Neuroscience and Biobehavioral Reviews 37 (2013) 625–657

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

A behavioral neuroenergetics theory of ADHD

Peter R. Killeen a,∗ , Vivienne A. Russell b , Joseph A. Sergeant c
a
Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, USA
b
Department of Human Biology, University of Cape Town, Faculty of Health Sciences, Observatory, 7925, South Africa
c
Vrije Universiteit, Department of Clinical Neuropsychology, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Energetic insufficiency in neurons due to inadequate lactate supply is implicated in several neuropatholo-
Received 2 February 2012 gies, including attention-deficit/hyperactivity disorder (ADHD). By formalizing the mechanism and
Received in revised form 2 February 2013 implications of such constraints on function, the behavioral Neuroenergetics Theory (NeT) predicts the
Accepted 18 February 2013
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
Keywords:
mixture of Wald distributions from the attentive state, and ex-Wald distributions after attentional lapses.
ADHD
It is inferred from the model that ADHD participants can bring only 75–85% of the neurocognitive energy
Astrocyte
Attention
to bear on tasks, and allocate only about 85% of the cognitive resources of comparison groups. Parameters
Cadherin derived from the model in specific tasks predict performance in other tasks, and in clinical conditions
Diffusion model often associated with ADHD. The primary action of therapeutic stimulants is to increase norepinephrine
Energy in active regions of the brain. This activates glial adrenoceptors, increasing the release of lactate from
Lactate astrocytes to fuel depleted neurons. The theory is aligned with other approaches and integrated with
Memory more general theories of ADHD. Therapeutic implications are explored.
Fatigue © 2013 Elsevier Ltd. All rights reserved.
Neuropsychology
Norepinephrine
Vigilance

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
2. Exemplary phenomena to be explained . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
2.1. Defining characteristics and comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
2.2. Putative role of hypoenergetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3. Neuroenergetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.1. The astrocyte-neuron lactate shuttle (ANLS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.2. A compartment model of neuroenergetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
3.2.1. Premises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
3.2.2. Neurophysiological bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
3.2.3. Mathematical bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
3.2.4. Averaged data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
3.3. Translating the basic model into response measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
3.4. Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
3.4.1. Inconspicuous stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
3.4.2. Conspicuous stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
4. Applications to data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
4.1. Sustained attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
4.2. Event rate: inter-stimulus interval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
4.3. The role of inhibition: the stop task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

∗ Corresponding author. Tel.: +1 480 967 0560; fax: +1 480 965 8544.
E-mail address: Killeen@asu.edu (P.R. Killeen).

0149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neubiorev.2013.02.011
626 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657

4.4. Working memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

4.5. Motor control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
4.6. Reinforcement frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
4.7. Delay discounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
4.8. Spectral analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
4.9. Executive functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
5. Embedding NeT in a causal framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
5.1. Proximate models of ADHD: its definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
5.1.1. Attention deficit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
5.1.2. Hyperactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
5.1.3. Impulsivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
5.1.4. Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
5.2. Ultimate models of ADHD: NeT and other theories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
5.3. Ultimate material bases: genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
5.4. The final causes of ADHD: what functions are served? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
6. The role of pharmacological agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
7. Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
7.1. The neuroenergetics mass-action model (NEMA) and the behavioral neuroenergetics theory (NeT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
7.2. Implications for therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Appendix A. Attention drift and recapture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Appendix B. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Appendix C. Sessional analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650

Under Review, Neuroscience & Biobehavioral Reviews are differentially impacted—the right prefrontal cortex, basal gan-
glia, and vermis of the cerebellum—are smaller in individuals
1. Introduction with ADHD, and they also take up less glucose when activated
(Castellanos et al., 2001; Hart et al., 2012; Paloyelis et al., 2007;
the engine is intact, but there is a problem with the petrol supply Vaidya et al., 2005; Yu-Feng et al., 2007).
(Van der Meere, 2002) How does one translate this hypoenergetic hypothesis into
testable predictions? The strategy of this paper is to develop a
The human brain is distinguished from that of other species by cartoon compartment model of the neural energetics required
a cerebral cortex enlarged to support the development of language to support rapid neural firing—the neuroenergetics mass-action
and complex social behavior. Constituting only 2% of the body’s model (NEMA). Whereas the actual energetic process is very com-
weight, it utilizes 25% of total glucose production, for perception, plex (see Section 3), NEMA suffices to trace the time-course of
response generation, and the intrinsic neuronal processing that critical processes at a level that contacts the relevant behav-
informed responses require (Zhang and Raichle, 2010). Not only do ioral data, adumbrated in Section 2. Thereafter (Section 4) the
humans possess more neurons than other species, those neurons simplest of process models is adduced to map the behavior of
are hungrier, due to their expansive dendritic arbors and long- persons with ADHD and matched control groups to the neu-
range projecting axons throughout that large volume (Sherwood roenergetic processes—the behavioral neuroenergetics theory of
et al., 2006). The transport and refinement of their food stock, glu- ADHD (NeT). It is a behavioral theory because, whereas we exploit
cose, from blood vessels is mediated by glial cells, which, in the data collected under various cognitive rubrics such as inhibi-
human brain, are about as numerous as neurons (Azevedo et al., tion, inattention, working memory, and executive function, our
2009). Astrocytes ferry glucose from capillaries, store it as glycogen, theory neither invokes these, nor explains its data in terms of
and convert it to lactate, the primary fuel of rapidly firing neu- them. It is neurobehavioral. It combines a drift model of response
rons. Astroglia also assist the neuron in providing other nutrients, times from the attentive state with a Markov model of the
maintaining the composition of the extracellular fluid and clearing lapse and recovery of attention. In Section 5, NeT is related to
neurotransmitters from the synaptic cleft. other theories of ADHD, such as the cognitive-energetics the-
Todd and Botteron (2001) suggested that some forms of neu- ory (Sergeant, 2005), and provides the biological definition of
ropsychiatric disorder may be viewed as cortical energy-deficit energy pools, and quantitative predictions of task effects missing
syndromes secondary to hypofunctionality of catecholamine sys- from that theory. Section 6 reviews the role of pharmacological
tems that regulate astrocyte glucose and glycogen metabolism. agents. Section 7 summarizes these results, reviews predictions
This suggestion was examined in detail by Russell et al. (2006), of the theory, and draws implications for future research and
who explored its implications for attention-deficit hyperactivity treatment.
disorder (ADHD). They hypothesized that ADHD symptoms, par-
ticularly the marked intra-individual variation that characterizes
them, may arise as a result of impaired lactate production by astro- 2. Exemplary phenomena to be explained
cytes that is, insufficient to meet energy demands, resulting in a
supply of adenosine triphosphate (ATP) inadequate to maintain ion The diagnosis of ADHD is a complex and controversial adjudi-
gradients across neuronal membranes. This would impair timing cation, as ADHD constitutes not so much a taxon as an extreme
of motor responses, leading to slow and variable reaction times in range of scores in a multidimensional character state (Coghill
energy-demanding tasks like complex cognition and rapid exter- and Sonuga-Barke, 2012), parts of which range are also occu-
nally paced responding, such as finger tapping–especially when pied by other psychiatric disorders. It is therefore necessary to
regulated by the characteristically unmyelinated, energetically delimit the phenomenon and clarify the domain of the proposed
inefficient axons of dopaminergic neurons. Some areas of the brain theory.
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
2.1. Defining characteristics and comorbidities
Inspection of the Diagnostic and Statistical Manual (DSM-
IV, American-Psychiatric-Association, 1994), and the forthcoming
DSM-5, reveals that attention deficits are a primary symptom in
widely ranging disorders such as schizophrenia, depression and
anxiety. ADHD is associated with symptoms of inattention or
hyperactivity/impulsivity, qualified by age and context. Some of
the categorizing symptoms of inattention are: careless mistakes in
work; difficulty sustaining attention; difficulty in organizing and
failure to finish tasks; frequent distraction and loss of things; forget-
fulness. Some of the categorizing symptoms of hyperactivity are:
fidgeting, squirming, running about; difficulty in quiet play; exces-
sive talking. Individuals must have a minimum number of the first
type or of the second, or a combination of both to be categorized or
specified. Recent overviews of this disorder are available for both
professionals (Stanford and Tannock, 2012) and the general public
(Nigg, 2006).
Only a minority of individuals diagnosed with ADHD have only
ADHD; the majority (about 2/3) have other comorbid conditions.
One report from the Multimodal Treatment Study of Children with
ADHD (MTA: Jensen et al., 2001; Landau et al., 2012) found that 14%
also had anxiety disorder, 30% also had oppositional-defiant disor-
der or conduct disorder, and 25% had all three disorders. Depression
is common with ADHD, especially among girls (Angold et al., 1999).
Kessler et al. (2006) found even greater comorbidities of ADHD
with mood and anxiety disorders. There are also strong associations
with other conditions, such as learning disabilities (Willcutt et al.,
2010b) and impaired motor coordination (Lingam et al., 2010).
There are many possible reasons for this heavy burden of comorbid-
ity, thoughtfully discussed by Taylor (2010). Most observers agree
that ADHD is not simply a single disorder of executive function, but
rather a complex syndrome of impairments that overlap substan-
tially with other disorders (Polanczyk et al., 2007). The focus of this
paper is primarily on the symptom of attention deficit, in particular
as manifest in neuropsychological tests; secondarily on hyperactiv-
ity; and only discursively on the related comorbidities. But there is a
common theme to many of these associated syndromes: comorbid-
ity among ADHD, reading disabilities and mathematical disabilities
“is due to common genetic risk factors that lead to slow processing
speed” (Willcutt et al., 2010b, p. 533). NeT attributes the slow
processing speed to insufficient neuronal energy supply, and the
consequent fatigue of rapidly firing neural networks. In turn, this
leads to erratic performance and diffusion of attention. Our the-
ory only pertains to this constellation of neurophysiology and its
functional impact on behavior. It does not attempt to predict all of
the symptoms used to categorize children with ADHD in the DSM.
The differences among individuals may be due to the parts of the
brain that are most affected by the neuroglial insufficiencies that we
posit (de Zeeuw et al., 2012; Hart et al., 2013; Tafazoli et al., 2012),
loci that may be a semi-random aspect of development, and to the
functional heterogeneity of astrocytes (Theis and Giaume, 2012).
The similarities among subtypes (Toplak et al., 2009) and related
disorders (Banaschewski et al., 2005) may be due to a shared core
deficit in energy resupply to neurons.
2.2. Putative role of hypoenergetics
A number of strands of evidence are converging on energy insuf-
ficiency as a prominent factor in ADHD. Resting state MRI indicates
clear differences between ADHD and typically developing con-
trols (TDC) (Castellanos et al., 2005; Uddin et al., 2008). The BOLD
response measured by MRI indicates that the ability to summon
glucose for oxidative metabolism, required for the restoration of ion
gradients in the fronto-parietal system, is impaired in persons with
ADHD (Cortese et al., 2012; Zametkin et al., 1990). Individuals with
627
ADHD employ learning and memorial strategies that involve less
effort than controls (Egeland et al., 2010), are less adept at learning
and memory (Andersen et al., 2012; Itami and Uno, 2002), and are
less able to sustain attention beyond the first few moments of a
novel task (Sykes et al., 1973). Individuals with ADHD do not acti-
vate fronto-striatal regions in the same manner as TDCs in cognitive
tasks, but seem to rely on more diffuse networks of regions, includ-
ing more posterior and dorsolateral prefrontal regions (Durston
et al., 2003; cf. van Mourik et al., 2005). Individuals with ADHD
may have a deficiency in enzymes related to energy supply, which
prevents or delays development of fronto-striatal circuitry; or they
may require more energy than normal individuals because they
have not developed energy-efficient neural networks, including
fully myelinated axons (Fair et al., 2010; Nagel et al., 2011).
Impulsiveness and difficulty in carrying through plans for future
actions may be in part a consequence of impaired ability of starved
fast-spiking GABAergic interneurons to inhibit the upper motor
neurons that control the inappropriate responses (Koós and Tepper,
1999). This is especially the case for inhibitory circuits, because
GABAergic interneurons are “special-needs” elements: cortical
pyramidal neurons take up about 25% more sodium than the
theoretical minimum required to generate action potentials, but
fast-spiking GABAergic interneurons, with their rapidly rising and
falling action potentials, fail to completely inactivate sodium chan-
nels, thereby allowing twice as much sodium to enter the neuron
(Carter and Bean, 2009). This inefficiency entails that substantially
more ATP is necessary to re-establish their sodium gradients, which
increases the vulnerability of inhibitory GABAergic interneurons
to deficiencies in energy supply. Again, this may contribute to the
impulsiveness that is characteristic of some categories of ADHD.
Another common accompaniment of ADHD is clumsiness—poor
co-ordination of fine and gross body movements (for reviews see
Dyck et al., 2011; Gillberg and Kadesjö, 2003; Sergeant et al., 2006).
Poor performance in speeded reaction time tasks, slow and vari-
able reaction times, and premature responses are widely reported
(Karalunas et al., 2012b; Van Meel et al., 2005). The organization of
motor output is dependent on temporal synchronization of neural
firing in cortico-striato-thalamo-cortical and cortico-cerebellar-
thalamo-cortical circuits (Smith et al., 2003), and thus particularly
sensitive to impaired signaling, as seen in data reported by, for
example, Noreika et al. (2013). Motivation cannot account for all
of the differences between groups (Van Meel et al., 2005). Deficient
action monitoring and error processing (also energy-demanding
processes) are often associated with ADHD, leading to unrealistic
expectations by affected individuals, and increasing their difficulty
in learning from mistakes (Albrecht et al., 2008; Durston et al., 2003;
Sergeant and van der Meere, 1988). These are just some of the key
features that a comprehensive theory of ADHD must explain.
Many similar deficits are found in other developmental disor-
ders, and many symptoms that are significantly associated with
classification are not found in every child with ADHD. The classifi-
cation “ADHD” is not a taxon (Coghill and Sonuga-Barke, 2012). As
Dyck et al. (2011) noted, there is no evidence of “zones of rarity”
between developmental disabilities: “with the exception of men-
tal retardation, the results imply there are no natural boundaries
between disorders or between disorders and normality”. Our the-
ory is not about an endophenotype for ADHD: it is a characterization
of a hypothesized brain disorder and its behavioral sequelae that
is especially relevant to ADHD. It may characterize aspects of other
developmental disorders as well.
Further evidence for the energy-deficiency hypothesis of ADHD
is provided by the recent finding that N-acetylaspartate (NAA) lev-
els are altered in ADHD (Perlov et al., 2009; Yang et al., 2010).
NAA is a neuron-specific energy storage and transport form of
acetyl coenzyme A (Ariyannur et al., 2010). Clinical improvement
brought about by treatment with methylphenidate is accompanied
628 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
by increased NAA in the anterior cingulate cortex of treatment-
naïve adults with ADHD (Kronenberg et al., 2008), and in various
brain locations in children with ADHD (Wiguna et al., 2012).
The anterior cingulate cortex plays an essential role in error
processing—recognizing and learning from mistakes—which is one
of the deficits associated with ADHD (Bush et al., 1999; Durston
et al., 2003; Itami and Uno, 2002; Van Meel et al., 2007). NAA
is important not only for energy metabolism, but also for lipid
synthesis, required for the formation of myelin sheaths, and as
a component of a molecular water pump in myelinated neurons
(Baslow, 2002). The myelin sheath makes neurotransmission much
more energy efficient (Zhu et al., 2012), and its disturbance in ADHD
(Nagel et al., 2011) indicates that axonal transmission of informa-
tion is more energetically costly, and—key to our thesis—slower
(Harris and Attwell, 2012) and more variable (Walhovd and Fjell,
2007). NAA levels are considered a surrogate marker of neural
integrity in general, and are irregular in other psychiatric disor-
ders, for example, multiple sclerosis (Rigotti et al., 2011), which
has behavioral symptoms in common with ADHD. We attempt to
integrate these strands of evidence with a model of the neuroen-
ergetics of the individual neurons, and the consequent effects of
insufficient energy on the mass action of ensembles of neurons.
3. Neuroenergetics
In this section we describe how the release of glutamate by
neurons stimulates astroglia, both directly and through secondary
release of norepinephrine from neural varicosities. That stimula-
tion increases the glial cells’ uptake and metabolism of glucose, to
energize its own responsibilities in clearing glutamate, transfor-
ming it into glutamine, and transferring it back to the neuron. That
stimulation also causes the glia to produce lactate, which is a cru-
cial fuel for the neuron. It is our thesis that this complementarity
between astrocyte and neuron fails in ADHD. It is not clear pre-
cisely why this failure occurs, but we speculate about this below
(Section 3.1). The remainder of this section outlines in detail how
this energetic process is known to occur in the normal case. This
neurophysiological basis for attentional disorders such as ADHD
constitutes our behavioral neuroenergetics theory, NeT.
Glia metabolize glucose to lactate which is released for use by
neurons to produce ATP, the energy currency of the cell. Neurons
metabolize glucose primarily in the pentose phosphate pathway
to support protein synthesis and other housekeeping functions,
including glutathione regeneration, which protects the neuron
from reactive oxygen species (Bélanger et al., 2011). Metabolism
of glucose becomes rate-limiting when precise timing is required
for the synchronization of neural networks firing at different fre-
quencies (e.g. theta and gamma) in different brain areas (Kann
et al., 2011), which is associated with short-term learning (Fell and
Axmacher, 2011). In such cases, alternative intraneuronal energy
stores, such as creatine phosphate and NAA, are utilized to produce
ATP (Ariyannur et al., 2010; Friedman and Roberts, 1994). These
stores also become depleted by the precisely timed patterns of
firing of neural networks that are needed over extended periods
to maintain long-term potentiation (LTP) of synaptic strength
(Richter and Klann, 2009). Astrocytic glycogen breakdown and lac-
tate release are essential for the maintenance of LTP elicited in vivo
(Newman et al., 2011; Suzuki et al., 2011), and for the long-term
memory that LTP enables (Costa-Mattioli et al., 2009; Mayford et al.,
2012; Newman et al., 2011; Suzuki et al., 2011)—a kind of mem-
ory that is at disadvantage in ADHD (Rhodes et al., 2011). The
ATP generated within the astrocyte in response to the above pro-
cess permits it to convert glutamate to glutamine for return to the
neuron (the glutamate-glutamine shuttle), for recycling into gluta-
mate (Magistretti, 2009). Astrocytes, we are learning, are involved
in neuronal computational processes in a “plethora” of ways (Min
et al., 2012), including the ability to limit neuronal excitability, limit
release probability, and silence synapses (Pannasch et al., 2011).
3.1. The astrocyte-neuron lactate shuttle (ANLS)
A major part of the ATP used by neurons is for post-synaptic
restoration of ion gradients and transmission of action potentials
(Attwell and Laughlin, 2001; but see Harris et al., 2012). The neu-
ron’s supply of energy for these processes involves a complex set of
reactions that starts with intra-neural resources, and quickly there-
after engages extracellular and glial-supplied lactate (Aubert et al.,
2005; Pellerin et al., 2007). Although neurons can produce ATP
by metabolizing glucose (Hyder et al., 2006), this is less efficient
than utilizing lactate, and so they have net lactate consumption
(Jakoby et al., 2012; Pellerin et al., 2007). The astrocyte-neuron lac-
tate shuttle (ANLS), controversial a decade ago, is now accepted
as the primary source of energy to fuel sustained neuronal activity
(e.g., Brown and Ransom, 2007). The first 5–12 s of neural activity is
powered by oxidative metabolism within the neuron using stored
creatine phosphate and NAA. During this time, the neuron begins
to draw on the reservoir of extracellular lactate (Hu, 2002; Hu and
Wilson, 1997; Mangia et al., 2003, 2006). Glutamate released by
the neuron during stimulation is co-transported with sodium ions
into the astrocytes (Fig. 1). Elevated levels of potassium resulting
from neural activity indirectly stimulate soluble adenylyl cyclase
receptors on the astrocytes (Choi et al., 2012, p. 1094), causing
glycogen breakdown, enhancing glycolysis, and releasing lactate
into the extracellular space, where it is available to neurons for use
as an energy substrate (Bélanger et al., 2011). Depletion of ATP used
to re-establish the sodium gradient across the membrane further
stimulates glucose uptake by the astrocyte, which can be metabo-
lized to lactate or used to produce ATP (Bélanger et al., 2011). The
resulting ATP maintains glutamate transport into astrocytes and
supports its conversion to glutamine, which is shuttled to the neu-
rons to restore their pools of neurotransmitters (Magistretti, 2009;
Pellerin et al., 2007). Surplus lactate enters the extracellular reser-
voir, where its availability to the neuron favors lactate oxidation as
the neuron’s primary source of energy to support sustained neural
firing (Hyder et al., 2006; Wyss et al., 2011). Glial lactate is the major
contributor to neuronal oxidative phosphorylation of ADP to ATP
(Hertz et al., 2006). Glutamate also stimulates release of norepi-
nephrine from nearby varicosities in axons (Russell, 2001; Russell
and Wiggins, 2000), which, acting on ␤-adrenoceptors, further
stimulates astrocytes to take up glucose and produce additional
lactate (Gibbs et al., 2008b; Todd and Botteron, 2001). Such stim-
ulation has been shown to enhance memory (Gibbs et al., 2008a;
Hutchinson et al., 2007). The learning of new tasks differentially
induces gliogenesis in the medial prefrontal cortex (Rapanelli et al.,
2011). Fig. 1 sketches some of the key elements of this process.
Work of Caesar et al. (2008) draws a timeline of lactate pro-
duction, stimulated by activation of cerebellar climbing fibers, and
the ensuing glutamate-stimulated glycolysis, in astrocytes (Fig. 2).
After elicitation by glutamate, lactate production rises to exceed
baseline extracellular levels, with diffusion into local neurons
replenishing their stores. At cessation of stimulation lactate slowly
falls to the pre-stimulation levels. As shown, the half-life of both
processes is several minutes. Cloutier et al. (2009) have constructed
a relatively complete physiologically based pharmacokinetic model
of such processes involving 34 differential equations, with the ANLS
playing a key role. We shall maintain emphasis on the ANLS as a
key bottleneck in the process, but not engage those equations in
our model.
Failure of this supply chain at any one of the reactions can
undermine functionality of the neuron, increasing variability in
responding as the neuron fatigues, and require that alternate
circuits be recruited to guide behavior. Therapeutic agents such
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657 629

