Divergent thinking modulates interactions between episodic memory and schema knowledge: Controlled and spontaneous episodic retrieval processes.

The ability to generate novel ideas, known as divergent thinking, depends on both semantic knowledge and episodic memory. Semantic knowledge and episodic memory are known to interact to support memory decisions, but how they may interact to support divergent thinking is unknown. Moreover, it is debated whether divergent thinking relies on spontaneous or controlled retrieval processes. We addressed these questions by examining whether divergent thinking ability relates to interactions between semantic knowledge and different episodic memory processes. Participants completed the alternate uses task of divergent thinking, and completed a memory task in which they searched for target objects in schema-congruent or schema-incongruent locations within scenes. In a subsequent test, participants indicated where in each scene the target object had been located previously (i.e., spatial accuracy test), and provided confidence-based recognition memory judgments that indexed distinct episodic memory processes (i.e., recollection, familiarity, and unconscious memory) for the scenes. We found that higher divergent thinking ability-specifically in terms of the number of ideas generated-was related to (1) more of a benefit from recollection (a controlled process) and unconscious memory (a spontaneous process) on spatial accuracy and (2) beneficial differences in how semantic knowledge was combined with recollection and unconscious memory to influence spatial accuracy. In contrast, there were no effects with respect to familiarity (a spontaneous process). These findings indicate that divergent thinking is related to both controlled and spontaneous memory processes, and suggest that divergent thinking is related to the ability to flexibly combine semantic knowledge with episodic memory.

Lung microenvironments harbor Mycobacterium tuberculosis phenotypes with distinct treatment responses.

Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance are poorly understood. A pharmacodynamic marker called the RS ratio® quantifies ongoing rRNA synthesis based on the abundance of newly synthesized precursor rRNA relative to mature structural rRNA. Application of the RS ratio in the C3HeB/FeJ mouse model demonstrated that Mycobacterium tuberculosis populations residing in different tissue microenvironments are phenotypically distinct and respond differently to drug treatment with rifampin, isoniazid, or bedaquiline. This work provides a foundational basis required to address how anatomic and pathologic microenvironmental niches may contribute to long treatment duration and drug tolerance during the treatment of human tuberculosis.

Drug distribution and efficacy of the DprE1 inhibitor BTZ-043 in the C3HeB/FeJ mouse tuberculosis model.

BTZ-043, a suicide inhibitor of the Mycobacterium tuberculosis cell wall synthesis decaprenylphosphoryl-beta-D-ribose 2' epimerase, is under clinical development as a potential new anti-tuberculosis agent. BTZ-043 is potent and bactericidal in vitro but has limited activity against non-growing bacilli in rabbit caseum. To better understand its behavior in vivo, BTZ-043 was evaluated for efficacy and spatial drug distribution as a single agent in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon Mycobacterium tuberculosis infection. BTZ-043 promoted significant reductions in lung and spleen bacterial burdens in the C3HeB/FeJ mouse model after 2 months of therapy. BTZ-043 penetrates cellular and necrotic lesions and was retained at levels above the serum-shifted minimal inhibitory concentration in caseum. The calculated rate of kill was found to be highest and dose-dependent during the second month of treatment. BTZ-043 treatment was associated with improved histology scores of pulmonary lesions, especially compared to control mice, which experienced advanced fulminant neutrophilic alveolitis in the absence of treatment. These positive treatment responses to BTZ-043 monotherapy in a mouse model of advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in the caseum, and its high potency and bactericidal nature at drug concentrations achieved in necrotic lesions.

Model-Based Meta-Analysis of Relapsing Mouse Model Studies from the Critical Path to Tuberculosis Drug Regimens Initiative Database.

Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease-related cause of death worldwide, necessitating the development of new and improved treatment regimens. Nonclinical evaluation of candidate drug combinations via the relapsing mouse model (RMM) is an important step in regimen development, through which candidate regimens that provide the greatest decrease in the probability of relapse following treatment in mice may be identified for further development. Although RMM studies are a critical tool to evaluate regimen efficacy, making comprehensive "apples to apples" comparisons of regimen performance in the RMM has been a challenge in large part due to the need to evaluate and adjust for variability across studies arising from differences in design and execution. To address this knowledge gap, we performed a model-based meta-analysis on data for 17 unique regimens obtained from a total of 1592 mice across 28 RMM studies. Specifically, a mixed-effects logistic regression model was developed that described the treatment duration-dependent probability of relapse for each regimen and identified relevant covariates contributing to interstudy variability. Using the model, covariate-normalized metrics of interest, namely, treatment duration required to reach 50% and 10% relapse probability, were derived and used to compare relative regimen performance. Overall, the model-based meta-analysis approach presented herein enabled cross-study comparison of efficacy in the RMM and provided a framework whereby data from emerging studies may be analyzed in the context of historical data to aid in selecting candidate drug combinations for clinical evaluation as TB drug regimens.

Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments.

Murine tuberculosis drug efficacy studies have historically monitored bacterial burden based on CFU of Mycobacterium tuberculosis in lung homogenate. In an alternative approach, a recently described molecular pharmacodynamic marker called the RS ratio quantifies drug effect on a fundamental cellular process, ongoing rRNA synthesis. Here, we evaluated the ability of different pharmacodynamic markers to distinguish between treatments in three BALB/c mouse experiments at two institutions. We confirmed that different pharmacodynamic markers measure distinct biological responses. We found that a combination of pharmacodynamic markers distinguishes between treatments better than any single marker. The combination of the RS ratio with CFU showed the greatest ability to recapitulate the rank order of regimen treatment-shortening activity, providing proof of concept that simultaneous assessment of pharmacodynamic markers measuring different properties will enhance insight gained from animal models and accelerate development of new combination regimens. These results suggest potential for a new era in which antimicrobial therapies are evaluated not only on culture-based measures of bacterial burden but also on molecular assays that indicate how drugs impact the physiological state of the pathogen.

Markers of a plant-based diet relate to memory and executive function in older adults.

BACKGROUND: Although it is known that plant-based foods are important for physical health, little is known about the relationship between plant-based foods and cognitive health. Emerging evidence suggests that some macronutrients may influence cognition, but it is unclear which domains of cognition are involved; more importantly, it is unknown how a plant-based diet relates to cognition. OBJECTIVE: To examine associations between a plant-based dietary pattern and cognitive functioning. METHODS: Participants were 3,039 older adults who participated in the 2011-2014 waves of the National Health and Nutrition Examination Survey (NHANES). The present cross-sectional study used data on macronutrient intake from 24-hour dietary interviews, as well as performance on tests of long-term memory and executive function (i.e., delayed word recall, digit symbol substitution test, and animal fluency). Principal component analysis was used to extract a dietary pattern consistent with a plant-based diet. RESULTS: Greater adherence to a dietary pattern consistent with a plant-based diet was related to better performance on all cognitive tasks. Secondary analyses indicated that the associations between a plant-based dietary pattern and executive function accounted for the association between a plant-based dietary pattern and memory. Furthermore, this same plant-based dietary pattern was associated with reduced baseline inflammation in a separate dataset. CONCLUSIONS: Experimental manipulations are needed to determine the potential causal relations of these associations, but these results suggest that a plant-based diet relates to better cognition, especially through improved executive control. Future work should also attempt to extend these results by examining potential mechanisms underlying these associations, such as reduced inflammation.

Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 Inhibitors TBA-7371, PBTZ169, and OPC-167832.

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

Why do we retrace our visual steps? Semantic and episodic memory in gaze reinstatement.

