Control of the superior colliculus by the lateral prefrontal cortex

Several decades of patient, functional imaging and neurophysiological studies have supported a model in which the lateral prefrontal cortex (PFC) acts to suppress unwanted saccades by inhibiting activity in the oculomotor system. However, recent results from combined PFC deactivation and neural recordings of the superior colliculus in monkeys demonstrate that the primary influence of the PFC on the oculomotor system is excitatory, and stands in direct contradiction to the inhibitory model of PFC function. Although erroneous saccades towards a visual stimulus are commonly labelled reflexive in patients with PFC damage or dysfunction, the latencies of most of these saccades are outside of the range of express saccades, which are triggered directly by the visual stimulus. Deactivation and pharmacological manipulation studies in monkeys suggest that response errors following PFC damage or dysfunction are not the result of a failure in response suppression but can best be understood in the context of a failure to maintain and implement the proper task set.     

Design and analysis of group sequential clinical trials with multiple primary endpoints

In many phase III clinical trials, it is desirable to separately assess the treatment effect on two or more primary endpoints. Consider the MERIT-HF study, where two endpoints of primary interest were time to death and the earliest of time to first hospitalization or death (The International Steering Committee on Behalf of the MERIT-HF Study Group, 1997, American Journal of Cardiology 80[9B], 54J-58J). It is possible that treatment has no effect on death but a beneficial effect on first hospitalization time, or it has a detrimental effect on death but no effect on hospitalization. A good clinical trial design should permit early stopping as soon as the treatment effect on both endpoints becomes clear. Previous work in this area has not resolved how to stop the study early when one or more endpoints have no treatment effect or how to assess and control the many possible error rates for concluding wrong hypotheses. In this article, we develop a general methodology for group sequential clinical trials with multiple primary endpoints. This method uses a global alpha-spending function to control the overall type I error and a multiple decision rule to control error rates for concluding wrong alternative hypotheses. The method is demonstrated with two simulated examples based on the MERIT-HF study.     

Toward a culture-bound syndrome-based insanity defense?

The American Psychiatric Association's recent inclusion of a Glossary of Culture-Bound Syndromes within DSM-IV draws upon decades of medical anthropological and cultural psychiatric research to afford culture-bound syndromes (CBSs) a newfound legitimacy within professional Western psychiatric nosology. While DSM-IV's recognition of the CBS concept as a category of psychosocial distress has important clinical implications for mental health care practitioners throughout the world, it also has significant legal implications. Given that several CBSs involve a degree of psychological impairment that may satisfy the standard for legal insanity under certain circumstances, this essay focuses on the potential emergence of an insanity defense based on the claim that an immigrant or minority defendant was suffering from a CBS at the time of his or her criminal act. Aimed at initiating interdisciplinary debate over the reification of the CBS concept, the essay discusses the theoretical ambiguity and status of CBSs within professional Western psychiatry, describes what a CBS-based insanity defense might look like, and considers the relevant challenges facing medical anthropologists and cultural psychiatrists, on the one hand, and legal practitioners, on the other. The essay identifies a pressing need for interdisciplinary debate concerning the validity, scope, and viability of CBS-based insanity defenses.     

Differential Sensitivity of Prefrontal Cortex and Hippocampus to Alcohol-Induced Toxicity

The prefrontal cortex (PFC) is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus. This increased vulnerability is evidenced by elevated oxidative stress-induced DNA damage and enhanced expression of apoptotic markers in PFC neurons. We also found that one-carbon metabolism (OCM) impairment plays a significant role in alcohol toxicity to the PFC seen from the difference in the effects of acute and chronic alcohol exposure on DNA repair and from exaggeration of the damaging effects upon additional OCM impairment in mice deficient in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR). Given that damage to the PFC leads to loss of executive function and addiction, our study may shed light on the mechanism of alcohol addiction.     