Fig. 1. The supply chain for adenosine triphosphate (ATP) production, that powers the neuron. Release of glutamate (yellow circles) stimulates glucose uptake (blue arrow)
and glycolysis in the astrocyte to produce lactate. The lactate diffuses into the extracellular space, to be absorbed by the neuron for ATP production, for restoration of ionic
gradients, and resequestration and encapsulation of neurotransmitters. Astrocytes also convert glutamate to glutamine, which is shuttled to the neurons to restore their
pools of neurotransmitters (yellow arrows). Glutamate, acting on AMPA receptors, stimulates norepinephrine release (red circles) from nearby noradrenergic varicosities.
These act on ␤-adrenoceptors, to further stimulate glucose uptake and glycogenolysis, causing astrocytes to produce more lactate to support sustained neural firing.

as amphetamine that block the monoamine transporters maintain
high extracellular concentrations of norepinephrine. Those raised
levels stimulate both cAMP and lactate production in astrocytes,
and can help compensate for any of several potential energetic
bottlenecks (Pellerin and Magistretti, 2011; Sorg and Magistretti,
1991).
3.2. A compartment model of neuroenergetics
Relatively complete models of energetic supply are available,
but their many parameters overpower the available behavioral
data. A simpler phenomenological model may suffice to translate
the fundamental energetic processes into behavioral predictions.
That is assayed here.

3.2.1. Premises
We present here the neurophysiological and mathematical
bases of our theory. NeT posits a particular brain dysfunction
(neural hypoenergetics) characteristic of individuals with ADHD.
Ancillary to this is a general model of response times based on
inferred neural processing speed and attentional processes, NEMA.
It bridges the neurophysiological facts, from the neuroenergetics of
individual neurons through the mass action of ensembles of neurons to
measures of behavior. Essentially, NeT calls upon NEMA as a sub-
routine to deliver predictions, and to interpret extant data from
studies of ADHD in terms relevant to the theory.

3.2.2. Neurophysiological bases

Fig. 2. Proportional change in extracellular concentration of lactate in rats’ cere-
bellar cortex elicited by stimulation of the climbing fibers. Data from Caesar et al.
(2008); curve from Eq. (2), with s = d = 0.005/s. Both are rescaled to start at 0 and
asymptote at 1.
Action potentials, postsynaptic potentials, and the subse-
quent resetting of ion gradients and clearance of glutamate, are
energy-demanding processes critical for high rates of informa-
tion transmission (Attwell and Gibb, 2005; Howarth et al., 2012;
630 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Strelnikov, 2010). Both neurons and glia bear these costs. These are
the underlying facts on which we base the neuroenergetic part of
our theory. The singular premise that one or more of these pro-
cesses is disordered in ADHD constitutes our theory, NeT.
• During stimulation, neuronal energy is initially provided by mito-
chondrial oxidative processes, and later as a byproduct of glial
(astrocyte) processes (Mangia et al., 2003).
• Glutamate released by neurons is taken up by the astrocytes,
powered by sodium influx. The ATP used to re-establish the
sodium gradient stimulates glycolysis, which restores the ATP
and also generates lactate (Hyder et al., 2006; Kasischke et al.,
2004).
• Additional energy may be recruited by astrocytes from their
glycogen stores (Benarroch, 2010). Such glycogenolysis is
facilitated by noradrenergic stimulation of the astrocytes’ ␤-
adrenoceptors (Fillenz et al., 1999; Hertz et al., 2010).
• Lactate is transported to the extracellular neuropil, where it is
taken up by neurons as their preferred energy source (Pellerin
et al., 2007).
• The release of glutamate from presynaptic terminals is propor-
tional to: (a) the frequency of action potentials, and (b) the
size of the readily releasable pool of vesicles, maintained by the
astrocyte’s glutamate-glutamine shuttle. Both are impaired by
insufficient supplies of glucose or lactate (Magistretti, 2009).
3.2.3. Mathematical bases
The key premises in translating the above theory into a model
that enables quantitative predictions (NEMA) are:
• The depletion of energetic resources by neurons is a linear func-
tion of both the rate of stimulation (Smith et al., 2002), and the
available energy (Leegsma-Vogt et al., 2004), implying (pseudo)
first order kinetics as captured by Figs. 2 and 3 and Eqs. (1–2)
(given below).
• The repletion of energy to the neuron involves classic
Michaelis–Menten processes (Aubert and Costalat, 2007; Pellerin
et al., 2007) that may also be approximated by (pseudo) first order
kinetics, as in Figs. 2 and 3 and Eqs. (1–2).
• The simplicity of these relations despite the complexity of the
energy supply is due to mass action of ensembles of neurons.
“The apparent paradox of a range of energy-consuming processes
being proportional to a single electrical activity [stimulation fre-
quency] may be resolved if these processes are all coupled to
the averaged rate of the electrical activity” such as “the firing
of an ensemble of pyramidal neurons” (Smith et al., 2002). Such
“coherent functional networks” have been noted by Deco et al.
(2010).
• When such first order kinetics are averaged over individuals
or epochs having different rate constants, the resulting average
time-course is transformed into a power function, Eq. (4) (below).
Fig. 3. The neuroenergetics model. Major parts of the energy budget are postsy-
naptic processing and propagation of action potentials, both an increasing function
of the frequency of stimulation. After several seconds of firing the neuron relies on
lactate provided by the astrocyte in the ANLS. The hypothesis of this paper is that in
ADHD the cost of transmission of action potentials (c) may be increased, or the rate
of supply of lactate (s) may be compromised.
• Each astrocyte services scores of neurons, and connects to
thousands of others, whose excitatory and inhibitory interactions
may be treated as a random additive process, represented as a
random walk with drift, Eq. (5) (below).
• The ability to maintain attention to a task, like all responses,
covaries with the energy available for it. Response-time distribu-
tions are then mixtures of processes issuing from the inattentive
and attentive states (Fig. 5).
Fig. 3 entails:
dE
= −cfE + s(EM − E) c, f, s ≥ 0 (1)
dt
where E is the energy available to the neuron/glia process in the
form of ATP, both endogenous to the neuron and derived from lac-
tate shuttled from the astrocyte. (There is an implicit constant of
proportionality in both c and f that converts lactate to available
energy). EM is maximum energy—that in a fully rested neuron—and
is set here to 1, so the basic model concerns proportional changes,
and requires rescaling to speak to the units in which physiological
variables are measured. The first addend has the energy decreasing
proportionate (−c) to the rate of stimulation (f) and the current
energy level, as consistent with the first bullet of this section. The
second addend has the rate of repletion increasing proportionate
(s) to the neuron’s deficit, EM − E, consistent with the second bullet
point. Call the initial energy (at t = 0) E0 . Then the solution of Eq. (1)
is:
Et = E∞ + (E0 − E∞ )e−(s+cf )t (2)
The available energy changes exponentially from E0 to E∞ . For
the data analyzed in this paper we assume the subject starts in a
rested state, and thus set E0 to 1. The rate of approach to equilibrium
at E∞ depends on the sum of the rates of repletion and depletion,
s + cf. As t → ∞, the available energy stabilizes at an asymptotic
value E∞ that depends on the ratio of demand, fc, to supply s:
s 1
E∞ = = (3)
s + cf 1 + fc/s
If the rate of supply, s, is slow, or the cost of neural processing, c,
is high, Eq. (3) predicts a lower asymptotic energy. Eq. (3) is concave
in s, so that variable rates of supply will also cause deficits below
an invariant supply at the same mean rate. This is the prediction
for ADHD.
Because the supply from the astrocyte complements the
demand from the neuron, this system describes the changes in
extracellular lactate shown in Fig. 2, where the origin from the pre-
stimulation average concentration was set to 0, and the change
rescaled by dividing by the imputed asymptote 23 ␮M. Eq. (2)
draws the curve through those data. Upon glutamate signaling,
lactate supply rises at the rate s + cf = (0.005 + 0.005)/s. When the
stimulation stops, f goes to baseline (here 0), glutamate exocy-
tosis decreases to baseline, reducing the stimulus for glycolysis
and letting extracellular lactate decrease exponentially at the rate
of 0.005 ␮M/s. These are relatively slow processes, with half-lives
of several minutes. The above bullet points constitute the neuro-
physiological and mathematical bases of our theory.
3.2.4. Averaged data
Eq. (2) provides the core model of change in energy as a function
of time, but it applies only when there is no variance in the param-
eters. When exponential processes are averaged over data sets in
which the rate constants vary among elements, as in ensemble fir-
ing, the resulting curves morph into power functions, as derived for
exponential constituents by Killeen (2001), and for a range of con-
stituent distributions by Murre and Chessa (2011). Eq. (2) becomes:
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Et = E∞ + (E0 − E∞ )t − t≥1
where the exponent  (rho) increases with s + cf.
3.3. Translating the basic model into response measures
In this section we present the key NEMA equations and illustrate
their use in data from archival studies of ADHD.
The speed of information processing is tightly coupled to the
energy resources available: it has been estimated that one mole
of glucose must be oxidized for each mole of neurotransmitter
recycled (Shulman et al., 2004). The result of these coordinated
excitatory and inhibitory neurotransmissions may be treated as a
random walk toward a decision, a Brownian motion with “drift”
toward an action. The speed of the progress, v, at any point in
time is proportional to the energy available for it, Et , as given by
Eq. (2) or Eq. (4). The times for completion of such a large series
of additive and subtractive (inhibitory) computations—the time
of first passage—progressing at the speed v is given by the Wald
distribution:
C 2
f (t) = √ e−(C−vt) /2t t>0
2t 3
The conditions necessary for a process to be characterized by
Eq. (5), and for such inverse Gaussian distributions, when summed,
to yield a distribution of the same form, are given by Folks and
Chhikara (1978). A clear and thorough review of the properties of
the distribution may be found in Chhikara and Folks (1989). Eq. (5)
gives the distributions of times for processes proceeding at the rate
of v to cross a criterion C for the first time. The value of C depends
on the informational demands in all stages, and on the complete-
ness with which the individual processes that information. If more
information is needed for one task than for another, the value of
C will be larger for that task. In general C should be thought of as
a stopping criterion, giving a measure of the number of computa-
tions involved in generating a response. More complex tasks will
require more computations to succeed. Individuals must generally
make speed-accuracy tradeoffs, in the light of both task demands,
and the resources available to them. Thus the value of C may also
be strategically biased. With experience, that bias may become the
habitual default.
An additional parameter in the denominator of the exponent of
Eq. (5), the variance in drift rate, is absorbed into C and v. If drift
rate is more variable for individuals with ADHD, as expected from
NeT, it would provide one explanation for the lower values of those
parameters found for affected individuals, as documented below.
C is a cousin of the criterion in signal detection theory (SDT). In
NEMA it is (proportional to) the number of computations before
a positive response. In SDT it is the amount of evidence necessary
for a positive response. If that evidence accumulated as a biased
random walk, the models converge, as the case in general drift
models, which have separate criteria for the relative amount of evi-
dence necessary for a positive or negative response. The difference
of those criteria gives a measure of bias, as in SDT. Drift models
typically let the speed of drift, v, depend on problem difficulty. In
NEMA, drift rate is tied to the available energy, which determines
processing speed, while the information processed determines C.
Eq. (5) is a special case of the inverse Gaussian distribution
(Chhikara and Folks, 1989; Folks and Chhikara, 1978; Heathcote,
2004). For parsimony we set the velocity of propagation of the
decision, v, proportional to the available energy in relevant neu-
ral ensembles, v = kEt , 0 ≤ Et ≤ 1. The units of v in this paper are
m s−1 . The constant k is set to 1, entailing that C must be under-
stood as relative to this unknown constant that bridges from ATP
to the velocity of propagation of information. This is the basic mod-
ule of NEMA, which translates neuroenergetics into predictions
631
(4) Table 1
Parameters for the neuroenergetics mass-action model (NEMA).
Parameter Module
Energetics
Et Energy available in the form of lactate in the neuron/glial
system (v in Eq. (5))
Predicted by Eq. (2) or Eq. (4) as a proportion of the
maximum energy, EM
E∞ Equilibrium energy given by Eq. (3), or fit as free parameter
 Rate of approach to asymptote for group data, increasing
with s + cf
Attention
 Probability of a lapse of attention in any 1 s period
˛ Probability of a return of attention in any 1 s period
 Attentional inertia: mean time required to refocus lapsed
attention, or to shift set
Response time
E Average available energy, determining speed of neural
computation
C Computational resources allocated for a response; Criterion
in drift model
Derived measures
(5) C/E Mean response time from attentive state
C/E3 Response-time variance from attentive state
(CE)−1/2 Coefficient of variation from attentive state
[1 − (1 − ) ]
s
Expected additional reattentional latency s seconds into trial
[1 − (1 − ) ]
s 2
Expected additional reattentional variance s seconds into
trial
of response characteristics. NEMA’s parameters are summarized
in Table 1. The mean of Eq. (5) is  = C/E, its standard deviation
(C/E3 )1/2 , and its coefficient of variation (CV) is (CE)−1/2 . E may be
√
estimated directly as /. It is a skewed distribution with a coef-
ficient of kurtosis equal to thrice the CV. These statistics are heavily
dependent on the speed of propagation: halving the velocity E
doubles the mean, and more than doubles the standard deviation.
This explains why variability is more diagnostic of slowed neural
processing speed than are means. For the basic time-course data,
there are three key parameters in the model, , which is governed
by the sum of the rates of depletion and repletion, E∞ , the equilib-
rium energy level of the glial/neuron system, governed by the ratio
of the rates of repletion and depletion, and C, the response crite-
rion. When only summary statistics rather than time-courses are
available, the basic model reduces to two parameters: the average
available energy E, and the criterion C. When additional data are
available concerning attentional processes, the model expands to
include two additional parameters: the probability of attentional
lapses (), and the probability (˛; or latency, ) of return to atten-
tion, discussed below (Section 3.4.1 and Appendix A).
The use of a diffusion model such as Eq. (5) as a lingua franca
between neural and behavioral processes is not novel. Ratcliff and
McKoon (2008) review the rapid advances being made in inte-
grating such models of decision processes with neural data. That
literature makes close contact with neurophysiological reports.
Here, with focus on human subjects, the analysis must be hypo-
thetical. With the emergence of animal models of ADHD, better
reification can be expected. With additional parameters this class
of models can also accommodate error rates, as demonstrated in
the elegant applications of drift models to ADHD in the work by
Mulder et al. (2010) and Karalunas et al. (2012a). Although these
models provide a more complete description of neuropsychological
data on short ISI experiments, they do not include the attentional
loop of NEMA as shown in Fig. 5, and therefore do not address inter-
stimulus-interval (ISI) effects. Huang-Pollock et al. (2012) provide
a current and perceptive review of the utility of such drift models
for analyzing data from ADHD populations.
Amongst the few studies that report full response-time distri-
butions for ADHD subjects is that of Querne and Berquin (2009),
632 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 4. Relative frequency distributions of response times on trials with a cor-
rect response for four groups of children (Querne and Berquin, 2009). The curves
are Wald densities (Eq. (5)), with parameters displayed in the bottom panel. HI
is Hyperactive–Impulsive; IA is Inattentive; and C is Combined types. As they are
arrayed in this figure, the criterion C decreased across groups, as did the available
energetic resources E, except for HI (Hyperactive Impulsive), which marshaled sub-
stantial energy but held the laxest criterion. NEMA accounts for 96% of the variance
in the data.
which serves to illustrate the simplest deployment of the model
advocated here. Querne and Berquin matched four groups of 16
children for age and sex, and distinguished by membership in
three subtypes of ADHD (HI: Hyperactive–Impulsive; IA: Inatten-
tive; C: Combined; distinguished by the numbers of hyperactive
and impulsive symptoms) or a control group. About every 3 s a
visual target was presented which required discriminating higher
vs. lower positions on a screen. The resulting response-time distri-
butions are shown in Fig. 4.
A marked difference in control and ADHD distributions is obvi-
ous; but how should this be interpreted? The parameters required
to fit the distributions tell the story: the criterion C (proportional
to the number of Computations made before a response) decreased
from Control through IA and Combined subtypes, to the HI sub-
type. This is consistent with the Combined and HI subtypes having
the greatest number of hyperactivity/impulsivity symptoms. The
energy available for the task, E (an indicator of the speed of
processing, equal to v in Eq. (5)), was greatest for the control group,
less for the Inattentive subtype, still less for the Combined subtype,
Fig. 5. The neuroenergetics model—NEMA. Trials start in the attentive state A. By
the end of 1 time period, attention will have lapsed with probability . Upon appear-
ance of a target stimulus, if the subject is in the A state a response is prepared and
emitted according to the Wald distribution (Eq. (5)). If the subject is in the ∼A state,
he must first re-attend, to perceive the stimulus and initiate the response. In exper-
iments with inconspicuous stimuli (vigilance or detection experiments), attention
drifts back to A at a rate of ˛ . In experiments with salient stimuli (performance
experiments, analyzed in this paper), conspicuous target stimuli capture attention,
driving ˛ larger. In that case the predicted response distribution is ex-Wald. The
latency to recapture attention adds the exponential process, with mean  = 1/˛ .
This additional latency is engaged with probability 1 − p(A), as given by Eq. (8). The
final distribution of responses is a mixture of the Wald and ex-Wald.
but second only to controls in the Hyperactive–Impulsive subtype.
The lowest values of E in the Inattentive and Combined groups, the
latter 68% of the value for TDC, are consistent with their having
the largest number of inattention symptoms. The higher energy of
the Hyperactive–Impulsive fuels the impulsivity, and along with
the lowered criterion speeds responses, including a disproportion-
ate number of errors of commission. Although this profile has face
validity with regard to the symptoms that are characteristic of these
groups, it is not a priori clear why the Hyperactive–Impulsive sub-
type should have the highest E of the ADHD subtypes, yet the lowest
criterion for action. Perhaps it is just that, given the constellation
of combinations of E and C that are possible for individuals with
ADHD, those with this combination—high E and low C—are indeed
hyperactive/impulsive.
Eq. (5) is closely related to other distributions. The ex-Gaussian,
a convolution of exponential and normal random variables, is
increasingly popular in describing response-time data from stud-
ies of ADHD. It mimics the Wald distribution (Gottlob, 2004;
Van Zandt and Ratcliff, 1995). The next section shows that an
analogous distribution, a convolution of exponential and Wald
variates—the ex-Wald—provides the necessary final step in this
theory of response times.
3.4. Attention
The above development carries the implicit assumption that
the subjects are always “on task”—that their behavior is under
the control of stimuli that are interesting to the experimenter or
teacher. This may be the case for brief experiments with keen
subjects, but it is obviously not in extended experiments on
individuals with attention deficits. Subjects generally begin an
activity or experimental trial in an attentive state, but all may
experience lapses of attention thereafter, ranging from attentional
blinks to attentional fugues. Attention then may drift back to
the task (Section 3.4.1) or be captured by the appearance of
the target stimulus (Section 3.4.2). Such attentional fugues are
correlated with functional connectivity in the visual cortex, and
with response-time variability (Prado and Weissman, 2011).
This section explicates how NEMA deals with attentional drift
and recapture. NEMA is the tool we deploy for highlighting the
differences between special populations (Nesse and Stein, 2012).
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
NeT is a theory of the mechanisms of ADHD and its consequences.
It predicts differences in parameters returned by NEMA, when
used to model the behavior of ADHD and TDC (Section 4).
3.4.1. Inconspicuous stimuli
Our model for this drift of attention from and then back to the
task, NEMA, starts with the simplest of Markov chains, diagrammed
in Fig. 5. Trial initiation brings the individual to attention, A, from
which he lapses with a probability  (lambda) into a non-attending
state, ∼A. If a target stimulus occurs while the subject is in the
A state, a perception/decision process is initiated, and a response
emitted according to the Wald distribution. If attention has wan-
dered, it will wander back to the task (State A) with probability ˛
(alpha). The long run probability of being in A is p∞ (A) = ˛/(˛ + ),
and of being inattentive, its complement /(˛ + ). For  > 0, NEMA
predicts that the probability of being on task decreases approx-
imately exponentially through a trial, from 1.0 toward p∞ (A). In
signal detection experiments, this process predicts the probability
of a hit. The probability of maintaining focused attention during a
trial of length t decreases with t approximately as e− t . Once in the
∼A state, the time to return to the attentive state is exponentially
distributed with mean of  (tau). (See Appendix A for a more precise
statement of this process).
3.4.2. Conspicuous stimuli
The symmetry of Fig. 5 is broken by the ability of salient stimuli
to recapture attention. Vagrant attention that would only drift
back to the task with probability ˛ may be captured by the abrupt
appearance of a target stimulus (Egeth and Yantis, 1997). This is
called stimulus-driven attention. Different neural systems subserve
stimulus-driven and goal directed attention (Asplund et al., 2010;
Corbetta and Shulman, 2002; Sarter et al., 2005). The appearance
of the target essentially jumps ˛ up to a large probability of
transition back to A. Such on-demand attentional shifts are not
immediate, but require up to ½ s in standard laboratory experi-
ments (Shulman et al., 1979; Sperling and Reeves, 1980). We call
this time to recover attention attentional inertia, and represent its
mean by . Attentional recapture adds an exponentially distributed
attentional latency to a Wald-distributed perception-response
latency, resulting in an ex-Wald distribution. This distribution
was well characterized by Schwarz (2001) and recently applied to
response latencies (Palmer et al., 2011). Responses issuing from
the attentive state are Wald distributed (Eq. (5)), while those from
the inattentive state add the attentional recapture process, trans-
forming it into an ex-Wald distribution. The expected response
times will be a Wald distribution from the attentive state with
probability p(A) and an ex-Wald distribution from the inattentive
state with probability p(∼A) = 1 − p(A), as shown in Fig. 5. The
resulting mixture has a mean:
C analyzed here.
= + p(∼A) E>0
E
and standard deviation