When we look at repeated scenes, we tend to visit similar regions each time-a phenomenon known as resampling Resampling has long been attributed to episodic memory, but the relationship between resampling and episodic memory has recently been found to be less consistent than assumed. A possibility that has yet to be fully considered is that factors unrelated to episodic memory may generate resampling: for example, other factors such as semantic memory and visual salience that are consistently present each time an image is viewed and are independent of specific prior viewing instances. We addressed this possibility by tracking participants' eyes during scene viewing to examine how semantic memory, indexed by the semantic informativeness of scene regions (i.e., meaning), is involved in resampling. We found that viewing more meaningful regions predicted resampling, as did episodic familiarity strength. Furthermore, we found that meaning interacted with familiarity strength to predict resampling. Specifically, the effect of meaning on resampling was attenuated in the presence of strong episodic memory, and vice versa. These results suggest that episodic and semantic memory are each involved in resampling behavior and are in competition rather than synergistically increasing resampling. More generally, this suggests that episodic and semantic memory may compete to guide attention.

Determining the mechanisms through which recent life stress predicts working memory impairments: precision or capacity?

Prior research has found that recent life stress exposure is related to poorer working memory performance, but it remains unclear which aspects of working memory are related to stress. To address this important issue, we examined the extent to which recent life stress exposure was associated with working memory capacity (i.e., the number of items that can be held in working memory) and working memory precision (i.e., the quality of representations of items held within working memory) in a sample of 260 healthy young adults (Mage = 19.95 years old; range = 18-33). Recent life stress exposure and working memory were assessed with the Stress and Adversity Inventory for Daily Stress (Daily STRAIN) and color wheel task, respectively. We found that recent life stress was selectively associated with lower working memory capacity; moreover, the association of recent life stress with capacity was significantly stronger in magnitude than the non-significant association of recent life stress with precision. These associations were robust while controlling for potential confounds, including demographic factors, negative affect, and cumulative lifetime stress exposure. These results thus suggest that stress-related degradations in working memory capacity may help explain how recent life stress exposure affects working memory performance.

Effectiveness of wraparound versus case management for children and adolescents: results of a randomized study.

In this study, we compared service experiences and outcomes for youths with serious emotional disorder (SED) randomly assigned to care coordination via a defined wraparound process (n = 47) versus more traditional intensive case management (ICM; n = 46) The wraparound group received more mean hours of care management and services; however, there ultimately were no group differences in restrictiveness of residential placement, emotional and behavioral symptoms, or functioning. Wraparound implementation fidelity was found to be poor. Organizational culture and climate, and worker morale, were poorer for the wraparound providers than the ICM group. Results suggest that, for less-impaired youths with SED, less intensive options such as ICM may be equally effective to poor-quality wraparound delivered in the absence of wraparound implementation supports and favorable system conditions.

How schema knowledge influences memory in older adults: Filling in the gaps, or leading memory astray?

Age-related declines in episodic memory do not affect all types of mnemonic information equally: when to-be-remembered information is in line with one's prior knowledge, or schema-congruent, older adults often show no impairments. There are two major accounts of this effect: One proposes that schemas compensate for memory failures in aging, and the other proposes that schemas instead actively impair older adults' otherwise intact memory for incongruent information. However, the evidence thus far is inconclusive, likely due to methodological constraints in teasing apart these complex underlying dynamics. We developed a paradigm that separately examines the contributions of underlying memory and schema knowledge to a final memory decision, allowing these dynamics to be examined directly. In the present study, healthy older and younger adults first searched for target objects in congruent or incongruent locations within scenes. In a subsequent test, participants indicated where in each scene the target had been located previously, and provided confidence-based recognition memory judgments that indexed underlying memory, in terms of recollection and familiarity, for the background scenes. We found that age-related increases in schema effects on target location spatial recall were predicted and statistically mediated by age-related increases in underlying memory failures, specifically within recollection. We also found that, relative to younger adults, older adults had poorer spatial memory precision within recollected scenes but slightly better precision within familiar scenes-and age increases in schema bias were primarily exhibited within recollected scenes. Interestingly, however, there were also slight age-related increases in schema effects that could not be explained by memory deficits alone, outlining a role for active schema influences as well. Together, these findings support the account that age-related schema effects on memory are compensatory in that they are driven primarily by underlying memory failures, and further suggest that age-related deficits in memory precision may also drive schema effects.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Eye movements dissociate between perceiving, sensing, and unconscious change detection in scenes.