The repair rate of radiation-induced DNA damage: a stochastic interpretation based on the gamma function

There is a large body of evidence that stress-induced DNA damage may be responsible for cell lethality, cancer proneness and/or immune reaction. However, statistical features of their repair rate remain poorly documented. In order to interpret the shape of the radiation-induced DNA damage repair curves with a minimum of biological assumptions, we introduced the concept of repair probability, specific to any individual radiation-induced DNA damage, whatever its biochemical type. We strengthened the apparent paradox that the repair rate of a population of DNA damage is time-dependent even if the repair rate of the individual DNA damage is constant. Hence, the existing models, based on a dual approach of the DNA repair may be insufficient for describing the DNA repair rate over a large range of repair times. Since the repair probability of DNA damage cannot be assessed individually, the measurement of the DNA repair rate is assumed to consist in determining the instantaneous mean of all repair probabilities. The relevance of this model was examined with different endpoints: cell species, genotypes, radiation type and chromatin condensation. The Euler's Gamma function was shown to provide the distribution the most consistent with such hypotheses. Furthermore, formulas, deduced from the Gamma distribution, were found to be compatible with our previous model, empirically defined but based on a variable repair half-time.     

The human amygdala and orbital prefrontal cortex in behavioural regulation

Survival in complex environments depends on an ability to optimize future behaviour based on past experience. Learning from experience enables an organism to generate predictive expectancies regarding probable future states of the world, enabling deployment of flexible behavioural strategies. However, behavioural flexibility cannot rely on predictive expectancies alone and options for action need to be deployed in a manner that is responsive to a changing environment. Important moderators on learning-based predictions include those provided by context and inputs regarding an organism's current state, including its physiological state. In this paper, I consider human experimental approaches using functional magnetic resonance imaging that have addressed the role of the amygdala and prefrontal cortex (PFC), in particular the orbital PFC, in acquiring predictive information regarding the probable value of future events, updating this information, and shaping behaviour and decision processes on the basis of these value representations.     

The parental obligation to expand a child's range of open futures when making genetic trait selections for their child

As parents become increasingly able to make genetic trait selections on behalf of their children, they will need ethical guidance in deciding what genetic traits to select. Dena Davis has argued that parents act unethically if they make selections that constrain their child's range of futures. But some selections may expand the child's range of futures. And other selections may shift the child's range of futures, without either constraining or expanding that range. I contend that not only would parents act unethically if they make selections that constrain the range of their child's futures, they would act unethically if they make selections that shift the range of their child's futures, because selections that shift the range of the child's futures would allow parents to over-determine their child's futures. Thus, I contend that parents would act ethically only if they make selections that expand their child's range of futures.     

Calling by Concluding Sentinels: Coordinating Cooperation or Revealing Risk?

Efficient cooperation requires effective coordination of individual contributions to the cooperative behaviour. Most social birds and mammals involved in cooperation produce a range of vocalisations, which may be important in regulating both individual contributions and the combined group effort. Here we investigate the role of a specific call in regulating cooperative sentinel behaviour in pied babblers (Turdoides bicolor). 'Fast-rate chuck' calls are often given by sentinels as they finish guard bouts and may potentially coordinate the rotation of individuals as sentinels, minimising time without a sentinel, or may signal the presence or absence of predators, regulating the onset of the subsequent sentinel bout. We ask (i) when fast-rate chuck calls are given and (ii) what effect they have on the interval between sentinel bouts. Contrary to expectation, we find little evidence that these calls are involved in regulating the pied babbler sentinel system: observations revealed that their utterance is influenced only marginally by wind conditions and not at all by habitat, while observations and experimental playback showed that the giving of these calls has no effect on inter-bout interval. We conclude that pied babblers do not seem to call at the end of a sentinel bout to maximise the efficiency of this cooperative act, but may use vocalisations at this stage to influence more individually driven behaviours.     