C The heart of NeT for analysis of special populations is its pre-
= + p(∼A) 2
E3
Most experiments analyzed in this paper used conspicuous,
abrupt-onset stimuli, so that stimulus-driven attention preempts
goal-driven attention. To reduce parameter load and simplify the
attentional model, the probability of drift back to attention, ˛, is
therefore set to 0 until the presentation of the stimulus, and thence
to a larger value close to 1. This permits a simple expression (see
Appendix A) for the probability of being in the inattentive state as
a function of time since trial onset t:
P(∼A) = 1 − p(A) = 1 − e t
633
Table 2
Parameters for the curves in Figs. 6 and 7.
Parameter Börger et al. (1999)
Group
Control ADHD
 0.23 0.09
E∞ 0.51 0.00
C 400 400
 (s) 0.38 0.48
The probability of return, given stimulus onset, is a similar
exponential-integral process with a rate constant of ˛ rather than
 . These rate constants are primed because they are the continu-
ous analogues of the probabilities shown in Fig. 5, denoted by ˛ and
, the default parameters of NEMA. In the case that the probability
of an attentional lapse approaches zero ( → 0), NEMA’s statistics
reduce to those of the basic Wald distribution, the first addends in
Eqs. (6–7). The mixture is dominated by the Wald density because
the response, governed by the Wald process, is made on every trial
(every one that contributes data to these measures), and the addi-
tional lag due to inattention on only a portion of the trials. Adding
the inattention factor to the model of the data in Fig. 4 increased the
goodness of fit to over 97%, imputing larger values of  for the ADHD
groups. Because the fit of the simple Wald model was already excel-
lent, however, little reliable information could be gleaned from that
amplification.
Vigilance is sustained hard work (Kaplan and Berman, 2010;
Sarter et al., 2006; Warm et al., 2008). It is a core implication of our
theory that the resources to maintain attention decrease as energy
depletes through the course of a session (Eqs. (2 and 4)), with con-
comitant increases in the probability of lapses in attention (). This
is due to fatigue of neural circuits responsible for processing task-
relevant stimuli. When analyzing sessional data we assume that
the probability of maintaining attention (1 − ) is proportional to
the available energetic resources, 1 −  = kEt , so that  = 1 − kEt . In
most experiments analyzed here, only summary statistics are avail-
able, so that estimates of E and  reflect the average operation of
those processes over the course of the session. Table 1 is a memo-
randum of these parameters. NEMA is now applied to a range of the
available neuropsychological tasks employed in ADHD research, to
help us evaluate the validity of NeT.
4. Applications to data
Swanson et al. (Swanson et al., 2010; also see Willcutt et al.,
2008; Williams et al., 2010) summarized the meta-analyses of
neuropsychological tasks for ADHD reported by (Nigg, 2005) and
(Willcutt et al., 2005). Those tests with the largest effect sizes are
(6)
4.1. Sustained attention
(7)
diction of differential rates of repletion of energetic stores, causing
increased probability of attentional lapses, a slowing of response
times and consequent increases in variance of those times. Such
fatigue is, of course, a hallmark of the performance of all humans
on sustained detection or performance tasks: all show decrements
over the course of a session, attributed to attentional lapses as a
result of boredom or resource depletion (Grier et al., 2003; Helton
and Warm, 2008; Mackworth, 1956; Parasurman and Davies, 1982;
Pattyn et al., 2008). An example of the greater difficulty had by indi-
viduals with ADHD is provided by Börger et al. (1999), who tested
(8) 21 ADHD boys without comorbid disorders, either medication naïve
634 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 6. Top: The probability of not making off-task responses during a CPT for 21 boys
with ADHD and 16 control boys. In this and all other figures, triangles represent the
ADHD group and controls are represented by circles. Bottom: Means and standard
deviations of response times on that task. Data from Börger et al. (1999); curves from
NEMA, with parameters in Table 2, accounting for a median 76% of the variance in
the data.
or abstinent for 24 h, on a continuous performance task (CPT, see,
e.g., Riccio et al., 2002). Sixteen age-matched normal boys consti-
tuted the control group. In the CPT either a target letter (Q; 20%
trials) or foil (O; 80% trials) was presented for 700 ms every 4 s. The
investigators measured on task behavior as the probability that no
irrelevant response, such as bodily movements, occurred. The prob-
ability of such full attention is shown in Fig. 6, along with the model
performance. The model predictions are derived from Eqs. (4 and
8), with the probability of maintaining attention (i.e., not lapsing)
from one second to the next set proportional to available energy,
1 −  = 1.5Et , and waning with it as a function of time through the
session. Table 2 lists the key parameters for the Börger et al. (1999)
study, and Appendix B provides modeling details. By the end of the
session, the ADHD subtype manifested about 86% of the energy of
the TDC.
Off-task responses were made at relatively high levels that
increased throughout the course of the session, making undivided
attention increasingly scarce. Given these observations of the actual
behavior, wayward attention must be recognized as a viable expla-
nation for increased latencies in these experimenter-paced tasks.
Other research (Teicher et al., 2004) shows that methylphenidate
increases accuracy in this task with the probable mechanism being
a decrease in the entry into “distracted states”. Both the asymp-
totic energy levels (E∞ ), and the rate of approach to those levels (),
depend on the rate of energetic supply to the neurons. Therefore
we predict that these parameters will be larger for controls than for
ADHD. Table 2 shows that this was indeed the case, consistent with
this prediction. Controls also recovered from lapses more quickly
( = 0.38 s vs. 0.48 s). Both groups made about the same nominal
number of neural computations (C).
Fig. 7. Top: The probability of not making any off-task response during a CPT trial
for 17 boys with ADHD (triangles) and 15 control boys (circles). Bottom: Means and
standard deviations of response times on that task. Data from Börger and van der
Meere (2000), are shown as symbols; predictions by NEMA, using the parameters
that drew Fig. 6, are drawn as lines. They account for a median of 45% of the variance
in the data.
Börger and van der Meere (2000) replicated their previous
experiment in one that reported irrelevant movements, such as
looking away from the screen, using fixed (4 s) ITIs and variable ITIs.
Because some of the tasks were similar—although they employed
different samples of subjects—it is possible to predict the course
of attention, and response-time measures, based on the parame-
ters from Börger et al. (1999). Fig. 7 shows that NEMA was able to
predict the general lay of the data, although the control subjects in
this experiment paid better attention than predicted, and latencies
were shorter than predicted. Such deviations may be due to proce-
dural differences, as the subjects were on the average 1 year older
than in the prior study.
The above results replicate in the laboratory the common obser-
vation of off-task behavior in the classroom manifest by all children,
but in particular by those with ADHD (Rapport et al., 2009b; Sawyer
et al., 2001). Similar data have recently been found in working
memory tasks, with decreasing orientation on tasks as a function
of load, with large differences between ADHDs and controls (Kofler
et al., 2010). The present theory does not predict the temporal
patterning of inattention that Börger et al. found—their children
were able to shift their discursive behavior between trial onset and
target presentation into parts of the interval that would interfere
minimally with detection rates. This is a good example of strategic
reallocation of attention, one that preserves energetic resources of
the modules relevant to on task behavior to when they are most
needed. The implications of such patterning are discussed in Sec-
tion 5.1.1.
NeT predicts a divergence in the performance of ADHD and TDC,
with the former performing worse over the course of the session.
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657 635

This is a reliable finding: for instance, in a large study, Epstein et al.

(2003) found that the increased variability of RTs over the course
of the session was “highly associated with most ADHD symptoms”.
In a meta-analysis Huang-Pollock et al. (2012) found reliable evi-
dence for performance-over-time differences between groups. But
a number of papers report no interaction effect between ADHD
and controls for the deterioration in performance as a function of
time on task (e.g., Rapport et al., 2009b). Stins et al. (2005) found
that children with ADHD performed more slowly, less accurately,
more impulsively, and with less stability than controls. There was
an increase in errors for ADHD and controls as a function of time on
task, also as predicted, but those curves were parallel, with no hint
of faster deterioration for ADHD. There are several possible reasons
for this. One is that the task was essentially self-paced, so the partic-
ipants were not forced into a speed-accuracy tradeoff: individuals
with ADHD could just slow down a bit more over the session to
maintain their (already compromised) accuracy. Furthermore, this
test was embedded in a series of other tests. Divergence in rates
is predicted over the first few minutes of testing; after 10 min,
performances arising from Eq. (4) will have convergent slopes at
divergent levels: the theory does not predict a significant differ-
ence in slopes late in testing (see Fig. C1). In the Stins et al. study,
the CPT was embedded in a day of testing, and each task was prac-
ticed “as long as necessary” for the child to understand the tasks
well enough to perform accurately on it. Under those conditions we
predict no measurable interaction, and that was what was found.
Had the training occurred on a prior day, and groups tested on this
task alone the next day, NeT must predict that an interaction in
RT, and in RT variability, with group, would have been found, with
ADHD deteriorating at a faster rate than TDC.
Fig. 8. Top panel: Data from Hervey et al. (2006) comparing response times from
4.2. Event rate: inter-stimulus interval ADHD children (triangles) and controls (circles) on the Conners CPT. Curves are from
NEMA. With parameters shown in Table 3, they account for 98% of the variance in
the data. Bottom panel: Data from Epstein et al. (2006) comparing response times
It is assumed in Fig. 5 that the beginning of a trial calls the sub- as a function of medication status on the day of testing, using the same task and
ject to attention, which he leaves each second with probability . procedure. Triangles represent ADHD off medication, and circles ADHD on medica-
ADHD individuals lapse more quickly because the neural circuits tion. The curves are predictions from the model using the parameters from the top
panel, and account for 97% of the variance in the data.
processing the target location and the top–down template for the
awaited target stimulus fatigue more quickly, and at the same time
the circuits processing distractors are refreshed. If trials are quickly the average (267 ms) for ADHD than for controls (184 ms). These
paced, there is a good chance that the target stimulus will elicit a data provide little leverage on the values of E and C, which here
response directly from the initial attention state. If the trial dura- serve only to set the 0 s ISI intercepts. The near identical perfor-
tion, or ISI, or pre-warning period is long, there is a greater chance mance at the 1 s ISI is unusual for ADHD and TDC groups (but see
that attention will have wandered, and must return to the atten- Kuntsi et al., 2009); NEMA translates this similarity into similar val-
tive state before a response can be made. In the present studies the ues of E. This is inconsistent with the prediction of NeT, and other
appearance of the target forces the issue and recaptures attention. theories that predict RT data, that persons with ADHD will have
The recovery adds an average of s to the latencies and  2 to the slower and more variable RTs; and therefore counts as evidence
variance of the eventual response. against those theories. On the other hand, most studies find such
When data are averaged over a session information is lost about differences (Tamm et al., 2012), counting as evidence for those the-
changes in energy levels and increases in mean and variance of ories. The preponderance of evidence supports NeT’s predictions.
response times throughout. That decrease in degrees of freedom in A number of studies were published from the MTA using exactly
the data evokes a corresponding decrease in the degrees of free- the same procedures. This greatly reduces random-effects variance
dom of the model:  is retired, and energy is set at the estimated in comparing them (Killeen, 2007), and should make it possible
average value for the session, E. All of the effects of ISI are due to predict results of other studies using similar parameter values.
to the Greek parameters  (probability of attentional lapse) and Epstein et al. (2006) used the same CPT for 316 ADHD-C children
 (attentional inertia). Fig. 8 shows data from the large-scale MTA from four study sites, when on and off medication. (The Hervey et al.
assessment using the Conners’ CPT-II. In the top panel, Hervey et al. data were a subset of these). Results were separately analyzed for
(2006) report the results from of 65 ADHD children and adoles- 190 children who took stimulant medication on the day of the test,
cents who had previously taken themselves off medication, with and 126 who did not. Children were not randomly assigned, but
matched controls. Means and standard deviations of both groups rather self-selected off medication sometime before these trials.
increased with ISI, with the ADHD group lying above the controls in The model and parameters used in the top panel of Fig. 8 draw the
both cases. E and C set the origin of the curves at ISI = 0: C/E sets the curves through the Epstein data in the bottom panel of Fig. 8. In
√
means, and (C/E3 ) sets the standard deviations. Visual inspection both panels the ADHD off medication were selected in like man-
of Fig. 8 shows that these curves converge toward ISI 0, thus permit- ner from the same cohort—individuals having taken themselves
ting us to set E and C to similar values across groups. They increase off medication for an indeterminate length of time. It is therefore
therefrom due to attentional lapses. Those lapses increased with not surprising that these data and parameters are so similar. Some-

