Consistent Implementation of Decisions in the Brain

Despite the complexity and variability of decision processes, motor responses are generally stereotypical and independent of decision difficulty. How is this consistency achieved? Through an engineering analogy we consider how and why a system should be designed to realise not only flexible decision-making, but also consistent decision implementation. We specifically consider neurobiologically-plausible accumulator models of decision-making, in which decisions are made when a decision threshold is reached. To trade-off between the speed and accuracy of the decision in these models, one can either adjust the thresholds themselves or, equivalently, fix the thresholds and adjust baseline activation. Here we review how this equivalence can be implemented in such models. We then argue that manipulating baseline activation is preferable as it realises consistent decision implementation by ensuring consistency of motor inputs, summarise empirical evidence in support of this hypothesis, and suggest that it could be a general principle of decision making and implementation. Our goal is therefore to review how neurobiologically-plausible models of decision-making can manipulate speed-accuracy trade-offs using different mechanisms, to consider which of these mechanisms has more desirable decision-implementation properties, and then review the relevant neuroscientific data on which mechanism brains actually use.     

Design, Development and Decisions

Evolutionary ideas and modern biological knowledge have important roles to play in the understanding of human behaviour. Nevertheless, it is deeply misleading to regard humans as robots in the grip of their genes. A well designed brain should respond to the consequences of behaviour; if an understanding of the likely consequences can be achieved without actually performing the act, then a person who knows that they will be rewarded or punished for certain acts is bound to be influenced by that knowledge. A brain designed in that way facilitates the evolution of societies with explicit social approval of certain activities and explicit disapproval of others. The evolutionary approach to psychology does not imply that individuals do not make free choices. Individuals clearly do make a big difference to what happens in their lives through their decisions. They may be surprised by the consequences of their own actions. A well designed brain should be able to anticipate the consequences of various courses of action and choose between them on the basis of their likely costs and benefits. Planning before doing is clearly of great advantage. People do make well considered decisions and they benefit from doing so.     

Decisions in Force Field Development: An Alternative to Those Described by Roterman et al.

Abstract

We attempt to give an alternate point of view of the analysis by Roterman et al. (J. Biolmol. Struct. Dyn. 7, 415 (1989)). In particular, we argue for the use of flexible geometry and explicit inclusion of solvent effects in analyzing φ psi; maps of peptides.     

Better Informing Decision Making with Multiple Outcomes Cost-Effectiveness Analysis under Uncertainty in Cost-Disutility Space

Introduction

Comparing multiple, diverse outcomes with cost-effectiveness analysis (CEA) is important, yet challenging in areas like palliative care where domains are unamenable to integration with survival. Generic multi-attribute utility values exclude important domains and non-health outcomes, while partial analyses—where outcomes are considered separately, with their joint relationship under uncertainty ignored—lead to incorrect inference regarding preferred strategies.

Objective

The objective of this paper is to consider whether such decision making can be better informed with alternative presentation and summary measures, extending methods previously shown to have advantages in multiple strategy comparison.

Methods

Multiple outcomes CEA of a home-based palliative care model (PEACH) relative to usual care is undertaken in cost disutility (CDU) space and compared with analysis on the cost-effectiveness plane. Summary measures developed for comparing strategies across potential threshold values for multiple outcomes include: expected net loss (ENL) planes quantifying differences in expected net benefit; the ENL contour identifying preferred strategies minimising ENL and their expected value of perfect information; and cost-effectiveness acceptability planes showing probability of strategies minimising ENL.

Results

Conventional analysis suggests PEACH is cost-effective when the threshold value per additional day at home ( ₁) exceeds $1,068 or dominated by usual care when only the proportion of home deaths is considered. In contrast, neither alternative dominate in CDU space where cost and outcomes are jointly considered, with the optimal strategy depending on threshold values. For example, PEACH minimises ENL when ₁=$2,000 and ₂=$2,000 (threshold value for dying at home), with a 51.6% chance of PEACH being cost-effective.

Conclusion

Comparison in CDU space and associated summary measures have distinct advantages to multiple domain comparisons, aiding transparent and robust joint comparison of costs and multiple effects under uncertainty across potential threshold values for effect, better informing net benefit assessment and related reimbursement and research decisions.     

Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

The skeleton as an organ is widely distributed throughout the entire vertebrate body. Wnt signaling has emerged to play major roles in almost all aspects of skeletal development and homeostasis. Because abnormal Wnt signaling causes various human skeletal diseases, Wnt signaling has become a focal point of intensive studies in skeletal development and disease. As a result, promising effective therapeutic agents for bone diseases are being developed by targeting the Wnt signaling pathway. Understanding the functional mechanisms of Wnt signaling in skeletal biology and diseases highlights how basic and clinical studies can stimulate each other to push a quick and productive advancement of the entire field. Here we review the current understanding of Wnt signaling in critical aspects of skeletal biology such as bone development, remodeling, mechanotransduction, and fracture healing. We took special efforts to place fundamentally important discoveries in the context of human skeletal diseases.The skeleton has many important functions related to human health. Aside from the classical functions of the skeleton in structural support and movement, the bone matrix forms a major reservoir of calcium and other inorganic ions, and bone cells are active regulators of calcium homeostasis. Recent data suggest that bone cells can secrete hormones (e.g., FGF23 and osteocalcin) and likely play a physiologically significant role in regulating phosphate and energy homeostasis. It has emerged that Wnt signaling plays a major role controlling multiple aspects of skeletal development and maintenance. Thus, understanding how the Wnt pathway controls skeletal growth and homeostasis has broad implications for human health and disease.Cartilage and bone define the skeleton and are produced by chondrocytes and osteoblasts, respectively. During embryonic development, bones are formed by two distinct processes: intramembranous and endochondral ossification (Fig. 1A). A number of cranial bones and the lateral portion of the clavicles are formed by intramembranous ossification. In this process, mesenchymal progenitor cells condense and differentiate directly into bone-forming osteoblasts. The majority of bones in our body are formed by endochondral ossification, during which mesenchymal progenitor cells condense and differentiate first into cartilage-forming chondrocytes to generate an avascular template of the future bone. Chondrocytes in these templates undergo a program of proliferation and progressive cellular maturation. Eventually, they exit the cell cycle and become pre-hypertrophic, then terminally differentiating into hypertrophic chondrocytes, which are eliminated ultimately by apoptosis. Hypertrophic chondrocytes produce a matrix that is calcified and functions as a scaffold for new bone formation. Concomitant with chondrocyte hypertrophy, osteoclasts, osteoblasts, and blood vessels migrate in from perichondral regions and remodel this template into bone.Open in a separate windowFigure 1.Mechanisms of skeleton formation. (A) Bones can form by either intramembranous or endochondral ossification. Both processes are initiated by the condensation of mesenchymal cells. During intramembranous ossification, mesenchymal cells differentiate directly into osteoblasts and deposit bone. During endochondral ossification, mesenchymal cells differentiate into chondrocytes and first make a cartilage intermediate. Chondrocytes in the center of the bone initiate a growth plate, stop proliferating, and undergo hypertrophy. Hypertrophic chondrocytes mineralize their matrix and undergo apoptosis, attracting blood vessels and osteoblasts that remodel the intermediate into bone. (B) The first histologic sign of synovial joint formation is the gathering and flattening of cells, forming the interzone. Cavitation occurs within the presumptive joint separating the two cartilaginous structures. Remodeling and maturation proceed to give rise to the mature synovial joint. Wnt signaling plays a significant role in controlling almost all aspects of skeleton formation. Osteoblasts (purple); chondrocytes (blue); osteochondroprogenitor cells (brown).The developing skeletal elements are often segmented to form joints, which are required to support mobility. Synovial joints, which allow movement via smooth articulation between bones, form when chondrogenic cells in a newly formed cartilage undergo a program of dedifferentiation and flattening to form an interzone (Fig. 1B). Cavitation occurs within the flattened cells, allowing physical separation of the skeletal elements, and the formation of the synovial cavity. Cells and tissues in and around the interzone are remodeled at the same time to form the articular cartilage and other joint structures. Failure to form or maintain joints leads to joint fusion or osteoarthritis, a major skeletal disease.Following its formation, bone remains a regenerative tissue and is maintained during postnatal life by continuous remodeling. This highly active, homeostatic process is required for its functions and is controlled by three cell types: osteoblasts on the bone surface that deposit new bone matrix; osteocytes embedded in bone that are terminally differentiated from osteoblasts and function as mechanical and metabolic sensors; and the matrix-resorbing osteoclasts (Fig. 2). Osteoblasts are derived from mesenchymal stem cells (MSCs), whereas osteoclasts differentiate from hematopoietic progenitors. Decreased bone mass may be due to reduced osteoblast function or elevated osteoclast activity, and, conversely, increased bone mass may result from increased osteoblast function or decreased osteoclast activity. The precise balance of formation and resorption is critical for maintaining normal bone mass, and alterations in this balance lead to common bone diseases such as osteoporosis and osteopetrosis.Open in a separate windowFigure 2.Anatomy of bone. Cortical and trabecular bone represent the two major forms of bone. Osteoblasts (dark purple) are present on the surface and form new bone. Osteocytes (brown) are terminally differentiated osteoblasts that have become embedded in bone and communicate information to one another and to cells on the surface to regulate bone homeostasis. Osteoclasts (blue) are of hematopoietic origin and catabolize bone. A major function of Wnt/β-catenin signaling in osteoblasts is to suppress RANKL and to promote OPG production, thereby inhibiting osteoclast formation.There are two major bone types, cortical and trabecular, which show different anatomical properties (Fig. 2). Cortical (or compact) bone is the solid, densely packed bone that forms the outer layer of most bones and gives strength and rigidity. Trabecular (or cancellous) bone is present mostly in the marrow cavities of long bones and is the dominant bone type in vertebral bodies. Trabecular bone forms a porous, cobweb-like network of trabeculae whose large surface area is thought to facilitate the metabolic activity of bones mediated by osteoblasts and osteoclasts. Trabeculae are sites of active remodeling and will often orient in the direction of mechanical loading, dissipating the energy of loading and adding to bone strength. It is trabecular bone, rather than cortical bone, which is most severely affected in osteoporosis.The Wnt/β-catenin pathway plays a major role in controlling skeletal development and homeostasis, which are the focus of this work. We focus not only on differentiation of skeletal cells and formation of skeletal tissues, but also on the role of the Wnt/β-catenin signaling pathway on bone homeostasis, mechanotransduction, and wound healing, paying particular attention to human and mouse studies.     

