Medicine by Alexandros G. Sfakianakis: 03/07/18

Τετάρτη 7 Μαρτίου 2018

Diagnosing diabetes mellitus in patients with porphyria cutanea tarda

Abstract

The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus. HbA1c, fasting glucose, or oral glucose tolerance are the current available tests, with HbA1c as first choice. Measuring HbA1c requires no fasting, however HbA1c can be false low if the patient is treated with phlebotomy or has liver cirrhosis or chronic hepatitis. Instead fasting glucose and oral glucose tolerance tests can be used if the patient is not acutely ill. If either of the tests give a result in the diagnostic range, the test should be repeated if the patient has no clinical symptoms of diabetes. Diagnosing diabetes mellitus is important for the purpose of early intervention, and this review provides the knowledge needed to diagnose this special patient group properly.

THE AUTHORS REPLY

RE: “A MULTINOMIAL REGRESSION APPROACH TO MODEL OUTCOME HETEROGENEITY”

Mycobacterium gordonae-associated skin infection in an immunocompetent patient

Psoriasis and subclinical atherosclerosis in a Chinese population

Malignant atrophic papulosis with motor aphasia and intestinal perforation: A case report and review of published works

Abstract

Malignant atrophic papulosis (MAP) is a rare type of obliterating vasculopathy that can present as pure cutaneous lesions or a systemic entity affecting multiple organs. Systemic disease, such as gastrointestinal or central nervous system involvement, may predispose the patients to poorer or even fatal outcomes. We present a 30-year-old female patient with systemic manifestation of MAP 10 days after delivery of a full-term pregnancy who subsequently developed motor aphasia and intestinal perforation. The patient was administrated empirical treatment with an antiplatelet, anticoagulant, methylprednisolone sodium succinate and alprostadil. Antibiotics were administrated due to intestinal perforation and secondary sepsis. Despite all treatment, the patient died a week later. We summarized all the previous reports of MAP based on thorough review of previous published work. Overall, this is the first patient with MAP combined with motor aphasia and intestinal perforation and may provide insights for future studies on the treatment of this disease.

Surgical Site Identification with Personal Digital Device: A Prospective Pilot Study

Publication date: Available online 7 March 2018
Source:Journal of the American Academy of Dermatology
Author(s): Leon Chen, Adam M. Parsons, Alexander B. Aria, Ana M. Ciurea, Anisha B. Patel, Christopher Chan, John R. Griffin, Tri H. Nguyen, Michael R. Migden
BackgroundVarious means to facilitate accurate biopsy site identification have been proposed.ObjectiveTo determine the accuracy of biopsy site identification using photos taken with a patient's digital device by a dermatologist versus professional medical photography.MethodsPhotographs of circled biopsy sites were taken with personal digital devices by the principal investigator (PI). Another set of photographs were taken by a professional photographer. Secondary photographs were taken of the biopsy site location pointed to by the staff and PI based on the personal digital device image and professional medical photography, respectively. Based on secondary photographs, two independent dermatologists determined if the skin biopsy locations pointed out by the staff were consistent with the ones pointed out by PI.ResultsPer Dermatologist A, the staff correctly identified all 53/53 biopsy sites. Per Dermatologist B, the staff were correct on 51/53 observations. Dermatologist C, the final arbiter, concurred with Dermatologist A in the two cases that Dermatologist B was not certain of the biopsy site location.LimitationsThe mean interval from initial biopsy to re-identification of the site was 36.2 days.ConclusionUtilizing patients' personal digital devices is a cost-effective, HIPAA compliant, and readily available means to identify skin biopsy sites.

Teaser

Many novel means of biopsy site identification have been proposed., This is a pilot study comparing the accuracy of biopsy site identification with personal digital device photography to professional medical photography., Personal digital device photography is a cost-effective, HIPPA complaint, and readily available means to accurately identify biopsy sites.

Pathologist Characteristics Associated with Accuracy and Reproducibility of Melanocytic Skin Lesion Interpretation