the ISI as 1 − p(A) = 1 − e− t , with recapture of attention slower on what more surprising is the equivalent performance of the matched
636 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Table 3
Parameters for the curves in Figs. 8 and 9.
Hervey et al. (2006) Leth-Steensen et al. (2000)
Parameter Control ADHD Control
E 0.46 0.46 0.24
C 147 144 138
 0.34 0.34 0.21
 (s) 0.18 0.27 0.20
control group in the top panel, and the ADHD group on medication
in the bottom panel.
Hervey et al. (2006) fitted the ex-Gaussian distribution to their
data. The ex-Gaussian is a response-time (RT) model comprising
an exponential distribution convolved with a normal distribution.
The authors made two claims, one of which we view as true: “The
greater number of abnormally long RTs of children with ADHD
[i.e., those governed by the exponential process] reflect atten-
tional lapses on some but not all trials.” This is precisely the claim
of our attentional model. Finding that the mean of the Gaussian
process was smaller for ADHD, they went on to argue that this
“contradicts previous interpretation that children with ADHD have
slower than normal responding”. In fact, ADHD children did not
respond more slowly than TDCs at the 1 s ITI (see Fig. 8); but typ-
ically they do (Tamm et al., 2012). The mean of an ex-Gaussian
distribution is  + . Hervey inferred that, because  was not larger
for ADHD, ADHD do not respond more slowly than TDC (as atten-
tional differences are partitioned out in ). But that logic is valid
only if responses issuing from the attentive state are normally dis-
tributed, so that the mean of the normal part of the ex-Gaussian, ,
constitutes a “true” measure of speed of responding, one uncon-
taminated by inattention. But in general “RT distributions are
decidedly nonnormal—they are almost always skewed to the right”
(Wagenmakers and Brown, 2007). Tau in the ex-Gaussian does
some of the work intrinsic to the Wald, and some of the work
of the attentional lapse measured by our . If one takes the ex
out of the ex-Gaussian, it leaves a normal distribution that cannot
fit the vast majority of RT data. Inferences from the ex-Gaussian
parameters are not to some “true” distribution that characterizes
normal response times; they are to a chimera whose constituent
parameters must be treated with caution.
The importance of the right tail of the response distribution as a
discriminant of ADHD and control groups has been noted by many
observers, in particular Leth-Steensen et al. (2000). They showed
that the exponential parameter in the ex-Gaussian distribution that
they fit to their data permitted almost perfect discrimination of
those groups. That parameter,  (tau), is similar to the exponential
time constant  in our ex-Wald model. An important difference is
that in NEMA,  is derived from a theory of attention and inter-
preted as attentional inertia, mixed into an already skewed Wald
distribution with probability p(∼A).
Leth-Steensen et al. (2000) reported full distributions of
response times for different groups and different ISIs, setting a
rich and important exercise for our model. These authors presented
four circles on a computer screen for 2, 4 or 8 s, in counterbalanced
blocks, to 17 ADHD and 18 non-ADHD aged-matched control chil-
dren. At the end of the fore period, one circle was colored in, and
remained on until the subject responded to a computer key (S, F,
J, or L). Approximately 80 trials were conducted at each of the fore
period durations. The resulting distributions of response times are
shown in Fig. 9.
The ADHD boys marshaled less energy for the task (only 55% that
of the controls) and had a lower criterion for making a response
(see Table 3). This was a long experiment, so that the low levels
of energy (E) are not surprising. The probability of lapsing, gov-
erned by  in Eq. (8), controls the proportion of the ex-Wald that
is mixed with the Wald density, and is responsible for the differ-
ences between the columns. Lambdas were somewhat different for
the two groups, leading to probabilities of inattention by the time
of the target stimulus of 0.31, 0.53, and 0.78 (controls) and 0.38,
ADHD
0.62, and 0.85 (ADHD) for the 2, 4, and 8 s stimuli. The major factor
0.13
in the difference between rows was the attentional inertia , the
96
0.27 time required for recapturing attention and initiating the response
0.43 process (Oosterlaan and Sergeant, 1998b), which was twice as long
for the ADHD sample. This greater attentional inertia for individ-
uals with ADHD is consistent with the greater difficulty they have
in cued task switching (Cepeda et al., 2000; Kramer et al., 2001).
The parameters  and  play a similar role, and are thus con-
founded (almost collinear) in NEMA. Increases in one, caused
perhaps by sampling error, can lead to decreases in the other.
Because of this, care must be taken in interpreting their precise
values. The probability of attention lapsing by 1 s is . The product
 therefore gives the expected temporal cost of lapses of attention
at that point in time, and may be a more stable index of between-
group differences than either of its components. Table 1 gives the
general calculation for expected temporal cost of inattention.
Experimental tactics to maintain attention on the task, such as
jittering the time of onset of the target, may substantially reduce .
If such a tactic had been employed by Leth-Steensen et al. (2000)
at the shortest ISI and had driven  to 0, it would have cut the
exponential tail off the ex-Wald, and substantially reduced  in the
ex-Gaussians fit to such data. We predict in such a case decreases
in their coefficients of variation (CV) from 0.24 to 0.18 for TDC, and
a larger one, from 0.38 to 0.28 for ADHD, as the expected cost of
lapsing is greater for ADHD. Lee et al. (2012) performed such an
experiment using fixed and variable ISIs of 1.5 s, and found reduc-
tions in the ex-Gaussian  when the ISI was varied, as expected in
the above scenario. The correlations of the above CVs with those
reported by Lee et al. is r = 0.98.
One may question why parameters such as  and  should not be
essentially invariant within groups across studies that used similar
stimuli and procedures, and whether their differences are problem-
atic for NeT. The simple reason for their difference is that the data
are different, and NEMA interprets those data differences in terms
of differences in these parameters. The data are different because
in most cases the participants are different, with different histo-
ries and different ages and different nuances of testing procedure.
Curves drawn with fixed representative parameters would reflect
the trends in all of these studies (see, e.g., Fig. C1), and that is the
standard target for most theories. Predicting precise neuropsychol-
ogical parameters from epidemiological data is a challenge of the
future for NeT, as it is for all theories of ADHD.
NeT has, nevertheless, predictive validity. Consider for exam-
ple a study by Rucklidge and Tannock (2002) testing children with
ADHD, with reading disabilities (RD), with a combination of the
two, and TDCs, on a variety of tasks, including the stop-signal task.
The values of E computed from their “go” reaction times ranged
from 0.164 for TDC to 0.096 for combined ADHD + RD. Ten years
later Gooch et al. (2011) reported a similar study on children with
ADHD and with dyslexia; and another similar study the next year
(Gooch et al., 2012). The correlation between values of E for Ruck-
lidge and Tannock’s four groups and the latters’ were 0.929 and
0.952 respectively. The correlation between the energy levels in
the two recent studies was 0.978. Values of E for ADHD were 0.73,
0.84, and 0.87 of those for TDC in the three studies, respectively.
The median correlation among studies for C was 0.918; lower, as
expected, because C depends on task difficulty and strategic speed-
accuracy tradeoffs unique to each experiment. Correlations are not
the same as point predictions, as they can be high when the range
of variables is different between the studies, as was the case here.
Nonetheless, by the standards of psychology (Richard et al., 2003),
and of public health (Fig. 1 in Huesmann, 2007), these results are
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 9. The response-time distributions of 17 ADHD boys (bottom panels) and 18 age-matched control boys (top panels) on a continuous performance task (Leth-Steensen
et al., 2000). The parameter in each column gives the ISI. NEMA draws the curves using the parameters in Table 3, and accounts for 97% of the variance in the data.
encouraging. Of course, cognitive slowing is not the only difference
between these groups (Willcutt et al., 2010a).
One fact that NeT must predict is that the performance of indi-
viduals with ADHD will be both slower and more variable than that
of controls, and increasingly so as a function of increasing ISI. How-
ever, a recent meta-analysis concluded that there was no effect of
event rate on RT variability (Metin et al., 2012). The authors did find
the interactions that NeT predicts for mean and variance between
group and event rate, but the latter did not achieve statistical sig-
nificance (p ranged from 0.03 to 0.11 in the within-study analysis).
The data analyzed were the differences in standard deviations nor-
malized by the pooled standard deviations—the effect size metric
d. Because standard deviations were in both the numerator and
denominator of d, and they were expected to be larger under this
manipulation for ADHD, such pooling is inappropriate, as it will bias
effect sizes low. In a different meta-analysis of effect sizes, Toplak
et al. (2008) avoided such pooling because “an underlying assump-
tion of this statistic [d] is that the impact of treatment will not
change the homogeneity of variance of the two sample means being
compared”, and “that was well-documented to not be the case”.
Therefore, Toplak et al. (2008) normalized by the standard devi-
ation of the control group alone. We predict that, had Metin et al.
adopted a similar conservative strategy, they would have found the
interactions predicted by NeT (as in fact they did), and furthermore
that they would have achieved statistical significance.
4.3. The role of inhibition: the stop task
Some of the major theories of ADHD identify poorer inhibitory
control as a prime deficit. Mounting evidence, however, sug-
gests that motor inhibition (as a factor distinct from other motor
responses) is not a major problem in ADHD (Alderson et al., 2007).
There are, of course, other types of inhibition, but the evidence
for their role in ADHD is mixed at best (Nigg, 2001; Shallice et al.,
2002). In the laboratory, inhibitory motor control is often assessed
using the stop-signal paradigm (SSP) (Barkley, 1997a; Lijffijt et al.,
2005; Oosterlaan et al., 1998). In SSP, on some of the trials the sub-
ject must interrupt an already-initiated response. To do so requires
the processing of the stop signal itself, and the initiation of a new
response to suppress the response, or to decelerate the hand. Like
all response latencies, SSRT will be greater for ADHD (Nigg, 2001;
Sergeant et al., 2002). Scheres et al. (2003) found that inhibitory
control in children with ADHD improved under methylphenidate
compared to placebo in two out of three types of inhibition that
637
they measured. However, all of the relevant stop-signal response
times were linear functions of the go signal response times. Both
improved under methylphenidate by roughly the same amount, so
that there was little differential effect on the stop response. Because
all responses are slower and more variable in ADHD persons, and
all are improved by methylphenidate, there is no reason to single
out a subset, be it inhibitory or excitatory, for special note.
The SSP is an ideal test of the hypothesis that poorer inhibitory
control is the core deficit in ADHD (Barkley et al., 2007). It is also
a test of NeT, as our theory predicts greater latency and variabil-
ity in task reengagement, which has been noted (Oosterlaan and
Sergeant, 1998b), but posits no special role for inhibitory processes.
Three meta-analyses of these experiments have come to the same
conclusion (Alderson et al., 2007; Lijffijt et al., 2005; Oosterlaan
et al., 1998): whereas there are marked differences in response
times and variability between ADHD persons and controls, there is
no evidence that inhibitory responses to the stop signal are a special
class: the proportional delay in the stop signal necessary to achieve
50% successful inhibitions is not generally significantly different
between ADHD and controls. “Deficits in ADHD reflect slower and
more variable responding to visually presented stimuli and concur-
rent processing of a second stimulus, rather than deficits of motor
behavioral inhibition” (Alderson et al., 2008, p. 989).
The slower and more variable reaction times in children
with ADHD have alternately been attributed to “slower cogni-
tive processing (Kalff et al., 2005), slower motor speed (Van Meel
et al., 2005), deficient cognitive energetic resources (Sergeant et al.,
1999), and deficient attentional processes (Lijffijt et al., 2005)”
(Alderson et al., 2008, p. 996). NeT is consistent with all of these
attributions. Inhibitory signaling in the brain does not directly
recruit extrinsic energetic resources (Chatton et al., 2003), but is
regulated by operation of the glutamate-glutamine shuttle, as glu-
tamate is needed for GABA synthesis. That shuttle is activated by
(non-inhibitory) glutamatergic neurons (Liang et al., 2006; Calvetti
and Somersalo, 2012). To the extent that those are handicapped by
energetic dysfunction, to that extent GABAergic circuits would be
consequentially handicappped.
4.4. Working memory
Attentional allocation (Engle, 2002; Kane et al., 2001) and lapses
(Kenemans et al., 2005; Kofler et al., 2010) play important roles in
working memory capacity. It should therefore not be surprising
that the largest effect sizes in laboratory tests distinguishing ADHD
638 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 10. The performance of a dozen ADHD (triangles) and control (circles) boys on
two working memory tasks (Rapport et al., 2008). NEMA draws the lines through
the data using the parameters in Table 4, accounting for a median of 94% of the data
variance.
from control groups involved working memory (Martinussen et al.,
2005; Swanson et al., 2010). Working memory is that facility which
permits us to hold a number of stimuli in mind while performing
mental operations on them, while ignoring irrelevant stimuli. Typ-
ical tasks involve attending to a stream of stimuli, and operating on
the set to generate a sequence of responses (Cowan, 2008). Even
in studies where SSRTs of ADHD participants are as fast as those
of controls, there may be a significant deficit in the former’s work-
ing memory (Clark et al., 2007; in this case the working memory
of those with ADHD was nonetheless correlated with their SSRT).
An experiment by Rapport et al. (2008) provides a clear example,
and dramatically displays differences between ADHD and control
populations. In one visuospatial condition these authors presented
a sequence of 3, 4, 5, or 6 circles (the set size, SS) in a 3 × 3 matrix
on a computer screen, at the rate of 1/s. Thereupon subjects had to
reproduce the positions of the stimuli on a keyboard matrix, in the
same order, except that the single (randomly chosen) stimulus of
color had to be entered last. In a phonological task, a sequence of
3 . . . 6 symbols, all numbers except for one letter, were presented.
The subjects had to say the numbers they had seen, but rearranged
into ascending order, with the letter being said last.
Fig. 10 shows the results of this experiment for 12 ADHD boys
and 11 TDC, as presented in the authors’ Fig. 3. The top panel shows
the number of stimuli correctly reported per trial for each group, on
visual and phonological working memory tasks. This demonstrates
Table 4
Parameters for the curves in Fig. 10.
Visuospatial Phonological
Parameter Control ADHD Control ADHD
E 0.077 0.005 0.102 0.068
k (C = k·SS) 13.8 7.8 15.1 15.1
a large difference between groups, and that the visuospatial task
was more difficult than the phonological one. The second and third
panels break this summary performance down into accuracy for
each set size.
How does NeT speak to such data? The core of the theory as
implemented in NEMA is its predication of differences in speed
of neural computation, with C representing the criterial number
of computations in terms of E, the energy available to speed them
along. These two parameters characterize a random walk with drift,
resulting in a Wald distribution of task completion. Many processes
are operating in this complex task, but the over-writing of mem-
ory for old stimuli by the output process and by the presentation
of new stimuli is among the most important (e.g., Killeen, 2001; Qi
et al., 2010). It is clear that the requisite number of neural computa-
tions must increase with set size, and that the more quickly stimuli
can be processed, the fewer that will be overwritten by the next,
while awaiting their turn to be used. Assume for simplicity that
the necessary number of calculations for each correct response, C,
is proportional to the set size that must be manipulated for it. In
this experiment, C calculations need to be completed during the
time from one stimulus onset until the next, 1 s later. The propor-
tion of calculations that will complete during the 1 s trial is given
by the area under the Wald distribution from 0 to 1 s. Multiplying
the area under the Wald (probability of completion) by the number
presented per trial (number of attempts) to get the expected num-
ber of stimuli correct, the dependent variables in Fig. 10. E differs
between groups, and C is proportional to set size. For the parame-
ters shown in Table 4, NEMA draws the lines through those three
panels of data.
Even with the simplifications, NEMA is able to recover the data
within experimental sampling error. Criteria increase with set size
(SS), as k·SS, for instance, as 45, 60, . . ., etc. in the phonological task.
The energy available for the tasks in the ADHD group is substantially
less than that available in the control group for the visuospatial
task. It is clear that when the key processes are treated as time-
limited computations—here limited by over-written and fading
memory traces, and the paced onslaught of new stimuli—simple
assumptions about differential speeds of computations in ADHD
and control samples permit good characterization of the data.
Why should C increase proportionate to set size? This param-
eter typically blends both the demand characteristics of the task
with the resources that the individual brings to bear. As set size
increases, there is much more to process—each position must be
held in mind for each stimulus before any response can be made.
If a single stimulus-location memory requires 15 computations, 6
will require 90. Within the confines of a 1-s trial, this means that the
probability of a successful completion for each one—the area under
the Wald from 0 to 1 s—will decrease as that distribution flattens
with increases in C. In the visuospatial task, where energy of the
ADHD group was severely compromised, there was also an appar-
ent decrease in the proportion of computations that they made.
(There are not enough data here to be sure of this, as k could be held
constant at 13 for both groups and incur only a few percent decrease
in r2 .) Interestingly, the phonological task made less severe ener-
getic demands on both groups, and separate values of k provided no
improvement in fitting those data. The larger difference between
ADHD and control groups for the visuospatial task is consistent with
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 11. The parameters of ADHD (triangles) and control (circles) children on three
working memory tasks of differing difficulty (Buzy et al., 2009). The values of these
energetic parameters are inferred via Eq. (9) from the authors’ report of the param-
eters of the ex-Gaussian distribution of response times.
the meta-analyses reported earlier (Martinussen et al., 2005), and is
a byproduct of the differences in demands of the task and resources
of the individuals.
Although this implementation of NEMA is straightforward, it
is rare to find reports of experimental data that are sufficient to
effect like analyses. Fortunately, there is a simple way to reinterpret
archival data. Increasingly researchers are reporting the parame-
ters of ex-Gaussian densities fit to their RT data. The ex-Gaussian is
a widely used descriptive distribution. It utilizes three parameters,
rather than the two of the Wald (in the simple model); or the three
(of the sessional model, which must add  to track waning energy);
or the four (of the attentional model, which must add non-zero
values for  and ). It is possible, however, to approximate many
data with the simple drift/Wald model, as was shown in Fig. 4. The
two parameters of that model are easily inferred from those of the
ex-Gaussian by the method of matching moments (see Appendix B
for details):