Mitigation of an anthracycline-induced cardiomyopathy by pretreatment with razoxane: a quantitative morphological assessment

A quantitative evaluation of structural modifications was undertaken in the myocardium of daunorubicin (DNR)-treated and razoxane (RZ)-protected mice. BDF1 mice were injected with DNR, 15 mg/kg; a second group of mice was subjected to the same conditions but, in addition, received a pretreatment of RZ, 200 mg/kg. Representative cubes of myocardial tissue were processed for viewing with the electron microscope. Five hundred myocardial cells in each group were examined for the presence of lesions which had been categorized as early, moderate, or advanced. Contrasting the total number of demonstrable lesions in each group revealed a statistically significant reduction of 38% in abnormalities present in RZ-protected mice. By category, RZ-pretreated mice showed a mitigation in the appearance of early and moderate alterations and a striking reduction in the incidence of advanced, irreversible lesions. These results indicate that the cardiomyopathy associated with DNR administration can be ameliorated by pretreatment with RZ; this protective effect is markedly exerted by preventing the development of severe, irreversible lesions in the murine myocardium; the initial, non-transient structural alteration subsequent to DNR-exposure appears to affect the myocardial sarcoplasmic reticulum.     

Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder

Background

Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.

Methodology/Principal Findings

We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.

Conclusions/Significance

Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.     

Gibberellic acid by solid state fermentation: Consistent and improved yields

Five strains each of Gibberella fujikuroi and Fusarium monoliforme were screened to select G. fujikuroi P-3, a strain capable of giving consistent production of gibberellic acid (GA(3)) by solid state fermentation (SSF). The comparative production of GA(3) by SSF and submerged fermentation (SmF) indicated better productivity with the former technique. The accumulation of GA(3) was 1.626 times higher in the case of SSF. On the basis of available carbohydrates in the media, the percent conversions were 0.096 and 0.156 in SmF and SSF, respectively. The use of coarse wheat bran of the particle size of 0.3-0.4 cm resulted in an increase of 2.5 times in the yield of GA(3). The enrichment of commercial wheat bran with soluble starch gave enhanced accumulation to an extent of 3.5 times. The relation between GA(3) production and cell growth in SSF was similar to that encountered in SmF. The consistent and improved yields to a tune of 1.22 g GA(3) per kilogram dry moldy bran (DMB) establish the potential and feasibility of SSF for the production of GA(3) by G. fujikuroi P-3. On preliminary cost analysis, a net savings of about 60% and 50% on fermentation medium cost and the expenditure on down-stream processing, respectively, as compared to the presently employed SmF technique was evident.     