Detecting visual changes can be based on perceiving, whereby one can identify a specific detail that has changed, on sensing, whereby one knows that there is a change but is unable to identify what changed, or on unconscious change detection, whereby one is unaware of any change even though the change influences one's behavior. Prior work has indicated that the processes underlying these different types of change detection are functionally and neurally distinct, but the attentional mechanisms that are related to these different types of change detection remain largely unknown. In the current experiment, we examined eye movements during a change detection task in globally manipulated scenes, and participants indicated their change detection confidence on a scale that allowed us to isolate perceiving, sensing, and unconscious change detection. For perceiving-based change detection, but not sensing-based or unconscious change detection, participants were more likely to preferentially revisit highly changed scene regions across the first and second presentation of the scene (i.e., resampling). This increase in resampling started within 250 ms of the test scene onset, suggesting that the effect began within the first two fixations. In addition, changed scenes were related to more clustered (i.e., less dispersed) eye movements than unchanged scenes, particularly when the subjects were highly confident that no change had occurred - providing evidence for change detection outside of conscious awareness. The results indicate that perceiving, sensing, and unconscious change detection responses are related to partially distinct patterns of eye movements.

Episodic memory processes modulate how schema knowledge is used in spatial memory decisions.

Schema knowledge can dramatically affect how we encode and retrieve memories. Current models propose that schema information is combined with episodic memory at retrieval to influence memory decisions, but it is not known how the strength or type of episodic memory (i.e., unconscious memory versus familiarity versus recollection) influences the extent to which schema information is incorporated into memory decisions. To address this question, we had participants search for target objects in semantically expected (i.e., congruent) locations or in unusual (i.e., incongruent) locations within scenes. In a subsequent test, participants indicated where in each scene the target had been located previously, then provided confidence-based recognition memory judgments that indexed recollection, familiarity strength, and unconscious memory for the scenes. In both an initial online study (n = 133) and replication (n = 59), target location recall was more accurate for targets that had been located in schema-congruent rather than incongruent locations; importantly, this effect was strongest for new scenes, decreased with unconscious memory, decreased further with familiarity strength, and was eliminated entirely for recollected scenes. Moreover, when participants recollected an incongruent scene but did not correctly remember the target location, they were still biased away from congruent regions-suggesting that detrimental schema bias was suppressed in the presence of recollection even when precise target location information was not remembered. The results indicate that episodic memory modulates how schemas are used: Schema knowledge contributes to spatial memory judgments primarily when episodic memory fails to provide precise information, and recollection can override schema bias completely.

Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens.

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

The spatial distribution of attention predicts familiarity strength during encoding and retrieval.

The memories we form are determined by what we attend to, and conversely, what we attend to is influenced by our memory for past experiences. Although we know that shifts of attention via eye movements are related to memory during encoding and retrieval, the role of specific memory processes in this relationship is unclear. There is evidence that attention may be especially important for some forms of memory (i.e., conscious recollection), and less so for others (i.e., familiarity-based recognition and unconscious influences of memory), but results are conflicting with respect to both the memory processes and eye movement patterns involved. To address this, we used a confidence-based method of isolating eye movement indices of spatial attention that are related to different memory processes (i.e., recollection, familiarity strength, and unconscious memory) during encoding and retrieval of real-world scenes. We also developed a new method of measuring the dispersion of eye movements, which proved to be more sensitive to memory processing than previously used measures. Specifically, in 2 studies, we found that familiarity strength-that is, changes in subjective reports of memory confidence-increased with (a) more dispersed patterns of viewing during encoding, (b) less dispersed viewing during retrieval, and (c) greater overlap in regions viewed between encoding and retrieval (i.e., resampling). Recollection was also related to these eye movements in a similar manner, though the associations with recollection were less consistent across experiments. Furthermore, we found no evidence for effects related to unconscious influences of memory. These findings indicate that attentional processes during viewing may not preferentially relate to recollection, and that the spatial distribution of eye movements is directly related to familiarity-based memory during encoding and retrieval. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Digital Image Analysis of Heterogeneous Tuberculosis Pulmonary Pathology in Non-Clinical Animal Models using Deep Convolutional Neural Networks.

