadence, step length and WISCI-II between both groups. We conclude that 20 sessions of daily high-frequency rTMS combined with Lokomat gait training can lead to clinical improvement of gait in motor incomplete SCI. Such combined treatment improved motor strength in lower extremity in incomplete SCI subjects and in upper extremity in those with cervical SCI.