Publication date: Available online 7 March 2018
Source:Journal of the American Academy of Dermatology
Author(s): David E. Elder, Mike Piepkorn, Raymond L. Barnhill, Gary M. Longton, Heidi D. Nelson, Stevan R. Knezevich, Margaret S. Pepe, Patricia A. Carney, Linda J. Titus, Tracy Onega, Anna N.A. Tosteson, Martin A. Weinstock, Joann G. Elmore
BackgroundDiagnostic interpretations of melanocytic skin lesions vary widely among pathologists, yet the underlying reasons remain unclear.ObjectiveIdentify pathologist characteristics associated with rates of accuracy and reproducibility.MethodsPathologists independently interpreted the same set of biopsies of melanocytic lesions on two occasions. Diagnoses were categorized into one of five classes according to the MPATH-Dx^© system. Reproducibility was determined by pathologists' concordance of diagnoses across two occasions. Accuracy was defined by concordance with a consensus reference standard. Associations of pathologist characteristics with reproducibility and accuracy were assessed individually and in multivariable logistic regression models.ResultsRates of diagnostic reproducibility and accuracy were highest among pathologists with board certification and/or fellowship training in dermatopathology, and those with ≥5 years of experience. In addition, accuracy was high among pathologists with higher caseload composition and volume of melanocytic lesions.LimitationsData gathered in a test set situation using a classification tool not currently in clinical use.ConclusionDiagnoses are more accurate among pathologists with specialty training and those with more experience interpreting melanocytic lesions. These findings support the practice of referring difficult cases to more experienced pathologists to improve diagnostic accuracy, although the impact on patient outcomes of these referrals requires additional research.

Hygiene practices: Are they protective factors for eczema symptoms?

Abstract

Introduction

Exact etiology and proper treatment of eczema are still unknown. The hygiene hypothesis and epidermal barrier dysfunction hypothesis attempted to give some plausible explanations for these issues but they still remain unclear. The identification of factors, including hygiene practices, related to eczema symptoms (ES) could shed some light on these matters. Therefore, this study aimed to determine risk factors related to ES and the ES prevalence in two disparate areas in terms of urbanization in Aceh, Indonesia.

Methods

A cross-sectional study with convenience sampling was conducted among schoolchildren living in urban and rural Aceh. Data on ES, socio-demographic characteristics, environmental factors, partial ablution and other hygiene related factors were collected by parental questionnaires. In addition, children's anthropometric measurements were also collected.

Results

The prevalence of current ES in the study population was 21%. When stratifying by residency, the prevalence of ES in urban and rural area was 20.93% versus 21.05%. Partial ablution was independently associated with a reduced risk of ES (OR = 0.36; 95% CI 0.13–0.96). Important risk factors for ES were paternal history of allergic disease (OR = 4.09%; 95% CI 1.51–11.11) and belonging to the older group of schoolchildren (10–13 years old) (OR = 2.57; 95% CI 1.03–6.40).

Conclusions

There were no significant differences in the prevalence of ES between urban and rural settings, and partial ablution had a protective effect on ES. These findings support the epidermal barrier dysfunction hypothesis as a possible pathway of eczema.

Hygiene practices that involves frequent washing without detergents, such as partial ablution, seem to be protective for eczema symptoms. This finding is in line with the epidermal barrier dysfunction hypothesis.

Surgical Site Identification with Personal Digital Device: A Prospective Pilot Study

Pathologist Characteristics Associated with Accuracy and Reproducibility of Melanocytic Skin Lesion Interpretation

Diagnostic interpretations of melanocytic skin lesions vary widely among pathologists, yet the underlying reasons remain unclear.

Poster Abstracts

Symposia and Oral Abstracts

Effects of platelet-rich plasma on tissue-engineered vascularized flaps in an in vivo chamber

We investigated the reproducibility of creating a vascularized tissue flap in an in vivo tissue engineering chamber by incubating a vascular pedicle imbedded in a collagen sponge with activated platelet-rich plasma (aPRP) and basic fibroblast growth factor (bFGF).

Coupling loss characteristics of runoff-sediment-adsorbed and dissolved nitrogen and phosphorus on bare loess slope

Abstract

Soil and nutrient loss is a common natural phenomenon but it exhibits unclear understanding especially on bare loess soil with variable rainfall intensity and slope gradient, which makes it difficult to design control measures for agricultural diffuse pollution. We employ 30 artificial simulated rainfalls (six rainfall intensities and five slope gradients) to quantify the coupling loss correlation of runoff-sediment-adsorbed and dissolved nitrogen and phosphorus on bare loess slope. Here, we show that effects of rainfall intensity on runoff yield was stronger than slope gradient with prolongation of rainfall duration, and the effect of slope gradient on runoff yield reduced gradually with increased rainfall intensity. But the magnitude of initial sediment yield increased significantly from an average value of 6.98 g at 5° to 36.08 g at 25° with increased slope gradient. The main factor of sediment yield would be changed alternately with the dual increase of slope gradient and rainfall intensity. Dissolved total nitrogen (TN) and dissolved total phosphorus (TP) concentrations both showed significant fluctuations with rainfall intensity and slope gradient, and dissolved TP concentration was far less than dissolved TN. Under the double influences of rainfall intensity and slope gradient, adsorbed TN concentration accounted for 7–82% of TN loss concentration with an average of 58.6% which was the main loss form of soil nitrogen, adsorbed TP concentration accounted for 91.8–98.7% of TP loss concentration with an average of 96.6% which was also the predominant loss pathway of soil phosphorus. Nitrate nitrogen (NO₃⁻-N) accounted for 14.59–73.92% of dissolved TN loss, and ammonia nitrogen (NH₄⁺-N) accounted for 1.48–18.03%. NO₃⁻-N was the main loss pattern of TN in runoff. Correlation between dissolved TN, runoff yield, and rainfall intensity was obvious, and a significant correlation was also found between adsorbed TP, sediment yield, and slope gradient. Our results provide the underlying insights needed to guide the control of nitrogen and phosphorus loss on loess hills.