+
E=
2 + 2 (9)
C = ( + )E
All of the Greek parameters here belong to the ex-Gaussian.
The utility of this recoding is seen with the data of Buzy et al.
(2009), who studied 25 children with ADHD and 24 TDC on a visual
serial addition task with different task difficulties. The task required
the addition of two sequentially presented numbers, and judgment
of whether that sum equaled a third number presented simulta-
neously with the second. The task difficulty was manipulated by
using small (sum less than 5), medium (sum less than 10) and large
(sum less than 19) digits. Fig. 11 shows the values of E and C imputed
from Table 2 of Buzy et al.
The energy available for allocation did not vary much across task
difficulty (unfilled symbols), but was uniformly lower for ADHD
than for control, as expected from NeT. On the average, the ADHD
group commanded only 75% as much energy as did controls. We
might have expected a greater covariation of energy with task dif-
ficulty. Buzy et al. (2009) increased memory load over two 2–3 h
sessions. They did not randomize exposure because pilot experi-
ments had shown that many children first exposed to the high task
difficulty would balk. That they didn’t balk when finally exposed to
that condition suggests that learning had occurred, which might
have reduced the energetic demands of the moderate and high
difficulty tasks experienced later in testing.
Given fixed resources, different for the two groups, increased
task difficulty entails reduced numbers of computations, as seen
in the top of Fig. 11. This is the classic speed-accuracy tradeoff.
639
Fig. 12. Variability of 11 ADHD (triangles) and 11 control (circles) boys on a syn-
chronized tapping task. Data from Rubia et al. (1999). The predictions from NEMA
account for 57% of the variance in these data.
The criteria for emitting a response (C) dropped across both groups
as difficulty increased, most markedly for the ADHD group. This
should lead to more errors—as in fact it did: accuracy for the ADHD
group was lower than for controls, and decreased linearly with load.
Whereas we might expect the criterion to increase with task dif-
ficulty, under the time-demands of fading memory traces these
subjects made a necessary speed-accuracy tradeoff by skimping
on processing in the most difficult conditions. The same situation
might occur in the classroom: student-paced work can allow ade-
quate time for children to muster the resources necessary for a
high criterion, whereas instructor paced work may entail the speed-
accuracy tradeoffs manifest as reduced values of C seen in Fig. 11,
and characterized as impulsive behavior.
Visuospatial working memory is one of the most effective labo-
ratory discriminators between ADHD and TDC (Martinussen et al.,
2005; but see Marzocchi et al., 2008; Nigg, 2005). Speed of visual
information processing has been shown to be a predictor of fatigue
in elementary and junior-high students (Mizuno et al., 2011). Both
reduced response speed and increased psychological fatigue may
be a common outcome of neural fatigue, caused by an inadequate
lactate supply to critical neural networks. Verbal working memory
is also affected in ADHD, but to a lesser extent than visuospatial
(Martinussen et al., 2005). The processing component of working
memory tasks share a common resource pool, with storage aspects
depending on domain-specific verbal and visual resources (Alloway
et al., 2006, p. 1698). Why visuospatial storage should be more
affected than phonological/verbal storage in ADHD is uncertain,
although ADHD persons also have relatively greater difficulty in
visually cued timing tasks than in auditorially cued timing tasks
(Toplak and Tannock, 2005).
In an extensive overview of dual-process theories of psycho-
logical processes, Barrett et al. (2004, p. 554) observe that the
“ability to engage in controlled processing in attention-demanding
circumstances, especially those that require the suppression or
inhibition of automatic processing, is related to individual differ-
ences in [working memory capacity]”. Fig. 10 provides evidence
that differences in that capacity may be attributed to deficiencies
in speed of neural computation (E), and a compromised number
of computations (C) that can be perfected within a temporal enve-
lope shaped by fading traces and ongoing stimulation. This close
association of processing speed and working memory is attested
by recent analyses utilizing drift models (Karalunas and Huang-
Pollock, 2013).
4.5. Motor control
One of the areas of the brain affected in ADHD is the cerebellum
(Berquin et al., 1998; Hart et al., 2012), which is implicated in simple
640 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 13. Variability of 101 ADHD + ODD teenagers (triangles) and 39 control (circles)
teenagers on a time reproduction task. Data from Barkley et al. (2001). The lines are
from a timing model that assumed that the probability of missing an internal time
signal was greater for ADHD (8%) than for controls (4%). They account for 99% of the
variance in the data.
conditioning, motor control, and timing of stimuli and responses in
the deci-second range. Simple motor coordination tasks show reli-
able differences between ADHDs and TDCs (e.g., Jacobi-Polishook
et al., 2009; Killeen et al., 2012; Kooistra et al., 2009; Meyer and
Sagvolden, 2006; Sergeant, 2005). In an early study of motor tim-
ing, Rubia et al. (1999) asked 11 ADHD and 11 control boys to tap
in synchrony with visual stimuli, which appeared at one of five
intervals. The abscissae of Fig. 12 displays the average produced
intervals, and the ordinate the standard deviations. NEMA predicts
a tight relationship between these variables, governed by the avail-
able energy and criterion. Given that the mean of the produced
interval is M = C/E, and variance is C/E3 , we can replace C with ME
√ TDCs and ADHDs, shown in Figs. 7 and 8; this is a general find-
in the latter and predict that the standard deviation  = M/E. The
curves show these values, under the assumption that E for con-
trols is 0.24, and that for ADHDs is 63% of that value, 0.15. Some
of the deviation of the data from these trend lines may be due to
sampling error in these small samples. A similar experiment (Rubia
et al., 2003) and analysis returned comparable values of E of 0.28
for TDC and 0.13 for ADHD. When the ADHDs were given placebo,
single, or double doses of methylphenidate, E increased from 0.14
to 0.16 to 0.24, the last value close to that of controls in this and the
prior study.
Tiffin-Richards et al. (2004) conducted a variety of tapping tasks
and found no differences between ADHD and control groups. Their
task typically involved only 12 repetitions in the synchronization
phase (as opposed to 60 in the study of Rubia et al. shown in Fig. 12),
which, as the authors noted, may have been inadequate to bring out
systematic differences—differences that we predict should start out
minimal and increase with increasing time on task. A recent meta-
analysis (Noreika et al., 2013) demonstrated that individuals with
ADHD had difficulty in a variety of tasks requiring timing of short,
intermediate and long intervals.
Timing of longer intervals consists of a concatenation of elemen-
tal units akin to those involved in Fig. 12 (Cassenti, 2011), with the
Wald distribution governing the variance of the elements, and the
rules of their combination (Killeen and Weiss, 1987) determining
their Weber functions (Fetterman and Killeen, 1990). An example
is given in Fig. 13, whose data were reported by Barkley et al. (2001)
for 100 teenagers with ADHD and ODD, compared to 39 matched
controls. Participants were given six intervals, ranging from 2 to
60 s, to estimate and reproduce. The authors reported the absolute
deviation from target time. In a Gaussian distribution, the aver-
age absolute deviation from the mean (AD) is proportional to the
√ their controls—it is their inability to maintain monotone behavior
standard deviation (AD = (2/)SD). Barkley et al. computed devia-
tions from the target duration, so his measures include any constant
error in the participants’ responses. Nonetheless, the measures will,
to a first approximation, be comparable and may be analyzed with
a standard timing model (Killeen, 2002; Killeen and Taylor, 2000).
This model predicts a linear relationship between the mean and
standard deviation, with the slope of the function being the Weber
fraction, w = [p(1 − p)]1/2 . The parameter p gives the probability that
transmission of information from one step in the accumulation
process to the next will occur without error. That probability is
p = 0.957 for controls and 0.919 for ADHDs. (These probabilities
can be related to the area under appropriate Wald distributions
for each of the composite steps, a nuance not indulged here.) Very
similar data were reported by Kerns et al. (2001), with comparable
compatibility with the timing model.
The decreased probability of transmitting timing information
from one stage to the next in persons with ADHD is consistent with
research that shows an important role for attention in the timing
process (Buhusi, 2003; Fortin, 2003). When attention is distracted
by concurrent stimulation or tasks, both the mean and variance of
temporal estimates or productions are affected, either due to the
failure to reset or increment the counts, or to fading control by
earlier count information due to competition in memory from con-
current tasks (Buhusi and Meck, 2009). Thus, over two wide ranges
of timing tasks, models based on NeT and NEMA (Fig. 12) or at least
consistent with them (Fig. 13) provide good (if cursory) descrip-
tions of the data. Timing in ADHD persons is certainly handicapped
by attentional, memorial and processing limitations. It is less clear
that it is a handicapper, however—that is, that it plays a causal role
in other deficits.
4.6. Reinforcement frequency
Rapidly paced trials clearly result in better performance for both
ing. According to NEMA, this effect is due to the recall of attention
by trial initiation, and its subsequent drift (Fig. 5). Other events
that focus attention include the presence of the experimenter, the
appearance of target stimuli, and the delivery of reinforcers. There
are numerous demonstrations in the literature that more frequent
presentation of stimuli (sometimes misleadingly called incentives)
is more effective than infrequent presentation for both ADHD and
TDC. Nevertheless, there are few demonstrations that the mecha-
nism is through reinforcement, or otherwise incentivizing the task.
Reinforcers typically signal trial initiation, they should work as well
as other salient stimuli. There is little evidence that they lead to bet-
ter performance, or that they differentially increase motivation in
ADHD (Oosterlaan and Sergeant, 1998a). A major review of the lit-
erature (Luman et al., 2005) found the results to be mixed, with
some evidence that frequent scheduling of reinforcement effected
a greater improvement in ADHD than TDC—but ceiling effects on
TDC limited the interpretability of those results. When feedback is
given on every trial, neither the frequency nor magnitude of rein-
forcement has any effect on speed of learning in ADHD children
(Luman et al., 2009). Thus, it is not clear that frequency of rein-
forcement needs to be considered to improve our theory’s account
of the data.
The inability of individuals with ADHD to sustain attention is
often taken as prima facie evidence for their lack of motivation,
or lack of investment of effort. But appropriate contingencies of
reinforcement work at least as well with ADHD children as with
controls (Drechsler et al., 2010; Luman et al., 2005). NeT claims
that these tasks are harder for individuals with ADHD due to their
inadequate energy resources: it is not lack of motivation, nor lack
of appreciation of reinforcement, which differentiates them from
in the face of rapidly declining resources. This may lead to future
avoidance of situations that place such painful demands on them
(Sonuga-Barke, 2005).
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
4.7. Delay discounting
For a delayed reinforcer to make contact with a response,
some memorial trace of that response must be present when rein-
forcement occurs (Killeen, 2011). Where working memories are
foreshortened by energetic insufficiency, we expect steeper delay
of reinforcement gradients (Johansen et al., 2007, 2009). Given a
choice between small immediate and larger delayed outcomes,
ADHD persons often prefer the immediate outcome somewhat
more than do controls (Luman et al., 2010; Marco et al., 2009;
Sonuga-Barke et al., 2008), which is evidence either of steeper gra-
dients or of a blunted effectiveness (i.e. faster decreasing marginal
utility) of larger payoffs. But there are inconsistencies in this
literature, suggesting that when real delays are involved, and
other factors such as age and intelligence are controlled for, the
effects can be small (Banaschewski et al., 2012; Scheres et al.,
2006).
The above research involves real delays to real
goods—experiential discounting. It plays out over a much smaller
range of delays and magnitudes of goods, and delivers discount
gradients that are steeper by orders of magnitude, than other
research included under the rubric delay discounting. When a
person is given a hypothetical choice to buy or sell a good some
time in the future, the value of that good is discounted as a
function of the delay incurred. This is rational: when an outcome
is long delayed, we are denied the use of it—and of the money
we trade for it—until the delay has elapsed. Discount functions
are graphs of the present value of a delayed good, relative to
the value of the same good delivered immediately, plotted as
a function of delay. An individual whose discount function is
steeper than the norm is often called impulsive (even though his
decisions may be deliberate, well-considered, and perhaps even
prudent). Various classes of individuals have been shown to be
more impulsive than the norm, or than their contrasting control
group. Young individuals discount more steeply than older ones,
poor more steeply than rich, addicts more steeply than sober, less
intelligent more steeply than more intelligent, and ADHD more
steeply than TDC (Madden and Bickel, 2009; Paloyelis et al., 2009).
Evaluation of imaginary deferred outcomes, or forbearance during
the delay to real ones, would be difficult for individuals with ADHD
during the delay. Experience has inculcated the attractions of the
immediate—especially when “deferred” often means “denied”
(Biederman et al., 2004).
There are two importantly different ways to frame the behav-
ior of the subjects in these situations. Consider an automobile
whose delivery is delayed for 3 years. The individual may com-
pute the current dollar value of the automobile, and discount
that dollar value. Or he may compute the utility of that car
now vs. 3 years hence, and base his decision on that evalua-
tion. Individuals tend to discount consumable goods at different
rates than money (Estle et al., 2007). If they converted to dol-
lar value and discounted that, however, this would not happen.
Therefore people discount utility, not dollar value. But if util-
ity is not a linear function of monetary value (and the law of
decreasing marginal utility (Bernoulli, 1738/1954) stipulates that
it is not), then goods of large magnitude must be discounted at a
lower rate in time than goods of small magnitude (Killeen, 2009).
This effect has been found, and christened the magnitude effect
(Green et al., 1997). Experiments that vary both the delay and
the magnitude of a delayed good permit us to concurrently estab-
lish discount rates for increasing time and increasing magnitude,
but there are few such that use ADHD subjects (Barkley et al.,
2001; Paloyelis et al., 2010a)—too few to draw firm conclusions
about their rate of magnitude discounting, especially so given the
genetic differences that add variance to these measures (Paloyelis
et al., 2010a). Therefore a simpler discounting model, a rational
641
(exponential) decay of utility as a function of psychological delay
(Killeen, 2009), will accommodate delay-discounting data from
ADHD participants:
ˇ
vt = v0 e−kt (10)
Here, v0 is the immediate value, k is the discount rate, and ˇ (beta) is
the psychophysical parameter for future time. Typically, ˇ is around
0.5 for young adults, less for children, and increases with maturity.
In the three studies we have analyzed (Crean et al., 2000; Hurst
et al., 2011; Paloyelis et al., 2010a), Eq. (10) provided an excel-
lent fit to the data, did not require different parameter values of
ˇ between ADHD and TDC, and showed substantially greater dis-
counting, indexed by k, for ADHD. (Given the dependence of ˇ on IQ,
if that is not matched, some of the steeper discounting would be due
to lower IQ in the ADHD sample.) Given the generally greater liabil-
ities of ADHD-Combined subtype seen in the present analyses, it is
not surprising that this is also the subtype most likely to show the
steepest discount functions (Paloyelis et al., 2010b; Scheres et al.,
2008).
The difficulty in maintaining fixed attention over extended
periods that persons with ADHD experience would reasonably
make them averse to entering situations where such extended con-
sideration is necessary. Like Sonuga-Barke (2002, 2003), we suspect
that learned aversions to the extended attentional requirements
of deferred outcomes may be the mechanism of steeper discount-
ing in the hypothetical tasks. It is perhaps therefore not surprising
that methylphenidate reduces experiential discount rates but not
hypothetical discount rates (Shiels et al., 2009), which should
have greater inertia due to learning history (Nevin and Grace,
2001).
4.8. Spectral analyses
The present analysis predicts slowing of response time through
extended performance, and predicts that the slowing will be greater
for ADHD than for TDC. This is a common finding (e.g., Berlin
et al., 2003; Huang-Pollock et al., 2012; Johnson et al., 2007), more
evident in response times and event-related potentials (Heinrich
et al., 2001) than other dependent variables. Spectral analyses
using fast Fourier transformation of a series of response times will
reflect that sessional difference, showing more energy (informa-
tion, power) at low frequencies (e.g., Gilden and Hancock, 2007),
because those frequencies correspond to slow changes over the
course of the session that we here identify as attentional fatigue.
If the series of response times is detrended to remove such fatigue
effects and render the series stationary, NeT predicts that the differ-
ences in spectra between ADHD persons and controls will decrease
or disappear. If the data are only approximately detrended, by
analyzing residuals from a linear regression (e.g., Johnson et al.,
2007), the overall effect will be reduced, and may be moved from
lowest to slightly higher frequencies, depending on where the
deviation between the fatigue trend line and its linear approxi-
mation is greatest. As an example, picture a straight line drawn
through the sessional trends of Fig. 6. The deviations between
those fatigue curves and the straight line will be zero at two
points, but loom large about 30% of the way into the session.
When these residuals are transformed to the frequency domain,
they will indicate unusual power corresponding to that period.
Absent a rationale for doing otherwise, however, NeT predicts
that with a properly detrended time series (e.g., by analyzing the
residuals from a power function such as Eq. (4)), there will be
no substantial differences between ADHD and TDC in their power
spectra. Recent analyses validate this prediction (Karalunas et al.,
2012b).
642 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
4.9. Executive functioning
Epstein et al. (2011) extended the above handful of tasks by
studying a battery of neuropsychological tasks for ADHD (51 com-
bined subtype, 53 inattentive subtype), and control (47) children.
The tasks were: (a) The Attentional Network Test (ANT, Rueda
et al., 2004) that involved a difficult discrimination of the orien-
tation of stimuli on a screen in the context of distractors; (b) a
stop-signal task (Verbruggen and Logan, 2008), with “go” responses
interrupted on 25% of the trials by a stop signal, presented at a lag
sufficient to inhibit just half the responses; (c) an N-Back task, in
which subjects had to press a key if the current stimulus was the
same as the prior one, which happened on 30% of the trials; (d) a
Choice task, in which subjects had to press one key if a circle was
presented, and another if a square was presented, which happened
with equal frequency; and (e) a Go/No-Go task, which required that
subjects hit the space key for target stimuli—any letter but X—and
not respond when an X was presented, which happened on 10% of
the trials.
The authors presented stimuli paced at 1, 2 and 4 s, but did
not break out all performances by those lags. They reported mean,
standard deviation and coefficient of variation on all tasks, and
the ex-Gaussian . Those summary statistics were converted to
the model parameters by Eq. (9), and are shown in Fig. 14 (left
panel). Neural computations C were greatest for the ANT task,
and least for the simple Go/No-Go task. That processing showed a
very similar pattern across populations, with inattentive subtypes
investing proportionally less than controls, and combined subtypes
slightly less than inattentive. A similar pattern was seen for ener-
getic support (E), with the only nonmonotonicity being for the
choice task, which was less energetically demanding than N-back,
but to which no more or less was given in the way of computational
resources.
Unfortunately, we have no way of predicting a priori the
demands that various tasks will place on resources, even though
Fig. 14. Left panel: The resources expended on each of the tasks (C), and the energy
available (E) to reach those criteria. ANT = Attentional Network Test; S-Sig = Stop Sig-
nal; G/N-G = Go/No-Go. Right panel: Assuming proportional insufficiencies of energy
(84% for Inattentive, and 77% Combined type) and computation (86% for Inattentive,
83% for Combined type) in each of the groups recovers the data, accounting for over
90% of its variance.
Data from Epstein et al. (2011).
we can certainly manipulate them in an ordinal fashion within
the same type of task, as shown previously in Fig. 11. We may
ask, however, how well the following characterization will predict
performance: ADHD will have less available energy, and whatever
computational resources TDC bring to bear on each of the tasks,
ADHD will commit proportionally less. In particular, assume that
the Inattentive subtype has only 84% of the energy of TDC, and com-
mand 86% of the resources (C) that they do. And assume that the
Combined subtype is worse off, with 77% of the energy of TDC,
and 83% of the resources. These generalizations predict the data,
as shown in the right panel of Fig. 14. This means that, as far as
may be inferred from response-time distributions, these tasks did
not strongly interact with subtypes: that is, they did not contribute
unique information.
It is obvious that the parameters depend on an interaction
of the task difficulty (Fig. 14), time-constraints on the resources
that may be allocated (whether those are dictated by task pac-
ing or memory decay) and characteristics of the individual subjects
(Figs. 14 and 15). We surmise that insufficiencies in energy—here
