Reconstruction of neocortex: Organelles, compartments, cells, circuits, and activity.

We assembled a semi-automated reconstruction of L2/3 mouse primary visual cortex from ∼250 × 140 × 90 µm3 of electron microscopic images, including pyramidal and non-pyramidal neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, nuclei, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are publicly available, along with tools for programmatic and three-dimensional interactive access. Brief vignettes illustrate the breadth of potential applications relating structure to function in cortical circuits and neuronal cell biology. Mitochondria and synapse organization are characterized as a function of path length from the soma. Pyramidal connectivity motif frequencies are predicted accurately using a configuration model of random graphs. Pyramidal cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. Sample code shows data access and analysis.

The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Oligodendrocyte precursor cells ingest axons in the mouse neocortex.

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmission electron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.

Erector Spinae Plane Block on Postoperative Pain and Opioid Consumption After Lumbar Spine Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PURPOSE: Evaluate the effectiveness of the erector spinae plane (ESP) block in lumbar spine surgeries. DESIGN: Systematic review with meta-analysis. METHODS: PubMed, Cochrane Library, CINAHL, Google Scholar, and other gray literature were searched for eligible studies. Risk ratio (RR), mean difference (MD), and standardized mean difference were used to estimate outcomes with suitable effect models. The quality of evidence was assessed using the Risk of Bias algorithm and the grades of recommendation, assessment, development, and evaluation (GRADE) approach. FINDINGS: Twenty-two randomized controlled trials involving 1,327 patients were included. The erector spinae plane (ESP) block demonstrated a lower cumulative pain score within the first 48 hours at rest (MD, -1.03; 95% CI, -1.19 to -0.87; P < .00001) and during activity (MD, -1.16; 95% CI, -1.24 to -1.08; P < .00001). In addition, ESP block decreased opioid consumption (MD, -6.25; 95% CI, -8.33 to -4.17; P < .00001) and prolonged the time to first analgesic rescue (MD, 5.66; 95% CI, 3.11-8.20; P < .0001) resulting in fewer patients requesting rescue analgesic (RR, 0.33; 95% CI, 0.13-0.83; P = .02), lower incidence of postoperative nausea and vomiting (RR, 0.29; 95% CI, 0.10-0.79; P = .02) with improved patient satisfaction score (standardized mean difference, 2.17; 95% CI, 1.40-2.94; P < .00001). CONCLUSIONS: ESP block can provide effective postoperative pain control for lumbar spine surgery, improve patient satisfaction, and reduce the amount of postoperative opioid use.

Protocol for the Mason: Health Starts Here prospective cohort study of young adult college students.

BACKGROUND: Young adulthood is a period of increasing independence for the 40% of young adults enrolled in U.S. colleges. Previous research indicates differences in how students' health behaviors develop and vary by gender, race, ethnicity, and socioeconomic status. George Mason University is a state institution that enrolls a highly diverse student population, making it an ideal setting to launch a longitudinal cohort study using multiple research methods to evaluate the effects of health behaviors on physical and psychological functioning, especially during the COVID-19 pandemic. RESULTS: Mason: Health Starts Here was developed as a longitudinal cohort study of successive waves of first year students that aims to improve understanding of the natural history and determinants of young adults' physical health, mental health, and their role in college completion. The study recruits first year students who are 18 to 24 years old and able to read and understand English. All incoming first year students are recruited through various methods to participate in a longitudinal cohort for 4 years. Data collection occurs in fall and spring semesters, with online surveys conducted in both semesters and in-person clinic visits conducted in the fall. Students receive physical examinations during clinic visits and provide biospecimens (blood and saliva). CONCLUSIONS: The study will produce new knowledge to help understand the development of health-related behaviors during young adulthood. A long-term goal of the cohort study is to support the design of effective, low-cost interventions to encourage young adults' consistent performance of healthful behaviors, improve their mental health, and improve academic performance.