Characterization of industrial odor sources in Binhai New Area of Tianjin, China

Abstract

Samples were collected from six different organized industrial odor sources in Tianjin Binhai New Area, including pharmacy, paint spraying, oil refinery, petrochemical, resin synthesis, and rubber manufacturing. Chemical analysis was conducted to identify and quantify major odorous volatile organic compounds (VOCs) and subsequently, establish source profiles. Olfactory measurement was used to characterize the sensory stimulating intensity of odorous VOCs and express them as odor concentration. The TVOC mass concentrations of these six sources were between 10.9 and 225.3 mg/m³. Toluene was the most abundant component in profiles of both pharmacy and spraying sources with abundances of 79.1 and 94%, respectively. The petrochemical source was characterized by high levels of o,m,p-xylene (more than 60%). Sulfides were identified almost solely in the rubber manufacturing source. High levels of styrene were found in the resin synthesis source, whereas the oil refinery source was dominated by halocarbons. The odor concentration of oil refinery, spraying, rubber manufacturing, and resin synthesis all exceeded the Chinese emission standards for odor pollutants (GB14554-93) during the study period. Based on industrial processing analysis and factor analysis, toluene, m,p-xylene, carbon disulfide, toluene, three types of halogenated hydrocarbons, and styrene were the markers of pharmacy, petrochemical, rubber manufacturing, spraying, oil refinery, and resin synthesis sources, respectively. Production process and factor analysis methods were used to identify the markers of each odor source, which were based on instrument analysis and olfactory measurement.

Scarring in Patients With PIK3CA -Related Overgrowth Syndromes

This observational study examines the frequency of excessive scarring after surgery in patients with PIK3CA-related overgrowth.

Death by Gun Violence—Guns Are Not the Problem—Reply

In Reply We thank Dr Boyd for reading and thinking about our editorial on gun violence. Dr Boyd's argument rests on his belief that rural areas are safer because of more guns. Unfortunately, the data say otherwise. In an analysis of injury deaths in all 3141 US counties, there was no significant difference in the rate of firearm deaths in the most rural counties compared with the most urban counties. Dr Boyd also fails to recognize that over 60% of firearm deaths in the United States are suicides, and that there is a strong linear relationship between the number of guns in a state and the overall suicide rate. Suicide rates are higher in rural than urban areas and for youth, the rural-urban difference is increasing.

Health-Related Quality of Life in Frontal Fibrosing Alopecia

This cohort study evaluates the association between frontal fibrosing alopecia and health-related quality of life.

Facial Neutrophilic Dermatosis Mimicking Iododerma Associated With IBD

This case report describes a patient with facial neutrophilic dermatosis mimicking iododerma and associated with inflammatory bowel disease.

Death by Gun Violence—Guns Are Not the Problem

To the Editor I read with interest the editorial by Bauchner et al regarding gun violence and wish to offer a different opinion. My family and I live on a farm in a rural area near Nashville, Tennessee. Crime, including violent crime, is essentially unheard of in our part of the county. I believe that this stems, in part, from the well-known fact that those of us living here are armed. We have rifles and shotguns in our homes and pistols in our vehicles and/or on our persons.

Four Staging Systems for Cutaneous Squamous Cell Carcinoma

This nested case-control study assesses the validity and usefulness of 4 staging systems for cutaneous squamous cell carcinoma using population-based data.

Revised Mohs Surgery Appropriate Use Criteria for Superficial BCC

This Viewpoint discusses the process of reevaluating Mohs surgery appropriate use criteria for primary superficial basal cell carcinoma.

Roles of Prefrontal Cortex and Mediodorsal Thalamus in Task Engagement and Behavioral Flexibility

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed "task engagement," may enable context-dependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision-making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4–7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.