84% and 77% for the ADHD subtypes—are characteristic traits,
whereas resource allocation is also a function of task, setting,
training and motivation of the individuals. The former is more
immediately affected by pharmacotherapy, the latter by accuracy-
speed tradeoffs that may have become habitual, but which the
breathing space given by increased energy allows to shift toward
accuracy. When errors of commission are made on such tasks,
there is often a post-error slowing, suggesting the recalibration and
increase in resources dedicated to the task (see the review by Shiels
and Hawk, 2010).
The agreement between data and theory shown in the right
panel of Fig. 14 used a substantial number of degrees of freedom
from the data, being based on values of C and E inferred from the
control group, and proportionate decreases in them for the ADHD
groups. With those values in hand, however, it may be possible
to project results in similar experiments. Klein et al. (2006) tested
55 children with ADHD, most Combined subtype, and matched
controls, on the stop-signal, Go/No-Go, and 1-back tests. The pre-
dictions for similar conditions and groups from the Epstein et al.
(2011) experiments (the ordinates in Fig. 14) are plotted as the
abscissae in Fig. 15. Against them are plotted the data obtained by
Klein et al. It is clear that the predictions fail, as the length of the
y-axis is 60% that of the x-axis. In the Klein study the trials were
much more rapidly paced, and testing was briefer, putting gen-
tler demands on energy. If these subjects, older by an average of
2 years, commanded 37% more energy, and required only 84% as
Fig. 15. The predictions for the conditions of Epstein et al. (2011) shown in the
previous figure are applied to data of Klein et al. (2006) found in similar assessments.
Triangles represent ADHD performance, circles controls. Despite the obvious strong
correlation, the predictions account for none of the variance in the data, which they
systematically overestimate (note the different ranges of the ordinates).
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 16. The resources expended on a stop-signal task (filled circles) and the aver-
age energy available (open circles) as a function of the dosage of methylphenidate
(MPH).
Based on data from Scheres et al. (2003).
many computations, NEMA’s predictions would account for over
77% of the variance in the data. Shifts in the key parameters are
not unexpected in light of those differences in age and pacing. NeT
therefore cannot predict a priori the exact values for E for ADHD
vs. TDC. Furthermore, in the effort to be parsimonious, we ask the
key parameters to absorb the effects of other potential modera-
tors (e.g., training trials, embedding in other tasks, length of trials,
presence or absence of experimenter, age, degree of severity of
symptoms, etc.), and this will increase their variability from one
study to the next. Until we can make all such predictions precisely,
however, based on the conditions of the test and the characteristics
of the subjects, or of the underlying neural information processing
(Crumiller et al., 2011), this theory, and all that attempt similar
predictions, may be considered incomplete. Thus, the difference in
estimates for E and C between experiments such as those analyzed
here remains a target for future exploration.
Scheres et al. (2003) reported the mean and variance of response
times on a stop-signal task under various doses of methylphenidate.
Fig. 16 shows the values of C and E computed from those statistics.
It is clear that available energy increases with methylphenidate
dosage, allowing additional precision in computation while still
empowering faster response times.
5. Embedding NeT in a causal framework
Killeen et al. (2012) proposed an explanatory framework for
ADHD based on the four kinds of knowledge that comprise under-
standing: that of the causes, substrates, functions, and of the models
by which we define and interpret a thing. Each kind has both a prox-
imate (immediate, molecular) core and an ultimate (longer-term,
molar) shell. The present paper has been concerned with the prox-
imate material causes of ADHD, the machinery that appears to be
broken. It is important to situate this perspective within the other
kinds of knowledge: formal (definitions, models and theories), effi-
cient (causes of symptoms and syndrome), and final (what sustains
the behavior, and what sustains the syndrome).
5.1. Proximate models of ADHD: its definition
The definition of ADHD has evolved over the years, along with
the criteria for categorization. ADHD shares many comorbidities,
being more common in association with other psychiatric cat-
egories than by itself. Anxiety, depression, oppositional-defiant
disorder, conduct disorder, and learning disabilities are not
uncommon correlates of ADHD. Clinical definition of ADHD has
evolved from that of Kramer and Pollnow (1930) to a list
of symptoms validated in careful clinical histories. Symptoms
643
cluster around two major dimensions: attention deficit, and
hyperactive–impulsive, with many children satisfying the criteria
for both (ADHD-Combined subtype). There is an important unitary
component to ADHD symptoms as well as those separable dimen-
sional (Normand et al., 2012), one that we hypothesize may have
something to do with a shared energetic insufficiency.
5.1.1. Attention deficit
Individuals with ADHD do not really have an attention
deficit—they have an attention surfeit: they attend too well to new
stimuli, quickly shifting attention to novel features of their environ-
ment (Landau et al., 2012). “Is often easily distracted” and “Often
has trouble keeping attention on tasks” are two of the DSM-IV crite-
ria for categorization. It is concentration—sustained attention—that
is problematic in ADHD. Sustained behavior requires sustained fir-
ing of functional groups of neurons. But after 10 s those neurons
require additional supplies of lactate, and it takes several minutes
for astrocytes to fully ramp up production to whatever level they
may. NeT entails a deficit in sustained monotone activity, be it
sensory, cognitive or motoric. Lapses of attention follow from the
cumulating energetic cost of sustaining attention, manifest in con-
trols, but more marked in ADHDs (Alberts and van der Meere, 1992).
Lapses are preceded by reduced activity in the anterior cingulate
and right prefrontal regions (Weissman et al., 2006). During these
lapses, the original neural complexes can begin to recover from the
prolonged demand. Individuals with ADHD can strategically time
their inattention. This can leave them better situated to exploit
attentional resources when most needed, as toward the end of a
long scheduled delay (Börger and van der Meere, 2000). On the trial
before an omission error on such tasks, response times lengthen.
After those omissions, they return close to baseline (Epstein et al.,
2010). The lengthening suggests fatigue and increased probability
of lapsed attention. The post omission quickening may be inter-
preted as a restoration of energy, as a secondary benefit of that
lapse. Shifts of attention in self-paced tasks (including loosely mon-
itored classroom tasks) are more frequent for children with ADHD
(Kofler et al., 2008b) and may mitigate some of the fatigue effects
(van Mourik et al., 2007). (The variety of stimulation available in
electronic games may sustain attention due to the quickly shifting
nature of their targets and sub-goals.) It is such shifts in utiliza-
tion of alternate functional units that contribute substantially to
response variability (Prado et al., 2011). As children mature, they
may condition alternative functional networks (Deco et al., 2010),
which can relieve the primary ones. Perhaps this is one of the rea-
sons for the decrease in the prevalence of ADHD in adulthood.
5.1.2. Hyperactivity
Whereas a deficit in sustained attention is a core prediction of
NeT, that theory does not predict hyperactivity. The best that we
can offer is a post hoc hypothesis. When attention to a primary
task becomes difficult due to energy depletion, shifts of attention
to other stimuli are inevitable. We predict a much higher rate of
endogenous task switching in ADHD than in TDC. Whereas this
prediction may seem obvious (Kofler et al., 2008b), laboratory evi-
dence for it is scant, although higher levels of entropy (a measure of
diversity of behavior) have been demonstrated in an animal model
of ADHD (Johansen et al., 2007). Some of the diversity of behav-
ior called hyperactive may be attention/task-shifting, driven by the
quick dissipation of energetic resources for sustaining monotone
tasks. Some of it may be a poorly socialized manifestation of play
behavior (Panksepp, 2007). It is strongly context-dependent (Dane
et al., 2000). As a reviewer noted, the data in Fig. 4 show that E
was not much lower for HI than for controls, and was larger than
for the other categories. Hyperactivity–impulsivity is clearly asso-
ciated with lower values of C, inordinate to the modest decrease in
E that such individuals may suffer.
644 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Rapport et al. (2009a) and associates (Alderson et al., 2012)
have noted that increased levels of activity in ADHD are correlated
with demands on working memory. Heightened motor activity may
increase sympathetic tone, providing the arousal necessary (Barry
et al., 2005) to a hypoactivated prefrontal cortex (Fan et al., 2012).
It is conceivable that HI is a subtype that is able to use such activ-
ity to stimulate NE mediated energetic resupply, much as some of
us will bounce a foot to maintain attention during a long collo-
quium, or manuscript such as this. But there is another possibility,
one that reverses this causal arrow. It has been established that
activity of the locus coeruleus norepinephrine arousal system is
necessary for optimal attentional performance (Arnsten and Rubia,
2012; Dietrich et al., 2012; Howells et al., 2012). To the extent that
activation of the noradrenergic system generates motor activity,
Rapport’s analysis is consistent with our theory, and may explain
some of the vigor of behavior called hyperactivity. The decrease in
impulsivity scores under task demand (Raiker et al., 2012) sup-
ports the hypothesis that such tasks provoke the locus coeruleus to
release norepinephrine in the prefrontal cortex (Aston-Jones and
Cohen, 2005; for a recent review of the role of the locus coeruleus
in ADHD, see Imeraj et al., 2012). Hyperactivity may thus be a
byproduct, rather than instrumental component, of this syndrome.
Possibly, of course, causality flows in both directions (Kievit et al.,
2011).
5.1.3. Impulsivity
As inattention is a sin of omission, impulsivity is a sin of commis-
sion. The many definitions of impulsivity (Evenden, 1999; Robbins
et al., 2012) are helpfully reviewed by Dalley et al. (2011). In the case
of ADHD, the three that are diagnostic in the DSM-IV are “often
blurts out answers before questions have been completed; often
has difficulty awaiting turn; often interrupts or intrudes on others”.
In addition, many of the symptoms listed under hyperactivity (e.g.,
“often leaves seat in classroom”) could as easily be called impulsive.
All of these symptoms may be thought of as a “failure of inhibi-
tion”, which motivated one of the major theories of ADHD (Barkley,
1997b). But failures of inhibition have been harder to document in
the laboratory in paradigms such as the stop-signal task (Alderson
et al., 2007; Winstanley et al., 2006).
The lower energetic resources of ADHD persons, and the (pos-
sibly compensatory) decreases in the caution (C) with which a
response is made, entail responding “before all of the data are in”
(Sergeant and Scholten, 1985). Given the smaller working memory
capacity of the typical individual with ADHD, a response delayed
is often forgotten. Prudence may dictate a response at the point
at which more starts being lost than retained. Balancing the pros
and cons of an action, while holding it in abeyance, is often beyond
the reach of a compromised working memory, just as is conjur-
ing the long-term consequences of short-term action. If delayed
goods are discounted, then delayed consequences in general will
be discounted. This all may occur for the same reason: a decrease
in the criterion for responding, possibly as a compensation for the
deficit in energetic resources necessary to persist in carrying out
the computation; possibly as an attempt to exploit memorial traces
before they have faded beyond recall; eventually, possibly becom-
ing established as a character trait. Vaughn et al. (2011) found some
evidence for the long-term persistence of impulsivity in ADHD chil-
dren and controls at intervals of 2 and 3 years. Analysis of their CPT
data revealed increases in E and C for the controls; in contrast, the
values of E and C were smaller for ADHD children, and showed little
to no improvement over time.
We have asserted that smaller values of C are the hallmark of
impulsive responding. What is the evidence for that assertion? In an
important article on impulsivity and inhibition, Logan et al. (1997)
measured the RT to the go signal in a stop-signal task. A novelty
of their study was an independent measurement of impulsivity
Fig. 17. The inferred values of C from RT data are plotted as a function of the individ-
uals’ score on a personality inventory of impulsivity (data from Logan et al., 1997).
The predicted strong negative correlation between impulsivity and C is manifest.
using a 9-point personality inventory. Fig. 17 displays the values of
C inferred via Eq. (9) from their data for individuals scoring at each
level of the inventory. The correlation between C and impulsivity
was greater than the correlation between mean RT and impulsi-
vity. This study validates our interpretation of the criterion C as a
(inverse) measure of impulsivity.
5.1.4. Comorbidity
In populations at large many different kinds of abilities (e.g.,
selective attention, sustained attention, episodic memory retrieval,
problem solving, spatial working memory, etc.) are positively cor-
related. This robust phenomenon has been called the “positive
manifold”. One explanation for it, stemming from early factor
analysis and later structural equation modeling, is based on the
ability to statistically refer these abilities to a principal common
factor. Spearman (1904) called the factor g, identifying it with
general intelligence. It was a small step to reify the concept, and
then to search for the causes of variation in g. There is another
interpretation of the manifold, however, due to a contemporary
of Spearman. Instead of the manifold being caused by some sin-
gle “thing” such as a general computational ability (g) affecting
all tasks, each task constituting the psychometric battery may
sample resources from elements of a distributed neural system
(Bartholomew et al., 2009). If there are strengths (or weakness)
in disparate parts of the brain that are shared by different tasks, the
task performances will be positively correlated. There need be no
common latent factor that causes genius—or dysfunction—no cen-
tral executive or working memory module that is better or worse
than average. All that is required is mutual exploitation of various
unnamed parts of the brain that are better or worse than average
(Marcus, 2006), parts that will vary between individuals and tasks
(Uttal, 2012). Such covariation is manifest also in the manifold of
correlated symptoms within and across DSM categories (Cramer
et al., 2010). If distributed systems analysis of the manifold is cor-
rect, it is unlikely that an endophenotype of ADHD can be found,
and even less likely that it would have any single name.
If neuroenergetic insufficiency is a cause of ADHD, there is no
reason to expect its action to be restricted to just those parts of the
cortex that govern the behaviors associated with the DSM-5 crite-
ria for ADHD. Increased variability of performance over intervals
of time is seen in many psychiatric disorders. The semi-random
failure of myelination or energy transport mechanisms in different
regions of the brain (Cherkasova and Hechtman, 2009) may give
rise to both the similarities and the differences between ADHD and
the many other psychopathologies that may be comorbid with it
(Larson et al., 2011). Consider again the data collected by Rucklidge
and Tannock (2002) on children with ADHD, reading disabilities
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. 18. Ordinates: The time to name 50 numbers, letters, colors and objects in an
experiment by Rucklidge and Tannock (2002). Abcissae: The predictions from NEMA,
based on the energy available to participants on a stop-signal task, and the number
of computations C necessary for TDC on the naming tasks.
(RD), both, and TDC. In addition to the stop-signal RT task, from
which we inferred values of E and C mentioned above, they con-
ducted four rapid naming tasks, for 50 numbers, letters, colors and
objects (such as pictures of books, chairs, etc.). The dependent vari-
able was total times to name all objects, in each series. We cannot
predict the values of C required for each of these lists of unique
items, but we can estimate them from the behavior of the TDC,
as their total time divided by their values of E estimated from the
stop-signal task. Then, given the values of E estimated for the clini-
cal groups in the stop-signal task, we can predict how long it should
take them to complete the naming. Fig. 18 shows the predictions
of the behavior of these special populations in novel experimental
paradigms.
In the earlier instantiation of NeT (Russell et al., 2006), the
overlap in symptoms and therapy with two other psychiatric
classifications, phenylketonuria and narcolepsy, were reviewed.
Sleep disturbances are also noted in ADHD (Imeraj et al., 2012;
Sergeant, 2005), and restful sleep is important for effective synaptic
energy use (Harris et al., 2012). Modafinil is the pharmacothe-
rapy of choice in narcolepsy, and also has therapeutic value in
the treatment of ADHD. In addition to its effect on the dopamine
transporter (Zolkowska et al., 2009), modafinil acts on the norepi-
nephrine transporter as well as the ␣2 - and ␤-adrenergic receptors
(Minzenberg and Carter, 2007). The latter are associated with the
stimulation of astroglia, eliciting the increased availability of lactate
to empower the propagation of neural signals.
In light of the additional emphasis that our theory places on
astrocytic adrenoceptors, it must predict that whenever those are
compromised, symptoms similar to those that are diagnostic of
ADHD should result. Multiple sclerosis (MS) is a clear test case.
Astrocytic ␤2 -adrenoceptors are lost in MS (DeKeyser et al., 2004).
And, in fact, patients with MS have slowed information processing,
more variable response latencies, and impaired working memory
(Hoffmann et al., 2007). They may suffer from focused, divided and
sustained attention deficits: the severity of MS is “robustly cor-
related” with their processing speed (De Sonneville et al., 2002).
Patients show a substantially smaller increase in activation of
various brain regions than healthy controls as task complexity
increases, and “have reduced functional reserve for cognition rel-
evant to memory” (Cader et al., 2006). Modafinil relieves their
associated fatigue (Rammohan et al., 2002), and methylphenidate
improves their attentional performance (Harel et al., 2009).
5.2. Ultimate models of ADHD: NeT and other theories
The present behavioral neuroenergetics theory of ADHD, NeT,
has many themes in common with other treatments of ADHD. It is
645
consistent with the dynamic-developmental theory (DDT, Johansen
et al., 2005; Sagvolden et al., 2005) in that it predicts steeper delay
of reinforcement gradients, as a byproduct of the over-writing of a
more limited working memory by events that intervene between
stimulus and response—or between response and reinforcement.
The posited mechanisms are different, however: in DDT those are
dopamine-based (Johansen et al., 2002), and in NeT norepinephrine
based. As one of the proponents of DDT noted, “A challenge for
reinforcement theories of ADHD is to link the concepts of memory
and attention used in our analyses of behavior to the corresponding
concepts used in cognitive psychology” (Johansen et al., 2009). The
present theory takes a step in that direction.
Our theory is also consistent with the working memory the-
ory of ADHD (e.g., Kofler et al., 2008a, 2011; Sarver et al., 2012),
which posits deficiencies in working memory to be the core feature
of ADHD, from which others devolve. NeT, however, views com-
promised working memory as a sequela to energetic insufficiency,
which may directly affect other processes (e.g., motor coordination)
without mediation by working memory. The effects of ADHD per-
vade basic processes, as well as higher-order ones such as executive
function and working memory (Mulder et al., 2010).
Tripp and Wickens (2008) recently promulgated a dopamine
transfer deficit (DTD) theory of ADHD based on the impairments
in learning about predictors of reinforcement that are effected by
dopamine. Their theory has made successful predictions of the
effects of methylphenidate on delay discounting, and on the effects
of intermittent reinforcement in ADHD. Research has shown that
stimulus–response coupling is impaired in ADHD (Luman et al.,
2009), as they would predict, as is learning (Mayes and Calhoun,
2007). The data on intermittent reinforcement and ADHD are mixed
(Kollins et al., 1997). A comprehensive review of the issues rele-
vant to evaluating DTD and other theories of ADHD is provided
by Luman et al. (2010). Because DTD is based on impaired dopa-
minergic function, its premises are different than those of NeT.
Indeed, many other theories of ADHD, predicated on the efficacy
of methylphenidate, premise a hypodopaminergic (or sometimes
a hyperdopaminergic) condition as casual in ADHD (Gonon, 2009).
Energetic insufficiency is the core aspect of NeT, one mitigated by
norepinephrine, not dopamine.
NeT has perhaps the greatest resonance with Sergeant’s
cognitive-energetics theory (CEM, e.g., Sergeant et al., 1999,
2003; Sergeant, 2000, 2005). This theory incorporates features of
Barkley’s inhibition model and resource demand imbalance model
(Turgay et al., 2012) and Sonuga-Barke’s delay aversion model
(Marco et al., 2009). It comprises three levels, with three energetic
pools corresponding to the encoding, central processing and motor
organization stages, organized by the executive control system at
top, where liabilities in working memory and inhibition are to be
found. At the intermediate level, there are no differential liabilities
in encoding or central processing: liabilities are concentrated in
motor organization or timing (Noreika et al., 2013). The cognitive
energetic theory has been criticized because its energetic pools are
unobserved hypothetical constructs (Rapport et al., 2001). The cur-
rent behavioral neuroenergetics theory of ADHD, NeT, moves them
to center-stage: there are energetic pools associated with all cere-
bral actions, and these consist of the ATP immediately available to
the neurons, backed up by astrocytic glycogen, and by the astro-
cytes’ ability to convert that into lactate to provide the long-term
energy required by sustained neuronal firing. The central construct
of NeT, the energy available to the neurons in the form of lactate
