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

 

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dc.contributor.author Russell, Vivienne en_ZA
dc.contributor.author Oades, Robert en_ZA
dc.contributor.author Tannock, Rosemary en_ZA
dc.contributor.author Killeen, Peter en_ZA
dc.contributor.author Auerbach, Judith en_ZA
dc.contributor.author Johansen, Espen en_ZA
dc.contributor.author Sagvolden, Terje en_ZA
dc.date.accessioned 2015-10-12T10:59:25Z
dc.date.available 2015-10-12T10:59:25Z
dc.date.issued 2006 en_ZA
dc.identifier.citation Russell, V. A., Oades, R. D., Tannock, R., Killeen, P. R., Auerbach, J. G., Johansen, E. B., & Sagvolden, T. (2006). Response variability in attention-deficit/hyperactivity disorder: a neuronal and glial energetics hypothesis. Behav Brain Funct, 2(30), 23. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/14200
dc.identifier.uri http://dx.doi.org/10.1186/1744-9081-2-30
dc.description.abstract 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 (alpha1, alpha2 and beta-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. en_ZA
dc.language.iso eng en_ZA
dc.publisher BioMed Central Ltd en_ZA
dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution License en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_ZA
dc.source Behavioral and Brain Functions en_ZA
dc.source.uri http://www.behavioralandbrainfunctions.com en_ZA
dc.subject.other Attention-Deficit/Hyperactivity Disorder en_ZA
dc.title Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis en_ZA
dc.type Journal Article en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Department of Human Biology en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Russell, V., Oades, R., Tannock, R., Killeen, P., Auerbach, J., Johansen, E., & Sagvolden, T. (2006). Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis. <i>Behavioral and Brain Functions</i>, http://hdl.handle.net/11427/14200 en_ZA
dc.identifier.chicagocitation Russell, Vivienne, Robert Oades, Rosemary Tannock, Peter Killeen, Judith Auerbach, Espen Johansen, and Terje Sagvolden "Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis." <i>Behavioral and Brain Functions</i> (2006) http://hdl.handle.net/11427/14200 en_ZA
dc.identifier.vancouvercitation Russell V, Oades R, Tannock R, Killeen P, Auerbach J, Johansen E, et al. Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis. Behavioral and Brain Functions. 2006; http://hdl.handle.net/11427/14200. en_ZA
dc.identifier.ris TY - Journal Article AU - Russell, Vivienne AU - Oades, Robert AU - Tannock, Rosemary AU - Killeen, Peter AU - Auerbach, Judith AU - Johansen, Espen AU - Sagvolden, Terje AB - 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 (alpha1, alpha2 and beta-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. DA - 2006 DB - OpenUCT DO - 10.1186/1744-9081-2-30 DP - University of Cape Town J1 - Behavioral and Brain Functions LK - https://open.uct.ac.za PB - University of Cape Town PY - 2006 T1 - Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis TI - Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis UR - http://hdl.handle.net/11427/14200 ER - en_ZA


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