SIGNIFICANCE STATEMENT When rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated compared with task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex and thus represents a form of "top-down" regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task-dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing.

Brain Transcriptome Databases: A User's Guide

Transcriptional programs instruct the generation and maintenance of diverse subtypes of neural cells, establishment of distinct brain regions, formation and function of neural circuits, and ultimately behavior. Spatiotemporal and cell type-specific analyses of the transcriptome, the sum total of all RNA transcripts in a cell or an organ, can provide insights into the role of genes in brain development and function, and their potential contribution to disorders of the brain. In the previous decade, advances in sequencing technology and funding from the National Institutes of Health and private foundations for large-scale genomics projects have led to a growing collection of brain transcriptome databases. These valuable resources provide rich and high-quality datasets with spatiotemporal, cell type-specific, and single-cell precision. Most importantly, many of these databases are publicly available via user-friendly web interface, making the information accessible to individual scientists without the need for advanced computational expertise. Here, we highlight key publicly available brain transcriptome databases, summarize the tissue sources and methods used to generate the data, and discuss their utility for neuroscience research.

Sleep Deprivation Distinctly Alters Glutamate Transporter 1 Apposition and Excitatory Transmission to Orexin and MCH Neurons

Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep–wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep–wake neurons in the male rat following 6 h sleep deprivation (SD) or following 6 h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin neurons in the lateral hypothalamus compared with Rest. Reduced GLT1 apposition was associated with tonic presynaptic inhibition of excitatory transmission to these neurons due to the activation of Group III metabotropic glutamate receptors, an effect mimicked by a GLT1 inhibitor in the Rest condition. In contrast, SD resulted in increased GLT1 apposition with sleep-promoting melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus. Functionally, this decreased the postsynaptic response of MCH neurons to high-frequency synaptic activation without changing presynaptic glutamate release. The changes in GLT1 apposition with orexin and MCH neurons were reversed after 3 h of sleep opportunity following 6 h SD. These SD effects were specific to orexin and MCH neurons, as no change in GLT1 apposition was seen in basal forebrain cholinergic or parvalbumin-positive GABA neurons. Thus, within a single hypothalamic area, GLT1 differentially regulates excitatory transmission to wake- and sleep-promoting neurons depending on sleep history. These processes may constitute novel astrocyte-mediated homeostatic mechanisms controlling sleep–wake behavior.

SIGNIFICANCE STATEMENT Sleep–wake cycles are regulated by the alternate activation of sleep- and wake-promoting neurons. Whether and how astrocytes can regulate this reciprocal neuronal activity are unclear. Here we report that, within the lateral hypothalamus, where functionally opposite wake-promoting orexin neurons and sleep-promoting melanin-concentrating hormone neurons codistribute, the glutamate transporter GLT1, mainly present on astrocytes, distinctly modulates excitatory transmission in a cell-type-specific manner and according to sleep history. Specifically, GLT1 is reduced around the somata of orexin neurons while increased around melanin-concentrating hormone neurons following sleep deprivation, resulting in different forms of synaptic plasticity. Thus, astrocytes can fine-tune the excitability of functionally discrete neurons via glutamate transport, which may represent novel regulatory mechanisms for sleep.

Movement Variability Is Processed Bilaterally by Inferior Parietal Lobule

Overlapping Role of SCYL1 and SCYL3 in Maintaining Motor Neuron Viability

Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located Huntingtin, elongation factor 3, protein phosphatase 2A, yeast kinase TOR1 repeats, and an overall disorganized C-terminal segment. In mammals, three family members encoded by genes Scyl1, Scyl2, and Scyl3 have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. Here, we show that the biochemical and cell biological properties of SCYL3 are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack of Scyl3 in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused by Scyl1 deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large-caliber axons in peripheral nerves occurred at an earlier age in Scyl1/Scyl3 double-deficient mice than in Scyl1-deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 in vivo and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study.

SIGNIFICANCE STATEMENT SCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well established roles in neuronal function. Herein, we uncover the role of SCYL3 in maintaining motor neuron viability. Although targeted disruption of Scyl3 in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss of Scyl1, a novel motor neuron disease gene in humans. Scyl1 and Scyl3 double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than did Scyl1-deficient mice. Thus, we show that SCYL1 and SCYL3 play overlapping roles in maintaining motor neuronal viability in vivo and confirm that SCYL family members are critical regulators of neuronal function and survival.