Toward Actionable Practice Parameters for "Dual Diagnosis": Principles of Assessment and Management for Co-Occurring Psychiatric and Intellectual/Developmental Disability.

PURPOSE OF REVIEW: Although treatment algorithms and parameters for best practice are readily available for all major syndromes of psychiatric impairment, the occurrence of psychiatric syndromes in individuals with intellectual and developmental disability (IDD) invokes serious contextual challenges for interpretation of symptoms, diagnosis, and optimization of treatment, both for clinicians and for the service sectors in which care and support of individuals with IDD are delivered. Recognizing that there exist very few definitive resources for best practice under the circumstance of this form of "dual diagnosis," the Missouri Department of Mental Health convened an expert panel to conduct a focused review and synthesis of the relevant scientific literature from which to develop guidance in the form of decision support to clinicians. This article summarizes the findings for three of the most common and impairing clusters of psychiatric symptoms that co-occur with IDD-aggression, depression, and addictions. RECENT FINDINGS: Individuals with IDD are at high risk for the development of psychiatric symptoms (PS), which often manifest uniquely in IDD and for which evidence for effective intervention is steadily accruing. Interventions that are commonly implemented in the IDD service sector (e.g., functional communication training and positive behavioral support planning) are capable of mitigating severe behavioral impairment, yet rarely invoked when dual diagnosis patients are seen in the psychiatric service sector. Conversely, state-of-the-art interventions for traumatic stress, pharmacotherapy, and psychotherapy have proven capable of improving behavioral impairments in IDD but are typically restricted to the psychiatric service sector, where there exist significant barriers to access for patients with IDD, including limitations imposed by diagnostic eligibility and practitioner experience. Bridging these gaps in knowledge and clinical capacity across the respective IDD and PS service sectors should be of very high priority in strategizing the care and support of IDD patients with serious co-occurring psychiatric conditions.

SynapseCLR: Uncovering features of synapses in primary visual cortex through contrastive representation learning.

3D electron microscopy (EM) connectomics image volumes are surpassing 1 mm3, providing information-dense, multi-scale visualizations of brain circuitry and necessitating scalable analysis techniques. We present SynapseCLR, a self-supervised contrastive learning method for 3D EM data, and use it to extract features of synapses from mouse visual cortex. SynapseCLR feature representations separate synapses by appearance and functionally important structural annotations. We demonstrate SynapseCLR's utility for valuable downstream tasks, including one-shot identification of defective synapse segmentations, dataset-wide similarity-based querying, and accurate imputation of annotations for unlabeled synapses, using manual annotation of only 0.2% of the dataset's synapses. In particular, excitatory versus inhibitory neuronal types can be assigned with >99.8% accuracy to individual synapses and highly truncated neurites, enabling neurite-enhanced connectomics analysis. Finally, we present a data-driven, unsupervised study of synaptic structural variation on the representation manifold, revealing its intrinsic axes of variation and showing that representations contain inhibitory subtype information.

Neuronal accumulation of hyperphosphorylated tau protein predicts stable memory impairment in people living with HIV.

OBJECTIVES: As lifespans increase in people with HIV (PWH), there is concern that age-related neurodegenerative disorders may contribute to cognitive decline. We asked whether brain accumulation of Alzheimer's disease (AD)-associated proteins amyloid-beta (Aß) and hyperphosphorylated tau (p-tau) predicted cognitive performance in middle-aged PWH. METHODS: In a prospectively followed, cognitively-characterized autopsy sample of 135 PWH, we used immunohistochemistry to assess Aß plaques and neuronal p-tau in medial temporal and lateral frontal lobes. These pathologies were tested for associations with cognitive performance in seven domains: motor, speed of information processing, working memory, memory encoding, memory retrieval, verbal fluency, and abstraction/executive function. Univariate and multivariate analyses accounting for HIV-associated variables, reading level, and comorbidities were conducted. Longitudinal trajectories of memory functions were evaluated in 60 individuals with a median follow-up of 6.0 years. RESULTS: In this population with mean age 51.4 ± 0.9 years, 58% displayed neuronal p-tau and 29% Aß plaques. Neuronal p-tau, but not Aß, predicted worse memory encoding and retrieval, but not other cognitive functions. With an ordinal hierarchy of neuronal p-tau locations (entorhinal, hippocampal, neocortical), decreased memory performance correlated with neocortical distribution. Memory function trajectories could not be distinguished between individuals with and without neuronal p-tau, and over 80% of the sample showed no change over time. CONCLUSION: In this middle-aged sample, neuronal p-tau accumulation contributes to memory deficits, but is not associated with accelerated decline in function over time. In the absence of AD-like deterioration, other etiologies for neuronal p-tau in cognitively impaired PWH must be considered.

