Peter R. Killeen

An Alternative to Null-Hypothesis Significance Tests

The statistic P rep estimates the probability of replicating an effect. It captures traditional publication criteria for signal-to-noise ratio, while avoiding parametric inference and the resulting Bayesian dilemma. In concert with effect size and replication intervals, P rep provides all of the information now used in evaluating research, while avoiding many of the pitfalls of traditional statistical inference.

Mathematical principles of reinforcement.

Effective conditioning requires a correlation between the experimenters definition of a response and an organisms, but an animals perception of its behavior differs from ours. These experiments explore various definitions of the response, using the slopes of learning curves to infer which comes closest to the organisms definition. The resulting exponentially weighted moving average provides a model of memory that is used to ground a quantitative theory of reinforcement. The theory assumes that: incentives excite behavior and focus the excitement on responses that are contemporaneous in memory. The correlation between the organisms memory and the behavior measured by the experimenter is given by coupling coefficients, which are derived for various schedules of reinforcement. The coupling coefficients for simple schedules may be concatenated to predict the effects of complex schedules. The coefficients are inserted into a generic model of arousal and temporal constraint to predict response rates under any scheduling arrangement. The theory posits a response-indexed decay of memory, not a time-indexed one. It requires that incentives displace memory for the responses that occur before them, and may truncate the representation of the response that brings them about. As a contiguity-weighted correlation model, it bridges opposing views of the reinforcement process. By placing the short-term memory of behavior in so central a role, it provides a behavioral account of a key cognitive process.

Response variability in Attention-Deficit/Hyperactivity Disorder: A neuronal and glial energetics hypothesis

1. AbstractBackgroundCurrent concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD.The hypothesisWe propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing).Testing the hypothesisMulti-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca2+), as well as astrocyte function (α1, α2 and β-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin).Implications of the hypothesisThe hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype – namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well.

The Spontaneously Hypertensive Rat model of ADHD – the importance of selecting the appropriate reference strain

Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl. The use of WKY/NCrl, outbred Wistar, Sprague Dawley or other rat strains as controls for SHRs may produce spurious neurobiological differences. Consequently, data may be misinterpreted if insufficient care is taken in the selection of the control group. It appears likely that the use of different control strains may underlie some of the discrepancies in results and interpretations in studies involving the SHR and WKY. Finally, we argue that WKY rats obtained from Charles River, Germany (WKY/NCrl) provide a promising model for the predominantly inattentive subtype of ADHD (ADHD-PI); in this case also the WKY/NHsd substrain should be used as control.

Chronic stress impairs spatial memory and motivation for reward without disrupting motor ability and motivation to explore.

This study uses an operant, behavioral model to assess the daily changes in the decay rate of short-term memory, motivation, and motor ability in rats exposed to chronic restraint. Restraint decreased reward-related motivation by 50% without altering memory decay rate or motor ability. Moreover, chronic restraint impaired hippocampal-dependent spatial memory on the Y maze (4-hr delay) and produced CA3 dendritic retraction without altering hippocampal-independent maze navigation (1-min delay) or locomotion. Thus, mechanisms underlying motivation for food reward differ from those underlying Y maze exploration, and neurobiological substrates of spatial memory, such as the hippocampus, differ from those that underlie short-term memory. Chronic restraint produces functional, neuromorphological, and physiological alterations that parallel symptoms of depression in humans.

An additive-utility model of delay discounting.

Goods remote in temporal, spatial, or social distance, or in likelihood, exert less control over our behavior than those more proximate. The decay of influence with distance, of perennial interest to behavioral economists, has had a renaissance in the study of delay discounting. By developing discount functions from marginal utilities, this article provides a framework that resolves several anomalies of intertemporal choice. Utilities are inferred to be power functions of monetary value, delay, and probability. Utility, not value, is discounted, with decisions made by adding the utility of a good to the disutility of a delay or contingency. The theory reduces to standard treatments, such as exponential, hyperbolic and hyperboloid, and exponential-power; naturally predicts magnitude effects and other asymmetries; is consistent with subadditivity, immediacy, and certainty effects; returns conjointly measured determinations of monetary utility and temporal distance functions; and is extensible to other dimensions of distance.

Central place foraging in Rattus norvegicus

Abstract Rats could accumulate food pellets by responding on one lever, and then gain access to them by responding on a second lever N times (experiment 1), by ceasing to respond on the first lever for D seconds (experiment 2), or by making a single, vigorous response of force W on the second lever (experiment 3). The design may be viewed as an analogue of central place foraging. As N (distance), D (time), or W (effort) increased, load (the average number of pellets accumulated before they were eaten) also increased. It appeared that delay mediated the effect of the other independent variables. A simple model of central place foraging was shown to accommodate the data.

How the propagation of error through stochastic counters affects time discrimination and other psychophysical judgments.

The performance of fallible counters is investigated in the context of pacemaker-counter models of interval timing. Failure to reliably transmit signals from one stage of a counter to the next generates periodicity in mean and variance of counts registered, with means power functions of input and standard deviations approximately proportional to the means (Webers law). The transition diagrams and matrices of the counter are self-similar: Their eigenvalues have a fractal form and closely approximate Julia sets. The distributions of counts registered and of hitting times approximate Weibull densities, which provide the foundation for a signal-detection model of discrimination. Different schemes for weighting the values of each stage may be established by conditioning. As higher order stages of a cascade come on-line the veridicality of lower order stages degrades, leading to scale-invariance in error. The capacity of a counter is more likely to be limited by fallible transmission between stages than by a paucity of stages. Probabilities of successful transmission between stages of a binary counter around 0.98 yield predictions consistent with performance in temporal discrimination and production and with channel capacities for identification of unidimensional stimuli.

Origins of altered reinforcement effects in ADHD

Attention-deficit/hyperactivity disorder (ADHD), characterized by hyperactivity, impulsiveness and deficient sustained attention, is one of the most common and persistent behavioral disorders of childhood. ADHD is associated with catecholamine dysfunction. The catecholamines are important for response selection and memory formation, and dopamine in particular is important for reinforcement of successful behavior. The convergence of dopaminergic mesolimbic and glutamatergic corticostriatal synapses upon individual neostriatal neurons provides a favorable substrate for a three-factor synaptic modification rule underlying acquisition of associations between stimuli in a particular context, responses, and reinforcers. The change in associative strength as a function of delay between key stimuli or responses, and reinforcement, is known as the delay of reinforcement gradient. The gradient is altered by vicissitudes of attention, intrusions of irrelevant events, lapses of memory, and fluctuations in dopamine function. Theoretical and experimental analyses of these moderating factors will help to determine just how reinforcement processes are altered in ADHD. Such analyses can only help to improve treatment strategies for ADHD.

The failure of Weber's law in time perception and production

Webers law--constancy of the coefficient of variation--is an apparently ubiquitous feature of time perception, and forms the foundation of several theories of timing. We sought evidence for Webers law in temporal production and categorization experiments. The production task required pigeons to switch between keys within a specified temporal window. The categorization task required them to classify a stimulus duration as either short or long. Weber fractions did not descend to a horizontal asymptote, but were U-shaped: they decreased as a function of target duration, and increased again at intermediate and long durations. This pattern conforms neither to Webers law, nor to its generalized form (Getty, D.J., 1975. Discrimination of short temporal intervals: a comparison of two models. Percept. Psychophys. 18, 1-8). A model of counter failure accommodated the U-shaped pattern.