A behavioral neuroenergetics theory of ADHD

Abstract

Energetic insufficiency in neurons due to inadequate lactate supply is implicated in several neuropathologies, including attention-deficit/hyperactivity disorder (ADHD). By formalizing the mechanism and implications of such constraints on function, the behavioral Neuroenergetics Theory (NeT) predicts the results of many neuropsychological tasks involving individuals with ADHD and kindred dysfunctions, and entails many novel predictions. The associated diffusion model predicts that response times will follow a mixture of Wald distributions from the attentive state, and ex-Wald distributions after attentional lapses. It is inferred from the model that ADHD participants can bring only 75–85% of the neurocognitive energy to bear on tasks, and allocate only about 85% of the cognitive resources of comparison groups. Parameters derived from the model in specific tasks predict performance in other tasks, and in clinical conditions often associated with ADHD. The primary action of therapeutic stimulants is to increase norepinephrine in active regions of the brain. This activates glial adrenoceptors, increasing the release of lactate from astrocytes to fuel depleted neurons. The theory is aligned with other approaches and integrated with more general theories of ADHD. Therapeutic implications are explored.

Introduction

the engine is intact, but there is a problem with the petrol supply

(Van der Meere, 2002)

The human brain is distinguished from that of other species by a cerebral cortex enlarged to support the development of language and complex social behavior. Constituting only 2% of the body's weight, it utilizes 25% of total glucose production, for perception, response generation, and the intrinsic neuronal processing that informed responses require (Zhang and Raichle, 2010). Not only do humans possess more neurons than other species, those neurons are hungrier, due to their expansive dendritic arbors and long-range projecting axons throughout that large volume (Sherwood et al., 2006). The transport and refinement of their food stock, glucose, from blood vessels is mediated by glial cells, which, in the human brain, are about as numerous as neurons (Azevedo et al., 2009). Astrocytes ferry glucose from capillaries, store it as glycogen, and convert it to lactate, the primary fuel of rapidly firing neurons. Astroglia also assist the neuron in providing other nutrients, maintaining the composition of the extracellular fluid and clearing neurotransmitters from the synaptic cleft.

Todd and Botteron (2001) suggested that some forms of neuropsychiatric disorder may be viewed as cortical energy-deficit syndromes secondary to hypofunctionality of catecholamine systems that regulate astrocyte glucose and glycogen metabolism. This suggestion was examined in detail by Russell et al. (2006), who explored its implications for attention-deficit hyperactivity disorder (ADHD). They hypothesized that ADHD symptoms, particularly the marked intra-individual variation that characterizes them, may arise as a result of impaired lactate production by astrocytes that is, insufficient to meet energy demands, resulting in a supply of adenosine triphosphate (ATP) inadequate to maintain ion gradients across neuronal membranes. This would impair timing of motor responses, leading to slow and variable reaction times in energy-demanding tasks like complex cognition and rapid externally paced responding, such as finger tapping–especially when regulated by the characteristically unmyelinated, energetically inefficient axons of dopaminergic neurons. Some areas of the brain are differentially impacted—the right prefrontal cortex, basal ganglia, and vermis of the cerebellum—are smaller in individuals with ADHD, and they also take up less glucose when activated (Castellanos et al., 2001, Hart et al., 2012, Paloyelis et al., 2007, Vaidya et al., 2005, Yu-Feng et al., 2007).

How does one translate this hypoenergetic hypothesis into testable predictions? The strategy of this paper is to develop a cartoon compartment model of the neural energetics required to support rapid neural firing—the neuroenergetics mass-action model (NEMA). Whereas the actual energetic process is very complex (see Section 3), NEMA suffices to trace the time-course of critical processes at a level that contacts the relevant behavioral data, adumbrated in Section 2. Thereafter (Section 4) the simplest of process models is adduced to map the behavior of persons with ADHD and matched control groups to the neuroenergetic processes—the behavioral neuroenergetics theory of ADHD (NeT). It is a behavioral theory because, whereas we exploit data collected under various cognitive rubrics such as inhibition, inattention, working memory, and executive function, our theory neither invokes these, nor explains its data in terms of them. It is neurobehavioral. It combines a drift model of response times from the attentive state with a Markov model of the lapse and recovery of attention. In Section 5, NeT is related to other theories of ADHD, such as the cognitive-energetics theory (Sergeant, 2005), and provides the biological definition of energy pools, and quantitative predictions of task effects missing from that theory. Section 6 reviews the role of pharmacological agents. Section 7 summarizes these results, reviews predictions of the theory, and draws implications for future research and treatment.