that enables sustained attention, is represented by the variable E.
That letter could as well stand for the central energetic resource in
cognitive energetics, which is both directly available to computa-
tional processes, and which, through attention switching, helps
empower other cognitive processes such as stimulus encoding
and response organization (Kaplan and Berman, 2010; Sergeant
646 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
et al., 2006). That construct plays a key role in another cognitive-
energetics theory of motivated cognition (Kruglanski et al., 2012)
under the rubrics potential driving force, and energy supply.
5.3. Ultimate material bases: genetics
ADHD is highly heritable (Asherson and Gurling, 2012), jus-
tifying the search for genetic substrates. In a review of five
genome-wide association studies, Franke et al. (2009) noted that,
whereas few of the ‘classic’ candidate genes, such as DAT4 a
dopamine transporter gene, showed a reliable association with
ADHD, the cell adhesion molecule cadherin CDH13 was the most
common associate among the studies (also see Banaschewski et al.,
2010). CDH13 is associated with many of the symptoms of ADHD
(Mick et al., 2011), and with impaired working memory (Arias-
Vásquez et al., 2011). CDH13 plays many roles in the brain (Rivero
et al., 2012), among them a negative growth regulator for astrocytes
(Huang et al., 2003). It is highly expressed in brain regions that have
reduced volume in ADHD (Takeuchi et al., 2000). It is our hypothesis
that one of the reasons for a failure of the ANLS may be impair-
ment of astrocyte growth, and of their junctions with neurons
(Togashi et al., 2009). Mice carrying a dominant negative form of the
astrocyte-neuron adhesion molecule SynCAM1 displayed ADHD-
like behavior that was attenuated by d,l-amphetamine (Sandau
et al., 2012). This provides further support for impaired astrocyte-
neuron communication playing a role in ADHD.
As the psychometric literature shows, there may be many
different biological pathways to the manifestation of ADHD-like
symptoms. Other causes of hypoenergetics leading to slower neural
processing might include mitochondrial dysfunction, hyperpolar-
ization of neurons requiring additional energy to maintain their
regular firing, failure of tight junctions to maintain cell polarity,
and so on. Depending on the parts of the brain involved, these
may be viewed as different presentations of ADHD, comorbidities of
ADHD, or a different dysfunction altogether with some ADHD-like
symptoms. In such cases, treatments with stimulants may be less
effective in increasing the ATP ultimately available to the neuron.
5.4. The final causes of ADHD: what functions are served?
The last of the four causes to be explicated concerns function.
What is the immediate function of the symptoms of ADHD, and
what is the ultimate function, if any, of the syndrome? In the case
of symptoms, attention wanders because, perforce, it must. Dis-
cursive behavior exploits undepleted elements of the CNS, towards
which attention is naturally drawn, away from the fatigued ele-
ments. While off task, neurons involved in the target task have the
chance to replete, making a change of attention not only a relief,
but also a strategy.
For the syndrome, the question of function is more unsettled.
Many articles on ADHD open with a list of its costs to society and
the individual. Unexplained is why these, severe as they are, have
not eliminated the genotype. The marginally higher rate of procre-
ation for young adults with ADHD (Weiss et al., 1985) can be only
part of the answer. Another must be that there are environments
in which ADHD traits have some advantage (Killeen et al., 2012;
Landau et al., 2012; Williams and Taylor, 2006). Stressful environ-
ments, in utero or in development, can precipitate the emergence
of ADHD (Cohen, 2010). Fugacious attention (due to lowered E) and
impulsivity (lowered C) can lead adolescents out of those environ-
ments. Quick responding and breadth of attention have survival
advantage in the novel environments they then encounter (Weiss
and Hechtman, 1993). ADHD is Nature’s Plan B, the escape hatch
from James’s (1890, p. 121) “enormous flywheel of society [that]
keeps us all within the bounds of ordinance, and . . . prevents the
hardest and most repulsive walks of life from being deserted by
those brought up to tread therein.” Despite its attendant risks, Plan
B works well enough to keep characteristics of ADHD an important
part of the character of Homo sapiens.
6. The role of pharmacological agents
All pharmacotherapies for ADHD facilitate catecholamine
function, either by increasing extracellular concentrations
of norepinephrine and dopamine (the transporter block-
ers: methylphenidate, amphetamine, atomoxetine, modafinil,
desipramine, and monoamine oxidase inhibitors), or by acting
directly on noradrenergic receptors (guanfacine, an ␣2A-
adrenoceptor agonist). Some of these are stimulants, some
not; what they have in common is their ability to stimulate the
release of lactate from astrocytes. The prefrontal cortex is the
prime target of these drugs, mediating top–down regulation
of motor, cognitive, and emotional function through reciprocal
connections with sensory and limbic association cortices, basal
ganglia and cerebellum (Arnsten, 2011). At large behaviorally
activating doses, psychostimulants produce large and widespread
increases in extracellular levels of brain catecholamines (Berridge
and Devilbiss, 2011). Low, cognition-enhancing doses exert
regionally restricted actions, elevating extracellular catecholamine
levels and enhancing neuronal signal processing by activating ␣2-
adrenoceptors and dopamine D1 receptors within the prefrontal
cortex (Berridge and Devilbiss, 2011; Gamo et al., 2010).
On top of these common effects, such drugs have unique
effects on different brain systems, and thus on function. Nor-
epinephrine and dopamine have complementary effects on the
strength of network connections in the prefrontal cortex, and func-
tion to co-ordinate cognitive state with physiological demands
(Arnsten, 2011). The effects of the catecholamines are both
receptor and region specific: Guanfacine, an ␣2-adrenoceptor ago-
nist, improved prefrontal cortex function (i.e., performance in
working memory, attention stop-signal tasks, Bari et al., 2011)
but did not improve performance in a spatial memory task,
which was largely dependent on hippocampal function (Decamp
et al., 2011). Norepinephrine actually strengthens connectivity
in the lateral prefrontal cortex via ␣2A-adrenoceptor activation.
That is because such activation inhibits cAMP formation, closing
the hyperpolarization-activated cyclic nucleotide-gated (HCN) K+
channels, which reduces shunting and allows the network to inter-
connect (Brennan and Arnsten, 2008). Dopamine shapes network
inputs through activation of D1 receptors (Arnsten and Pliszka,
2011). Activation of ␤-adrenoceptors in the medial prefrontal cor-
tex enhances memory consolidation (Barsegyan et al., 2010) and
rodent performance in the stop-signal task, and alters neural cir-
cuits that control impulsivity (Bari et al., 2011).
Underlying this diversity of action in diverse brain areas are
functions common across areas. Upon neuronal glutamate release,
astrocytes provide lactate as the preferred neuronal energy source
(Wyss et al., 2011). Norepinephrine activates ␤-adrenoceptors,
stimulating glycogenolysis in astrocytes, which then produce lac-
tate from glucose and release it to provide the fuel necessary
for rapid persistent neuron firing (Pellerin and Magistretti, 2011;
Sorg and Magistretti, 1991). The ␣2A-adrenoceptors do not stim-
ulate glycogenolysis and lactate production, but they may have
a long-term effect by increasing glycogen synthesis in astrocytes
(Hutchinson et al., 2011; Subbarao and Hertz, 1990), thus increas-
ing the stores of energy in astrocytes. An ample supply of glycogen
offers some protection against hypoglycemic neural injury (Brown
and Ransom, 2007). Glycogen is depleted during the day and
restored during sleep, which may provide some explanation for
why the afternoon is a period of risk for ADHD, the irregular sleep
patterns associated with it, and the potential of melatonin, as an
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
aid to sleep onset, to be of general use in the treatment of ADHD
(Imeraj et al., 2012).
As Biederman and Spencer (1999) had observed, evidence now
strongly supports a key role for norepinephrine in ADHD: the “over-
whelming majority” of the drugs that are effective in treating ADHD
have important effects on the noradrenergic system (del Campo
et al., 2011), none of the drugs used to treat ADHD act exclusively on
the dopaminergic system, and some of the drugs (e.g., atomoxetine)
work primarily to block norepinephrine uptake. Methylphenidate
is about equally effective in blocking norepinephrine transporters
as it is in blocking dopamine transporters (Han and Gu, 2006).
Atomoxetine, which is equally effective as methylphenidate in
treating ADHD symptoms (Hanwella et al., 2011; Hazell et al.,
2011), increases both dopamine and norepinephrine in the pre-
frontal cortex of the rat, but unlike methylphenidate, does not
increase dopamine levels in the striatum or nucleus accumbens
(Bymaster et al., 2002). Dopaminergic theories of ADHD often
assert a reinforcement deficit that the action of methylphenidate
at these sites meliorates. The present theory posits no dopamine-
related reinforcement deficit, and is therefore unembarrassed
by the efficacy of atomoxetine despite its inactivity in these
regions.
7. Summary and conclusions
7.1. The neuroenergetics mass-action model (NEMA) and the
behavioral neuroenergetics theory (NeT)
ADHD is clinically heterogeneous, and research into this dis-
order is diverse—not only in the methodologies used, but also
the range of results reported. There is a need to integrate the
diverse findings. Over 300 meta-analyses have been conducted
in an attempt to increase analytic power in specifying differ-
ences between ADHD and TDCs. This is an empirical, inductive
form of integration. Theoretical modeling—for example the dual
pathway theory and its revision (Sonuga-Barke et al., 2010)—is
a retroductive form of integration. Progress in understanding
ADHD has become crucially dependent upon the quantitative
predictions that theory affords; predictions that, when cor-
rect help to substantiate the theory, and when off the mark,
help to improve it. This paper integrates substantial domains
within the field of ADHD research theoretically, and attempts
to further demonstrate the quantitative predictability of find-
ings between diverse domains based upon the mathematical
model, NEMA, acting under the direction of our general theory,
NeT.
NeT is a theory of response slowing and attentional fugacity
characteristic of ADHD. Its central thesis is that neurons may not be
adequately resupplied with the energetic resources—lactate—that
they require for prolonged, precisely timed firing. This could occur
because of failures in any one of the components that are involved
in the astrocyte-neuron lactate shuttle (Fig. 1). To translate this
premise into predictions, we sketched a minimal dynamic model
of supply and demand (Fig. 3 and Eq. (1)), and generalized it to the
case of ensembles of neurons (Eq. (4)). Rate of firing is closely cou-
pled to the energy available to reestablish gradients and reposition
glutamate vesicles, so that energetic course was taken as predictive
of the speed of information processing. Assuming in addition that
a criterial number of computations (C) are necessary for a response
leads to the inverse Gaussian distribution of response times called
the Wald distribution (Eq. (5)).
It is difficult to persist in an activity, be it perceptual, cog-
nitive, or motor, absent the requisite energy. Behavior wanders.
Fig. 5 provides the apposite model of lapse and recollection of
attention, and consequent response execution: NEMA. This model,
647
whose parameters are summarized in Table 1, instantiates the
core predictions of NeT: all of the derived measures will be
greater for individuals with ADHD than for TDC. NEMA is then
applied to the psychoneurological data that are the most discrim-
inating of ADHD. These reanalyses all pointed to a reduction of
15–25% in the speed (E) and completeness (C) of neural infor-
mation processing in ADHD. NEMA is a general model, applicable
to response times and variabilities for all populations. It may be
extended to other dependent variables (e.g., Fig. 10). NeT makes
general predictions for specific populations (here, ADHD), for the
time-course of slowing of information processing, and the underly-
ing neural processes responsible for them, and calls upon NEMA to
translate those into specific predictions relevant to experimental
data.
In their overview of the role of computational models in cogni-
tive neuroscience, Cowell et al. (2012) noted five critical properties
of a computational model that require explication. Whereas ours is
a deterministic rather than connectionist model, those properties
merit review here as well.
1. Levels of biological organization. These may range from the
organism embedded in its environment, down through systems
to the CNS, to synapses, to molecules. The levels of material
causes invoked by NeT are principally at the neuroglial level
(Fig. 1), with diffusion upward toward systems and downward
toward genetic mechanisms.
2. The problem space. If levels constitute the domain of a model,
the problem space constitutes its range, previewed in Section
2 of this paper. For NeT this is processing speed, manifest in
response-time distributions (Figs. 4 and 9), their means and vari-
ances (Figs. 8 and 14), attentional fugacity (Fig. 6), impaired
working memory capacity (Figs. 10 and 11), coordination and
timing (Figs. 12 and 13).
3. Biological plausibility. NeT is grounded in the neuroscientific
data that indicate neuroenergetic insufficiencies as a basis of the
phenomena in its problem space. If those are falsified, then NeT
must be rejected and NEMA orphaned.
4. Parsimony. In order to constrain the degrees of freedom in the
model, thus stabilizing the parameters, parsimony has been a
ubiquitous concern. No attempt was made to predict errors
of omission and commission, because the additional requisite
parameter (a second criterion) would absorb all the degrees
of freedom in most such data without enabling new predic-
tions. Table 1 arranges the parameters, with only one application
(Fig. 6, tracing the evolution of behavior over time for two groups
on three variables) requiring five parameters, and most four or
fewer parameters. Given that our goal has been accurate depic-
tion of the data, which we have generally achieved, we would
be surprised to find more parsimonious models able to give a
comparable account of existing data.
5. Predictions. Sometimes trends suffice: “The key property of the
simulations is the qualitative . . . trends in the data that emerge”
(Cowell et al., 2012). We offer a set of such qualitative predictions
for future research:
• Rate of approach to asymptotic performance depends on the
sum of rates of supply and demand (Eq. (3)); where supply is
compromised, as in ANLS failure, that approach will be slower;
but where cost is increased, as in poor myelination or more
intense processing demands, the approach will be faster.
• Interventions, such as the use of stimulants, which increase
energetic supplies will increase the rate of approach to asymp-
totic performance.
• Whenever astrocytic adrenoceptors are compromised, symp-
toms similar to those that are diagnostic of ADHD should result.
• All medications that are effective in ameliorating pha-
sic symptoms of ADHD will do so by stimulating lactate
648 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
release from astrocytes in relevant brain systems. Such drugs
(both stimulants and non-stimulants) may act by increasing
extracellular levels of the catecholamines—particularly, nor-
epinephrine, which stimulates energy repletion, and thus will
improve performance.
• Conversely, any treatment that stimulates astrocytes to take up
glucose, convert it to lactate and release lactate into the extra-
cellular space in response to signals of elevated extracellular
glutamate or K+ levels will ameliorate ADHD symptoms.
• Dopamine insufficiency plays no role in ADHD. Norepi-
nephrine is an effective therapeutic agent because of its ability
to stimulate astrocytes to release lactate.
• Because of the energy demands involved in neural synchro-
nization and maintenance of LTP, both essential for learning,
individuals with ADHD will be disadvantaged in complex tasks
involving learning, particularly at slow rates of stimulation,
where attention is also more likely to lapse.
• Because of astrocytic involvement in memory formation and
consolidation, individuals with ADHD will be disadvantaged in
complex tasks involving memory.
• Because of their difficulty in maintaining sustained neural
firing in functional systems, in situations requiring focused
attention the performance of individuals with ADHD will be
inferior to that of controls.
• Wandering of attention and discursive action will be especially
pronounced for individuals with ADHD in monotone environ-
ments.
• Group performances will diverge with time-through-trial
(Fig. A1).
• Group performances will diverge with time-on-task (Fig. C1).
• Spectra of latencies that have not been detrended will show
greatest discrepancies at low frequencies corresponding to the
first few minutes on task.
• Tonic catecholaminergic stimulation will be less effective than
phasic stimulation due to down-regulation.
• Comorbid dysfunctions may co-occur because affected indi-
viduals suffer a similar neurocomputational slowing in
particular portions of the brain, apart from other factors that
distinguish the disorders (Fig. 18).
• Quality of performance of ADHD will be improved in self-paced
tasks, where, to a limited extent, their slower processing does
not incur an accuracy penalty. Accuracy scores will be less
discriminating of groups in such tasks.
Sometimes quantitative predictions are also possible.
• We have assayed such in the curves of Figs. 7, 8, 15 and 18.
• We predict that all the derived indices of performance in
Table 1 will be of greater magnitude for ADHD than for TDC.
√
• We predict that E = M/SD, the ratio of the square root of the
mean RT to its standard deviation, will be of smaller magni-
tude for ADHD than for TDC. C = M3/2 /SD will be smallest for
individuals presenting as Hyperactive–Impulsive, and more
discriminating of groups on experimenter paced than on self-
paced tasks.
7.2. Implications for therapy
Noradrenergic neurons innervate functionally distinct corti-
cal areas, exerting widespread effects on energy metabolism
(Pellerin and Magistretti, 2011). This implies that drugs that
tonically activate ␣2- or ␤-adrenoceptors might have some
therapeutic potential in treating ADHD symptoms. Such drugs have
been found to be beneficial in treating symptoms of inattention
and impulsivity in a rodent model (Arnsten and Pliszka, 2011):
Clenbuterol, a potent ␤2-adrenoceptor agonist, has been shown to
reduce premature responding, and improve visuospatial attention
and working memory (Pattij et al., 2011).
There is, however, a downside to tonic activation. Brains typi-
cally buffer tonic changes in levels of neurotransmitters. The most
widely used pharmacotherapies, therefore, are the psychostimu-
lants methylphenidate and amphetamine, which block dopamine
and norepinephrine transporters. Their action is more circum-
scribed, both temporally and spatially, to neural activity: just the
thing that needs support. The presence of glutamate stimulates nor-
epinephrine release from local axon varicosities in the prefrontal
cortex and hippocampus (Howells and Russell, 2008; Russell, 2001;
Russell and Wiggins, 2000). Noradrenergic regulation of lactate
release by astrocytes can thus be selectively enhanced in areas
of increased neural activity (Fusar-Poli et al., 2012; Magistretti,
2011). In contrast to tonic activation of adrenoceptors on both
glia and neurons, drugs that block the norepinephrine trans-
porter act locally to enhance the glutamate-stimulated increase
in extracellular norepinephrine, thereby increasing astrocyte pro-
duction of lactate and sustaining neural firing where and when
it is most needed. This reduces (although it does not eliminate)
the down-regulation (Fleckenstein et al., 2009; Simchon et al.,
2010), which leads to tolerance to pharmacotherapy (Swanson
et al., 1999; Vles et al., 2003; Yanofski, 2011). If our hypoth-
esis is scrutinized, it will lead to a diversification of research
that has, here-to-date, been dominated by the dopaminergic
hypothesis (Rastmanesh, 2010). If our hypothesis is sustained,
it may lead to discovery of other sites of neuro-intervention at
points where the energy transfer may be compromised (such
as the orexin system: Sakurai et al., 2010; Tsujino and Sakurai,
2009).
Because one of the points of focus in this article has been on
the pharmacotherapy of ADHD, it is essential to note in closing the
limitations of this approach. ADHD often persists into adulthood
(Spencer et al., 2007), but the beneficial effects of pharmacothe-
rapy seldom persist after it is discontinued, and interventions have
little to no lasting benefit on behavioral trajectories (Molina et al.,
2009). Non-pharmacological interventions have little impact on
core symptoms (Sonuga-Barke et al., 2013). There are no phar-
macotherapies for ADHD: there are only pharmaco-prostheses.
This is consistent with NeT, which posits no long-term structural
changes due to the transient facilitation of the astrocyte-neuron
lactate shuttle, or to other treatment regimens. As prostheses,
current medications give breathing space in which behavioral cop-
ing strategies may evolve or be trained (Chronis et al., 2006;
Fabiano et al., 2009; Pelham and Fabiano, 2008). Halperin and
Healey (2011) have urged a new approach to ADHD, a program
of directed play and exercise, which would not only have direct
benefits on brain growth and social skills, but also stimulate sym-
pathetic activity and norepinephrine release in the prefrontal
cortex (Barry et al., 2005; Rapport et al., 2009a), thereby nour-
ishing depleted neurons. Indeed, the authors’ proposed regimens
would benefit all children. They may cause a useful reframing
of our quest, from a treatment of ADHD as a psychiatric dis-
order, to prevention and treatment of symptoms that can put
every child at risk of failing to achieve their full potential in
life.
Acknowledgments
This article would not have been written without the early
support of the Norwegian Centre for Advanced Study, and
the leadership there of Terje Sagvolden. We thank Rosemary
Tannock for comments on the manuscript, and Paige Scalf for
reminding us of the attention and organizational deficits found
in MS patients. Two anonymous reviewers greatly sharpened the
arguments and text.
 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
Fig. A1. The drift of attention off target (out of the A state), given by Eqs. (A1 and
A2).
Appendix A. Attention drift and recapture
The attentional module in Fig. 5 is the state diagram of a simple
Markov chain. The probability of residence in either of the states as
a function of time may be predicted from its transition matrix, Eq.
(A1):
 