Protective Role of NF-{kappa}B in Inflammatory Demyelination

Regulation of Synapse Development by Vgat Deletion from ErbB4-Positive Interneurons

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter (Vgat) in ErbB4⁺ interneurons. We show that inhibitory axo–somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. Conversely, parvalbumin-positive (PV⁺)/ErbB4⁺ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV⁺ErbB4⁺ interneurons compared with ErbB4-only interneurons. Vgat deletion from ErbB4⁺ interneurons reduced axo–somatic or axo–axonic synapses from PV⁺ErbB4⁺ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV⁺ and/or ErbB4⁺ interneurons. Interestingly, perineuronal nets, extracellular matrix structures implicated in maturation, survival, protection, and plasticity of PV⁺ interneurons, were increased in the cortex of ErbB4-Vgat^–/– mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4⁺ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.

SIGNIFICANCE STATEMENT GABA has been implicated in neural development, but in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. Here, we ablated Vgat in ErbB4⁺ interneurons in an inducible manner. We provide evidence that the formation of inhibitory and excitatory synapses onto excitatory neurons requires Vgat in interneurons. In particular, inhibitory axo–somatic and axo–axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly.

Adaptive History Biases Result from Confidence-Weighted Accumulation of past Choices

Perceptual decision-making is biased by previous events, including the history of preceding choices: observers tend to repeat (or alternate) their judgments of the sensory environment more often than expected by chance. Computational models postulate that these so-called choice history biases result from the accumulation of internal decision signals across trials. Here, we provide psychophysical evidence for such a mechanism and its adaptive utility. Male and female human observers performed different variants of a challenging visual motion discrimination task near psychophysical threshold. In a first experiment, we decoupled categorical perceptual choices and motor responses on a trial-by-trial basis. Choice history bias was explained by previous perceptual choices, not motor responses, highlighting the importance of internal decision signals in action-independent formats. In a second experiment, observers performed the task in stimulus environments containing different levels of autocorrelation and providing no external feedback about choice correctness. Despite performing under overall high levels of uncertainty, observers adjusted both the strength and the sign of their choice history biases to these environments. When stimulus sequences were dominated by either repetitions or alternations, the individual degree of this adjustment of history bias was about as good a predictor of individual performance as individual perceptual sensitivity. The history bias adjustment scaled with two proxies for observers' confidence about their previous choices (accuracy and reaction time). Together, our results are consistent with the idea that action-independent, confidence-modulated decision variables are accumulated across choices in a flexible manner that depends on decision-makers' model of their environment.

SIGNIFICANCE STATEMENT Decisions based on sensory input are often influenced by the history of one's preceding choices, manifesting as a bias to systematically repeat (or alternate) choices. We here provide support for the idea that such choice history biases arise from the context-dependent accumulation of a quantity referred to as the decision variable: the variable's sign dictates the choice and its magnitude the confidence about choice correctness. We show that choices are accumulated in an action-independent format and a context-dependent manner, weighted by the confidence about their correctness. This confidence-weighted accumulation of choices enables decision-makers to flexibly adjust their behavior to different sensory environments. The bias adjustment can be as important for optimizing performance as one's sensitivity to the momentary sensory input.

The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor

Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. Previously, we have shown that lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration. However, it remains unknown whether the soluble form of LOTUS (s-LOTUS) also has an inhibitory action on NgR1 function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgR1-mediated signaling by inhibiting the molecular interaction between NgR1 and its coreceptor, p75 neurotrophin receptor (p75^NTR). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgR1. However, we identified p75^NTR as a novel LOTUS binding partner and found that s-LOTUS suppressed the interaction between p75^NTR and NgR1. s-LOTUS inhibited myelin-associated inhibitor (MAI)-induced RhoA activation in murine cortical neurons. Functional analyses revealed that s-LOTUS inhibited MAI-induced growth cone collapse and neurite outgrowth inhibition in chick DRG neurons. In addition, whereas olfactory bulb neurons of lotus-KO mice are sensitive to MAI due to a lack of LOTUS expression, treatment with s-LOTUS inhibited MAI-induced growth cone collapse in these neurons. Finally, we observed that s-LOTUS promoted axonal regeneration in optic nerve crush injury of mice (either sex). These findings suggest that s-LOTUS inhibits NgR1-mediated signaling, possibly by interfering with the interaction between NgR1 and p75^NTR. Therefore, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.

SIGNIFICANCE STATEMENT Nogo receptor type 1 (NgR1) is a receptor well known to inhibit neuronal regeneration in the CNS. Because the membrane-bound form of lateral olfactory tract usher substance (LOTUS) antagonizes NgR1 through a cis-type molecular interaction between LOTUS and NgR1, the soluble form of LOTUS (s-LOTUS) is expected to be a therapeutic agent for neuronal regeneration. In our present study, we show that s-LOTUS inhibits the interaction between NgR1 and p75^NTR, NgR1 ligand-induced RhoA activation, growth cone collapse, and neurite outgrowth inhibition and promotes axonal regeneration. Our results indicate that s-LOTUS inhibits NgR1-mediated signaling through a trans-type molecular interaction between LOTUS and NgR1 and, therefore, s-LOTUS may have therapeutic potential for neuronal regeneration.