Depression, Anxiety, Energy, and Fatigue Among Nurses Who Cared for Patients During the COVID-19 Pandemic: A Cross-Sectional Study.

Purpose of Study: Nurses around the world have faced challenges during the coronavirus disease 2019 (COVID-19) pandemic. This study examined the association between depression and anxiety and trait energy and trait fatigue, and baseline health status and work characteristics. Design of Study: A cross-sectional study. Methods: A survey was conducted to collect self-reported data from nurses involved in patient care in Northern Virginia. Depression and anxiety were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) depression and anxiety scales. To measure trait energy and trait fatigue, the Mental and Physical State and Trait Energy and Fatigue Scale (MPSTEFS) was used. Findings: There was a significant association between depression and energy (b=-0.46, t = -1.78, p < .001) and loneliness (b=1.38, t = 4.00, p < .001) and increased alcohol use (b=2.11, t = 2.04, p = .045). We also found that nurses with depression were significantly more likely to seek mental health counseling (b=-2.91, t = 2.54, p = 0.013), which was also the case for anxiety (b=3.13, t = 2.14, p = .036). Conclusions: Our study highlights the mental health burden among nurses who worked in the early phase of the COVID-19 pandemic and its association with increased alcohol use and loneliness. The findings may help healthcare leaders identify early signals of deterioration in nurses' well-being.

3D reconstruction of the cerebellar germinal layer reveals tunneling connections between developing granule cells.

The difficulty of retrieving high-resolution, in vivo evidence of the proliferative and migratory processes occurring in neural germinal zones has limited our understanding of neurodevelopmental mechanisms. Here, we used a connectomic approach using a high-resolution, serial-sectioning scanning electron microscopy volume to investigate the laminar cytoarchitecture of the transient external granular layer (EGL) of the developing cerebellum, where granule cells coordinate a series of mitotic and migratory events. By integrating image segmentation, three-dimensional reconstruction, and deep-learning approaches, we found and characterized anatomically complex intercellular connections bridging pairs of cerebellar granule cells throughout the EGL. Connected cells were either mitotic, migratory, or transitioning between these two cell stages, displaying a chronological continuum of proliferative and migratory events never previously observed in vivo at this resolution. This unprecedented ultrastructural characterization poses intriguing hypotheses about intercellular connectivity between developing progenitors and its possible role in the development of the central nervous system.

Correction to: Using a Nonconcurrent Multiple-Baseline Across-Participants Design to Examine the Effects of Individualized ACT at School.

[This corrects the article DOI: 10.1007/s40617-021-00558-8.].

Using a Nonconcurrent Multiple-Baseline Across-Participants Design to Examine the Effects of Individualized ACT at School.

The purpose of the current study was to examine the effectiveness of implementing acceptance and commitment therapy (ACT) with three students who displayed disruptive and off-task behaviors in a classroom. A nonconcurrent multiple-baseline across-participants design with an embedded reversal was used to compare the effects of individualized ACT exercises and treatment-control conditions on classroom behaviors that included on-task behavior, vocal disruption, physical aggression, and classroom disruption. Classroom behaviors were measured during 5-min direct observations using continuous 30-s interval recording. During baseline, all participants displayed low levels of on-task engagement and high or varying rates of challenging behaviors. When the individualized ACT intervention was implemented, participants' on-task and challenging behaviors improved compared to baseline and treatment-control conditions; treatment-control conditions produced mixed results. Implications for school-based treatment programs and collaborative transdisciplinary intervention strategies are discussed.