1−  

P=  (A1)
˛ 1−˛
The first row and column correspond to the A state, and the
second row and column to the ∼A state. The rows indicate the cur-
rent locus of attention, and the columns the probability that, after
1 step, attention will be in the state given by the columns. Thus, if
starting in A the probability of staying there after 1 step is 1 − ,
and the probability of drifting to inattention, ∼A, is . If in the ∼A
state, corresponding to the second row of the matrix, the probabil-
ity of returning to attention is ˛, and the probability of remaining
inattentive (the second column) is 1 − ˛.
To predict the probability of being in any of the states after s
steps, raise the matrix to the power s:
p(As ) = P s
Fig. A1 demonstrates the loss of attention with time, in the case
that  is 0.1, and where ˛ takes values indicated by the parameter.
The process approaches an asymptote, whence the probability
of finding the subject in the A state is given by:
˛ tion of the inter-stimulus interval, permitting us to infer the effect
P∞ (A) =
˛+
For brief and inconspicuous stimuli, this is the long-range prob-
ability of a successful detection. If the probability of drifting back
to attention is 0, as shown in the bottom curve in Fig. A1, then
the probability of maintaining attention is essentially a negative
exponential function of time:
P(A) = (1 − ) ≈ e− t
t estimates piecemeal, the likelihood of the ensemble of data is max-
In making the transition from a probability () and its geometric
evolution, to a rate ( ) and its exponential evolution, the numerical
1
value of the parameter must be adjusted:  = 0 e− t dt = 1 − e− .
For small values of , as called for if the probabilities were updated
on a millisecond time base, they are essentially equal:  ≈  . The
time base has been set to 1 s, however. This is to keep these tempo-
ral units in seconds, and to keep the parameter values in ranges that
are kinder to our intuitions. To convert from the rate constants (the
primed symbols) to probabilities, compute the cumulative proba-
bility of a transition occurring at the rate  over the course of 1 s,
as in the above equation. Inversely,  = −ln(1 − ). A probability
of  = 0.25 corresponds to a rate of approximately  = 0.22/s. The
649
mean time to the first lapse is the reciprocal of this, 4.5 s. Treat-
ment of ˛ is exactly the same. The mean time to the recapture of
attention is  = 1/˛ .
Blatent stimuli that are apprehended even if the subject is not
focussing on the target call the subject back to attention (Fig. 5).
The shift back is not instantaneous, but requires an average of s.
The simple form of the model in Fig. 5 may be retained by having
target onset precipitate the return to attention, driving ˛ from 0 (or
any other assigned value) to a larger value ˛ close to 1.0. Then the
transition approximates an exponential process, with the probabil-
1
ity of reattending during the first second ˛ = 0 e−˛ t dt = 1 − e−˛ .
Inversely, the mean time to recapture is  = 1/˛ = −1/ln(1 − ˛) s.
Values for  range around 1/3 s, corresponding to ˛ = 3/s, and ˛
around 0.95.
Appendix B. Data analysis
Consider first the data in Fig. 4. The model assumes that the
multiplicity of neural firings has the character of a random additive
walk toward C, whose time of first passage is given by the Wald
distribution (Eq. (5)). The parameters of that equation, the best val-
ues of E and C, are found by an iterative search that maximizes the
probability of the data given the model and its parameters. This
is similar to maximizing the sum of squares deviation between
model and data, which was the cost function for analysis of all
non-distributional data, such as means and standard deviations.
In the maximum likelihood case, binomial variability around the
predicted points gave the probability of the observed data given its
predicted locus, which was maximized using an iterative algorithm.
Consider next Fig. 6. The change in available energy is given by
Eq. (4), a power function with exponent  (rho) and right asymp-
tote of E∞ . Evaluation of that function, with the parameters given
in Table 2, gives the inferred change in energy (E) available to the
neurocomputations at any point in time. For simple Wald distri-
butions, the mean and variance of those passages are C/E and C/E3 ,
respectively. C remains invariant within group and task (after initial
learning of the task), but E changes as a function of energy deple-
(A2) tion. It is necessary to choose values of these three parameters: C,
and  and E∞ . From these latter two Et is derived for each of the
blocks of time into the session. That could immediately be done by
an iterative search that maximizes the probability of the data given
the model and its parameters. However, now we have a richer data
field, one that permits us to trace the course of attention as a func-
(A3) of changes in energy on the ability to remain focused on the task.
Here, and everywhere else in this paper, it is assumed for simplicity
that the probability of being attentive from 1 s to the next (1 − ) is
proportional to the available energy. Using the continuous (expo-
nential) form: (1 −  ) = kEt . In the study analyzed here, k took the
value 1.46. The cost of fugacious attention, , the time required
to recall attention, must also be estimated. Instead of doing these
(A4)
imized to estimate the value of k (from which  is derived), and .
Now the predicted densities are not Wald but a mixture of Wald and
a convolution of Wald and exponential, the ex-Wald, as depicted
in Fig. 5. The mean and variance of the Wald distribution are C/E
and C/E3 ; the recovery of attention adds to these (1 − p(A)) and
(1 − p(A)) 2 respectively. From Eq. (A4), the probability of atten-
tion is p(A) = e− t . Heathcote (2004) provides S-Plus functions for
fitting the ex-Wald to data. Because  is not weighted by 1 − p(A)
in that package, expect estimates of it to grow larger as attention
wanes.
Sometimes great pains are taken in the execution of an exper-
iment, but only cursory data, or, worse, inferential statistics, are
reported. (To compound this paucity of information, often positive
650 P.R. Killeen et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 625–657
effects that do not achieve significance are taken as evidence
against an effect, misleading the readers. Lack of strong (e.g., statis-
tically significant) evidence against a null hypothesis should never
be interpreted as evidence for that hypothesis; cf. Gallistel, 2009).
It is still possible to derive information of use to the theory. When
a distribution of data is fairly well described by a model such as
the ex-Gaussian, another model may be used to fit the same data,
one step removed, by the method of matching moments. In its
present avatar this is less sophisticated than it sounds. The mean
of the ex-Gaussian distribution is  + . Its variance is  2 +  2 . We
may set these equal to the mean and variance given above for the
Wald distribution, and solve, yielding the relation of Eq. (9). Given
only the mean and variance of the data, we may still proceed, by
setting  = 0. This uses less information from the data, and thus
gives an inferior triangulation of the NEMA parameters, but is often
adequate to display trends. In both cases, the attentional module
is omitted: the probability of an attentional lapse is de facto set
to  = 0. This leaves the basic Wald to make up for some of the
instances of lapsed attention by deflating its estimates of E (to make
up for the missing exponential term in the ex-Wald). As this will
happen for ADHD and TDC alike, comparative measures retain some
validity.
Not predicted here are the proportions of misses and false posi-
tives in continuous detection tasks. Error distributions can shift
between these as a function of strategy, often reported as the
decision threshold. The standard approach to modeling such data
is the two-boundary generalization of the drift model presented
here (e.g., Ratcliff and McKoon, 2008; Ratcliff and Rouder, 1998).
Whereas such approaches have been tremendously successful, they
are more complicated (Brown and Heathcote, 2008; Ratcliff and
Tuerlinckx, 2002; Wagenmakers et al., 2007), and add degrees of
freedom to the model that cannot be supported by most of the data
available in the literature on ADHD (but see, e.g., Huang-Pollock
et al., 2012; Karalunas and Huang-Pollock, 2013; Mulder et al.,
2010). In this paper simplicity was favored over those more sophis-
ticated models, at the cost of a more general account of probabilities
and latencies of correct and error response times.
An alternate analytic approach noted by a reviewer would be to
apply the model to data from a large sample, and show that NEMA
found no difference in E and C between individuals that were and
were not ADHD, on tests that did not discriminate them; but suc-
cessfully predicted differences for tests that did. We are confident
that this would work, but only if other diagnostic categories were
excluded, as they may share many of the symptoms of ADHD.
Appendix C. Sessional analysis
NeT predicts slower and more variable response times for ADHD
than TDC, and that these differences will increase with time on task.
This is because functional areas of the brain are depleting their ATP,
and lactate resupply is insufficient to generate all that is required.
This happens to TDC also, but to a lesser extent. The effects should be
reduced by interlacing a variety of activities, and by self-paced tasks
where lower computational speeds do not force accuracy trade-
offs. Yet, often only small to moderate effect sizes are found for
increasing divergence as a function of time on task (Huang-Pollock
et al., 2012). Why should this be the case? Fig. C1 depicts one of the
reasons given by NEMA. For representative parameters, available
energy decreases as a convex function of time. Although the differ-
ence between energy levels is greatest toward the end of a session,
the rate of divergence between them will be greatest toward the
beginning of the session. If, as typically the case, TDC have a slightly
higher criterion for responding, there will be little or no difference
in response rates at the start of the session (or possibly a crossover,
with ADHD faster, depending on the parameters). However, those
Fig. C1. Top: The decrease in energy available over the course of a session according
to Eq. (4), with  = 0.25 (ADHD) and 0.3 (TDC), and asymptotic energy of 0.02 and
0.20, respectively. Bottom: predicted means and standard deviation of response
times, given by Eqs. (6 and 7), with  = 0, and C = 130 and 160 for ADHD and TDC.
first few minutes are often spent on task orientation, practice trials,
or even other neuropsychological tests that deplete similar func-
tional units. Later in the session, although differences are maximal,
the rate of change in those differences becomes minimal.
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