Efforts to develop effective and safe drugs for treatment of tuberculosis require preclinical evaluation in animal models. Alongside efficacy testing of novel therapies, effects on pulmonary pathology and disease progression are monitored by using histopathology images from these infected animals. To compare the severity of disease across treatment cohorts, pathologists have historically assigned a semi-quantitative histopathology score that may be subjective in terms of their training, experience, and personal bias. Manual histopathology therefore has limitations regarding reproducibility between studies and pathologists, potentially masking successful treatments. This report describes a pathologist-assistive software tool that reduces these user limitations, while providing a rapid, quantitative scoring system for digital histopathology image analysis. The software, called 'Lesion Image Recognition and Analysis' (LIRA), employs convolutional neural networks to classify seven different pathology features, including three different lesion types from pulmonary tissues of the C3HeB/FeJ tuberculosis mouse model. LIRA was developed to improve the efficiency of histopathology analysis for mouse tuberculosis infection models, this approach has also broader applications to other disease models and tissues. The full source code and documentation is available from https://Github.com/TB-imaging/LIRA.

Conscious and unconscious memory differentially impact attention: Eye movements, visual search, and recognition processes.

A hotly debated question is whether memory influences attention through conscious or unconscious processes. To address this controversy, we measured eye movements while participants searched repeated real-world scenes for embedded targets, and we assessed memory for each scene using confidence-based methods to isolate different states of subjective memory awareness. We found that memory-informed eye movements during visual search were predicted both by conscious recollection, which led to a highly precise first eye movement toward the remembered location, and by unconscious memory, which increased search efficiency by gradually directing the eyes toward the target throughout the search trial. In contrast, these eye movement measures were not influenced by familiarity-based memory (i.e., changes in subjective reports of memory strength). The results indicate that conscious recollection and unconscious memory can each play distinct and complementary roles in guiding attention to facilitate efficient extraction of visual information.

Mild acute stress improves response speed without impairing accuracy or interference control in two selective attention tasks: Implications for theories of stress and cognition.

Acute stress is generally thought to impair performance on tasks thought to rely on selective attention. This effect has been well established for moderate to severe stressors, but no study has examined how a mild stressor-the most common type of stressor-influences selective attention. In addition, no study to date has examined how stress influences the component processes involved in overall selective attention task performance, such as controlled attention, automatic attentional activation, decision-making, and motor abilities. To address these issues, we randomly assigned 107 participants to a mild acute stress or control condition. As expected, the mild acute stress condition showed a small but significant increase in cortisol relative to the control condition. Following the stressor, we assessed attention with two separate flanker tasks. One of these tasks was optimized to investigate component attentional processes using computational cognitive modeling, whereas the other task employed mouse-tracking to illustrate how response conflict unfolded over time. The results for both tasks showed that mild acute stress decreased response time (i.e., increased response speed) without influencing accuracy or interference control. Further, computational modeling and mouse-tracking analyses indicated that these effects were due to faster motor action execution time for chosen actions. Intriguingly, however, cortisol responses were unrelated to any of the observed effects of mild stress. These results have implications for theories of stress and cognition, and highlight the importance of considering motor processes in understanding the effects of stress on cognitive task performance.