Neurons in Primate Entorhinal Cortex Represent Gaze Position in Multiple Spatial Reference Frames

Primates rely predominantly on vision to gather information from the environment and neurons representing visual space and gaze position are found in many brain areas. Within the medial temporal lobe, a brain region critical for memory, neurons in the entorhinal cortex of macaque monkeys exhibit spatial selectivity for gaze position. Specifically, the firing rate of single neurons reflects fixation location within a visual image (Killian et al., 2012). In the rodents, entorhinal cells such as grid cells, border cells, and head direction cells show spatial representations aligned to visual environmental features instead of the body (Hafting et al., 2005; Sargolini et al., 2006; Solstad et al., 2008; Diehl et al., 2017). However, it is not known whether similar allocentric representations exist in primate entorhinal cortex. Here, we recorded neural activity in the entorhinal cortex in two male rhesus monkeys during a naturalistic, free-viewing task. Our data reveal that a majority of entorhinal neurons represent gaze position and that simultaneously recorded neurons represent gaze position relative to distinct spatial reference frames, with some neurons aligned to the visual image and others aligned to the monkey's head position. Our results also show that entorhinal neural activity can be used to predict gaze position with a high degree of accuracy. These findings demonstrate that visuospatial representation is a fundamental property of entorhinal neurons in primates and suggest that entorhinal cortex may support relational memory and motor planning by coding attentional locus in distinct, behaviorally relevant frames of reference.

SIGNIFICANCE STATEMENT The entorhinal cortex, a brain area important for memory, shows striking spatial activity in rodents through grid cells, border cells, head direction cells, and nongrid spatial cells. The majority of entorhinal neurons signal the location of a rodent relative to visual environmental cues, representing the location of the animal relative to space in the world instead of the body. Recently, we found that entorhinal neurons can signal location of gaze while a monkey explores images visually. Here, we report that spatial entorhinal neurons are widespread in the monkey and these neurons are capable of showing a world-based spatial reference frame locked to the bounds of explored images. These results help connect the extensive findings in rodents to the primate.

This Week in The Journal

Dynamic Flexibility in Striatal-Cortical Circuits Supports Reinforcement Learning

Complex learned behaviors must involve the integrated action of distributed brain circuits. Although the contributions of individual regions to learning have been extensively investigated, much less is known about how distributed brain networks orchestrate their activity over the course of learning. To address this gap, we used fMRI combined with tools from dynamic network neuroscience to obtain time-resolved descriptions of network coordination during reinforcement learning in humans. We found that learning to associate visual cues with reward involves dynamic changes in network coupling between the striatum and distributed brain regions, including visual, orbitofrontal, and ventromedial prefrontal cortex (n = 22; 13 females). Moreover, we found that this flexibility in striatal network coupling correlates with participants' learning rate and inverse temperature, two parameters derived from reinforcement learning models. Finally, we found that episodic learning, measured separately in the same participants at the same time, was related to dynamic connectivity in distinct brain networks. These results suggest that dynamic changes in striatal-centered networks provide a mechanism for information integration during reinforcement learning.

SIGNIFICANCE STATEMENT Learning from the outcomes of actions, referred to as reinforcement learning, is an essential part of life. The roles of individual brain regions in reinforcement learning have been well characterized in terms of updating values for actions or cues. Missing from this account, however, is an understanding of how different brain areas interact during learning to integrate sensory and value information. Here we characterize flexible striatal-cortical network dynamics that relate to reinforcement learning behavior.

Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury

The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that although inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.

SIGNIFICANCE STATEMENT Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.

Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the {mu}-Opioid Agonist Remifentanil

μ-Opioid receptor agonists are widely used within the contemporary treatment of pain, but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli, a phenomenon that has been, for example, reported after application of the fast-acting μ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 μg/kg body weight/min) compared with control in the brain, brainstem, and spinal cord in drug-naive male volunteers using fMRI. Subsequent to remifentanil suspension, we observed reduced heat pain thresholds and increased neuronal responses in pain-encoding as well as in key regions of the descending pain-modulatory system, such as the periaqueductal gray matter, the nucleus cuneiformis, and the rostral ventromedial medulla. Moreover, the spinal pain-related multivoxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that, already subsequent to a short-term infusion of the μ-opioid receptor agonist remifentanil, signaling in the descending pain-modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.