Hastening death and respect for dignity: Kantianism at the end of life

Suppose that a young athlete has just become quadriplegic. He expects to live several more decades, but out of self‐interest he autonomously chooses to engage in physician‐assisted suicide (PAS) or voluntary active euthanasia (VAE). Some of us are unsure whether he or his physician would be acting rightly in ending his life. One basis for such doubt is the notion that persons have dignity in a Kantian sense. This paper probes responses that David Velleman and Frances Kamm have suggested to the question of whether participating in PAS or VAE to benefit oneself, as the young man might, respects the dignity of persons, specified in an orthodox Kantian way. Velleman claims that it does not, while Kamm insists that, in certain circumstances, it does. I argue against Kamm's position. I go on to contend that while orthodox Kantianism might provide a basis for moral concern regarding the case of the young quadriplegic, it suffers from two serious shortcomings. First, it implies that terminally ill patients are wrong to request VAE or engage in PAS to avoid intense suffering, at least when this suffering has not yet overwhelmed their reason. Second, orthodox Kantianism implies that it is wrong for physicians to withdraw such patients from life‐sustaining treatments, even if they request it. To remedy these shortcomings, I sketch an unorthodox Kantian account of respect for the dignity of persons. This account promises to capture the idea that it would be morally problematic for doctors to help the young quadriplegic to die, but to avoid the shortcomings of an orthodox Kantian account.     

The effects of dominance on leadership and energetic gain: a dynamic game between pairs of social foragers

Although social behaviour can bring many benefits to an individual, there are also costs that may be incurred whenever the members of a social group interact. The formation of dominance hierarchies could offer a means of reducing some of the costs of social interaction, but individuals within the hierarchy may end up paying differing costs dependent upon their position within the hierarchy. These differing interaction costs may therefore influence the behaviour of the group, as subordinate individuals may experience very different benefits and costs to dominants when the group is conducting a given behaviour. Here, a state-dependent dynamic game is described which considers a pair of social foragers where there is a set dominance relationship within the pair. The model considers the case where the subordinate member of the pair pays an interference cost when it and the dominant individual conduct specific pairs of behaviours together. The model demonstrates that if the subordinate individual pays these energetic costs when it interacts with the dominant individual, this has effects upon the behaviour of both subordinate and the dominant individuals. Including interaction costs increases the amount of foraging behaviour both individuals conduct, with the behaviour of the pair being driven by the subordinate individual. The subordinate will tend to be the lighter individual for longer periods of time when interaction costs are imposed. This supports earlier suggestions that lighter individuals should act as the decision-maker within the pair, giving leadership-like behaviours that are based upon energetic state. Pre-existing properties of individuals such as their dominance will be less important for determining which individual makes the decisions for the pair. This suggests that, even with strict behavioural hierarchies, identifying which individual is the dominant one is not sufficient for identifying which one is the leader.     

Thinking about Possible People: A Comment on Tooley and Rachels

Most people believe it would be wrong to bring a child into the world if in all likelihood its life would be miserable. But if pain and suffering count against bringing someone into existence, why do pleasure and happiness not count in favour of bringing them into existence? Recently in this journal Michael Tooley has re‐affirmed his rights‐based explanation for this asymmetry. In a nutshell: to create an individual whose life is not worth living would be to wrong that individual – to create an obligation that cannot be fulfilled – but it is not possible to wrong an individual who is not brought into existence. In the same issue of this journal, in an article covering a range of arguments for and against the claim that it would be good for additional people to exist, Stuart Rachels objects to Tooley’s account on the ground that it has counterintuitive implications. His most interesting argument involves a Parfit‐style counterexample: a woman is about to take a fertility pill that will result in twins, one of whom will be healthy and the other of whom will not. Does it make a difference, morally speaking, if the woman knows which of the twins will be healthy and which will not? In this paper I argue that both Rachels’ criticism of Tooley’s rights‐based account, and Tooley’s own defence of it, are unsuccessful due to their failure to come to grips with the semantics of names for possible individuals. Both of them implicitly assume that it is possible to have a potential person in mind, in a way that misleads them about the fairness of actions that involve possible people. The significance of this extends to other areas such as abortion, population policy, and embryo experimentation, where examples involving possible people are common.     

Bovine tuberculosis in brushtail possums: models, dogma and data

Three different models of bovine tuberculosis (Tb) in brushtail possums were evaluated against their stated purpose, and testable assumptions and predictions evaluated against available data where possible. Not surprisingly, two of the models may be falsified based on currently available data with respect to either important model assumptions or predictions, and the third may suffer from being right for the wrong reason. This does not mean that these models are not useful. To the contrary, I argue that all models, especially those published in the scientific literature have largely addressed their stated purpose, and have contributed to our understanding of and ability to manage bovine tuberculosis infection in brushtail possum populations. No model, however, satisfactorily explains the pronounced spatial clustering of possum Tb, and the models critiqued have provided little strong inference as to the routes of transmission of Tb among possums. This situation is not helped by the scarcity of datasets on Tb in uncontrolled possum populations that are readily available to confront competing possum/Tb models with. As time passes, there is a very real risk that these data sets will be lost. This is of particular concern, as the expansion in the area of New Zealand under active possum management means the future opportunity to collect further data on Tb in uncontrolled possum populations is severely limited.     

