Animal models of attention-deficit hyperactivity disorder

Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional α(2)-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD

The choice of basic variables in current-density functional theory

The selection of basic variables in current-density functional theory and formal properties of the resulting formulations are critically examined. Focus is placed on the extent to which the Hohenberg--Kohn theorem, constrained-search approach and Lieb's formulation (in terms of convex and concave conjugation) of standard density-functional theory can be generalized to provide foundations for current-density functional theory. For the well-known case with the gauge-dependent paramagnetic current density as a basic variable, we find that the resulting total energy functional is not concave. It is shown that a simple redefinition of the scalar potential restores concavity and enables the application of convex analysis and convex/concave conjugation. As a result, the solution sets arising in potential-optimization problems can be given a simple characterization. We also review attempts to establish theories with the physical current density as a basic variable. Despite the appealing physical motivation behind this choice of basic variables, we find that the mathematical foundations of the theories proposed to date are unsatisfactory. Moreover, the analogy to standard density-functional theory is substantially weaker as neither the constrained-search approach nor the convex analysis framework carry over to a theory making use of the physical current density

Behavioral variability, elimination of responses, and delay-of-reinforcement gradients in SHR and WKY rats

© 2007 Johansen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Relevance of the slowly-varying electron gas to atoms, molecules, and solids

Under a certain scaling, the electron densities of finite systems become both large and slowly-varying, so that the gradient expansions of the density functionals for the Kohn-Sham kinetic and exchange energies become asymptotically exact to order $\nabla^2$. Neutral atoms of large $Z$ scale similarly, but a cusp correction at the nucleus requires generalizing the gradient expansion for exchange, producing the wrong gradient coefficient in the slowly-varying limit. Meta-generalized gradient approximations (meta-GGA's) recover both the slowly-varying and large-$Z$ limits. GGA correlation energies of large-Z atoms are found to be accurate.Comment: 5 pages, 4 figures, submitted at PR

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

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 Ca(2+)), as well as astrocyte function (α(1), α(2 )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

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

Surface Reconstruction, Hydration, and Adhesion of Epoxy to the (0001) Surface of α-Berlinite: Insights from Density Functional Theory Calculations

Phosphoric acid anodization (PAA) is a candidate for replacement of toxic chromates during the surface treatment of aluminum prior to gluing in the aerospace industry. During PAA, a layer of AlPO4 forms on top of the alumina layer. We apply density functional theory computations to investigate how the AlPO4 surface reorganizes and how it bonds to water and adhesives. As our AlPO4 model, we use the α-berlinite (0001) surface. Taking the structure of the α-quartz (0001) surface reported by Rignanese et al. (Rignanese, G.-M.; De Vita, A.; Charlier, J.-C.; Gonze, X.; Car, R., Phys. Rev. B 2000, 61, 13250−13255) as a starting point, we find that the α-berlinite surface reconstructs. The lowest energy structure for α-berlinite (0001) is found to have a buckled configuration, with three-coordinated phosphorus protruding out of the surface and a neighboring aluminum atom binding to five oxygens. Different structures for the hydrated surface AlPO4·0.25H2O are presented, of which the most stable involves hydroxylation of the aforementioned buckle and of a new phosphorus buckle, accompanied by formation of a P−Al dative bond. We report results for the adhesion of a glue fragment derived from bisphenol A to the surface. The lowest energy is found for a covalently bonded structure, mimicking the most stable hydroxylated structure. The adhesion energy of the glue increases strongly when it is covalently bonded to the surface rather than being hydrogen bonded, providing superior adhesion to the material.publishedVersio

Prediction of solute diffusivity in Al assisted by first-principles molecular dynamics

Ab initio calculations of the solid-state diffusivity of solute atoms in bulk aluminium have previously been based on transition state theory (TST), employing transition state searches and systematic assessments of single jumps together with appropriate models of jump frequencies and correlation factors like the five-frequency model. This work compared TST benchmark predictions of diffusivities with first-principles molecular dynamics (FPMD). The TST calculations were performed at unprecedented high precision, including the temperature dependent entropy of vacancy formation which has not been included in previous studies of diffusion in Al; this led to improved agreement with experimental data. It was furthermore demonstrated that FPMD can yield sufficient statistics to predict the frequency of single jumps, and FPMD was used to successfully predict the macroscopic diffusivity of Si in Al. The latter is not possible in systems with higher activation energies, but it was demonstrated that FPMD in such cases can identify which jumps are prevalent for a given defect configuration. Thus, information from FPMD can be used to simplify the calculation of correlation terms, prefactors and effective transition barriers with TST significantly. This can be particularly important for the study of more complicated defect configurations, where the number of distinct jumps rapidly increases to be intractable by systematic methods.acceptedVersio

Prediction of solute diffusivity in Al assisted by first-principles molecular dynamics

Ab initio calculations of the solid-state diffusivity of solute atoms in bulk aluminium have previously been based on transition state theory (TST), employing transition state searches and systematic assessments of single jumps together with appropriate models of jump frequencies and correlation factors like the five-frequency model. This work compared TST benchmark predictions of diffusivities with first-principles molecular dynamics (FPMD). The TST calculations were performed at unprecedented high precision, including the temperature dependent entropy of vacancy formation which has not been included in previous studies of diffusion in Al; this led to improved agreement with experimental data. It was furthermore demonstrated that FPMD can yield sufficient statistics to predict the frequency of single jumps, and FPMD was used to successfully predict the macroscopic diffusivity of Si in Al. The latter is not possible in systems with higher activation energies, but it was demonstrated that FPMD in such cases can identify which jumps are prevalent for a given defect configuration. Thus, information from FPMD can be used to simplify the calculation of correlation terms, prefactors and effective transition barriers with TST significantly. This can be particularly important for the study of more complicated defect configurations, where the number of distinct jumps rapidly increases to be intractable by systematic methods

Surface Reconstruction, Hydration, and Adhesion of Epoxy to the (0001) Surface of α-Berlinite: Insights from Density Functional Theory Calculations

Phosphoric acid anodization (PAA) is a candidate for replacement of toxic chromates during the surface treatment of aluminum prior to gluing in the aerospace industry. During PAA, a layer of AlPO4 forms on top of the alumina layer. We apply density functional theory computations to investigate how the AlPO4 surface reorganizes and how it bonds to water and adhesives. As our AlPO4 model, we use the α-berlinite (0001) surface. Taking the structure of the α-quartz (0001) surface reported by Rignanese et al. (Rignanese, G.-M.; De Vita, A.; Charlier, J.-C.; Gonze, X.; Car, R., Phys. Rev. B 2000, 61, 13250−13255) as a starting point, we find that the α-berlinite surface reconstructs. The lowest energy structure for α-berlinite (0001) is found to have a buckled configuration, with three-coordinated phosphorus protruding out of the surface and a neighboring aluminum atom binding to five oxygens. Different structures for the hydrated surface AlPO4·0.25H2O are presented, of which the most stable involves hydroxylation of the aforementioned buckle and of a new phosphorus buckle, accompanied by formation of a P−Al dative bond. We report results for the adhesion of a glue fragment derived from bisphenol A to the surface. The lowest energy is found for a covalently bonded structure, mimicking the most stable hydroxylated structure. The adhesion energy of the glue increases strongly when it is covalently bonded to the surface rather than being hydrogen bonded, providing superior adhesion to the material