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Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is characterized by a pattern of inattention, hyperactivity, and impulsivity that is cross-situational, persistent, and produces social and academic impairment. Research has shown that reinforcement processes are altered in ADHD. The dynamic developmental theory has suggested that a steepened delay-of-reinforcement gradient and deficient extinction of behavior produce behavioral symptoms of ADHD and increased behavioral variability. Method The present study investigated behavioral variability and elimination of non-target responses during acquisition in an animal model of ADHD, the spontaneously hypertensive rat (SHR), using Wistar Kyoto (WKY) rats as controls. The study also aimed at providing a novel approach to measuring delay-of-reinforcement gradients in the SHR and the WKY strains. The animals were tested in a modified operant chamber presenting 20 response alternatives. Nose pokes in a target hole produced water according to fixed interval (FI) schedules of reinforcement, while nose pokes in the remaining 19 holes either had no consequences or produced a sound or a short flickering of the houselight. The stimulus-producing holes were included to test whether light and sound act as sensory reinforcers in SHR. Data from the first six sessions testing FI 1 s were used for calculation of the initial distribution of responses. Additionally, Euclidean distance (measured from the center of each hole to the center of the target hole) and entropy (a measure of variability) were also calculated. Delay-of-reinforcement gradients were calculated across sessions by dividing the fixed interval into epochs and determining how much reinforcement of responses in one epoch contributed to responding in the next interval. Results Over the initial six sessions, behavior became clustered around the target hole. There was greater initial variability in SHR behavior, and slower elimination of inefficient responses compared to the WKY. There was little or no differential use of the stimulus-producing holes by either strain. For SHR, the reach of reinforcement (the delay-of-reinforcement gradient) was restricted to the preceding one second, whereas for WKY it extended about four times as far. Conclusion The present findings support previous studies showing increased behavioral variability in SHR relative to WKY controls. A possibly related phenomenon may be the slowed elimination of non-operant nose pokes in SHR observed in the present study. The findings provide support for a steepened delay-of-reinforcement gradient in SHR as suggested in the dynamic developmental theory of ADHD. Altered reinforcement processes characterized by a steeper and shorter delay-of-reinforcement gradient may define an ADHD endophenotype.

1. Abstract Background Current 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 hypothesis We 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 hypothesis Multi-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 hypothesis The 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.