Dynamic neuroplasticity after human prefrontal cortex damage

Memory and attention deficits are common after prefrontal cortex (PFC) damage, yet people generally recover some function over time. Recovery is thought to be dependent upon undamaged brain regions, but the temporal dynamics underlying cognitive recovery are poorly understood. Here, we provide evidence that the intact PFC compensates for damage in the lesioned PFC on a trial-by-trial basis dependent on cognitive load. The extent of this rapid functional compensation is indexed by transient increases in electrophysiological measures of attention and memory in the intact PFC, detectable within a second after stimulus presentation and only when the lesioned hemisphere is challenged. These observations provide evidence supporting a dynamic and flexible model of compensatory neural plasticity.     

Nonspecific Elicitation of Antibody-Forming Cells in the Mouse Spleen by Bacterial Lipopolysaccharide

Mechanisms of nonspecific elicitation of anti-sheep erythrocyte (SRBC) hemolytic antibody plaque-forming cells (PFC) in mouse spleens with an injection of bacterial endotoxin (lipopolysaccharide (LPS)) were studied in comparison with the genesis of naturally occurring ‘background’ PFC in normal mouse spleens and of rapidly arising PFC in mouse spleens after immunization with SRBC. The cytokinetic pattern of anti-SRBC PFC response after an injection of LPS was quite different from that of the response elicited after immunization with SRBC. In addition, even though LPS nonspecifically elicited anti-SRBC PFC response in mice, LPS could not confer any immunological memory on mouse immunocytes for a ‘secondary-type’ anti-SRBC PFC response to restimulation with LPS or SRBC. The administration of rabbit anti-mouse thymocyte immunoglobulin or anti-SRBC antiserum in mice markedly suppressed the PFC response after immunization with SRBC, but did not do so after stimulation with LPS. Neonatally thymectomized mice could still respond to stimulation with LPS, producing anti-SRBC PFC in their spleens. Injections of actinomycin D or cyclophosphamide into mice resulted in obvious reductions of the PFC responses elicited by either LPS or SRBC. However, injections of these immunosuppressive antisera or drugs did not affect the number of anti-SRBC PFC in normal mouse spleens. These results suggest that the geneses of anti-SRBC PFC developed under different conditions, i.e., background PFC, LPS-stimulated PFC, and antigen-stimulated PFC, are quite different from each other, and that the nonspecific elicitation of anti-SRBC PFC by LPS does not require the helper function of T lymphocytes. No obvious difference, however, was observed in the time of ontogenic maturation among these three different anti-SRBC PFC in the mouse spleens judging from when they were first manifested after birth.     

Behavioural differences between individuals and two populations of stickleback (Gasterosteus aculeatus)

Behavioural syndromes are correlations between behaviours in different functional contexts. Behavioural syndromes are attracting the attention of evolutionary biologists because they mean that different behaviours might not be free to evolve independently of one another. In a landmark study, Huntingford (1976) showed that individual stickleback which were bold toward predators were also aggressive toward conspecifics and active in an unfamiliar environment. Here, I revisited the activity-aggression-boldness syndrome in stickleback and tested the hypothesis that correlations between behaviours might act as evolutionary constraints. I measured a suite of behaviours on wild-caught individuals and their offspring from two different populations and calculated heritabilities and genetic correlations between the different behaviours. I found that these behaviours were phenotypically and genetically correlated in one population but not another. On average, boldness and aggression were negatively related to each other across the populations. These results suggest that behavioural syndromes don't always act as evolutionary constraints.     