The Effect of How Outcomes Are Framed on Decisions about Whether to Take Antihypertensive Medication: A Randomized Trial

Background

We conducted an Internet-based randomized trial comparing three valence framing presentations of the benefits of antihypertensive medication in preventing cardiovascular disease (CVD) for people with newly diagnosed hypertension to determine which framing presentation resulted in choices most consistent with participants'' values.

Methods and Findings

In this second in a series of televised trials in cooperation with the Norwegian Broadcasting Company, adult volunteers rated the relative importance of the consequences of taking antihypertensive medication using visual analogue scales (VAS). Participants viewed information (or no information) to which they were randomized and decided whether or not to take medication. We compared positive framing over 10 years (the number escaping CVD per 1000); negative framing over 10 years (the number that will have CVD) and negative framing per year over 10 years of the effects of antihypertensive medication on the 10-year risk for CVD for a 40 year-old man with newly diagnosed hypertension without other risk factors. Finally, all participants were shown all presentations and detailed patient information about hypertension and were asked to decide again. We calculated a relative importance score (RIS) by subtracting the VAS-scores for the undesirable consequences of antihypertensive medication from the VAS-score for the benefit of CVD risk reduction. We used logistic regression to determine the association between participants'' RIS and their choice. 1,528 participants completed the study. The statistically significant differences between the groups in the likelihood of choosing to take antihypertensive medication in relation to different values (RIS) increased as the RIS increased. Positively framed information lead to decisions most consistent with those made by everyone for the second, more fully informed decision. There was a statistically significant decrease in deciding to take antihypertensives on the second decision, both within groups and overall.

Conclusions

For decisions about taking antihypertensive medication for people with a relatively low baseline risk of CVD (70 per 1000 over 10 years), both positive and negative framing resulted in significantly more people deciding to take medication compared to what participants decided after being shown all three of the presentations.

Trial Registration

International Standard Randomised Controlled Trial Number Register ISRCTN 33771631     

Expression of the Kdp ATPase Is Consistent with Regulation by Turgor Pressure

The kdpFABC operon of Escherichia coli encodes the four protein subunits of the Kdp K⁺ transport system. Kdp is expressed when growth is limited by the availability of K⁺. Expression of Kdp is dependent on the products of the adjacent kdpDE operon, which encodes a pair of two-component regulators. Studies with kdp-lac fusions led to the suggestion that change in turgor pressure acts as the signal to express Kdp (L. A. Laimins, D. B. Rhoads, and W. Epstein, Proc. Natl. Acad. Sci. USA 78:464–468, 1981). More recently, effects of compatible solutes, among others, have been interpreted as inconsistent with the turgor model (H. Asha and J. Gowrishankar, J. Bacteriol. 175:4528–4537, 1993). We re-examined the effects of compatible solutes and of medium pH on expression of Kdp in studies in which growth rate was also measured. In all cases, Kdp expression correlated with the K⁺ concentration when growth began to slow. Making the reasonable but currently untestable assumptions that the reduction in growth rate by K⁺ limitation is due to a reduction in turgor and that addition of betaine does not increase turgor, we concluded that all of the data on Kdp expression are consistent with control by turgor pressure.     

Design and perception: Making the zoo experience real

The purpose of this paper is to encourage the application of theories of human behavior to zoo design so that zoo visitors are environmentally predisposed to learn from and enjoy what they experience. The ultimate goal is to increase public awareness and appreciation of the importance of habitat and its protection to wildlife conservation and to present zoo animals in such a way that their reason for being and rights to existence are intuitively self-evident to viewers. Many of the concepts and guidelines presented appear to be suitable subjects of behavioral research, whose findings would assist designers and other zoo professionals in continued improvement of the zoo visitor's experience.