SIGNIFICANCE STATEMENT Opioids are widely used in modern medicine, but, in addition to their known side effects, it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Using the fast-acting μ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers, this study demonstrates how signaling changes occur along the entire descending pain-modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly by revealing modified responses in pain-modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents, the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans.

Noise-Induced Dysregulation of Quaking RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss

Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation, and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, to hearing deficiency.

SIGNIFICANCE STATEMENT Auditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons, and allow for fast conduction of electrical impulses along the auditory nerve. Here we show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. Study of a conditional mouse model that specifically depleted QKI in glia showed that QKI deficiency alone was sufficient to elicit myelin-related abnormality and auditory functional declines. These results establish QKI as a key molecular target in the noise response and a causative agent in hearing loss.

Diminished Cortical Thickness Is Associated with Impulsive Choice in Adolescence

Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision-making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence.

SIGNIFICANCE STATEMENT Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision-making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence.

Induction and Relief of Curiosity Elicit Parietal and Frontal Activity

Curiosity is a basic biological drive, but little is known about its behavioral and neural mechanisms. We can be curious about several types of information. On the one hand, curiosity is a function of the expected value of information, serving primarily to help us maximize reward. On the other hand, curiosity can be a function of the uncertainty of information, helping us to update what we know. In the current studies, we aimed to disentangle the contribution of information uncertainty and expected value of rewards to curiosity in humans. To this end, we designed a lottery task in which uncertainty and expected value of trial outcomes were manipulated independently and examined how neural activity and behavioral measures of curiosity were modulated by these factors. Curiosity increased linearly with increased outcome uncertainty, both when curiosity was explicitly probed as well as when it was implicitly tested by people's willingness to wait. Increased expected value, however, did not strongly relate to these curiosity measures. Neuroimaging results showed greater BOLD response with increasing outcome uncertainty in parietal cortex at the time of curiosity induction. Outcome updating when curiosity was relieved resulted in an increased signal in the insula, orbitofrontal cortex, and parietal cortex. Furthermore, the insula showed a linear increase corresponding to the size of the information update. These results suggest that curiosity is monotonically related to the uncertainty about one's current world model, the induction and relief of which are associated with activity in parietal and insular cortices, respectively.

SIGNIFICANCE STATEMENT Humans are curious by nature. When you hear your phone beep, you probably feel the urge to check the message right away, even though the message itself likely does not give you a direct reward. In this study, we demonstrated that curiosity can be driven by outcome uncertainty, over and above of reward. The induction of curiosity was accompanied by increased activity in the parietal cortex, whereas the information update at the time of curiosity relief was associated with activity in insular cortex. These findings advance our understanding of the behavioral and neural constituents of curiosity, which lies at the core of human information seeking and serves to optimize the individual's current world model.

Ketamine Alters Lateral Prefrontal Oscillations in a Rule-Based Working Memory Task

Acute administration of N-methyl-D-aspartate receptor (NMDAR) antagonists in healthy humans and animals produces working memory deficits similar to those observed in schizophrenia. However, it is unclear whether they also lead to altered low-frequency (≤60 Hz) neural oscillatory activities similar to those associated with schizophrenia during working memory processes. Here, we recorded local field potentials (LFPs) and single-unit activity from the lateral prefrontal cortex (LPFC) of three male rhesus macaque monkeys while they performed a rule-based prosaccade and antisaccade working memory task both before and after systemic injections of a subanesthetic dose (≤0.7 mg/kg) of ketamine. Accompanying working-memory impairment, ketamine enhanced the low-gamma-band (30–60 Hz) and dampened the beta-band (13–30 Hz) oscillatory activities in the LPFC during both delay periods and intertrial intervals. It also increased task-related alpha-band activities, likely reflecting compromised attention. Beta-band oscillations may be especially relevant to working memory processes because stronger beta power weakly but significantly predicted shorter saccadic reaction time. Also in beta band, ketamine reduced the performance-related oscillation as well as the rule information encoded in the spectral power. Ketamine also reduced rule information in the spike field phase consistency in almost all frequencies up to 60 Hz. Our findings support NMDAR antagonists in nonhuman primates as a meaningful model for altered neural oscillations and synchrony, which reflect a disorganized network underlying the working memory deficits in schizophrenia.