Evolution of heterogeneous perceptual limits and indifference in competitive foraging

The collective behaviour of animal and human groups emerges from the individual decisions and actions of their constituent members. Recent research has revealed many ways in which the behaviour of groups can be influenced by differences amongst their constituent individuals. The existence of individual differences that have implications for collective behaviour raises important questions. How are these differences generated and maintained? Are individual differences driven by exogenous factors, or are they a response to the social dilemmas these groups face? Here I consider the classic case of patch selection by foraging agents under conditions of social competition. I introduce a multilevel model wherein the perceptual sensitivities of agents evolve in response to their foraging success or failure over repeated patch selections. This model reveals a bifurcation in the population, creating a class of agents with no perceptual sensitivity. These agents exploit the social environment to avoid the costs of accurate perception, relying on other agents to make fitness rewards insensitive to the choice of foraging patch. This provides a individual-based evolutionary basis for models incorporating perceptual limits that have been proposed to explain observed deviations from the Ideal Free Distribution (IFD) in empirical studies, while showing that the common assumption in such models that agents share identical sensory limits is likely false. Further analysis of the model shows how agents develop perceptual strategic niches in response to environmental variability. The emergence of agents insensitive to reward differences also has implications for societal resource allocation problems, including the use of financial and prediction markets as mechanisms for aggregating collective wisdom.     

How to fail in advertising: The potential of marketing theory to predict the community-level selection of defended prey

Economics and ecology both present us with a key challenge: scaling up from individual behaviour to community-level effects. As a result, biologists have frequently utilized theories and frameworks from economics in their attempt to better understand animal behaviour. In the study of predator–prey interactions, we face a particularly difficult task—understanding how predator choices and strategies will impact the ecology and evolution not just of individual prey species, but whole communities. However, a similar challenge has been encountered, and largely solved, in Marketing, which has created frameworks that successfully predict human consumer behaviour at the community level. We argue that by applying these frameworks to non-human consumers, we can leverage this predictive power to understand the behaviour of these key ecological actors in shaping the communities they act upon. We here use predator–prey interactions, as a case study, to demonstrate and discuss the potential of marketing and human-consumer theory in helping us bridge the gap from laboratory experiments to complex community dynamics.     

Lysosomal heterogeneity between and within cells with respect to resistance against oxidative stress

The prevailing opinion on lysosomal endurance is that, as long as the cells are still alive, these organelles are generally quite stable and, thus, do not induce cell damage by leaking their numerous powerful hydrolytic enzymes to the cytosol. We suggest that this opinion is basically wrong and consider that many lysosomes are quite vulnerable, especially to oxidative stress. Moreover, we suggest that cellular degeneration, including apoptosis as well as necrosis, follows upon lysosomal disruption. We have found differing stability of lysosomal membranes to oxidative stress, not only among different cell types, but also between cells of the same type and between lysosomes of individual cells. We suggest that cellular resistance to oxidative stress is mainly a function of three parameters: (i) the capacity to degrade hydrogen peroxide before it reaches, and may diffuse into, the acidic vacuolar compartment; (ii) the resistance to reactive oxygen species of lysosomal membranes; and (iii) the intralysosomal amounts of redox-active, low molecular weight iron. Iron-catalysed intralysosomal reactions, if pronounced enough, result in peroxidation and destabilization of the lysosomal membrane. Owing to differences in the cellular synthesis of hydrogen peroxide-degrading enzymes, degree of autophagocytotic degradation of iron-containing metalloproteins, lysosomal localization within the cytoplasm and intralysosomal iron chelation, the above three parameters may vary between both different and similar cells and between lysosomes of individual cells as well, explaining their observed variability with respect to resistance against oxidative stress This revised version was published online in November 2006 with corrections to the Cover Date.     

RESPECTING AUTONOMY WITHOUT DISCLOSING INFORMATION

There is widespread agreement that it would be both morally and legally wrong to treat a competent patient, or to carry out research with a competent participant, without the voluntary consent of that patient or research participant. Furthermore, in medical ethics it is generally taken that that consent must be informed. The most widely given reason for this has been that informed consent is needed to respect the patient's or research participant's autonomy. In this article I set out to challenge this claim by considering in detail each of the three most prominent ways in which ‘autonomy’ has been conceptualized in the medical ethics literature. I will argue that whilst these accounts support the claim that consent is needed if the treatment of competent patients, or research on competent individuals, is to respect their autonomy, they do not support the claim that informed consent is needed for this purpose.