Binary and analog variation of synapses between cortical pyramidal neurons.

Learning from experience depends at least in part on changes in neuronal connections. We present the largest map of connectivity to date between cortical neurons of a defined type (layer 2/3 [L2/3] pyramidal cells in mouse primary visual cortex), which was enabled by automated analysis of serial section electron microscopy images with improved handling of image defects (250 × 140 × 90 µm3 volume). We used the map to identify constraints on the learning algorithms employed by the cortex. Previous cortical studies modeled a continuum of synapse sizes by a log-normal distribution. A continuum is consistent with most neural network models of learning, in which synaptic strength is a continuously graded analog variable. Here, we show that synapse size, when restricted to synapses between L2/3 pyramidal cells, is well modeled by the sum of a binary variable and an analog variable drawn from a log-normal distribution. Two synapses sharing the same presynaptic and postsynaptic cells are known to be correlated in size. We show that the binary variables of the two synapses are highly correlated, while the analog variables are not. Binary variation could be the outcome of a Hebbian or other synaptic plasticity rule depending on activity signals that are relatively uniform across neuronal arbors, while analog variation may be dominated by other influences such as spontaneous dynamical fluctuations. We discuss the implications for the longstanding hypothesis that activity-dependent plasticity switches synapses between bistable states.

Risky Business: Increasing Risky Betting Through Rule-Governed Behavior.

The present study replicated and extended previous research by exploring the extent to which rules altered participants' engagement in risky betting in an electronic blackjack game. A multiple-baseline across-participants design with predetermined phase changes was used to assess 4 recreational gamblers' betting patterns in blackjack across 3 phases. During baseline, participants played blackjack with no exposure to rules. In the faulty rules phase, researchers gave participants a rule that suggested larger payouts would occur if gamblers played let-it-ride bets. Let-it-ride bets were placed after a winning hand and required participants to wager their entire winnings on the next hand. During the correct rules phase, researchers gave participants a rule that suggested that the let-it-ride bets did not result in larger payouts. Data on let-it-ride bets across each minute of play were collected. The results of the study demonstrated that the frequency of risky bets increased when participants were exposed to the incorrect rule. Following participants' exposure to correct rules, risky bets decreased, but most participants did not return to baseline rates.

Induction of labour indications and timing: A systematic analysis of clinical guidelines.

BACKGROUND: There is widespread and some unexplained variation in induction of labour rates between hospitals. Some practice variation may stem from variability in clinical guidelines. This review aimed to identify to what extent induction of labour guidelines provide consistent recommendations in relation to reasons for, and timing of, induction of labour and ascertain whether inconsistencies can be explained by variability guideline quality. METHOD: We conducted a systematic search of national and international English-language guidelines published between 2008 and 2018. General induction of labour guidelines and condition-specific guidelines containing induction of labour recommendations were searched. Guidelines were reviewed and extracted independently by two reviewers. Guideline quality was assessed using the Appraisal of Guidelines for Research and Evaluation II Instrument. FINDINGS: Forty nine guidelines of varying quality were included. Indications where guidelines had mostly consistent advice included prolonged pregnancy (induction between 41 and 42 weeks), preterm premature rupture of membranes, and term preeclampsia (induction when preeclampsia diagnosed ≥37 weeks). Guidelines were also consistent in agreeing on decreased fetal movements and oligohydramnios as valid indications for induction, although timing recommendations were absent or inconsistent. Common indications where there was little consensus on validity and/or timing of induction included gestational diabetes, fetal macrosomia, elevated maternal body mass index, and twin pregnancy. CONCLUSION: Substantial variation in clinical practice guidelines for indications for induction exists. As guidelines rated of similar quality presented conflicting recommendations, guideline variability was not explained by guideline quality. Guideline variability may partly account for unexplained variation in induction of labour rates.