SIGNIFICANCE STATEMENT Low doses of ketamine, an NMDAR blocker, produce working memory deficits similar to those observed in schizophrenia. In the lateral prefrontal cortex, a key brain region for working memory, we found that ketamine altered neural oscillatory activities in similar ways that differentiate schizophrenic patients and healthy subjects during both task and nontask periods. Ketamine induced stronger gamma (30–60 Hz) and weaker beta (13–30 Hz) oscillations, reflecting local hyperactivity and reduced long-range communications. Furthermore, ketamine reduced performance-related oscillatory activities, as well as the rule information encoded in the oscillations and in the synchrony between single-cell activities and oscillations. The ketamine model helps link the molecular and cellular basis of neural oscillatory changes to the working memory deficit in schizophrenia.

Abstract Memory Representations in the Ventromedial Prefrontal Cortex and Hippocampus Support Concept Generalization

Memory function involves both the ability to remember details of individual experiences and the ability to link information across events to create new knowledge. Prior research has identified the ventromedial prefrontal cortex (VMPFC) and the hippocampus as important for integrating across events in the service of generalization in episodic memory. The degree to which these memory integration mechanisms contribute to other forms of generalization, such as concept learning, is unclear. The present study used a concept-learning task in humans (both sexes) coupled with model-based fMRI to test whether VMPFC and hippocampus contribute to concept generalization, and whether they do so by maintaining specific category exemplars or abstract category representations. Two formal categorization models were fit to individual subject data: a prototype model that posits abstract category representations and an exemplar model that posits category representations based on individual category members. Latent variables from each of these models were entered into neuroimaging analyses to determine whether VMPFC and the hippocampus track prototype or exemplar information during concept generalization. Behavioral model fits indicated that almost three-quarters of the subjects relied on prototype information when making judgments about new category members. Paralleling prototype dominance in behavior, correlates of the prototype model were identified in VMPFC and the anterior hippocampus with no significant exemplar correlates. These results indicate that the VMPFC and portions of the hippocampus play a broad role in memory generalization and that they do so by representing abstract information integrated from multiple events.

SIGNIFICANCE STATEMENT Whether people represent concepts as a set of individual category members or by deriving generalized concept representations abstracted across exemplars has been debated. In episodic memory, generalized memory representations have been shown to arise through integration across events supported by the ventromedial prefrontal cortex (VMPFC) and hippocampus. The current study combined formal categorization models with fMRI data analysis to show that the VMPFC and anterior hippocampus represent abstract prototype information during concept generalization, contributing novel evidence of generalized concept representations in the brain. Results indicate that VMPFC–hippocampal memory integration mechanisms contribute to knowledge generalization across multiple cognitive domains, with the degree of abstraction of memory representations varying along the long axis of the hippocampus.

Bottom-Up and Top-Down Factors Differentially Influence Stimulus Representations Across Large-Scale Attentional Networks

Visual attention is thought to be supported by three large-scale frontoparietal networks: the frontoparietal control network (FPCN), the dorsal attention network (DAN), and the ventral attention network (VAN). The traditional view is that these networks support visual attention by biasing and evaluating sensory representations in visual cortical regions. However, recent evidence suggests that frontoparietal regions actively represent perceptual stimuli. Here, we assessed how perceptual stimuli are represented across large-scale frontoparietal and visual networks. Specifically, we tested whether representations of stimulus features across these networks are differentially sensitive to bottom-up and top-down factors. In a pair of pattern-based fMRI studies, male and female human subjects made perceptual decisions about face images that varied along two independent dimensions: gender and affect. Across studies, we interrupted bottom-up visual input using backward masks. Within studies, we manipulated which stimulus features were goal relevant (i.e., whether gender or affect was relevant) and task switching (i.e., whether the goal on the current trial matched the goal on the prior trial). We found that stimulus features could be reliably decoded from all four networks and, importantly, that subregions within each attentional network maintained coherent representations. Critically, the different attentional manipulations (interruption, goal relevance, and task switching) differentially influenced feature representations across networks. Whereas visual interruption had a relatively greater influence on representations in visual regions, goal relevance and task switching had a relatively greater influence on representations in frontoparietal networks. Therefore, large-scale brain networks can be dissociated according to how attention influences the feature representations that they maintain.

SIGNIFICANCE STATEMENT Visual attention is supported by multiple frontoparietal attentional networks. However, it remains unclear how stimulus features are represented within these networks and how they are influenced by attention. Here, we assessed feature representations in four large-scale networks using a perceptual decision-making paradigm in which we manipulated top-down and bottom-up factors. We found that top-down manipulations such as goal relevance and task switching modulated feature representations in attentional networks, whereas bottom-up manipulations such as interruption of visual processing had a relatively stronger influence on feature representations in visual regions. Together, these findings indicate that attentional networks actively represent stimulus features and that representations within different large-scale networks are influenced by different forms of attention.