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Abstract

BackgroundCurrent 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 ...

Functional Plasticity in Childhood Brain Disorders: When, What, How, and Whom to Assess

“…Those with sports concussion demonstrate substantial intraindividual variation (Rabinowitz and Arnett, 2013). Poor formation and supply of lactate may produce inefficient and variable performance in ADHD and other white matter disorders (Russell et al, 2006). …”

Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice

“…Glucocorticoid hormones modulate energy supply (Russell et al, 2006). Glucocorticoids not only can inhibit glucose transfer to neurons and astrocytes but also can curb the noradrenergic activity to reduce glycogen synthesis (Allaman et al, 2004).…”

Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the brain

“…Normotensive Wistar-Kyoto rats (WKY) are normally used as the control rats (1). Since SHR and SHRSP are not only used as rat models of essential hypertension and stroke, but also as rat models of attentiondeficit hyperactivity disorder (ADHD), studies using these rat models are expected to reveal genes not only related to hypertension and stroke, but also those related to ADHD (3)(4)(5)(6). In a previous study, as the first step of this project, we investigated gene expression profiles in adrenal glands in these 3 rats strains when the rats were 3 and 6 weeks of age (7).…”