Indications for, and timing of, planned caesarean section: A systematic analysis of clinical guidelines.

BACKGROUND: There has been a worldwide rise in planned caesarean sections over recent decades, with significant variations in practice between hospitals and countries. Guidelines are known to influence clinical decision-making and, potentially, unwarranted clinical variation. The aim of this study was to review guidelines for recommendations in relation to the timing and indications for planned caesarean section as well as recommendations around the process of decision-making. METHOD: A systematic search of national and international English-language guidelines published between 2008 and 2018 was undertaken. Guidelines were reviewed, assessed in terms of quality and extracted independently by two reviewers. FINDINGS: In total, 49 guidelines of varying quality were included. There was consistency between the guidelines in potential indications for caesarean section, although guidelines vary in terms of the level of detail. There was substantial variation in timing of birth, for example recommended timing of caesarean section for women with uncomplicated placenta praevia is between 36 and 39weeks depending on the guideline. Only 11 guidelines provided detailed guidance on shared decision-making. In general, national-level guidelines from Australia, and overseas, received higher quality ratings than regional guidelines. CONCLUSION: The majority of guidelines, regardless of their quality, provide very limited information to guide shared decision-making or the timing of planned caesarean section, two of the most vital aspects of guidance. National guidelines were generally of better quality than regional ones, suggesting these should be used as a template where possible and emphasis placed on improving national guidelines and minimising intra-country, regional, variability of guidelines.

Developmental Rewiring between Cerebellar Climbing Fibers and Purkinje Cells Begins with Positive Feedback Synapse Addition.

During postnatal development, cerebellar climbing fibers alter their innervation strengths onto supernumerary Purkinje cell targets, generating a one-to-few connectivity pattern in adulthood. To get insight about the processes responsible for this remapping, we reconstructed serial electron microscopy datasets from mice during the first postnatal week. Between days 3 and 7, individual climbing fibers selectively add many synapses onto a subset of Purkinje targets in a positive-feedback manner, without pruning synapses from other targets. Active zone sizes of synapses associated with powerful versus weak inputs are indistinguishable. Changes in synapse number are thus the predominant form of early developmental plasticity. Finally, the numbers of climbing fibers and Purkinje cells in a local region nearly match. Initial over-innervation of Purkinje cells by climbing fibers is therefore economical: the number of axons entering a region is enough to assure that each ultimately retains a postsynaptic target and that none branched there in vain.

Effects of delay fading and signals on self-control choices by children.

The current study is a systematic replication and extension of work by Schweitzer & Sulzer-Azaroff (1988). The effects of delay fading alone and in combination with signals on choices between larger, delayed reinforcers and smaller, immediate reinforcers by four children with language deficits were examined. For one of the two children exposed to delay fading alone, larger reinforcers were selected at longer delays relative to the initial self-control assessment. For all four children, the delay-fading-plus-signal condition resulted in selection of larger reinforcers at considerably longer delays relative to the self-control assessment.

Preliminary Evidence on the Efficacy of Mindfulness Combined with Traditional Classroom Management Strategies.

The current case study combined mindfulness-based strategies with a classroom behavior management treatment package, to assist teachers with managing 3rd grade student behaviors. Two teachers (Classroom teacher and Specials teacher) and six students within the same classroom were observed using a 5-min momentary time sampling procedure. A delayed multiple baseline across settings (e.g., Classroom teacher, Specials teacher) design was used to assess student behaviors across baseline (A), classroom behavior management treatment package (CBM) (B), CBM plus mindfulness (C), and CBM plus mindfulness and self-monitoring (D). Behavioral treatment alone increased on-task behaviors for four of six (66%) students compared to baseline; however, five of six (83%) students increased and sustained high rates of on-task behaviors when mindfulness exercises were added to the behavior analytic techniques. These preliminary results support the combination of mindfulness-based strategies with traditional behavior analytic interventions for increasing student on-task behaviors in classroom settings.